Appendix 5 Appendices Appendix 6

Health Technology Assessment 2010; Vol. 14: No. 37

Health Technology AssessmentNIHR HTA programmewww.hta.ac.uk

July 201010.3310/hta14370

A systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett’s oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin

D Fayter, M Corbett, M Heirs, D Fox and A Eastwood

Health Technology Assessment 2010; Vol. 14: No.371

Appendix 5 Pre-cancerous skin scoping

Appendix 6 Skin cancer scoping

Appendix 7 Barrett’s oesophagus scoping

Appendix 8 Oesophageal cancer scoping

Appendix 9 Lung cancer scoping

Appendix 10 Biliary tract cancer scoping

Appendix 11 Brain cancer scoping

Appendix 12 Head and neck cancer scoping

Appendix 13 Actinic keratosis data extraction

Appendix 14 Bowen’s disease data extraction

Appendix 15 Basal cell carcinoma data extraction

Appendix 16 Barrett’s oesophagus data extraction

Appendix 17 Oesophageal cancer data extraction

Appendix 18 Lung cancer data extraction

Appendix 19 Biliary tract cancer data extraction

Appendix 20 Brain cancer data extraction

Appendix 21 Head and neck cancer data extraction

Appendices Go to main text

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DOI: 10.3310/hta14370 Health Technology Assessment 2010; Vol. 14: No. 37

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131

One hundred and thirty-three publications, with study designs that did not meet the inclusion

criteria for the review, reported on patients with pre-cancerous skin conditions being treated with PDT. The references are listed below, in alphabetical order; they have not been categorised and may still contain a number of duplicate publications.

References1. Alexiades-Armenakas MR, Bernstein LJ, Chen

J, Jacobson L, Geronemus R. Laser-assisted photodynamic therapy of actinic keratoses: long-term follow-up. Lasers Surg Med 2003;15(Suppl.):45.

2. Alexiades-Armenakas MR, Geronemus RG. Laser-mediated photodynamic therapy of actinic keratoses. Arch Dermatol 2003;139:1313–20.

3. Ammann R, Hunziker T. Photodynamic therapy for mycosis fungoides after topical photosensitization with 5-aminolevulinic acid. J Am Acad Dermatol 1995;33:541.

4. Antoniou C, Katsambas A, Rigopoulos D, Palaskas E, Tsikrikas GN. Aminolevulinic acid: topical photodynamic therapy in skin cancers and solar keratoses. Skin Cancer 1996;11:81–4.

5. Attili S, Cochrane A, McNeill A, Camacho-Lopez M, Moseley H, Ibbotson S, et al. An open pilot study of ambulatory photodynamic therapy using a wearable, low-irradiance, organic LED light source in the treatment of nonmelanoma skin cancer. Br J Dermatol 2008;159:130–1.

6. Bakos RM, Bakos L, Ferlin E, Cestari T, Orlandini T, Rezende R, et al. [Photodynamic therapy with delta-aminolevulinic acid for superficial keratinocytic neoplasms.] An Bras Dermatol 2003;78:197–207.

7. Baptista J, Martinez C, Leite L, Cochito M. Our PDT experience in the treatment of non-melanoma skin cancer over the last 7 years. J Eur Acad Dermatol Venereol 2006;20:693–7.

8. Baptista J, Paris F, Serrao V, Cochito M. Topical photodynamic therapy and imiquimod cream in the treatment of actinic keratoses: a case report. Skin Cancer 2006;21:49–53.

9. Baron E, Domingo DS, Hsia A, Colussi V, Oleinick N, Foster T, et al. Silicon phthalocyanine photodynamic therapy for treatment of cutaneous neoplasms. J Invest Dermatol 2008;128:395.

10. Berking C, Herzinger T, Flaig MJ, Brenner M, Borelli C, Degitz K. The efficacy of photodynamic therapy in actinic cheilitis of the lower lip: a prospective study of 15 patients. Dermatol Surg 2007;33:825–30.

11. Berroeta L, Lewis-Jones MS, Evans AT, Ibbotson SH. Woringer-Kolopp (localized pagetoid reticulosis) treated with topical photodynamic therapy (PDT). Clin Exp Dermatol 2005;30:446–7.

12. Breuninger H, Bonnekoh B, Gollnick H. Photodynamic therapy with methylaminooxopentanoate (MetvixR) and a broad band light source (PhotoDyn 501): Experiences in complicated patients with actinic keratoses and basal cell carcinomas [Multiple letters]. JDDG (Journal of the German Society of Dermatology) 2005;3:397.

13. Britton JER, Goulden V, Stables G, Stringer M, Sheehan-Dare R. Investigation of the use of the pulsed dye laser in the treatment of Bowen’s disease using 5-aminolaevulinic acid phototherapy. Br J Dermatol 2005;153:780–4.

14. Brookes PT, Jhawar S, Hinton CP, Murdoch S, Usman T. Bowen’s disease of the nipple: a new method of treatment. Breast (Edinburgh, Scotland) 2005;14:65–7.

15. Buchanan RB, Carruth JA, McKenzie AL, Williams SR. Photodynamic therapy in the treatment of malignant tumours of the skin and head and neck. Eur J Surg Oncol 1989;15:400–6.

16. Cairnduff F, Stringer MR, Hudson EJ, Ash DV, Brown SB. Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer. Br J Cancer 1994;69:605–8.

17. Calzavara-Pinton PG. Repetitive photodynamic therapy with topical delta-aminolaevulinic acid as an appropriate approach to the routine treatment of superficial non-melanoma skin tumours. J Photochem Photobiol B 1995;29:53–7.

Appendix 5 Pre-cancerous skin scoping

Appendix 5

132

18. Calzavara-Pinton PG, Venturini M, Sala R, Capezzera R, Parrinello G, Specchia C, et al. Methylaminolaevulinate-based photodynamic therapy of Bowen’s disease and squamous cell carcinoma. Br J Dermatol 2008;159:137–44.

19. Calzavara-Pinton PG, Zane C, Facchetti F, Carlino A, Blanzuoli L, Marocolo D, et al. [Photodynamic therapy of non-melanoma skin tumours with topical delta-aminolevulinic acid.] G Ital Dermatol Venereol 1997;132:15–21.

20. Carruth JAS, Barrett JM, Barnes DWH, Buchanan RB, Sansom JM. A trial of photodynamic therapy for the treatment of tumors of the skin and head and neck, and the results of an experimental-study to determine the Interrelationships between the tissue effects of ionizing-radiation and photodynamic therapy. SPIE Proceedings Series 1993;1616:14–19.

21. Cavicchini S, Moretti D, Tanzi C, Tourlaki A. MAL-PDT in “difficult to treat’’ Bowen’s disease. J Invest Dermatol 2006;126:S36.

22. Ceylan C, Erboz S, Ozdemir F, Alper S. Topical photodynamic therapy for intraepidermal epithelioma. J Eur Acad Dermatol Venereol 2002;16:292–4.

23. Ceylan C, Erboz S, Ozdemir F, Kazandi A. [The effectiveness of topical photodynamic therapy in actinic.] Deri Hast Frengi Ars 2001;35:213–18.

24. Cochito M, Campos Lopes JM, Leite L. Topical photodynamic therapy in a case of Bowen’s disease of the face. Skin Cancer 1996;11:215–18.

25. Counters J, Zelickson B, Coles C, Selim M. A comparison of the V-beam and IPL in photodynamic therapy for reduction of actinic keratosis. Lasers Surg Med 2004;34:42.

26. de Haas ER, Sterenborg HJ, Neumann HA, Robinson DJ. The influence of light fractionation on the response of superficial skin cancer to aminolevulinic-acid photodynamic therapy. J Invest Dermatol 2006;126:S73.

27. de Haas ERM, de Vijlder HC, Sterenborg HJCM, Neumann HAM, Robinson DJ. Fractionated aminolevulinic acid-photodynamic therapy provides additional evidence for the use of PDT for non-melanoma skin cancer. J Eur Acad Dermatol Venereol 2008;22:426–30.

28. Dijkstra AT, Majoie IM, van Dongen JW, van Weelden H, van Vloten WA. Photodynamic therapy with violet light and topical 6-aminolaevulinic acid in the treatment of actinic keratosis, Bowen’s

disease and basal cell carcinoma. J Eur Acad Dermatol Venereol 2001;15:550–4.

29. Dragieva G, Hafner J, Dummer R, Schmid-Grendelmeier P, Roos M, Prinz BM, et al. Topical photodynamic therapy in the treatment of actinic keratoses and Bowen’s disease in transplant recipients. Transplantation 2004;77:115–21.

30. Erboz S, Ceylan C, Ozdemir F, Kazandi A, Ozol A. [Photodynamic treatment in solar keratosis.] Deri Hast Frengi Ars 1999;33:75–8.

31. Fernandez-Guarino M, Harto A, Perez-Garcia B, Martin-Gonzalez M, Urrutia S, Jaen P. Photodynamic therapy in disseminated superficial actinic porokeratosis. J Eur Acad Dermatol Venereol 2009;23:176–7.

32. Fijan S, Honigsmann H, Ortel B. Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine. Br J Dermatol 1995;133:282–8.

33. Fink-Puches R, Hofer A, Smolle J, Kerl H, Wolf P. Primary clinical response and long-term follow-up of solar keratoses treated with topically applied 5-aminolevulinic acid and irradiation by different wave bands of light. J Photochem Photobiol B 1997;41:145–51.

34. Fowler JF, Jr, Zax RH. Aminolevulinic acid hydrochloride with photodynamic therapy: efficacy outcomes and recurrence 4 years after treatment. Cutis 2002;69:2–7.

35. Fritsch C, Stege H, Saalmann G, Goerz G, Ruzicka T, Krutmann J. Green light is effective and less painful than red light in photodynamic therapy of facial solar keratoses. Photodermatol Photoimmunol Photomed 1997;13:181–5.

36. Gniazdowska B, Rueff F, Hillemanns P, Przybilla B. Allergic contact dermatitis from delta-aminolevulinic acid used for photodynamic therapy. Contact Dermatitis 1998;38:348–9.

37. Gold MH. Treatment of actinic cheilitis using photodynamic therapy with methylaminolevulinate: report of three cases [Commentary]. Dermatol Surg 2005;31:1348.

38. Goldman M, Atkin D. ALA/PDT in the treatment of actinic keratosis: spot versus confluent therapy. J Cosmetic Laser Ther 2003;5:107–10.

39. Gonzalez-Perez R, Garcia JG, Badiola IB, Calleja JMV, Sanchez SA, Diaz-Perez JL. [Topical photodynamic therapy with 5-amino levulinic acid: Experience at the Hospital of Cruces.] Actas Dermosifiliogr 1997;88:561–5.



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40. Guarneri C, Vaccaro M. Erosive pustular dermatosis of the scalp following topical methylaminolaevulinate photodynamic therapy. J Am Acad Dermatol 2009;60:521–2.

41. Gupta G, Morton CA, Whitehurst C, Moore JV, MacKie RM. Photodynamic therapy with meso-tetra(hydroxyphenyl) chlorin in the topical treatment of Bowen’s disease and basal cell carcinoma. Br J Dermatol 1999;141:385–6.

42. Ha XW, Sun XM, Xie JG, Fan XJ, Zhang YH, Mei QC, et al. Clinical use of hematoporphyrin derivative in malignant tumors. Chin Med J 1983;96:754–8.

43. Hauschild A, Lischner S, Lange-Asschenfeldt B, Egberts F. Treatment of actinic cheilitis using photodynamic therapy with methyl aminolevulinate: report of three cases. Dermatol Surg 2005;31:1344–7.

44. Hegyi J, Frey T, Arenberger P. The treatment of unilesional mycosis fungoides with methyl aminolevulinate-photodynamic therapy. J Eur Acad Dermatol Venereol 2008;22:1134–5.

45. Hyung SK, Jong YY, Kwang HC, Oh SK, Sang EM, Vinciullo C. Topical photodynamic therapy using intense pulsed light for treatment of actinic keratosis: clinical and histopathologic evaluation [Commentary]. Dermatol Surg 2005;31:33–7.

46. Itoh Y, Ninomiya Y, Henta T, Tajima S, Ishibashi A. Topical delta-aminolevulinic acid-based photodynamic therapy for Japanese actinic keratoses. J Dermatol 2000;27:513–18.

47. Jeffes EW, McCullough JL, Weinstein GD, Fergin PE, Nelson JS, Shull TF, et al. Photodynamic therapy of actinic keratosis with topical 5-aminolevulinic acid. A pilot dose-ranging study. Arch Dermatol 1997;133:727–32.

48. Jiraskova M, Jirasek L, Stork J, Vosmik F, Jirsa M. [Photodynamic diagnosis and therapy in dermatology. Experience with use of TPPS4 in skin diseases.] Cas Lek Cesk 2003;142:493–9.

49. Jiraskova M, Vosmik F, Krajsova I, Lapes M, Jirsa M. [Experience with photodynamic therapy in some skin affections.] Cesk Dermatol 1999;74:161–7.

50. Jiraskova M, Vosmik F, Lapes M, Jirsa M, Stadnik B. Experiences with local photodynamic therapy with TPPS4 and non-coherent light. Biomed Tech 1997;42(Suppl.):447–8.

51. Jones CM, Mang T, Cooper M, Wilson BD, Stoll HL, Jr. Photodynamic therapy in the treatment of Bowen’s disease. J Am Acad Dermatol 1992;27:979–82.

52. Jungersted JM, Dam TN, Bryld LE, Agner T. Allergic reactions to Metvix (ALA-ME). Contact Dermatitis 2008;58:184–6.

53. Kaae J, Philipsen PA, Haedersdal M, Wulf HC. Immediate whealing urticaria in red light exposed areas during photodynamic therapy. Acta Dermatol Venereol 2008;88:480–3.

54. Kacerovska D, Pizinger K, Majer F, Smid F. Photodynamic therapy of nonmelanoma skin cancer with topical hypericum perforatum extract: a pilot study. Photochem Photobiol 2008;84:779–85.

55. Kacerovska D, Pizinger K, Resl V, Cetkovska P, Jirsa M, Smid F. [Comparison of efficacy between the two photosensitizers in the photodynamic therapy of cutaneous tumours.] Cesko Dermatol 2006;81:148–52.

56. Karrer S, Baumler W, Abels C, Hohenleutner U, Landthaler M, Szeimies RM. Long-pulse dye laser for photodynamic therapy: investigations in vitro and in vivo. Lasers Surg Med 1999;25:51–9.

57. Karrer S, Szeimies RM, Landthaler M. Topical photodynamic therapy with 5-ala in the treatment of arsenic-induced skin tumors. SPIE Proceedings Series 1995;2371:222–5.

58. Karrer S, Szeimies RM, Sauerwald A, Landthaler M. Topical photodynamic therapy with 5-aminolevulinic acid in the treatment of actinic keratoses: a first clinical study. SPIE Proceedings Series 1996;2625:48–50.

59. Kasche A, Luderschmidt S, Ring J, Hein R. Photodynamic therapy induces less pain in patients treated with methyl aminolevulinate compared to aminolevulinic acid. J Drugs Dermatol 2006;5:353–6.

60. Kawczyk-Krupka A, Sieron A, Suwata-Jurczyk B, Adamek M. [Photodynamic therapy (PDT) using topically applied delta-aminolevulinic acid (ALA) for the treatment of malignant skin tumours.] Przegl Dermatol 2000;87:235–40.

61. Kerr AC, Ferguson J, Ibbotson SH. Acute phototoxicity with urticarial features during topical 5-aminolaevulinic acid photodynamic therapy. Clin Exp Dermatol 2007;32:201–2.

62. Kim EH, Kang HY, Lee E-S, Kim YC. Mycosis fungoides showing inCR to topical 5-aminolaevulinic acid phototherapy. Eur J Dermatol 2007;17:343–5.

63. Kim HS, Song KH, Kim KH. [Photodynamic therapy of actinic keratoses using 585nm dye laser and variable lights.] Korean J Dermatol 2005;43:53–9.

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64. Kim HS, Yoo JY, Cho KH, Kwon OS, Moon SE. Topical photodynamic therapy using intense pulsed light for treatment of actinic keratosis: clinical and histopathologic evaluation. Dermatol Surg 2005;31:33–6; discussion 6–7.

65. Kodama M, Watanabe D, Akita Y, Tamada Y, Matsumoto Y. Photodynamic therapy for the treatment of actinic cheilitis. Photodermatol Photoimmunol Photomed 2007;23:209–10.

66. Kreutzer K, Bonnekoh B, Franke I, Gollnick H. [Photodynamic therapy with methylaminooxopentanoate (Metvix) and a broad band light source (PhotoDyn 501): practical experiences in problem-patients with actinic keratoses and basal cell carcinomas.] JDDG (Journal of the German Society of Dermatology) 2004;2:992–9.

67. Lang S, Baumgartner R, Struck R, Leunig A, Gutmann R, Feyh J. [Photodynamic diagnosis and therapy of neoplasms of the facial skin after topical administration of 5-aminolevulinic acid.] Laryngorhinootologie 1995;74:85–9.

68. Lee JS, Kim YJ, Kang HY, Lee ES, Oh CH, Kim YC. [Topical photodynamic therapy for treatment of actinic keratosis using light-emitting diode (LED) device.] Korean J Dermatol 2005;43:469–74.

69. Loncaster JA, Moore JV, Allan D, Allan E. An ultrasound analysis of the response of Gorlin syndrome-related and sporadic basal cell carcinomas to aminolaevulinic acid photodynamic therapy. Photodiag Photodyn Ther 2005;2:149–55.

70. Marcus L. Photodynamic therapy for actinic keratosis followed by 5-fluorouracil reaction. Dermatol Surg 2003;29:1061–4; discussion 4–5.

71. Markham T, Sheahan K, Collins P. Topical 5-aminolaevulinic acid photodynamic therapy for tumour-stage mycosis fungoides. Br J Dermatol 2001;144:1262–3.

72. Maydan E, Nootheti PK, Goldman MP. Development of a keratoacanthoma after topical photodynamic therapy with 5-aminolevulinic acid. J Drugs Dermatol 2006;5:804–6.

73. McCaughan JS, Jr, Guy JT, Hicks W, Laufman L, Nims TA, Walker J. Photodynamic therapy for cutaneous and subcutaneous malignant neoplasms. Arch Surg 1989;124:211–16.

74. Mehta RK, Langmack K, Sarkany R, Norris PG. Light emitting diode lamp as a novel light source for photodynamic therapy. Br J Dermatol 1999;141:114–18.

75. Meijnders PJN, Star WM, De Bruijn RS, Treurniet-Donker AD, Van Mierlo MJM, Wijthoff SJM, et al. Clinical results of photodynamic therapy for superficial skin malignancies or actinic keratosis using topical 5-aminolaevulinic acid. Lasers Med Sci 1996;11:123–31.

76. Morton CA, Whitehurst C, McColl JH, Moore JV, MacKie RM. Photodynamic therapy for large or multiple patches of Bowen disease and basal cell carcinoma. Arch Dermatol 2001;137:319–24.

77. Morton CA, Whitehurst C, Moseley H, Moore JV, Mackie RM. Development of an alternative light source to lasers for photodynamic therapy: 3. Clinical evaluation in the treatment of pre-malignant non-melanoma skin cancer. Lasers Med Sci 1995;10:165–71.

78. Moseley H, Allen JW, Ibbotson S, Lesar A, McNeill A, Camacho-Lopez MA, et al. Ambulatory photodynamic therapy: a new concept in delivering photodynamic therapy. Br J Dermatol 2006;154:747–50.

79. Moseley H, Ibbotson S, Woods J, Brancaleon L, Lesar A, Goodman C, et al. Clinical and research applications of photodynamic therapy in dermatology: experience of the Scottish PDT Centre. Lasers Surg Med 2006;38:403–16.

80. Nagano T, Yamada Y, Ikeda T, Kamo T, Nishioka E, Nishigori C. [Successful treatment of superficial cutaneous malignant neoplasms with photodynamic therapy (PDT) using light-emitting diode (LED) light source.] Skin Res 2005;4:188–93.

81. Nayeemuddin FA, Wong M, Yell J, Rhodes LE. Topical photodynamic therapy in disseminated superficial actinic porokeratosis. Clin Exp Dermatol 2002;27:703–6.

82. Paoli J, Halldin C, Ericson MB, Wennberg AM. Nerve blocks provide effective pain relief during topical photodynamic therapy for extensive facial actinic keratoses. Clin Exp Dermatol 2008;33:559–64.

83. Park SY, Kim KT, Yoon TJ. [A case of actinic keratosis treated by topical photodynamic therapy with low intensity dye laser.] Korean J Dermatol 2006;44:636–8.

84. Parlette EC. Red light laser photodynamic therapy of Bowen’s disease. J Drugs Dermatol 2004;3:S22–4.

85. Pérez W J, González S, Goset K, Sánchez B, Zelaya G. [Photodynamic therapy in actinic keratoses and Bowen’s disease: preliminary report.] Rev Chil Dermatol 2003;19:256–60.



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86. Perrett CM, McGregor J, Proby C, Harwood C. A comparative study of topical 5-fluorouracil and topical photodynamic therapy using methylaminolevulinate for actinic keratosis and Bowen’s disease in organ transplant recipients. J Am Acad Dermatol 2006;54:A7.

87. Philipp CM, Muller U, Urban P, Berlien HP. Potential of systemic photosensitizers for PDT of skin malignancies. SPIE Proceedings Series 2008;6991:19.

88. Piaserico S, Belloni Fortina A, Rigotti P, Rossi B, Baldan N, Alaibac M, et al. Topical photodynamic therapy of actinic keratosis in renal transplant recipients. Transplant Proc 2007;39:1847–50.

89. Pinzi C, Campolmi P, Moretti S, Guasti A, Rossi R, Cappugi P. [Photodynamic therapy of primary and secondary (non-melanoma) skin tumors with topical delta-aminolevulinic acid.] G Ital Dermatol Venereol 2000;135:427–31.

90. Polak-Pacholczyk I, Lassota-Falczewska M, Bartkowiak R, Kaszuba A. [Photodynamic therapy of the precancerous states and non-melanoma skin cancers using the methyl-derivative of aminolevulinic acid (MAL-PDT).] Przegl Dermatol 2007;94:599–605.

91. Pons P, Pittau R, Boetto N, Garzon R, Aoki A. [Photodynamic therapy of neoplastic skin lesions: a two year experience.] Revista Argent Dermatol 2001;82:208–15.

92. Pons P, Pittau RF, Boetto NA, Garzon R, Aoki A. [Prototype of light source for photodynamic therapy in Centre of Electron Microscopy.] Rev Fac Cien Med Cordoba 2000;57:31–6.

93. Robinson PJ, Carruth JA, Fairris GM. Photodynamic therapy: a better treatment for widespread Bowen’s disease. Br J Dermatol 1988;119:59–61.

94. Rossi R, Mavilia L, Ghersetich I, Lotti T. Photodynamic therapy of actinic keratoses with methyl-aminolevulinate (METVIX). G Ital Dermatol Venereol 2005;140:381–7.

95. Runfola MA, Weber TK, Rodriguez-Bigas MA, Dougherty TJ, Petrelli NJ. Photodynamic therapy for residual neoplasms of the perianal skin. Dis Colon Rectum 2000;43:499–502.

96. Sandberg C, Stenquist B, Rosdahl I, Ros A-M, Synnerstad I, Karlsson M, et al. Important factors for pain during photodynamic therapy for actinic keratosis. Acta Dermatol Venereol 2006;86:404–8.

97. Sega GM, Keohane SG. MAL-PDT in the treatment of ‘field changes’ in patients with

previous nonmelanoma skin cancer. Br J Dermatol 2005;153:96.

98. Shim SD, Kim YC, Chung PS, Rhee CK. [A case of actinic keratosis treated with topical photodynamic therapy with a 632 nm diode laser.] Korean J Dermatol 2004;42:1221–4.

99. Sieron A, Kawczyk-Krupka A, Wojciech Cebula MA, Szygula M, Zieleznik W, Gruk M, et al. Photodynamic therapy (PDT) using topically applied delta-aminolevulinic acid (ALA) for the treatment of malignant skin tumors. Photodiag Photodyn Ther 2004;1:311–17.

100. Song KH, Lee CW, Kim KH. [Photodynamic treatment for precancerous disease.] Korean J Dermatol 2003;41:609–16.

101. Souza CS, Felicio LBA, Bentley MV, Tedesco AC, Ferreira J, Kurachi C, et al. Topical photodynamic therapy for Bowen’s disease of the digit in epidermolysis bullosa. Br J Dermatol 2005;153:672–4.

102. Stables GI, Stringer MR, Robinson DJ, Ash DV. Large patches of Bowen’s disease treated by topical aminolaevulinic acid photodynamic therapy. Br J Dermatol 1997;136:957–60.

103. Stables GI, Stringer MR, Robinson DJ, Ash DV. The treatment of Bowen’s disease by topical aminolaevulinic acid photodynamic therapy. Br J Dermatol 1998;139:74.

104. Stender IM, Wulf HC. Photodynamic therapy with 5-aminolevulinic acid in the treatment of actinic cheilitis. Br J Dermatol 1996;135:454–6.

105. Svanberg K, Andersson T, Killander D, Wang I, Stenram U, Andersson-Engels S, et al. Photodynamic therapy of non-melanoma malignant tumours of the skin using topical delta-amino levulinic acid sensitization and laser irradiation. Br J Dermatol 1994;130:743–51.

106. Szeimies RM, Karrer S, Sauerwald A, Landthaler M. Photodynamic therapy with topical application of 5-aminolevulinic acid in the treatment of actinic keratoses: an initial clinical study. Dermatology 1996;192:246–51.

107. Szeimies RM, Landthaler M. Treatment of Bowen’s disease with topical photodynamic therapy. J Dermatolog Treat 1993;4:207–9.

108. Szeimies RM, Landthaler M. [Topical photodynamic therapy in treatment of superficial skin tumors.] Hautarzt 1995;46:315–18.

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109. Tan B, Sinclair R, Foley P. Photodynamic therapy for subungual Bowen’s disease. Australas J Dermatol 2004;45:172–4.

110. Toll A, Parera Ma E, Velez M, Pujol RM. Photodynamic therapy with methyl aminolevulinate induces phototoxic reactions on areas of the nose adjacent to basal cell carcinomas and actinic keratoses. Dermatol Surg 2008;34:1145–7.

111. Toll A, Parera ME, Velez M, Pujol RM. Letter: photodynamic therapy with methyl aminolevulinate induces phototoxic reactions on areas of the nose adjacent to basal cell carcinomas and actinic keratoses. Dermatol Surg 2008;34:1145–7; discussion 7–8.

112. Tosca AD, Balas CJ, Stefanidou MP, Katsantonis JC, Georgiou S, Tzardi MN, et al. Prediction of ALA-PDT efficacy through remote color inspection and post therapy sequential histologic observations of skin malignancies. SPIE Proceedings Series 1997;3191:221–30.

113. Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA. A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol 2004;140:33–40.

114. Tschen E, Pariser D, Wong DS, Dunlap FE. Photodynamic therapy using aminolevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: long-term histopathologic results of a phase IV multicenter clinical trial. J Am Acad Dermatol 2005;52:P164.

115. Tschen EH, Wong DS, Pariser DM, Dunlap FE, Houlihan A, Ferdon MB, et al. Photodynamic therapy using aminolaevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: phase IV multicentre clinical trial with 12-month follow-up. Br J Dermatol 2006;155:1262–9.

116. Usmani N, Stables GI, Telfer NR, Stringer MR. Subungual Bowen’s disease treated by topical aminolevulinic acid-photodynamic therapy. J Am Acad Dermatol 2005;53:S273–6.

117. Usmani N, Telfer N, Stringer M, Stables G. Subungual Bowen’s disease treated by topical photodynamic therapy. J Am Acad Dermatol 2005;52:P164.

118. Vaicova M, Ettler K. [Our clinical experience with the use of photodynamic therapy in patients with the basal cell carcinoma and morbus Bowen (comparison of efficacy of two photosensitizers).] Cesk Dermatol 2004;79:200–4.

119. Varma S, Anstey A, Wilson H, Kurwa HA. Photodynamic therapy for the treatment of Bowen’s disease, solar keratoses, and superficial basal cell carcinomas: 12 months experience with a novel light source. Br J Dermatol 1998;139:19.

120. Varma S, Wilson H, Kurwa HA, Charman C. One year relapse rates for Bowen’s disease, basal cell carcinomas and solar keratoses treated by photodynamic therapy: analysis of 189 lesions. Br J Dermatol 1999;141:114–18.

121. Varma S, Wilson H, Kurwa HA, Gambles B, Charman C, Pearse AD, et al. Bowen’s disease, solar keratoses and superficial basal cell carcinomas treated by photodynamic therapy using a large-field incoherent light source. Br J Dermatol 2001;144:567–74.

122. Wang J, Gao M, Wen S, Wang M. Photodynamic therapy for 50 patients with skin cancers or precancerous lesions. Chin Med Sci J 1991;6:163–5.

123. Wang JB, Gao ML, Wen SJ, Wang MJ. Study of photodynamic therapy in skin cancers and precancerous lesions. SPIE Proceedings Series 1993;1616:139–42.

124. Wang XL, Wang HW, Guo MX, Xu SZ. Treatment of skin cancer and pre-cancer using topical ALA-PDT: a single hospital experience. Photodiag Photodyn Ther 2008;5:127–33.

125. Weisser H, Meyer-Rogge D, Meyer-Rogge E. [First experiences in medical practice with the new topical photosensitizer MAOP for actinic keratosis and basal cell carcinoma.] Aktuelle Dermatologie 2004;30:306–11.

126. Wennberg AM, Lindholm LE, Alpsten M, Larko O. Treatment of superficial basal cell carcinomas using topically applied delta-aminolaevulinic acid and a filtered xenon lamp. Arch Dermatol Res 1996;288:561–4.

127. Wolf P, Fink-Puches R, Cerroni L, Kerl H. Photodynamic therapy for mycosis fungoides after topical photosensitization with 5-aminolevulinic acid. J Am Acad Dermatol 1994;31:678–80.

128. Wolf P, Fink-Puches R, Reimann-Weber A, Kerl H. Development of malignant melanoma after repeated topical photodynamic therapy with 5-aminolevulinic acid at the exposed site. Dermatology 1997;194:53–4.

129. Wolf P, Rieger E, Kerl H. Topical photodynamic therapy with endogenous porphyrins after application of 5-aminolevulinic acid. An alternative treatment modality for solar keratoses,



137

superficial squamous cell carcinomas, and basal cell carcinomas? [Erratum published in J Am Acad Dermatol 1993;29(1):41.] J Am Acad Dermatol 1993;28:17–21.

130. Wolfe CM, Hatfield K, Cognetta AB, Jr. Cellulitis as a postprocedural complication of topical 5-aminolevulinic acid photodynamic therapy in the treatment of actinic keratosis. J Drugs Dermatol 2007;6:544–8.

131. Wong TW, Sheu HM, Lee JY, Fletcher RJ. Photodynamic therapy for Bowen’s disease

(squamous cell carcinoma in situ) of the digit. Dermatol Surg 2001;27:452–6.

132. Xu S, Wang X, Xu W. [Evaluation of photodynamic therapy of skin cancers with delta-aminolevulinic acid.] Med J Wuhan Univ 2003;24:86–9.

133. Zelickson B, Coles C. Treatment of actinic keratosis with PDT and chemical light patch. Lasers Surg Med 2003;15(Suppl.):167.



139

Two hundred and thirty-five publications, with study designs that did not meet the inclusion

criteria for the review, reported on patients with skin cancer being treated with PDT. The references are listed below in alphabetical order; they have not been categorised and may still contain a number of duplicate publications.

References1. Abels C, Karrer S, Baumler W, Goetz AE,

Landthaler M, Szeimies RM. Indocyanine green and laser light for the treatment of AIDS-associated cutaneous Kaposi’s sarcoma. Br J Cancer 1998;77:1021–4.

2. Alecu M, Ursaciuc C, Halalau F, Coman G, Merlevede W, Waelkens E, et al. Photodynamic treatment of basal cell carcinoma and squamous cell carcinoma with hypericin. Anticancer Res 1998;18:4651–4.

3. Allison RR, Mang TS, Wilson BD, Vongtama V. Tin ethyl etiopurpurin-induced photodynamic therapy for the treatment of human immunodeficiency virus-associated Kaposi’s sarcoma. Curr Ther Res Clin Exp 1998;59:23–7.

4. Alvanopoulos K, Antoniou C, Melpo P, Vareltzidis A, Katsambas A. Photodynamic therapy of superficial basal cell carcinomas using exogenous 5-aminolevulinic acid and 514-nm light. J Eur Acad Dermatol Venereol 1997;9:134–6.

5. Antoniou C, Katsambas A, Rigopoulos D, Palaskas E, Tsikrikas GN. Aminolevulinic acid: topical photodynamic therapy in skin cancers and solar keratoses. Skin Cancer 1996;11:81–4.

6. Attili S, Cochrane A, McNeill A, Camacho-Lopez M, Moseley H, Ibbotson S, et al. An open pilot study of ambulatory photodynamic therapy using a wearable, low-irradiance, organic LED light source in the treatment of nonmelanoma skin cancer. Br J Dermatol 2008;159:130–1.

7. Baas P, Saarnak AE, Oppelaar H, Neering H, Stewart FA. Photodynamic therapy with meta-tetrahydroxyphenylchlorin for basal cell carcinoma: a phase I/II study. Br J Dermatol 2001;145:75–8.

8. Bagnato VS, Kurachi C, Ferreira J, Marcassa LG, Sibata CH, Allison RR. PDT experience in

Brazil: a regional profile. Photodiag Photodyn Ther 2005;2:107–18.

9. Bakos RM, Bakos L, Ferlin E, Cestari T, Orlandini T, Rezende R, et al. [Photodynamic therapy with delta-aminolevulinic acid for superficial keratinocytic neoplasms.] An Bras Dermatol 2003;78:197–207.

10. Bandieramonte G, Marchesini R, Melloni E, Andreoli C, di Pietro S, Spinelli P, et al. Laser phototherapy following HpD administration in superficial neoplastic lesions. Tumori 1984;70:327–34.

11. Baptista J, Martinez C, Leite L, Cochito M. Our PDT experience in the treatment of non-melanoma skin cancer over the last 7 years. J Eur Acad Dermatol Venereol 2006;20:693–7.

12. Baron E, Domingo DS, Hsia A, Colussi V, Oleinick N, Foster T, et al. Silicon phthalocyanine photodynamic therapy for treatment of cutaneous neoplasms. J Invest Dermatol 2008;128:395.

13. Baron ED, Hanneman K, Scull HM, Hsia A, McCormick T, Oleinick NL, et al. Silicon phthalocyanine (Pc 4) photodynamic therapy for the treatment of pre-malignant and malignant skin conditions: an update. J Invest Dermatol 2005;125:942.

14. Bendsoe N, Persson L, Johansson A, Axelsson J, Svensson J, Grafe S, et al. Fluorescence monitoring of a topically applied liposomal Temoporfin formulation and photodynamic therapy of nonpigmented skin malignancies. J Environ Pathol Tox 2007;26:117–26.

15. Bendsoe N, Persson L, Johansson A, Axelsson J, Svensson J, Grafe S, et al. Fluorescence monitoring of a topically applied liposomal temoporfin formulation and photodynamic therapy of nonpigmented skin malignancies. J Environ Pathol Tox 2007;26:117–26.

16. Bernstein ZP, Wilson BD, Oseroff AR, Jones CM, Dozier SE, Brooks JS, et al. Photofrin photodynamic therapy for treatment of AIDS-related cutaneous Kaposi’s sarcoma. AIDS 1999;13:1697–704.

17. Betz CS, Rauschning W, Stranadko EP, Riabov MV, Albrecht V, Nifantiev NE, et al. Optimization of treatment parameters for Foscan-PDT of basal cell carcinomas. Lasers Surg Med 2008;40:300–11.

Appendix 6 Skin cancer scoping

Appendix 6

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18. Biel MA. Photodynamic therapy and the treatment of malignancies of the head and neck. SPIE Proceedings Series 1995;2392:55–62.

19. Bieniek A, Fraczek M, Cislo M, Maj J, Szybejko-Machaj G, Barancewicz-Losek M, et al. [Cancer of the skin of the nose. Epidemiology and treatment.] Dermatol Klin 2007;9:165–9.

20. Bloznelyte L, Cepulis V, Ponomarev I, Dougherty TJ. Intra-arterial PDT and ordinary PDT in head and neck cancer. SPIE Proceedings Series 1996;2675:76–9.

21. Bloznelyte L, Garlaite D, Felinskaite E. Differences of Photodamage in various malignant tissues which appear after application of Photodynamic therapy, using different laser systems. SPIE Proceedings Series 1995;2392:106–10.

22. Bogelund FS, Philipsen PA, Gniadecki R. Factors affecting the recurrence rate of basal cell carcinoma. Acta Dermatol Venereol 2007;87:330–4.

23. Breuninger H, Bonnekoh B, Gollnick H. [Photodynamic therapy with methylaminooxopentanoate (MetvixR) and a broad band light source (PhotoDyn 501): Experiences in complicated patients with actinic keratoses and basal cell carcinomas (multiple letters).] JDDG (Journal of the German Society of Dermatology) 2005;3:397.


25. Cairnduff F, Stringer MR, Hudson EJ, Ash DV, Brown SB. Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer. Br J Cancer 1994;69:605–8.

26. Calista D, Coccia L. Photodynamic therapy for the treatment of in situ squamous cell carcinoma of the left eyelid. Int J Dermatol 2008;47:1319–21.

27. Calzavara F, Tomio L. Photodynamic therapy: clinical experience at the Department of Radiotherapy at Padova General Hospital. J Photochem Photobiol B 1991;11:91–5.

28. Calzavara-Pinton PG. Repetitive photodynamic therapy with topical delta-aminolaevulinic acid as an appropriate approach to the routine treatment of superficial non-melanoma skin tumours. J Photochem Photobiol B 1995;29:53–7.

29. Calzavara-Pinton PG, Venturini M, Sala R, Capezzera R, Parrinello G, Specchia C, et al.

Methylaminolaevulinate-based photodynamic therapy of Bowen’s disease and squamous cell carcinoma. Br J Dermatol 2008;159:137–44.

30. Calzavara-Pinton PG, Zane C, Capezzera R, Venturini M, Sala R. MAL-PDT of in situ, microinvasive and invasive squamous cell carcinoma. J Invest Dermatol 2007;127:S44.

31. Calzavara-Pinton PG, Zane C, Facchetti F, Carlino A, Blanzuoli L, Marocolo D, et al. [Photodynamic therapy of non-melanoma skin tumours with topical delta-aminolevulinic acid.] G Ital Dermatol Venereol 1997;132:15–21.

32. Campbell SM, Morton CA, Alyahya R, Horton S, Pye A, Curnow A. Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma. Br J Dermatol 2008;159:387–93.

33. Cappugi P, Massi D, Salvini MD. Nodular basal cell carcinoma of the nose treated by photodynamic therapy (PDT). Photodynamic Therapy and Photodiagnosis in Clinical Practice, Brixen/Bressanone, 7–11 October, 2008. Poster session – CD12.

34. Cappugi P, Mavilia L, Campolmi P, Reali EF, Mori M, Rossi R. New proposal for the treatment of nodular basal cell carcinoma with intralesional 5-aminolevulinic acid. J Chemother 2004;16:491–3.

35. Carruth JAS, Barrett JM, Barnes DWH, Buchanan RB, Sansom JM. A trial of photodynamic therapy for the treatment of tumors of the skin and head and neck, and the results of an experimental-study to determine the interrelationships between the tissue effects of ionizing-radiation and photodynamic therapy. SPIE Proceedings Series 1993;1616:14–19.

36. Castro García J, Rincón Duran N, Gordon Parra M, Marcano Olaizola A, Aranguren L. Terapia fotodinámica: en cáncer de la piel. Rev Venez Oncol 2007;19:3–19.

37. Ceylan C, Ozdemir F, Erboz S, Kazandi A, Ozol A. [Topical photodynamic treatment in basal cell carcinoma.] Deri Hast Frengi Ars 1999;33:153–7.

38. Chapas A, Zeltser R, Geronemus R, Gilchrest B. Intralesional photodynamic therapy of nonmelanoma skin cancer. Lasers Surg Med 2006;38:27.

39. Chapas AM, Gilchrest BA. Broad area photodynamic therapy for treatment of multiple basal cell carcinomas in a patient with nevoid basal cell carcinoma syndrome. J Drugs Dermatol 2006;5:3–5.



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40. Christensen E, Skogvoll E, Viset T, Warloe T, Sundstrom S. Photodynamic therapy with 5-aminolaevulinic acid, dimethylsulfoxide and curettage in basal cell carcinoma: a 6-year clinical and histological follow-up. J Eur Acad Dermatol Venereol 2009;23:58–66.

41. Clark C, Bryden A, Dawe R, Moseley H, Ferguson J, Ibbotson SH. Topical 5-aminolaevulinic acid photodynamic therapy for cutaneous lesions: outcome and comparison of light sources. Photodermatol Photoimmunol Photomed 2003;19:134–41.

42. de Haas ERM, de Vijlder HC, Sterenborg HJCM, Neumann HAM, Robinson DJ. Fractionated aminolevulinic acid-photodynamic therapy provides additional evidence for the use of PDT for non-melanoma skin cancer. J Eur Acad Dermatol Venereol 2008;22:426–30.

43. Devirgiliis V, Panasiti V, Curzio M, Gobbi S, Rossi M, Roberti V, et al. Complete remission of nodular basal cell carcinoma after combined treatment with photodynamic therapy and imiquimod 5% cream. Dermatol Online J 2008;14.

44. Dijkstra AT, Majoie IM, van Dongen JW, van Weelden H, van Vloten WA. Photodynamic therapy with violet light and topical 6-aminolaevulinic acid in the treatment of actinic keratosis, Bowen’s disease and basal cell carcinoma. J Eur Acad Dermatol Venereol 2001;15:550–4.

45. Domaniecki J, Stanowski E, Graczyk A, Kalczak M, Struzyna J, Kwasny M, et al. Photodynamic method used for the treatment of malignant melanoma and Merkel cell carcinoma. SPIE Proceedings Series 1997;3188:122–7.

46. Dougherty TJ, Cooper MT, Mang TS. Cutaneous phototoxic occurrences in patients receiving Photofrin. Lasers Surg Med 1990;10:485–8.

47. Dougherty TJ, Kaufman JE, Goldfarb A, Weishaupt KR, Boyle D, Mittleman A. Photoradiation therapy for the treatment of malignant tumors. Cancer Res 1978;38:2628–35.

48. Edstrom DW, Hedblad MA. Long-term follow-up of photodynamic therapy for mycosis fungoides. Acta Dermatol Venereol 2008;88:288–90.

49. Edstrom DW, Porwit A, Ros AM. Photodynamic therapy with topical 5-aminolevulinic acid for mycosis fungoides: clinical and histological response. Acta Dermatol Venereol 2001;81:184–8.

50. Eibenschutz L, Marenda S, Mariani G, Ferrari A, Silipo V, Catricala C. MAL-PDT for the treatment of large basal cell carcinomas. J Invest Dermatol 2006;126:S16.

51. El-Far M, Setate A, El-Maddawy M. First initial clinical application of photodynamic therapy (PDT) in Egypt: two case reports. Laser Life Sci 1998;8:27–35.

52. Elliott S, Keller G, Razum N, Parks J, White R, Seiler A. Photodynamic therapy of nonmelanoma skin-cancer using a ktp-pumped dye-laser. SPIE Proceedings Series 1993;1881:2–9.

53. Elliott SL. The incidence and etiology of nonmelanoma skin cancer and selected management with photodynamic therapy. Laser Nursing 1992;6:83–91.

54. Evtushenko VA, Soldatov AN, Vusik MV, Reimer IV. Treatment of basal-cellular skin cancer and heavy concomitant diseases by a photodynamic therapeutic method with a dye laser LITT-PDT. SPIE Proceedings Series 2007;6938:32.

55. Fai D. MAL-PDT for the treatment of multiple basal cell carcinomas in a patient with Gorlin-Goltz syndrome. J Invest Dermatol 2006;126:S34-S.

56. Fijan S, Honigsmann H, Ortel B. Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine. Br J Dermatol 1995;133:282–8.

57. Filonenko E, Sokolov V, Sukhin D. Fluorescent diagnostics and photodynamic therapy of malignant cutaneous tumours. Photodynamic Therapy and Photodiagnosis in Clinical Practice, Brixen/Bressanone, 7–11 October, 2008. Poster session – SPO5.

58. Fink-Puches R, Soyer HP, Hofer A, Kerl H, Wolf P. Long-term follow-up and histological changes of superficial nonmelanoma skin cancers treated with topical delta-aminolevulinic acid photodynamic therapy. Arch Dermatol 1998;134:821–6.

59. Fink-Puches R, Wolf P, Kerl H. Photodynamic therapy of superficial basal cell carcinoma by instillation of aminolevulinic acid and irradiation with visible light. Arch Dermatol 1997;133:1494–5.

60. Gaal M, Gyulai R, Baltas E, Kui R, Olah J, Kemeny L. [Photodynamic therapy in dermatooncology.] Orv Hetil 2007;148:2227–33.

61. Gayl Schweitzer V. Photofrin-mediated photodynamic therapy for treatment of aggressive head and neck nonmelanomatous skin tumors in elderly patients. Laryngoscope 2001;111:1091–8.

62. Ghaffar SA, Clements SE, Lear JT. Epidermoid cysts mimicking recurrence of superficial basal cell carcinoma following photodynamic therapy. Clin Exp Dermatol 2007;32:223–4.

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63. Gonzalez-Perez R, Garcia JG, Badiola IB, Calleja JMV, Sanchez SA, Diaz-Perez JL. [Topical photodynamic therapy with 5-amino levulinic acid: Experience at the Hospital of Cruces.] Actas Dermosifiliogr 1997;88:561–5.

64. Gregory GF, Hopper C, Fan K, Grant WE, Bown SG, Speight PM. Photodynamic therapy and lip vermilion dysplasia: a pilot study. Eur J Cancer 1995;5:346–7.

65. Guillen C, Sanmartin O, Escudero A, Botella-Estrada R, Sevila A, Castejon P. Photodynamic therapy for in situ squamous cell carcinoma on chronic radiation dermatitis after photosensitization with 5-aminolaevulinic acid. J Eur Acad Dermatol Venereol 2000;14:298–300.

66. Gupta G, Morton CA, Whitehurst C, Moore JV, MacKie RM. Photodynamic therapy with meso-tetra(hydroxyphenyl) chlorin in the topical treatment of Bowen’s disease and basal cell carcinoma. Br J Dermatol 1999;141:385–6.


68. Haller JC, Cairnduff F, Slack G, Schofield J, Whitehurst C, Tunstall R, et al. Routine double treatments of superficial basal cell carcinomas using aminolaevulinic acid-based photodynamic therapy. Br J Dermatol 2000;143:1270–5.

69. Hanneken S, Sterzinger AA, Schulte KW, Reifenberger J. [Photodynamic therapy for a nevoid basal cell carcinoma syndrome.] Hautarzt 2005;56:363–4.

70. Harth Y, Bergman R, Gotfried V, Kimel S, Friedman-Birnbaum R. A case of basal cell carcinoma treated with photodynamic therapy: changes in histological features and bcl-2 expression. J Eur Acad Dermatol Venereol 1996;7:163–6.

71. Harth Y, Hirshovitz B. [Topical photodynamic therapy in basal and squamous cell carcinoma and penile Bowen’s disease with 20% aminolevulinic acid, and exposure to red light and infrared light.] Harefuah 1998;134:602–5.

72. Harth Y, Hirshowitz B, Kaplan B. Modified topical photodynamic therapy of superficial skin tumors, utilizing aminolevulinic acid, penetration enhancers, red light, and hyperthermia. Dermatol Surg 1998;24:723–6.

73. Hebeda KM, Huizing MT, Brouwer PA, van der Meulen FW, Hulsebosch HJ, Reiss P, et al.

Photodynamic therapy in AIDS-related cutaneous Kaposi’s sarcoma. J Acquir Immune Defic Syndr Hum Retrovirol 1995;10:61–70.

74. Heinritz H, Benzel W, Sroka R, Iro H. Photodynamic therapy of superficial skin tumors following local application of delta-aminolaevulinic acid. Adv Otorhinolaryngol 1995;49:48–52.

75. Hintschich C, Feyh J, Beyer-Machule C, Riedel K, Ludwig K. Photodynamic laser therapy of basal-cell carcinoma of the lid. Ger J Ophthalmol 1993;2:212–17.

76. Hoerauf H, Huttmann G, Diddens H, Thiele B, Laqua H. [Photodynamic therapy of eyelid basalioma after topical administration of delta-aminolevulinic acid.] Ophthalmologe 1994;91:824–9.

77. Horn M, Wolf P, Wulf HC, Warloe T, Fritsch C, Rhodes LE, et al. Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment. Br J Dermatol 2003;149:1242–9.

78. Hunzelmann VVN, Kubler AC. [Systemical photodynamic therapy for the treatment of nodular basalioma (case-report).] Z Hautkrankheiten 2000;75:712–14.

79. Hurlimann AF, Hanggi G, Panizzon RG. Photodynamic therapy of superficial basal cell carcinomas using topical 5-aminolevulinic acid in a nanocolloid lotion. Dermatology 1998;197:248–54.

80. Isanov T, Graschew G, Shopova M, Mitrov G, Mitev U, Jori G. Photodynamic therapy for the treatment of skin cancer. A case report. Radiobiol Radiother 1987;28:5–7.

81. Itkin A, Gilchrest BA. Delta-aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome. Dermatol Surg 2004;30:1054–61.

82. Itoh Y, Henta T, Ninomiya Y, Tajima S, Ishibashi A. Repeated 5-aminolevulinic acid-based photodynamic therapy following electro-curettage for pigmented basal cell carcinoma. J Dermatol 2000;27:10–15.

83. Jiraskova M, Jirasek L, Stork J, Vosmik F, Jirsa M. [Photodynamic diagnosis and therapy in dermatology. Experience with use of TPPS4 in skin diseases.] Cas Lek Cesk 2003;142:493–9.

84. Jiraskova M, Vosmik F, Krajsova I, Lapes M, Jirsa M. [Experience with photodynamic therapy in some skin affections.] Cesk Dermatol 1999;74:161–7.



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85. Jiraskova M, Vosmik F, Lapes M, Jirsa M, Stadnik B. Experiences with local photodynamic therapy with TPPS4 and non-coherent light. Biomed Tech 1997;42(Suppl.):447–8.

86. Jungersted JM, Dam TN, Bryld LE, Agner T. Allergic reactions to Metvix (ALA-ME). Contact Dermatitis 2008;58:184–6.

87. Kaae J, Philipsen PA, Haedersdal M, Wulf HC. Immediate whealing urticaria in red light exposed areas during photodynamic therapy. Acta Dermatol Venereol 2008;88:480–3.

88. Kacerovska D, Pizinger K, Majer F, Smid F. Photodynamic therapy of nonmelanoma skin cancer with topical hypericum perforatum extract: a pilot study. Photochem Photobiol 2008;84:779–85.

89. Kacerovska D, Pizinger K, Resl V, Cetkovska P, Jirsa M, Smid F. [Comparison of efficacy between the two photosensitizers in the photodynamic therapy of cutaneous tumours.] Cesk Dermatol 2006;81:148–52.

90. Kapinus VN, Kaplan MA. Photodynamic therapy of locally invasive cutaneous carcinoma. In: Laser Helsinki 2008, 13th International Congress of EMLA (European Medical Laser Association) in conjunction with EMLA Finland and MAL (Medical Acupuncture and Laser) in cooperation with ASLMS (American Society for Laser Medicine and Surgery); 2008; Helsinki. 2008.

91. Karagas MR, Stukel TA, Umland V, Tsoukas MM, Mott LA, Sorensen HT, et al. Reported use of photosensitizing medications and basal cell and squamous cell carcinoma of the skin: results of a population-based case-control study. J Invest Dermatol 2007;127:2901–3.

92. Karrer S, Szeimies RM, Hohenleutner U, Heine A, Landthaler M. Unilateral localized basaliomatosis: treatment with topical photodynamic therapy after application of 5-aminolevulinic acid. Dermatology 1995;190:218–22.

93. Karrer S, Szeimies RM, Landthaler M. Topical photodynamic therapy with 5-ala in the treatment of arsenic-induced skin tumors. SPIE Proceedings Series 1995;2371:222–5.

94. Kaviani A, Ataie-Fashtami L, Fateh M, Sheikhbahaee N, Ghodsi M, Zand N, et al. Photodynamic therapy of head and neck basal cell carcinoma according to different clinicopathologic features. Lasers Surg Med 2005;36:377–82.

95. Kawczyk-Krupka A, Sieron A, Suwata-Jurczyk B, Adamek M. [Photodynamic therapy (PDT) using topically applied delta-aminolevulinic acid (ALA) for the treatment of malignant skin tumours.] Przegl Dermatol 2000;87:235–40.

96. Keller GS, Razum NJ, Doiron DR. Photodynamic therapy for nonmelanoma skin cancer. Facial Plast Surg 1989;6:180–4.

97. Kennedy J. HPD photoradiation therapy for cancer at Kingston and Hamilton. Adv Exp Med Biol 1983;160:53–62.

98. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 1990;6:143–8.

99. Keohane S. Successful clearance of residual superficial basal cell carcinoma with MAL-PDT following Mohs surgery. J Am Acad Dermatol 2005;52:P164-P.

100. Kerr AC, Ferguson J, Ibbotson SH. Acute phototoxicity with urticarial features during topical 5-aminolaevulinic acid photodynamic therapy. Clin Exp Dermatol 2007;32:201–2.

101. Konig K, Boehncke WH, Ruck A, Kaufmann R, Steiner R, Sterry W. Photodynamic effects on T-Cells and skin-lesions of a patient with mycosis fungoides using porphyrin photosensitizers. SPIE Proceedings Series 1994;2086:268–76.

102. Kopera D, Cerroni L, Fink-Puches R, Kerl H. Different treatment modalities for the management of a patient with the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol 1996;34:937–9.

103. Kreutzer K, Bonnekoh B, Franke I, Gollnick H. [Photodynamic therapy with methylaminooxopentanoate (Metvix) and a broad band light source (PhotoDyn 501): practical experiences in problem-patients with actinic keratoses and basal cell carcinomas.] JDDG (Journal of the German Society of Dermatology) 2004;2:992–9.

104. Kubler AC, de Carpentier J, Hopper C, Leonard AG, Putnam G. Treatment of squamous cell carcinoma of the lip using Foscan-mediated photodynamic therapy. Int J Oral Maxillofac Surg 2001;30:504–9.

105. Kubler AC, Haase T, Staff C, Kahle B, Rheinwald M, Muhling J. Photodynamic therapy of primary nonmelanomatous skin tumours of the head and neck. Lasers Surg Med 1999;25:60–8.

106. Kuijpers DIM, Smeets NWJ, Krekels GAM, Thissen MRTM. Photodynamic therapy as adjuvant treatment of extensive basal cell carcinoma treated with Mohs micrographic surgery. Dermatol Surg 2004;30:794–8.

107. Lane JE, Allen JH, Lane TN, Lesher JL, Jr. Unilateral Basal cell carcinomas: an unusual entity

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treated with photodynamic therapy. J Cutan Med Surg 2005;9:336–40.

108. Lang S, Baumgartner R, Struck R, Leunig A, Gutmann R, Feyh J. [Photodynamic diagnosis and therapy of neoplasms of the facial skin after topical administration of 5-aminolevulinic acid.] Laryngorhinootologie 1995;74:85–9.

109. Langeland J. Successful treatment of superficial basal cell carcinoma with MAL-PDT: two case reports. J Am Acad Dermatol 2005;52:P165-P.

110. Leman JA, Dick DC, Morton CA. Topical 5-ALA photodynamic therapy for the treatment of cutaneous T-cell lymphoma. Clin Exp Dermatol 2002;27:516–18.

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Seven non-RCTs reported in 11 publications were identified, which reported on patients with

Barrett’s oesophagus being treated with PDT.1–11 These were originally to be included in the main systematic review; however, as 24 publications reporting 11 RCTs were identified, these less robust non-randomised designs were subsequently excluded from the review.

A further 96 publications with study designs that did not meet the inclusion criteria for the review were identified.12–107 The references are listed below in alphabetical order, they have not been categorised and may still contain a number of duplicate publications.

ReferencesNon-randomised controlled trials1. Gross SA, Gill KR, Wolfsen HC. Comparative

outcomes of photodynamic therapy and radiofrequency ablation for the treatment of Barrett’s esophagus with high grade dysplasia. Gastrointest Endosc 2008;67:A179.

2. Jamieson N, Mosse A, Thorpe S, Novelli M, Bown S, Lovat L. High-grade dysplasia in Barrett’s esophagus: successful ablation by photodynamic therapy with ALA requires intensive therapy. Gastroenterology 2003;124:A298.

3. Jamieson NF, Thorpe S, Mosse A, Bown SG, Lovat LB. High grade dysplasia in Barrett’s oesophagus: successful ablation by photodynamic therapy with ALA requires intensive therapy. Gut 2003;52:73.

4. Mackenzie G, Clark BR, Selvasekar C, Jamieson N, Novelli M, Thorpe S, et al. Photodynamic therapy with 5 aminolevulinic acid for high grade dysplasia in Barrett’s esophagus: longterm follow-up of 51 patients. Gastroenterology 2005;128:A238.

5. Mackenzie GD, Clark B, Selvasekar CR, Jamieson NF, Novelli MR, Thorpe SM, et al. Photodynamic therapy with 5 aminolevulinic acid for high grade dysplasia in Barrett’s oesophagus: long term follow-up of 51 patients. Gut 2005;54:53.

6. Mackenzie GD, Jamieson NF, Novelli MR, Mosse CA, Clark BR, Thorpe SM, et al. How light dosimetry influences the efficacy of photodynamic therapy with 5-aminolaevulinic acid for ablation of

high-grade dysplasia in Barrett’s esophagus. Lasers Med Sci 2008;23:203–10.

7. May A, Gossner L, Pech O, Fritz A, Gunter E, Mayer G, et al. Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus: acute-phase and intermediate results of a new treatment approach. Eur J Gastroenterol Hepatol 2002;14:1085–91.

8. Mellidez JC, Mackenzie G, Selvasekar C, Novelli M, Thorpe S, Mosse C, et al. Reversal of Barrett’s esophagus following photodynamic therapy using high dose 5 aminolevulinic acid activated by red or green laser light. Gastroenterology 2005;128:A239.

9. Panjehpour M, Overholt BF, Phan MN, Haydek JM. Optimization of light dosimetry for photodynamic therapy of Barrett’s esophagus: efficacy vs. incidence of stricture after treatment. Gastrointest Endosc 2005;61:13–18.

10. Panjehpour M, Phan MN, Overholt BF, Haydek JM. Optimization of light dosimetry for photodynamic therapy of Barrett’s esophagus. SPIE Proceedings Series 2004;5315:100–6.

11. Phan MN, Panjehpour M, Overholt BF. Optimization of photodynamic therapy for Barrett’s esophagus: treatment efficacy and stricture incidence as a function of light dose. Gastroenterology 2004;126:A178.

Other scoping publications12. Photodynamic therapy with porfimer sodium

for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. [Erratum published in Gastrointest Endosc 2005;62:488–498.] Gastrointest Endosc 2006;63:359.

13. Ackroyd R, Brown NJ, Davis MF, Stephenson TJ, Stoddard CJ, Reed MW. Aminolevulinic acid-induced photodynamic therapy: safe and effective ablation of dysplasia in Barrett’s esophagus. Dis Esophagus 2000;13:18–22.

14. Ackroyd R, Brown NJ, Davis MF, Stephenson TJ, Stoddard CJ, Reed MWR. Aminolaevulinic acid-induced photodynamic therapy in the treatment of dysplastic Barrett’s oesophagus and adenocarcinoma. Lasers Med Sci 1999;14:278–85.

Appendix 7 Barrett’s oesophagus scoping

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15. Ackroyd R, Kelty CJ, Brown NJ, Stephenson TJ, Stoddard CJ, Reed MWR. Eradication of dysplastic Barrett’s oesophagus using photodynamic therapy: long-term follow-up. Endoscopy 2003;35:496–501.

16. Attila T, Kortan P, Kandel GT, Marcon N. Photodynamic therapy (PDT) for Barrett’s esophagus with high grade dysplasia (BE-HGD). Gastrointest Endosc 2005;61:A127.

17. Ban S, Mino M, Nishioka NS, Puricelli W, Zukerberg LR, Shimizu M, et al. Histopathologic aspects of photodynamic therapy for dysplasia and early adenocarcinoma arising in Barrett’s esophagus. Am J Surg Pathol 2004;28:1466–73.

18. Barr H, Shepherd NA, Dix A, Roberts DJ, Tan WC, Krasner N. Eradication of high-grade dysplasia in columnar-lined (Barrett’s) oesophagus by photodynamic therapy with endogenously generated protoporphyrin IX. Lancet 1996;348:584–5.

19. Barr H, Tan WC, Shepherd NA, Krasner N. Photodynamic therapy (PDT) using 5-aminolaevulinic acid (5ALA) for oesophageal adenocarcinoma associated with Barrett’s metaplasia. Lasers Med Sci 1997;12:291–2.

20. Behrens A, May A, Gossner L, Gunter E, Pech O, Vieth M, et al. Curative treatment for high-grade intraepithelial neoplasia in Barrett’s esophagus. Endoscopy 2005;37:999–1005.

21. Buttar NS, Wang KK, Lutzke LS, Krishnadath KK, Anderson MA. Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett’s esophagus. Gastrointest Endosc 2001;54:682–8.

22. Chen WR, Huang Z, Korbelik M, Nordquist RE, Liu H. Photoimmunotherapy for cancer treatment. J Environ Pathol Tox 2006;25:281–91.

23. Etienne J, Canard JM. [Photodynamic therapy in liberal practice.] Acta Endoscopica 2007;37:397–8.

24. Etienne J, Dorme N, Bourg-Heckly G, Raimbert P, Fekete F. [Local curative treatment of superficial adenocarcinoma in Barrett’s esophagus. First results of photodynamic therapy with a new photosensitizer.] Bull Acad Natl Med 2000;184:1731–44; discussion 44–47.

25. Etienne J, Dorme N, Bourg-Heckly G, Raimbert P, Fekete F, Mercadier Mc, et al. Local curative treatment of superficial adenocarcinoma in Barrett’s esophagus. First results of photodynamic therapy with a new photosensitizer. Bull Acad Natl Med 2000;184:1731–47.

26. Etienne J, Dorme N, Bourg-Heckly G, Raimbert P, Flejou JF. Photodynamic therapy with green light and m-tetrahydroxyphenyl chlorin for intramucosal adenocarcinoma and high-grade dysplasia in Barrett’s esophagus. Gastrointest Endosc 2004;59:880–9.

27. Foroulis CN, Thorpe JAC. Photodynamic therapy (PDT) in Barrett’s esophagus with dysplasia or early cancer. Eur J Cardiothorac Surg 2006;29:30–4.

28. Globe J, Kelty CJ, Smythe A, Ackroyd R. The effect of photodynamic therapy (PDT) on oesophageal motility in Barrett’s oesophagus. Gut 2004;53:118.

29. Globe J, Smythe A, Kelty CJ, Reed MWR, Brown NJ, Ackroyd R. The effect of photodynamic therapy (PDT) on oesophageal motility and acid clearance in patients with Barrett’s oesophagus. J Photochem Photobiol B Biol 2006;85:17–22.

30. Go JT, Dumot JA, Lopez R, Vargo J, Zuccaro G, Falk G, et al. Photodynamic therapy in Barrett’s esophagus with high grade dysplasia and intra-mucosal carcinoma. Am J Gastroenterol 2006;101:66.

31. Gossner L, Stolte M, Sroka R, Rick K, May A, Hahn EG, et al. Photodynamic ablation of high-grade dysplasia and early cancer in Barrett’s esophagus by means of 5-aminolevulinic acid. Gastroenterology 1998;114:448–55.

32. Heller SJ, Van Dam J, Barr H. Eradication of high-grade dysplasia using 5-ALA and acid suppression: a (photo)dynamic duo. Gastroenterology 1997;112:2156–8.

33. Hemminger LL, Wolfsen HC. Photodynamic therapy for Barrett’s esophagus and high grade dysplasia: results of a patient satisfaction survey. Gastroenterol Nurs 2002;25:139–41.

34. Hinnen P, de Rooij FWM, Hop WCJ, Edixhoven A, van Dekken H, Wilson JHP, et al. Timing of 5-aminolaevulinic acid-induced photodynamic therapy for the treatment of patients with Barrett’s oesophagus. J Photochem Photobiol B Biol 2002;68:8–14.

35. Hur C, Wittenberg E, Nishioka NS, Gazelle GS. Quality of life in patients with various Barrett’s esophagus associated health states. Health Qual Life Outcomes 2006;4:45.

36. Ikeguchi M, Lightdale CJ, Choi YA, Bukowski K. A new light delivery system for photodynamic therapy with aminolevulinic acid (ALA) for treatment of high-grade dysplasia in Barrett’s esophagus. Gastrointest Endosc 2005;61:A233.

37. Jamieson N, Thorpe S, Mosse A, Novelli M, Lovat L, Bown S. Photodynamic therapy using mTHPC



153

for early Barrett’s-associated esophageal cancer. Gastroenterology 2003;124:A298.

38. Jamieson NF, Thorpe S, Masse A, Bown SG, Lovat LB. Photodynamic therapy using mTHPC for early Barrett’s-associated oesophageal cancers. Gut 2003;52:170.

39. Javaid B, Watt P, Krasner N. Photodynamic therapy (PDT) for oesophageal dysplasia and early carcinoma with mTHPC (m-tetrahydroxyphenyl chlorin): a preliminary study. Lasers Med Sci 2002;17:51–6.

40. Javaid B, Watt P, Krasner N, Brouwer PA. Oesophageal photodynamic therapy with mTHPC (m-tetra hydroxyphenyl chlorin) using a laser and a non-laser light source: a pilot study. SPIE Proceedings Series 2001;4156:262–5.

41. Jenkins JT, Charles A, Mitchell KG, Fullarton GM. Photodynamic therapy for Barretts’ adenocarcinoma associated with an Angelchik device. Photodiag Photodyn Ther 2005;2:197–200.

42. Kashtan H, Umansky M, Birkenfeld S, Scherubl H, Haddad R, Greenberg R, et al. Photodynamic therapy of Barrett’s esophagus with dysplasia using systemic aminolevulinic acid and a non-laser light source. A phase I/II study. Gastrointest Oncol 2002;4:153–7.

43. Kashtan H, Umansky M, Birkenfeld S, Scherubl H, Haddad R, Greenberg R, et al. Photodynamic therapy of Barrett’s esophagus with dysplasia using systemic aminolevulinic acid and a non-laser light source. A phase I/II study. Gastrointest Oncol 2002;4:153–8.

44. Keeley SB, Luketich JD, Landreneau RJ, Christie NA, Rivera MA, McGrath K. Using photodynamic therapy to cure esophageal cancer and Barrett’s high-grade dysplasia. Ann Surg Oncol 2006;13:85.

45. Keeley SB, Pennathur A, Gooding W, Landreneau RJ, Christie NA, Luketich J. Photodynamic therapy with curative intent for Barrett’s esophagus with high grade dysplasia and superficial esophageal cancer. Ann Surg Oncol 2007;14:2406–10.

46. Krishna M, Nakhleh RE, Hemminger LL, Wolfsen HC. Histologic characteristics and follow-up of 37 cases of Barrett’s esophagus with high grade dysplasia and intramucosal adenocarcinoma treated with photodynamic therapy. Lab Invest 2006;86:504.

47. Krishna M, Nakhleh RE, Hemminger LL, Wolfsen HC. Histologic characteristics and follow-up of 37 cases of Barrett’s esophagus with high grade dysplasia and intramucosal adenocarcinoma treated with photodynamic therapy. Mod Pathol 2006;19:504.

48. Krishnadath KK, Wang KK, Taniguchi K, Sebo TJ, Buttar NS, Anderson MA, et al. Persistent genetic abnormalities in Barrett’s esophagus after photodynamic therapy. Gastroenterology 2000;119:624–30.

49. Laukka MA, Wang KK. Initial results using low-dose photodynamic therapy in the treatment of Barrett’s esophagus. Gastrointest Endosc 1995;42:59–63.

50. Lovat LB, Jamieson NF, Novelli MR, Mosse CA, Selvasekar C, Mackenzie GD, et al. Photodynamic therapy with m-tetrahydroxyphenyl chlorin for high-grade dysplasia and early cancer in Barrett’s columnar lined esophagus. Gastrointest Endosc 2005;62:617–23.

51. Luketich JD, Fernando HC, Christie NA, Litle VR, Ferson PF, Buenaventura PO, et al. Photodynamic therapy in thoracic oncology: a single institution experience. SPIE Proceedings Series 2001;4248:28–33.

52. Macrae FA, Rajesekaram R, Thomas R, Bhathal PS. Photodynamic therapy in high grade dysplasia in Barrett’s oesophagus using 5 amino-laevulinic acid sensitization. Gastrointest Endosc 2004;59:A252.

53. Mino-Kenudosn M, Ban S, Deshpande V, Shimizu M, Lauwers GY. Buried dysplasia and early adenocarcinoma arising in Barrett esophagus (BE) after photodynamic therapy (PDT): not uncommon findings. Mod Pathol 2006;19:516.

54. Mino-Kenudson M, Ban S, Deshpande V, Shimizu M, Lauwers GY. Buried dysplasia and early adenocarcinoma arising in Barrett Esophagus (BE) after photodynamic therapy (PDT): not uncommon findings. Lab Invest 2006;86:114A.

55. Mino-Kenudson M, Ban S, Ohana M, Puricelli W, Deshpande V, Shimizu M, et al. Buried dysplasia and early adenocarcinoma arising in Barrett esophagus after porfimer-photodynamic therapy. Am J Surg Pathol 2007;31:403–9.

56. Mino-Kenudson M, Lauwers GY. Pathology of Barrett esophagus after photodynamic therapy. Mod Pathol 2007;20:550.

57. Moghissi K, Dixon K. The role of photodynamic therapy (PDT) in pre-malignant and malignant oesophageal lesions: can PDT compete with surgery? Laser Helsinki 2008, 13th International Congress of EMLA (European Medical Laser Association) in conjunction with EMLA Finland and MAL (Medical Acupuncture and Laser) in cooperation with ASLMS (American Society for Laser Medicine and Surgery), Helsinki, 2008.

58. Moghissi K, Dixon K, Thorpe JAC, Stringer MR. The role of photodynamic therapy (PDT)

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in oesophageal pre-neoplastic and malignant neoplastic lesions of the oesophagus: a review study. Photodynamic Therapy and Photodiagnosis in Clinical Practice, Brixen/Bressanone. 7–11 October 2008. Session 6 – invited lecture.

59. Ohana M, Mino-Kenudson M, Ban S, Puricelli W, Nishioka N. Frequent persistence of dysplasia by systematic pathological evaluation after photodynamic therapy for Barrett’s esophagus with high-grade dysplasia or early adenocarcinoma. Gastroenterology 2005;129:1109.

60. Ohana M, Mino-Kenudson M, Ban S, Puricelli W, Nishoka N. Frequent persistence of dysplasia by systematic pathological evaluation after photodynamic therapy for Barrett’s Esophagus with high-grade dysplasia or early adenocarcinoma. Gastrointest Endosc 2005;61:A94.

61. Ohana M, Mino-Kenudson M, Ban SC, Puricelli W, Nishioka N, Lauwers G. Frequent persistence of dysplasia by systematic pathological evaluation after photodynamic therapy for Barrett’s Esophagus with high-grade dysplasia or early adenocarcinoma. Gastroenterology 2005;128:A72.

62. Ortner MA, Zumbusch K, Liebetruth J, Ebert B, Fleige B, Dietel M, et al. Is topical delta-aminolevulinic acid adequate for photodynamic therapy in Barrett’s esophagus? A pilot study. Endoscopy 2002;34:611–16.

63. Overholt B, Panjehpour M, Tefftellar E, Rose M. Photodynamic therapy for treatment of early adenocarcinoma in Barrett’s esophagus. Gastrointest Endosc 1993;39:73–6.

64. Overholt BF, Panjehpour M. Photodynamic therapy in Barrett’s esophagus: reduction of specialized mucosa, ablation of dysplasia, and treatment of superficial esophageal cancer. Semin Surg Oncol 1995;11:372–6.

65. Overholt BF, Panjehpour M. Barrett’s esophagus: photodynamic therapy for ablation of dysplasia, reduction of specialized mucosa, and treatment of superficial esophageal cancer. Gastrointest Endosc 1995;42:64–70.

66. Overholt BF, Panjehpour M. Barretts esophagus – photodynamic therapy for ablation of dysplasia, reduction of specialized mucosa and treatment of superficial esophageal cancer. SPIE Proceedings Series 1995;2371:375–84.

67. Overholt BF, Panjehpour M. Photodynamic therapy in Barrett’s esophagus. J Clin Laser Med Surg 1996;14:245–9.

68. Overholt BF, Panjehpour M. Photodynamic therapy for Barrett’s esophagus: clinical update. Am J Gastroenterol 1996;91:1719–23.

69. Overholt BF, Panjehpour M. Photodynamic therapy for Barrett’s esophagus. Gastrointest Endosc Clin N Am 1997;7:207–20.

70. Overholt BF, Panjehpour M, Ayres M. Photodynamic therapy for Barrett’s esophagus: cardiac effects. Lasers Surg Med 1997;21:317–20.

71. Overholt BF, Panjehpour M, Halberg DL. Photodynamic therapy for Barrett’s esophagus with dysplasia and/or early stage carcinoma: long-term results. Gastrointest Endosc 2003;58:183–8.


73. Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett’s esophagus: follow-up in 100 patients. Gastrointest Endosc 1999;49:1–7.

74. Pacifico RJ, Wang KK, Wongkeesong L-M, Buttar NS, Lutzke LS. Combined endoscopic mucosal resection and photodynamic therapy versus esophagectomy for management of early adenocarcinoma in Barrett’s esophagus. Clin Gastroenterol Hepatol 2003;1:252–7.

75. Panjehpour M, Overholt BF, Dougherty TJ. Photodynamic therapy in Barrett’s esophagus: review of current results. SPIE Proceedings Series 1996;2675:20–8.

76. Panjehpour M, Overholt BF, Dougherty TJ. Photodynamic therapy of dysplasia in Barrett’s esophagus: an update. SPIE Proceedings Series 1997;2972:27–36.

77. Panjehpour M, Overholt BF, Haydek JM, Dougherty TJ. Photodynamic therapy with photofrin followed by thermal ablation for elimination of dysplasia and early cancer in Barrett’s esophagus: follow-up in 100 patients. SPIE Proceedings Series 1998;3247:14–24.

78. Panjehpour M, Overholt BF, Phan MN, Haydek JM, Robinson AF. Photodynamic therapy for Barrett’s esophagus using a 20-mm diameter light-delivery balloon (invited paper). SPIE Proceedings Series 2002;4612:13–20.

79. Panjehpour M, Phan MN, Overholt BF. Relationship between acute mucosal injury, treatment efficacy and esophageal stricture following photodynamic therapy of Barrett’s esophagus. Gastrointest Endosc 2004;59:A251.



155

80. Pech O, Gossner L, May A, Rabenstein T, Vieth M, Stolte M, et al. Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett’s cancer and high-grade intraepithelial neoplasia. Gastrointest Endosc 2005;62:24–30.

81. Pech O, Gossner L, May AD, Stolte M, Ell C. Long term results of PDT for early neoplasia in Barrett’s esophagus. Gastrointest Endosc 2004;59:A257.

82. Peters F, Kara M, Rosmolen W, Aalders M, Ten Kate F, Krishnadath K, et al. Poor results of 5-aminolevulinic acid-photodynamic therapy for residual high-grade dysplasia and early cancer in barrett esophagus after endoscopic resection. Endoscopy 2005;37:418–24.

83. Peters F, Kara M, Rosmolen W, ten Kate F, Bultje B, Krishnadath S, et al. Endoscopic resection combined with photodynamic therapy for high grade dysplasia and early cancer in Barrett’s esophagus. Gastrointest Endosc 2004;59:A251.

84. Peters FP, Kara MA, Rosmolen WD, Aalders MCG, Ten Kate FJW, Bultje BC, et al. Endoscopic treatment of high-grade dysplasia and early stage cancer in Barrett’s esophagus. Gastrointest Endosc 2005;61:506–14.

85. Prasad GA, Wang KK, Buttar NS, Wongkeesong L-M, Krishnadath KK, Nichols FC, III, et al. Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett’s esophagus. Gastroenterology 2007;132:1226–33.

86. Prasad GA, Wang KK, Buttar NS, Wongkeesong L-M, Lutzke LS, Borkenhagen LS. Predictors of stricture formation after photodynamic therapy for high-grade dysplasia in Barrett’s esophagus. Gastrointest Endosc 2007;65:60–6.

87. Rahmani EY, Rex DK, Ciaccia D, Turpin CS. Photodynamic therapy for ablation of esophageal high grade dysplasia and superficial cancer. Gastrointest Endosc 2000;51:3539.

88. Rahmani EY, Turpin C, Arney K. Photodynamic therapy for dysplastic Barrett’s esophagus and early esophageal adenocarcinoma should be first line therapy! Gastrointest Endosc 2004;59:A250.

89. Schembre DB, Huang JL, Lin OS, Cantone N, Low DE. Treatment of Barrett’s esophagus with early neoplasia: a comparison of endoscopic therapy and esophagectomy. Gastrointest Endosc 2008;67:595–601.

90. Schweitzer VG. Photodynamic therapy: 1994 treatment of benign and malignant upper aerodigestive tract disease. SPIE Proceedings Series 1995;2371:403–17.

91. Shah AK, Wolfsen HC, Hemminger LL, Shah AA, DeVault KR. Changes in esophageal motility after porfimer sodium photodynamic therapy for Barrett’s dysplasia and mucosal carcinoma. Dis Esophagus 2006;19:335–9.

92. Sylantiev C, Schoenfeld N, Mamet R, Groozman GB, Drory VE. Acute neuropathy mimicking porphyria induced by aminolevulinic acid during photodynamic therapy. Muscle Nerve 2005;31:390–3.

93. Triadafilopoulos G. Photodynamic therapy for the treatment of patients with Barrett’s high-grade dysplasia and mucosal adenocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2005;2:136–7.

94. van Hillegersberg R, Haringsma J, ten Kate FJW, Tytgat GNJ, van Lanschot JJB. Invasive carcinoma after endoscopic ablative therapy for high-grade dysplasia in Barrett’s oesophagus. Dig Surg 2003;20:440–4.

95. Wang KK, Buttar NS, Lutzke LS, Anderson MA, Krisnadath K. Long-term results of photodynamic therapy for Barrett’s esophagus. Gastrointest Endosc 2000;51:4915.

96. Wang KK, Gutta K, Laukka MA. Phototherapy of Barrett’s esophagus. SPIE Proceedings Series 1994;2133:33–8.

97. Wang KK, Song L, Buttar N, Papenfuss S, Lutzke L. Barretts esophagus after photodynamic therapy: Risk of cancer development during long term follow-up. Gastroenterology 2004;126:A50.

98. Weiss A, Wiesinger H, Owen D. Photodynamic therapy of high grade dysplasia in Barrett’s esophagus: results from treatment of 17 patients. Gastrointest Endosc 2005;61:A145.

99. Weiss AA, Wiesinger HAR, Owen D. Photodynamic therapy in Barrett’s esophagus: results of treatment of 17 patients. Can J Gastroenterol 2006;20:261–4.

100. Wolfsen HC, Hemminger LI. Photodynamic therapy for dysplastic Barrett’s esophagus and mucosal adenocarcinoma. Gastrointest Endosc 2004;59:A251.

101. Wolfsen HC, Hemminger LL, Raimondo M, Woodward TA. Photodynamic therapy and endoscopic mucosal resection for Barrett’s dysplasia and early esophageal adenocarcinoma. South Med J 2004;97:827–30.

102. Wolfsen HC, Hemminger LL, Wallace MB, Devault KR. Clinical experience of patients undergoing photodynamic therapy for Barrett’s dysplasia or cancer. Aliment Pharmacol Ther 2004;20:1125–31.

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103. Wolfsen HC, Ng CS. Cutaneous consequences of photodynamic therapy. Cutis 2002;69:140–2.

104. Wolfsen HC, Woodward TA. Photofrin PDT for Barrett’s esophagus and early esophageal cancer. Recent Advances in Diseases of the Esophagus, 8th World Congress of the International Society for Diseases of the Esophagus, Sao Paulo, Brazil, 2001. pp. 149–53.

105. Wolfsen HC, Woodward TA, Raimondo M. Photodynamic therapy for dysplastic Barrett

esophagus and early esophageal adenocarcinoma. Mayo Clin Proc 2002;77:1176–81.

106. Yachimski P, Puricelli WP, Nishioka NS. Patient predictors of esophageal stricture development after photodynamic therapy. Clin Gastroenterol Hepatol 2008;6:302–8.

107. Zopf T, Rosenbaum A, Apel D, Jakobs R, Arnold JC, Riemann JF. [Photodynamic therapy of dysplasias and early carcinomas in Barrett esophagus with a diode laser system: a pilot study.] Med Klin 2001;96:212–16.



157

One hundred and fifty publications, with study designs that did not meet the inclusion

criteria for the review, reported on patients with oesophageal cancer being treated with PDT. The references are listed below in alphabetical order; they have not been categorised and may still contain a number of duplicate publications.

References1. Anonymous. Photodynamic therapy effective for

swallowing problems. Oncology 1999;13:937.

2. Baconnier M, Phelip JM, Germain E, Durand A, Balosso J, Bichard P, et al. [External radiotherapy and photodynamic therapy for esophageal carcinoma: a dangerous association?] Gastroenterol Clin Biol 2008;32:221–3.

3. Bai XM, Shen GR, Chen WG, Guo T. Observation of curative effect photodynamic therapy for 42 cases of moderate or late stage in esophagus cancer. SPIE Proceedings Series 1998;3344:114–16.

4. Ban S, Mino M, Nishioka NS, Puricelli W, Zukerberg LR, Shimizu M, et al. Histopathologic aspects of photodynamic therapy for dysplasia and early adenocarcinoma arising in Barrett’s esophagus. Am J Surg Pathol 2004;28:1466–73.

5. Calzavara F, Tomio L. Photodynamic therapy: clinical experience at the Department of Radiotherapy at Padova General Hospital. J Photochem Photobiol B 1991;11:91–5.

6. Calzavara F, Tomio L, Corti L, Zorat PL, Barone I, Peracchia A, et al. Oesophageal cancer treated by photodynamic therapy alone or followed by radiation therapy. J Photochem Photobiol B 1990;6:167–74.

7. Calzavara F, Tomio L, Norberto L, Peracchia A, Corti L, Zorat PL, et al. Photodynamic therapy in the treatment of malignant tumours of the upper aerodigestive tract. Lasers Med Sci 1989;4:279–84.

8. Chissov VI, Sokolov VV, Trakhtenberg AK, Mamontov AS. Photodynamic therapy of early stage cancer of lung, esophagus, and stomach with two different photosensitizers. SPIE Proceedings Series 1995;2625:466–75.

9. Corti L, Noverto L, Belfontali S, Schaffer M. Long survival-rate in patients with esophagus cancer treated with PDT. In Waidelich W, Waidelich R, Hofstetter A, editors. Lasers in medicine. Munich, Germany: Springer-Verlag; 1993. pp. 268–71.

10. Corti L, Skarlatos J, Boso C, Cardin F, Kosma L, Koukourakis MI, et al. Outcome of patients receiving photodynamic therapy for early esophageal cancer. Int J Radiat Oncol Biol Phys 2000;47:419–24.

11. Craig C, Gray J, Macpherson M, Hodgson H, Zammit M, Fullarton G. Porfimer sodium photodynamic therapy in the treatment of early oesophageal carcinoma. Photodiag Photodyn Ther 2007;4:244–8.

12. Craig C, Macpherson M, Hodgson H, Gray J, Zammit M, Fullarton G. Photodynamic therapy of early oesophageal carcinoma. Gut 2006;55:76.

13. Craig CF, MacPherson M, Hodgson H, Gray J, Zammit M, Fullarton G. Photodynamic therapy is of benefit in treatment of early oesophageal carcinoma. Gastroenterology 2006;130:A414.

14. Dal Fante M, Lombardo L, Conio M, Mancini A, Spinelli P. [Photodynamic therapy of the superficial esophageal carcinoma in Barrett’s esophagus.] Giorn Ital Endosc Digest 1995;18:171–6.

15. Eickhoff A, Jakobs R, Weickert U, Hartmann D, Schilling D, Alsenbesy M, et al. Long-segment early squamous cell carcinoma of the proximal esophagus: curative treatment and long-term follow-up after 5-aminolevulinic acid (5-ALA)-photodynamic therapy. Endoscopy 2006;38:641–3.

16. Etienne J, Canard JM. [Photodynamic therapy in liberal practice.] Acta Endoscopica 2007;37:397–8.

17. Everette SS, Sethi A, DeCosta GB, Zfass AM. A 10 year, single center experience with PDT in esophageal lesions. Am J Gastroenterol 2006;101:94.

18. Fujimaki M, Nakayama K. Endoscopic laser treatment of superficial esophageal cancer. Semin Surg Oncol 1986;2:248–56.

19. Go JT, Dumot JA, Lopez R, Vargo J, Zuccaro G, Falk G, et al. Photodynamic therapy in Barrett’s esophagus with high grade dysplasia and intra-mucosal carcinoma. Am J Gastroenterol 2006;101:66.

Appendix 8 Oesophageal cancer scoping

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20. Goodell TT, Jacques SL, Gregory KW, Dougherty TJ. Evaluating clinical outcomes of PDT. SPIE Proceedings Series 2001;4248:1–9.

21. Gossner L, May A, Sroka R, Stolte M, Hahn EG, Ell C. Photodynamic destruction of high grade dysplasia and early carcinoma of the esophagus after the oral administration of 5-aminolevulinic acid. Cancer 1999;86:1921–8.

22. Gossner L, Stolte M, Sroka R, May A, Hahn EG, Ell C. [Photodynamic therapy of early squamous epithelial carcinomas and severe squamous epithelial dysplasias of the esophagus with 5-aminolevulinic acid.] Z Gastroenterologie 1998;36:19–26.

23. Grosjean P, Savary JF, Mizeret J, Wagnieres G, Woodtli A, Theumann JF, et al. Photodynamic therapy for cancer of the upper aerodigestive tract using tetra(m-hydroxyphenyl)chlorin. J Clin Laser Med Surg 1996;14:281–7.

24. Grosjean P, Savary JF, Wagnieres G, Mizeret J, Woodtli A, Fontolliet C, et al. [Phototherapy of pharyngeal, oesophageal and bronchial early squamous cell carcinomas after sensitisation by tetra (m-hydroxyphenyl) chlorin (mTHPC).] Med Chir Digest 1996;25:411–13.

25. Grosjean P, Savary JF, Wagnieres G, Mizeret J, Woodtli A, Theumann JF, et al. Tetra(m-hydroxyphenyl)chlorin clinical photodynamic therapy of early bronchial and oesophageal cancers. Lasers Med Sci 1996;11:227–35.

26. Ha BW, Kim JI, Hwang EM, Oh YK, Cheung DY, Park SH, et al. [A case of photodynamic therapy for early esophageal cancer recurred after esophagectomy.] Taehan Sohwagi Hakhoe chi) 2007;49:331–5.


28. Hayata Y, Kato H, Furuse K, Kusunoki Y, Suzuki S, Mimura S. Photodynamic therapy of 168 early stage cancers of the lung and oesophagus: a Japanese multi-centre study. Lasers Med Sci 1996;11:255–9.

29. Hayata Y, Kato H, Konaka C, Okitsu H, Suga S, Sayami P. [Laser endoscopy in photodynamic therapy.] Chirurgie 1988;59:81–9.

30. Hochain P, Ducrotte P, Paillot B, Touchais JY, Thorel JM, Petit A, et al. [Photodynamic therapy by coloring laser. Can it represent a therapeutic alternative for small epidermoid cancers of the esophagus?] Gastroenterol Clin Biol 1992;16:552–7.

31. Hochain P, Ducrotte P, Touchais JY, Paillot B, Hecketsweller P. Extended necrosis of the oesophageal wall after photodynamic therapy: report of two cases. Lasers Med Sci 1993;8:147–50.

32. Jamieson N, Thorpe S, Mosse A, Novelli M, Lovat L, Bown S. Photodynamic therapy using mTHPC for early Barretts-associated esophageal cancer. Gastroenterology 2003;124:A298.

33. Jamieson NF, Thorpe S, Masse A, Bown SG, Lovat LB. Photodynamic therapy using mTHPC for early Barrett’s-associated oesophageal cancers. Gut 2003;52:170.

34. Javaid B, Watt P, Krasner N. Photodynamic therapy (PDT) for oesophageal dysplasia and early carcinoma with mTHPC (m-tetrahydroxyphenyl chlorin): a preliminary study. Lasers Med Sci 2002;17:51–6.

35. Javaid B, Watt P, Krasner N, Brouwer PA. Oesophageal photodynamic therapy with mTHPC (m-tetra hydroxyphenyl chlorin) using a laser and a non-laser light source: a pilot study. SPIE Proceedings Series 2001;4156:262–5.

36. Karanov S, Kostadinov D, Shopova M, Kurtev P. Photodynamic therapy in lung and gastrointestinal cancers. J Photochem Photobiol B 1990;6:175–81.

37. Karanov S, Shopova M, Getov H. Photodynamic therapy in gastrointestinal cancer. Lasers Surg Med 1991;11:395–8.

38. Karasic DS, Pearson VE. Urticaria and respiratory distress due to porfimer sodium. Ann Pharmacother 2000;34:1208–9.

39. Kashtan H, Konikoff F, Haddad R, Skornick Y. Photodynamic therapy of cancer of the esophagus using systemic aminolevulinic acid and a non laser light source: a phase I/II study. Gastrointest Endosc 1999;49:760–4.

40. Kashtan H, Konikoff F, Haddad R, Umansky M, Skornick Y, Halpern Z. [Photodynamic therapy for dysphagia due to esophageal carcinoma.] Harefuah 1999;137:441–4.

41. Kato H, Kito T, Furuse K, Sakai E, Ito K, Mimura S, et al. [Photodynamic therapy in the early treatment of cancer.] Gan To Kagaku Ryoho 1990;17:1833–8.

42. Keeley SB, Luketich JD, Landreneau RJ, Christie NA, Rivera MA, McGrath K. Using photodynamic therapy to cure esophageal cancer and Barrett’s high-grade dysplasia. Ann Surg Oncol 2006;13:85.

43. Keeley SB, Pennathur A, Gooding W, Landreneau RJ, Christie NA, Luketich J. Photodynamic therapy with curative intent for Barrett’s esophagus with



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44. Kouzu T, Konno H, Sakuma Y, Hishikawa E, Onoda S, Isono K. The present condition and the future of PDT for esophageal carcinoma in Japan. Recent Advances in Bronchoesophagology: Proceedings of the 6th World Congress of Bronchoesophagology, Tokyo, Japan, 1990. Elsevier Science Publishers. pp. 41–8.

45. Lecleire S, Di Fiore F, Antonietti M, Ben-Soussan E, Hochain P, Lerebours E, et al. Nonoperable patients with superficial esophageal cancer treated by photodynamic therapy after chemoradiotherapy have more severe complications than patients treated in primary intent. Am J Gastroenterol 2008;103:2215–19.


47. Likier HM, Levine JG, Lightdale CJ. Photodynamic therapy for completely obstructing esophageal carcinoma. Gastrointest Endosc 1991;37:75–8.

48. Litle VR, Luketich JD, Christie NA, Buenaventura PO, Alvelo-Rivera M, McCaughan JS, et al. Photodynamic therapy as palliation for esophageal cancer: experience in 215 patients. Ann Thorac Surg 2003;76:1687–92; discussion 92–93.

49. Lovat LB, Jamieson NF, Novelli MR, Mosse CA, Selvasekar C, Mackenzie GD, et al. Photodynamic therapy with m-tetrahydroxyphenyl chlorin for high-grade dysplasia and early cancer in Barrett’s columnar lined esophagus. Gastrointest Endosc 2005;62:617–23.

50. Luketich JD, Christie NA, Buenaventura PO, Weigel TL, Keenan RJ, Nguyen NT. Endoscopic photodynamic therapy for obstructing esophageal cancer: 77 cases over a 2-year period. Surg Endosc 2000;14:653–7.


52. Luketich JD, Nguyen NT, Weigel TL, Keenan RJ, Ferson PF, Belani CP. Photodynamic therapy for treatment of malignant dysphagia. Surg Laparosc Endosc Percutan Tech 1999;9:171–5.

53. Maier A, Woltsche M, Fell B, Prettenhofer U, Domej W, Roger GM, et al. Local and systemic treatment in small cell carcinoma of the esophagus. Oncology Reports 2000;7:187–92.

54. Malhi-Chowla N, Wolfsen HC, DeVault KR. Esophageal dysmotility in patients undergoing photodynamic therapy. Mayo Clin Proc 2001;76:987–9.

55. Mall JW, Zuckermann-Becker H, Pollmann C, Opitz I, Rogalla P, Walter M. Esophageal necrosis and perforation of the left main bronchus following photodynamic therapy of esophageal carcinoma. Thorac Cardiovasc Surg 2002;50:111–13.

56. Marcon NE. Photodynamic therapy and cancer of the esophagus. Semin Oncol 1994;21:20–3.

57. Marcon NE. Photodynamic therapy and cancer of the esophagus. Semin Oncol 1994;21:20–3.

58. Maunoury V, Mordon S, Bulois P, Mirabel X, Hecquet B, Mariette C. Photodynamic therapy for early oesophageal cancer. Dig Liver Dis 2005;37:491–5.




62. McCaughan JS, Jr. Photodynamic therapy of skin and esophageal cancers. Cancer Invest 1990;8:407–16.

63. McCaughan JS. Photodynamic therapy versus Nd-Yag laser treatment of endobronchial or esophageal malignancies. Photodyn Ther Biomed Lasers 1992;1011:23–36.

64. McCaughan JS, Jr. Photodynamic therapy of endobronchial and esophageal tumors: an overview. J Clin Laser Med Surg 1996;14:223–33.

65. McCaughan JS, Jr. Photodynamic therapy for obstructive esophageal malignancies. Diagn Ther Endosc 1999;5:167–74.

66. McCaughan JS, Jr, Ellison EC, Guy JT, Hicks WJ, Jones JJ, Laufman LR, et al. Photodynamic therapy for esophageal malignancy: a prospective twelve-year study. Ann Thorac Surg 1996;62:1005–9; discussion 9–10.

67. McCaughan JS, Jr, Ellison EC, Guy JT, Hicks WJ, Jones JJ, Laufman LR, et al. Photodynamic therapy for esophageal malignancy: a prospective twelve-year study [Discussion]. Ann Thorac Surg 1996;62:1005–10.

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70. McCaughan JS, Jr, Nims TA, Guy JT, Hicks WJ, Williams TE, Jr, Laufman LR. Photodynamic therapy for esophageal tumors. Arch Surg 1989;124:74–80.

71. McCaughan JS, Jr, Williams TE, Jr, Bethel BH. Palliation of esophageal malignancy with photodynamic therapy. Ann Thorac Surg 1985;40:113–20.

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73. Messmann H, Szeimies RM, Baumler W, Knuchel R, Zirngibl H, Scholmerich J, et al. Enhanced effectiveness of photodynamic therapy with laser light fractionation in patients with esophageal cancer. Endoscopy 1997;29:275–80.

74. Mimura S, Ichii M, Imanishi K, Otani T, Okuda S. [Indications for and limitations of HpD photodynamic therapy for esophageal cancer and gastric cancer.] Gan To Kagaku Ryoho 1988;15:1440–4.

75. Mimura S, Narahara H, Ishihara R, Iishi H. Long-term survival after photodynamic therapy with Photofrin for superficial esophageal cancer and early gastric cancer. 14th World Congress of the International Society for Laser Surgery and Medicine, Chennai, India, 2001. pp. 41–5.

76. Mimura S, Otani T, Okuda S. Photodynamic therapy for superficial esophageal cancer using an excimer dye laser. Diagn Ther Endosc 1994;1:99–105.

77. Mlkvy P. [Photodynamic therapy of gastrointestinal tumours – a pilot study.] Lekarsky Obzor 2003;52:171–5.

78. Moghissi K. Comparison of endoscopic PDT with surgical resection for early oesophageal cancer. Photodiag Photodyn Ther 2008;5:A O-12.

79. Moghissi K, Dixon K. Photodynamic therapy (PDT) in esophageal cancer: a surgical view of its indications based on 14 years experience. Technol Cancer Res Treat 2003;2:319–26.

80. Moghissi K, Dixon K. The role of photodynamic therapy (PDT) in pre-malignant and malignant oesophageal lesions: can PDT compete with surgery? Laser Helsinki 2008, 13th International Congress of EMLA (European Medical Laser Association) in conjunction with EMLA Finland and MAL (Medical Acupuncture and Laser) in cooperation with ASLMS (American Society for Laser Medicine and Surgery); 2008; Helsinki. 2008.

81. Moghissi K, Dixon K, Hudson E, Stringer M. Photodynamic therapy of oesophageal cancer. Lasers Med Sci 1995;10:67–71.

82. Moghissi K, Dixon K, Thorpe JA, Stringer M, Moore PJ. The role of photodynamic therapy (PDT) in inoperable oesophageal cancer. Eur J Cardiothorac Surg 2000;17:95–100.

83. Moghissi K, Dixon K, Thorpe JAC, Stringer MR. The role of photodynamic therapy (PDT) in oesophageal pre-neoplastic and malignant neoplastic lesions of the oesophagus: a review study. Photodynamic Therapy and Photodiagnosis in Clinical Practice, Brixen/Bressanone, 7–11 October 2008. Session 6 – invited lecture.

84. Monnier P, Fontolliet C, Wagnieres G, Braichotte D, Vandenbergh H. Further appraisal of PDI and PDT of early squamous-cell carcinomas of the pharynx, esophagus and bronchi. Photodyn Ther Biomed Lasers 1992;1011:7–14.

85. Monnier P, Savary M, Fontolliet C, Wagnieres Chatelain GA, Cornaz P, Depeursinge C, et al. Photodetection and photodynamic therapy of ‘early’ squamous cell carcinomas of the pharynx, oesophagus and tracheo-bronchial tree. Lasers Med Sci 1990;5:149–68.

86. Monnier P, Savary M, Fontolliet C, Wagnieres G, Vandenbergh H, Chatelain A. Photodynamic therapy (PDT) of 25 early pharyngoesophageal carcinomas: results and complications. Dis Esophagus 1990;1:359–71.

87. Muto M, Yano T, Katada C, Mera K, Doi T, Ishikura S, et al. Salvage photodynamic therapy (PDT) for locoregional failure after definitive chemoradiotherapy (CRT) for esophageal cancer (EC). J Clin Oncol 2004;22:4171.

88. Nakamura T, Fukui H, Shirakawa K, Fujii Y, Fujimori T, Terano A. Photodynamic therapy of superficial esophageal cancer with a transparent hood. Gastrointest Endosc 2004;60:120–4.

89. Norberto L, Segalin A, Ruol A, Baessato M, Cusumano A, Bardini R, et al. Results after ND:YAG laser therapy and photo dynamic therapy (PDT) of



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90. Okunaka T, Kato H, Conaka C, Yamamoto H, Bonaminio A, Eckhauser ML. Photodynamic therapy of esophageal carcinoma. Surg Endosc 1990;4:150–3.

91. Okushima N, Muto Y, Kaburagi Y, Muroi M, Ide H, Suzuki S, et al. [Photodynamic therapy: its application for the treatment of esophageal cancer.] Nippon Geka Gakkai Zasshi 1989;90:1594–7.

92. Okushima N, Yoshida M, Muroi M. [Endoscopic photoradiation therapy for esophageal cancer.] Gastroenterol Endosc 1985;27:177–83.

93. Orth K, Ruck A, Beck G, Stanescu A, Beger HG. [Photodynamic therapy of small adenocarcinomas with methylene blue.] Chirurgie 1995;66:1254–7.

94. Orth K, Ruck A, Stanescu A, Beger HG. Intraluminal treatment of inoperable oesophageal tumours by intralesional photodynamic therapy with methylene blue. Lancet 1995;345:519–20.

95. Orth K, Stanescu A, Ruck A, Russ D, Beger HG. [Photodynamic ablation and argon-plasma coagulation of premalignant and early-stage malignant lesions of the oesophagus: an alternative to surgery?] Chirurgie 1999;70:431–8.

96. Overholt BF, Panjehpour M. Photodynamic therapy in Barrett’s esophagus: reduction of specialized mucosa, ablation of dysplasia, and treatment of superficial esophageal cancer. Semin Surg Oncol 1995;11:372–6.

97. Overholt BF, Panjehpour M. Barretts esophagus: photodynamic therapy for ablation of dysplasia, reduction of specialized mucosa and treatment of superficial esophageal cancer. SPIE Proceedings Series 1995;2371:375–84.

98. Overholt BF, Panjehpour M. Photodynamic therapy in Barrett’s esophagus. J Clin Laser Med Surg 1996;14:245–9.

99. Overholt BF, Panjehpour M. Photodynamic therapy for Barrett’s esophagus: clinical update. Am J Gastroenterol 1996;91:1719–23.

100. Overholt BF, Panjehpour M, Ayres M. Photodynamic therapy for Barrett’s esophagus: cardiac effects. Lasers Surg Med 1997;21:317–20.


102. Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett’s esophagus: follow-up in 100 patients. Gastrointest Endosc 1999;49:1–7.

103. Overholt BF, Panjehpour M, Teffetellar E, Rose M. Photodynamic therapy (PDT) utilizing photofrin for treatment of early esophageal cancer. SPIE Proceedings Series 1993;1881:35–40.

104. Pan LN, Zhang ZY, Li M, Su RL. [Effect of photodynamic therapy for esophageal carcinoma in near future.] World Chin J Digestol 2006;14:530–2.

105. Panjehpour M, Overholt BF, Haydek JM, Dougherty TJ. Photodynamic therapy with photofrin followed by thermal ablation for elimination of dysplasia and early cancer in Barrett’s esophagus: follow-up in 100 patients. SPIE Proceedings Series 1998;3247:14–24.

106. Patrice T, Foultier MT, Yactayo S, Adam F, Galmiche JP, Douet MC, et al. Endoscopic photodynamic therapy with hematoporphyrin derivative for primary treatment of gastrointestinal neoplasms in inoperable patients. Digestive Diseases & Sciences 1990;35:545–52.

107. Patrice T, Foultier MT, Yactayo S, Douet MC, Maloisel F, Le Bodic L. Endoscopic photodynamic therapy with haematoporphyrin derivative in gastroenterology. J Photochem Photobiol B 1990;6:157–65.

108. Pazurek M, Malecka-Panas E. Photodynamic therapy in the palliative treatment of esophageal cancer. Photodiag Photodyn Ther 2005;2:73–7.

109. Peters F, Kara M, Rosmolen W, Aalders M, Ten Kate F, Krishnadath K, et al. Poor results of 5-aminolevulinic acid-photodynamic therapy for residual high-grade dysplasia and early cancer in barrett esophagus after endoscopic resection. Endoscopy 2005;37:418–24.

110. Privalov VA, Lappa AV, Seliverstov OV, Faizrakhmanov AB, Yarovoy NN, Kochneva EV, et al. Clinical trials of a new chlorin photosensitizer for photodynamic therapy of malignant tumors. Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XI 2002;4612:178–89.

111. Radu A, Grosjean P, Fontolliet C, Wagnieres G, Woodtli A, Bergh HV, et al. Photodynamic therapy for 101 early cancers of the upper aerodigestive tract, the esophagus, and the bronchi: a single-institution experience. Diagn Ther Endosc 1999;5:145–54.

112. Rahmani EY, Rex DK, Ciaccia D, Turpin CS. Photodynamic therapy for ablation of esophageal

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113. Regula J, MacRobert AJ, Gorchein A, Buonaccorsi GA, Thorpe SM, Spencer GM, et al. Photosensitisation and photodynamic therapy of oesophageal, duodenal, and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX: a pilot study. Gut 1995;36:67–75.

114. Sanfilippo NJ, Hsi A, DeNittis AS, Ginsberg GG, Kochman ML, Friedberg JS, et al. Toxicity of photodynamic therapy after combined external beam radiotherapy and intraluminal brachytherapy for carcinoma of the upper aerodigestive tract. Lasers Surg Med 2001;28:278–81.

115. Savary JF, Monnier P, Fontolliet C, Mizeret J, Wagnieres G, Braichotte D, et al. Photodynamic therapy for early squamous cell carcinomas of the esophagus, bronchi, and mouth with m-tetra (hydroxyphenyl) chlorin. Arch Otolaryngol Head Neck Surg 1997;123:162–8.

116. Savary JF, Monnier P, Wagnieres G, Braichotte D, Fontolliet C, Vandenbergh H. Preliminary clinical-studies of photodynamic therapy with meso-tetrahydroxyphenyl chlorin (M-Thpc) as a photosensitizing agent for the treatment of early pharyngeal, esophageal and bronchial carcinomas. SPIE Proceedings Series 1994;2078:330–40.

117. Scheider DM, Siemens M, Cirocco M, Haber GB, Kandel G, Kortan P, et al. Photodynamic therapy for the treatment of tumor ingrowth in expandable esophageal stents. Endoscopy 1997;29:271–4.

118. Schweitzer VG. Photodynamic therapy – 1994 treatment of benign and malignant upper aerodigestive tract disease. SPIE Proceedings Series 1995;2371:403–17.

119. Schweitzer VG, Bologna S, Batra SK. Photodynamic therapy for treatment of esophageal cancer: a preliminary report. Laryngoscope 1993;103:699–703.

120. Schweitzer VG, Bologna S, Batra SK, Cummings C. Photodynamic therapy for treatment of esophageal cancer: a preliminary report [Discussion]. Laryngoscope 1993;103:699–703.

121. Segalin A, Little AG, Ruol A, Ferguson MK, Bardini R, Norberto L, et al. Surgical and endoscopic palliation of esophageal carcinoma. Ann Thorac Surg 1989;48:267–71.

122. Shah AK, Wolfsen HC, Hemminger LL, Shah AA, DeVault KR. Changes in esophageal motility after porfimer sodium photodynamic therapy for Barrett’s dysplasia and mucosal carcinoma. Dis Esophagus 2006;19:335–9.

123. Shim CS, Cheon YK, Jung IS, Ko BM, Cho JY, Lee JS, et al. Photodynamic therapy for early esophageal cancer. Gastrointest Endosc 2007;65:A149.

124. Sibille A, Lambert R, Souquet JC, Sabben G, Descos F. Long-term survival after photodynamic therapy for esophageal cancer. Gastroenterology 1995;108:337–44.

125. Smucler R. Surgical excision versus ALA-PDT-PDL versus laser coagulation with diode laser in treatment of basal cell carcinoma (2 years study). Lasers Surg Med 2005;36:S17.

126. Spinelli P, Dal FM. Photodynamic therapy of solid tumors. Semin Hematol 1992;29:142–54.

127. Spinelli P, Dalfante M, Mancini A, Massetti M. Endoscopic photodynamic therapy of early cancer and severe dysplasia of the esophagus. Photodyn Ther Biomed Lasers 1992;1011:262–5.

128. Spinelli P, Mancini A, Dal Fante M. Endoscopic treatment of gastrointestinal tumors: indications and results of laser photocoagulation and photodynamic therapy. Semin Surg Oncol 1995;11:307–18.


130. Sun Y, Guan SC. A study of the clinical-application of PDT to the treatment of alimentary-tract cancer and precancerous gastric diseases. SPIE Proceedings Series 1993;1616:122–6.

131. Tajiri H, Oguro Y. Laser endoscopic treatment for upper gastrointestinal cancers. J Laparoendosc Surg 1991;1:71–8.

132. Tan WC, Fulljames C, Stone N, Dix AJ, Shepherd N, Roberts DJ, et al. Photodynamic therapy using 5-aminolaevulinic acid for oesophageal adenocarcinoma associated with Barrett’s metaplasia. J Photochem Photobiol B 1999;53:75–80.

133. Tanaka T, Sueyoshi S, Fujita H, Toh U, Fujii T, Kubota M, et al. Photodynamic therapy for superficial esophageal carcinoma. Recent Advances in Diseases of the Esophagus, 8th World Congress of the International Society for Diseases of the Esophagus, Sao Paulo, Brazil, 2001. pp. 593–7.

134. Thomas RJ, Abbott M, Bhathal PS, St John DJ, Morstyn G. High-dose photoirradiation of esophageal cancer. Ann Surg 1987;206:193–9.

135. Tian ME, Qui SL, Ji Q. Preliminary results of hematoporphyrin derivative-laser treatment for 13



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137. Vandenbergh H. Photodynamic therapy and photodetection of early cancer in the upper aerodigestive tract, the tracheobronchial tree, the oesophagus and the urinary bladder. Hadron Ther Oncol 1994;1077:577–621.

138. Wolfsen HC, Hemminger LL, Raimondo M, Woodward TA. Photodynamic therapy and endoscopic mucosal resection for Barrett’s dysplasia and early esophageal adenocarcinoma. South Med J 2004;97:827–30.

139. Wolfsen HC, Hemminger LL, Wallace MB, Devault KR. Clinical experience of patients undergoing photodynamic therapy for Barrett’s dysplasia or cancer. Aliment Pharmacol Ther 2004;20:1125–31.

140. Wolfsen HC, Woodward TA. Photofrin PDT for Barrett’s esophagus and early esophageal cancer. Recent Advances in Diseases of the Esophagus, 8th World Congress of the International Society for Diseases of the Esophagus, Sao Paulo, Brazil. International Society for Diseases of the Esophagus; 2001. pp. 149–53.

141. Wolfsen HC, Woodward TA, Raimondo M. Photodynamic therapy for dysplastic Barrett esophagus and early esophageal adenocarcinoma. Mayo Clin Proc 2002;77:1176–81.

142. Woodward TA, Wolfsen HC, Anderson RR, Bartels KE, Bass LS, Garrett CG, et al. Photodynamic therapy (PDT) with endoscopic ultrasound for the treatment of esophageal cancer. SPIE Proceedings Series 2000;3907:422–5.

143. Xu K, Niu L, Guo Z, Zuo J. Endoscopic photodynamic therapy for symptomatic palliation in advanced esophageal cancer. Ann Oncol 2006;17:91.

144. Yachimski P, Puricelli WP, Nishioka NS. Patient predictors of esophageal stricture development after photodynamic therapy. Clin Gastroenterol Hepatol 2008;6:302–8.

145. Yano T, Muto M, Minashi K, Hattori S, Ohtsu A, Yoshida S. Endoscopic mucosal resection (EMR) and photodynamic therapy (PDT) as curative salvage treatments for local failure after definitive chemoradiotherapy (CRT) for esophageal Cancer(EC). Gastrointest Endosc 2007;65:A143.

146. Yano T, Muto M, Minashi K, Ohtsu A, Yoshida S. Photodynamic therapy as salvage treatment for local failures after definitive chemoradiotherapy for esophageal cancer. Gastrointest Endosc 2005;62:31–6.

147. Yoshida K, Suzuki S, Mimura S, Ichii M, Sakai H, Shimao H, et al. [Photodynamic therapy for superficial esophageal cancer: a phase III study using PHE and excimer dye laser]. Gan To Kagaku Ryoho 1993;20:2063–6.

148. Yoshida K, Suzuki S, Mimura S, Narahara H, Tanimura H, Nagai Y, et al. A clinical study of photodynamic therapy for superficial esophageal carcinoma by YAG-OPO laser. Diagn Ther Endosc 1998;4:173–6.

149. Zammit M, Fullarton G. Treatment of early upper gastrointestinal tumors using photodynamic therapy. Gastrointest Endosc 2004;59:A258.

150. Zopf T, Rosenbaum A, Apel D, Jakobs R, Arnold JC, Riemann JF. [Photodynamic therapy of dysplasias and early carcinomas in Barrett esophagus with a diode laser system – a pilot study]. Med Klin 2001;96:212–16.



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One hundred and seventy-seven publications, with study designs that did not meet the

inclusion criteria for the review, reported on patients with lung cancer being treated with PDT. Details are lacking for many of these publications, so the categorisations may not be reliable.

There are 10 observational comparative studies, with sample sizes ranging from 29 to 687, although the sample size is unclear for one-half of them.1–10 For some of these studies, all of the patients receive PDT, for others it is series of patients undergoing treatment for lung cancer, only a proportion of which receive PDT.

Eleven publications are described as trials but without a comparator group (Phase I/II/pilot studies), with sample sizes ranging from 9 to 54.11–21

One hundred and nineteen publications report case series;22–140 19 have over 100 patients, eight publications report on case series with between 50 and 100 patients, and 71 report less than 50 patients. For 21 publications it is not clear what the sample size is. Many of these publications are by the same authors and appear to be updated series of patients or duplicate reports published in different journals. Therefore, these publications may double count patients to a certain degree.

Thirty publications report less than 10 patients,141–170 16 of which are single case reports.142,143,146,147,149,151,152,155–157,161,163,164,166,167,169

A further seven publications remain uncategorised (e.g. the paper is unavailable, it is unclear what is being reported, or possible duplicate publication).171–177

ReferencesObservational comparative studies1. Furukawa K, Okunaka T, Yamamoto H, Tsuchida

T, Usuda J, Kumasaka H, et al. Effectiveness of photodynamic therapy and Nd-YAG laser treatment for obstructed tracheobronchial malignancies. Diagn Ther Endosc 1999;5:161–6.

2. Kato H, Okunaka T, Konaka C. Photodynamic therapy for bronchogenic carcinoma. Nippon Geka Gakkai Zasshi 1997;98:36–40.

3. McCaughan JS. Photodynamic therapy versus Nd-Yag laser treatment of endobronchial or esophageal malignancies. Photodyn Ther Biomed Lasers 1992;1011:23–36.

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7. McCaughan JS, Jr, Dougherty TJ. Photodynamic therapy repeated without reinjection of Photofrin (R) (porfimer sodium). SPIE 1998;3247:31–4.

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9. Moghissi K. Lasers in broncho-pulmonary cancer. Radiol Oncol 1994;28:359–64.

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Experimental non-comparative studies11. Calzavara F, Tomio L, Norberto L, Peracchia A,

Corti L, Zorat PL, et al. Photodynamic therapy in the treatment of malignant tumours of the upper aerodigestive tract. Lasers Med Sci 1989;4:279–84.

12. Friedberg JS, Metz JM, Stevenson J, Zhu T, Mick R, Smith D, et al. Increased survival and local control is observed for patients with stage 3B non-small cell lung cancer (NSCLC), secondary to malignant pleural effusions and gross pleural carcinomatosis, in a phase II trial combining surgery and photodynamic therapy. Chest 2002;122:166S.

13. Friedberg JS, Mick R, Stevenson JP, Zhu T, Busch TM, Shin D, et al. Phase II trial of pleural

Appendix 9 Lung cancer scoping

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photodynamic therapy and surgery for patients with non-small-cell lung cancer with pleural spread. J Clin Oncol 2004;22:2192–201.

14. Furuse K, Fukuoka M, Horai T, Hitomi S, Kato H, Hayata Y. Phase-II study of photodynamic therapy (PDT) with photofrin-II for hilar type early lung-cancer. Photodyn Ther Biomed Lasers 1992;1011:614–17.

15. Furuse K, Fukuoka M, Kato H, Horai T, Kubota K, Kodama N, et al. A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group. J Clin Oncol 1993;11:1852–7.

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19. Okunaka T, Kato H, Tsutsui H, Ishizumi T, Ichinose S, Kuroiwa Y. Photodynamic therapy for peripheral lung cancer. Lung Cancer 2004;43:77–82.

20. Sutedja T, Baas P, Stewart F, van Zandwijk N. A pilot study of photodynamic therapy in patients with inoperable non-small cell lung cancer. Eur J Cancer 1992;28A:1370–3.

21. Tomaselli F, Maier A, Pinter H, Stranzl H, Smolle-Juttner FM. Photodynamic therapy enhanced by hyperbaric oxygen in acute endoluminal palliation of malignant bronchial stenosis (clinical pilot study in 40 patients). Eur J Cardiothorac Surg 2001;19:549–54.

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172. Isaev VM, Zenger VG, Musatenko LI, Nasedkin AN, Petlev AA. [Updated laser technologies in otorhinolaryngology.] Vestn Otorinolaringol 2001;5:33–5.

173. Li PS. [Photoradiation treatment of broncho-pulmonary carcinoma with hematoporphyrin derivative and microwaves through broncho-fiberscopy.] Chung Hua Chieh Ho Ho Hu Hsi 1986;9:98–9.

174. Loewen GM, Pandey R, Bellnier D, Henderson B, Dougherty T. Endobronchial photodynamic therapy for lung cancer. Lasers Surg Med 2006;38:364–70.

175. Mantareva V, Kassabov K, Shopova M, Mueller S. Influence of photodynamic therapy on the delay of



173

metastasis development in Lewis lung carcinoma. SPIE 1994;2325:355–63.

176. Sanfilippo NJ, Hsi A, DeNittis AS, Ginsberg GG, Kochman ML, Friedberg JS, et al. Toxicity of photodynamic therapy after combined external beam radiotherapy and intraluminal brachytherapy

for carcinoma of the upper aerodigestive tract. Lasers Surg Med 2001;28:278–81.

177. Sutedja G, Risse R, Van Mourik JC, Postmus PE. Photodynamic therapy for treatment of bronchial carcinomas. Thorax 1994;49:289–90.



175

Thirty publications, with study designs that did not meet the inclusion criteria for the review

reported on patients with biliary tract cancer being treated with PDT. Details are lacking for many of these publications, so the categorisations may not be reliable.

There is one comparative study, which is published in Korean;1 the information is taken from the English abstract, which provides no methodological details. This study, of patients with advanced hilar cholangiocarcinoma, is a retrospective analysis of 27 patients who were treated with PDT under percutaneous cholangioscopy plus additional percutaneous biliary drainage compared with 20 patients who were treated with endoscopic biliary drainage alone.

Twelve publications are described as trials but without a comparator group (Phase I/II/pilot studies), with sample sizes ranging from 1 to 44.2–13 One of these, a Phase II trial of 24 patients with Bismuth III/IV cholangiocarcioma treated with PDT after sensitization with Ps, also reports a retrospective comparison with a historical control group of 20 patients who fulfilled the inclusion criteria for the prospective study.4

Seven publications report case series with at least 10 patients but all of them have less than 50 patients.14–20 Ten publications report fewer than 10 patients,21–30 three of which are single case reports.21–23

ReferencesObservational comparative studies1. Cheon YK, Cho YD, Baek SH, Cha SW, Moon JH,

Kim YS, et al. [Comparison of survival of advanced hilar cholangiocarcinoma after biliary drainage alone versus photodynamic therapy with external drainage][see comment.] Korean J Gastroenterol 2004;44:280–7.

Experimental non-comparative studies2. Berr F, Tannapfel A, Lamesch P, Wiedmann M.

Endoscopic palliation of bile duct cancer with photodynamic therapy. Hepatology 1997;26:200.

3. Berr F, Wiedmann M, Tannapfel A, Halm U, Kohlhaw KR, Schmidt F, et al. Photodynamic

therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. Hepatology 2000;31:291–8.

4. Dumoulin FL, Gerhardt T, Fuchs S, Scheurlen C, Neubrand M, Layer G, et al. Phase II study of photodynamic therapy and metal stent as palliative treatment for nonresectable hilar cholangiocarcinoma. Gastrointest Endosc 2003;57:860–7.

5. Harewood GC, Baron TH, Rumalla A, Wang KK, Gores GJ, Stadheim LM, et al. Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma. J Gastroenterol Hepatol 2005;20:415–20.

6. Kaya M, de Groen PC, Angulo P, Nagorney DM, Gunderson LL, Gores GJ, et al. Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience. Am J Gastroenterol 2001;96:1164–9.

7. Ortner MA, Liebetruth J, Mansmann U, Voderholzer W, Michetti P, Schachschal G, et al. Photodynamic therapy of malignant bile duct tumors. Gastroenterology 2003;124:A565.

8. Pereira SP, Aithal G, Devlin J, Meadows HM. Photostent 1: a phase II trial of porfimer sodium photodynamic therapy in locally advanced biliary tract carcinoma. Gut 2006;55:A116.

9. Pereira SP, Ayaru L, Rogowska A, Mosse A, Hatfield ARW, Bown SG. Photodynamic therapy of malignant biliary strictures using meso-tetrahydroxyphenylchlorin. Eur J Gastroenterol Hepatol 2007;19:479–85.

10. Pereira SP, Ragunath K, Devlin J, Meadows HM. Preliminary results of a phase II trial to examine the safety and efficacy of porfimer sodium photodynamic therapy (PDT) in locally advanced biliary tract carcinoma (BTC). J Clin Oncol 2005;23:A4180.

11. Wiedmann M, Berr F, Schiefke I, Witzigmann H, Kohlhaw K, Mossner J, et al. Photodynamic therapy in patients with non-resectable hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study. Gastrointest Endosc 2004;60:68–75.

Appendix 10 Biliary tract cancer scoping

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12. Wiedmann M, Caca K, Berr F, Schiefke I, Tannapfel A, Wittekind C, et al. Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: a phase II pilot study. Cancer 2003;97:2783–90.

13. Wolkersdorfer G, Emmanuel K, Denzer U, Puespoek A, Neureiter D, Kiesslich T, et al. P-150 Temoporfin improves tumoricidal efficacy of photodynamic therapy (PDT) for bile duct cancer. International Liver Cancer Association Annual Conference, Chicago, 2008. p. 60.

Case series (10 or more patients)14. Abulafi AM, Allardice JT, Williams NS, van Someren

N, Swain CP, Ainley C. Photodynamic therapy for malignant tumours of the ampulla of Vater. Gut 1995;36:853–6.

15. Itoi T, Sofuni A, Itokawa F, Shinohara Y, Takeda K, Nakamura K, et al. Salvage therapy in patients with unresectable hilar cholangiocarcinoma. Digestive Endoscopy 2006;18:232–8.

16. Maunoury V, Mordon S, Boyer J, Quentin V, Barthet M, Laugier R, et al. Results of a multicenter open study of photodynamic therapy (Photofrin) in 49 patients with cholangiocarcinoma. Photodynamic Therapy and Photodiagnosis in Clinical Practice, Brixen/Bressanone, 7–11 October 2008.

17. Ortner M. Photodynamic therapy for cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2001;8:137–9.

18. Prasad GA, Wang KK, Baron TH, Buttar NS, Wongkeesong L-M, Roberts LR, et al. Factors associated with increased survival after photodynamic therapy for cholangiocarcinoma. Clin Gastroenterol Hepatol 2007;5:743–8.

19. Shim CS, Cheon YK, Cha SW, Bhandari S, Kim YS, Cho YD, et al. Percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and role of intraductal ultrasonography (IDUS) in the follow-up and response assessment. Gastrointest Endosc 2003;57:A199.

20. Shim CS, Cheon YK, Cha SW, Bhandari S, Moon JH, Cho YD, et al. Prospective study of the effectiveness of percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment. Endoscopy 2005;37:425–33.

Case reports (single case or fewer than 10 patients)21. Berr F, Tannapfel A, Lamesch P, Pahernik S,

Wiedmann M, Halm U, et al. Neoadjuvant photodynamic therapy before curative resection of proximal bile duct carcinoma. J Hepatol 2000;32:352–7.

22. Burdick JS, Magee D, Miller G, Wright KB. Biliary photodynamic therapy alternative delivery technique. Endoscopy 2000;32:S63.

23. McCaughan JS, Jr, Mertens BF, Cho C, Barabash RD, Payton HW. Photodynamic therapy to treat tumors of the extrahepatic biliary ducts. A case report. Arch Surg 1991;126:111–13.

24. Nanashima A, Yamaguchi H, Shibasaki S, Ide N, Sawai T, Tsuji T, et al. Adjuvant photodynamic therapy for bile duct carcinoma after surgery: a preliminary study. J Gastroenterol 2004;39:1095–101.

25. Ortner MA, Liebetruth J, Schreiber S, Hanft M, Wruck U, Fusco V, et al. Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology 1998;114:536–42.

26. Rumalla A, Baron TH, Wang KK, Gores GJ, Stadheim LM, de Groen PC. Endoscopic application of photodynamic therapy for cholangiocarcinoma. Gastrointest Endosc 2001;53:500–4.

27. Suzuki S, Inaba K, Yokoi Y, Ohata K, Ota S, Azuma M, et al. Photodynamic therapy for malignant biliary obstruction: a case series. Endoscopy 2004;36:83–7.

28. Zoepf T, Jakobs R, Arnold JC, Apel D, Rosenbaum A, Riemann JF. Photodynamic therapy for palliation of nonresectable bile duct cancer – preliminary results with a new diode laser system. Am J Gastroenterol 2001;96:2093–7.

29. Zoepf T, Jakobs R, Rosenbaum A, Apel D, Arnold JC, Riemann JF. Photodynamic therapy with 5-aminolevulinic acid is not effective in bile duct cancer. Gastrointest Endosc 2001;54:763–6.

30. Zoepf T, Jakobs R, Arnold JC, Apel D. Photodynamic therapy (PDT) for palliation of non resectable bile duct cancer: first results with a new diode laser system. Gastroenterology 1999;116:G2357.



177

Forty-three publications, with study designs that did not meet the inclusion criteria for

the review, reported on patients with brain cancer being treated with PDT. Details are lacking for many of these publications, so the categorisations may not be reliable.

There are two studies with some form of comparison group, but both studies are poorly reported and lack methodological details.1–2

One comparative study reports the results of a Phase II trial of PDD/PDT in 26 patients with WHO grade IV recurrent glioblastoma who were sensitised with mTHPC (FOSCAN) prior to fluorescent guided resection and intraoperative PDT after 4 days.2 This group of patients was compared with a control group of matched patients, but no details of how they were matched are provided.

The other comparative study reported on 30 patients [27 glioma (nine of which were recurrences), two malignant meningioma, two metastatic brain cancer] treated with high-dose PDT (haematoporphyrin derivative and pumped dye laser) in addition to craniotomy with a radical or partial excision of the tumour.1 The authors state that 30 comparable patients who were treated with surgery alone were selected at random as control subjects, but no details are provided so it is not clear how these patients were selected.

Thirteen publications are described as being trials but without a comparator group, the number of patients ranging from 3 to 186.3–15 Some of the publications appear to be related, either potential duplicate publications or reporting different outcomes for the same patients.

Twenty-two publications report case series with at least 10 patients16–37 and six publications report less than 10 patients,38–43 two of which are single case reports.38–43 Of the 22 publications, four had between 50 and 100 patients,26,27,29,30 and only three had more than 100 patients (one of which included various treatments and so not all patients will have undergone PDT).32,33,35

Many of the publications appear to be from the same clinical groups (14 are authored by Muller et al. and six by Kostron et al.) and there may well be significant overlap in the results presented (updating as more patients have been treated). Muller et al. began two RCTs that were not completed (see Chapter 11, Stopped trials) and some of the publications authored by them appear to report characteristics of the cohort of trial patients, but not comparative results.

ReferencesObservational comparative studies1. Chen ZQ, Wu S, Zhu SG. Adjuvant photodynamic

therapy in surgical management of cerebral tumors. SPIE 1993;1616:94–7.

2. Kostron H, Fiegele T, Akatuna E. Combination of FOSCAN mediated fluorescence guided resection and photodynamic treatment as new therapeutic concept for malignant brain tumors. Med Laser Appl 2006;21:285–90.

Experimental non-comparative studies3. Fedulov AS, Sakovich II, Sliakhtsin SV, Trukhachova

TV. PDT of high-grade gliomas with Fotolon. Results of an open-label randomized clinical trial. Photodiagn Photodyn Ther 2008;5(Suppl. 1):S7.

4. Kostron H, Fritsch E, Grunert V. Photodynamic therapy of malignant brain tumours: a phase I/II trial. Br J Neurosurg 1988;2:241–8.

5. Laws ER, Jr, Cortese DA, Kinsey JH, Eagan RT, Anderson RE. Photoradiation therapy in the treatment of malignant brain tumors: a phase I (feasibility) study. Neurosurgery 1981;9:672–8.

6. Marks PV, Belchetz PE, Saxena A, Igbaseimokumo U, Thomson S, Nelson M, et al. Effect of photodynamic therapy on recurrent pituitary adenomas: clinical phase I/II trial: an early report. Br J Neurosurg 2000;14:317–25.

7. Muller P, Wilson B, Dougherty TJ. Photodynamic therapy of supratentorial gliomas. SPIE 1997;2972:14–26.

8. Muller P, Wilson B, Lilge L, Hitchcock M, Hertzel F, Chen Q, et al. Photodynamic therapy of malignant brain tumors: results from a Phase II trial and

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demographics from a Phase III trial [Abstract.] Can J Neurol Sci 1999;26:S31.

9. Muller P, Wilson B, Lilge L, Varma S, Bogaards A, Fullagar, et al. Clinical studies of photodynamic therapy for malignant brain tumors: facial nerve palsy after temporal fossa photoillumination. SPIE 2003;4952:97–103.

10. Muller P, Wilson B, Lilge L, Yang V, Hetzel, Chen Q, et al. Photofrin: Photodynamic therapy for malignant brain tumors. SPIE 2001;4248:34–45.

11. Muller P, Wilson B, Lilge L, Yang V, Hitchcock M, Hetzel F, et al. Clinical trials of photodynamic therapy of malignant brain tumors. SPIE 2000;3909:10–19.

12. Muller P, Wilson B, Lilge L, Yang V, Varma A, Bogaars A, et al. Clinical studies of photodynamic therapy for malignant brain tumors: Karnofsky score and neurological score in patients with recurrent gloms treated with Photofrin-PDT. SPIE 2002;4612:40–7.

13. Origitano TC, Reichman OH. Photodynamic therapy for intracranial neoplasms: development of an image-based computer-assisted protocol for photodynamic therapy of intracranial neoplasms. Neurosurgery 1993;32:587–95, discussion 95–96.

14. Rosenthal MA, Kavar B, Uren S, Kaye AH. Promising survival in patients with high-grade gliomas following therapy with a novel boronated porphyrin. J Clin Neurosci 2003;10:425–7.

15. Varma AK, Muller PJ. Cranial neuropathies after intracranial Photofrin-photodynamic therapy for malignant supratentorial gliomas: a report on 3 cases. Surg Neurol 2008;70:190–3.

Case series (10 or more patients)16. Beck TJ, Kreth FW, Beyer W, Mehrkens JH,

Obermeier A, Stepp H, et al. Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX. Lasers Surg Med 2007;39:386–93.

17. Chen L-f, Ke Y-q, Yang Z-l, Wang S-q, Xu R-x. [Effect of photodynamic therapy combined with interstitial chemotherapy for gliomas.] Di Yi Jun Yi Da Xue Xue Bao 2005;25:116–18.

18. Kaneko S. Clinical results of stereotactic intratumoral photodynamic therapy for malignant brain tumors. Clin Lasers Diagn 2000;1:222–30.

19. Kaye AH, Morstyn G, Brownbill D. Adjuvant high-dose photoradiation therapy in the treatment of cerebral glioma: a phase 1–2 study. J Neurosurg 1987;67:500–5.

20. Kostron H, Grunert V. [Photodynamic therapy of malignant brain tumors.] Wien Klin Wochenschr 1987;99:389–92.

21. Kostron H, Obwegeser A, Jakober R, Zimmermann A, Rueck A, Dougherty TJ. Experimental and clinical results of mTHPC (Foscan R)-mediated photodynamic therapy for malignant brain tumors. SPIE 1998;3247:40–5.

22. Kostron H, Plangger C, Fritsch E, Maier H. Photodynamic treatment of malignant brain tumors. Wien Klin Wochenschr 1990;102:531–5.

23. Kostron H, Weiser G, Fritsch E, Grunert V. Photodynamic therapy of malignant brain tumors: clinical and neuropathological results. Photochem Photobiol 1987;46:937–43.

24. McCulloch GA, Forbes IJ, See KL, Cowled PA, Jacka FJ, Ward AD. Phototherapy in malignant brain tumors. Prog Clin Biol Res 1984;170:709–17.

25. Mehrkens J, Stummer W, Beck T, Tonn J, Kreth F. Interstitial photodynamic therapy of recurrent malignant gliomas using 5-aminolevulinic acid (5-ALA). Neuro Oncol 2005;7:110.

26. Muller P, Wilson B. Photodynamic therapy of malignant brain-tumors – supplementary postoperative light delivery by implanted optical fibers: field fractionation. SPIE 1991;1426:254–65.

27. Muller P, Wilson B, Dougherty TJ. Photodynamic therapy of supratentorial gliomas. SPIE 1998;3247:2–13.

28. Muller PJ, Wilson BC. Photodynamic therapy of malignant primary brain tumours: clinical effects, post-operative ICP, and light penetration of the brain. Photochem Photobiol 1987;46:929–35.

29. Muller PJ, Wilson BC. Photodynamic therapy of malignant brain tumours. Can J Neurol Sci 1990;17:193–8.

30. Muller PJ, Wilson BC. Photodynamic therapy for recurrent supratentorial gliomas. Semin Surg Oncol 1995;11:346–54.

31. Muller PJ, Wilson BC. Photodynamic therapy for malignant newly diagnosed supratentorial gliomas. J Clin Laser Med Surg 1996;14:263–70.

32. Muller PJ, Wilson BC. Photodynamic therapy of brain tumors: a work in progress. Lasers Surg Med 2006;38:384–9.

33. Obwegeser A, Ortler M, Seiwald M, Ulmer H, Kostron H. Therapy of glioblastoma multiforme: a cumulative experience of 10 years. Acta Neurochir 1995;137:29–33.



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34. Schmidt MH, Meyer GA, Reichert KW, Cheng J, Krouwer HG, Ozker K, et al. Evaluation of photodynamic therapy near functional brain tissue in patients with recurrent brain tumors. J Neurooncol 2004;67:201–7.

35. Stylli SS, Kaye AH, MacGregor L, Howes M, Rajendra P. Photodynamic therapy of high grade gliom: long term survival. J Clin Neurosci 2005;12:389–98.

36. Zhu SG. [Application of adjuvant photodynamic therapy in the treatment of malignant brain tumors.] Chin J Clin Oncol 1993;20:894–6.

37. Zhu SG, Wu S, Chen ZQ, Sun W. Photodynamic therapy of recurrent cerebral glioma. SPIE 1993;1616:115–18.

Case reports (single case or fewer than 10 patients)38. Benzer A, Putensen C, Kostron H. Photodynamic

therapy. Lancet 1989;2:382–3.

39. Kaneko S. [Photoradiation therapy (PRT). 7. Clinical study of photoradiation therapy: clinical

application and efficacy. d. Brain neoplasms.] Nippon Rinsho 1987;45:817–25.

40. Muller PJ, Wilson BC. Photodynamic therapy: cavitary photoillumination of malignant cerebral tumours using a laser coupled inflatable balloon. Can J Neurol Sci 1985;12:371–3.

41. Perria C, Carai M, Falzoi A, Orunesu G, Rocca A, Massarelli G, et al. Photodynamic therapy of malignant brain tumors: clinical results of, difficulties with, questions about, and future prospects for the neurosurgical applications. Neurosurgery 1988;23:557–63.

42. Powers SK, Cush SS, Walstad DL, Kwock L. Stereotactic intratumoral photodynamic therapy for recurrent malignant brain tumors. Neurosurgery 1991;29:688–95; discussion 95–96.

43. Stummer W, Beck T, Beyer W, Mehrkens JH, Obermeier A, Etminan N, et al. Long-sustaining response in a patient with non-resectable, distant recurrence of glioblastoma multiforme treated by interstitial photodynamic therapy using 5-ALA: case report. J Neurooncol 2008;87:103–9.



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One hundred and twenty-nine publications, with study designs that did not meet the

inclusion criteria for the review, reported on patients with head and neck cancer being treated with PDT. Details are lacking for many of these publications, so the categorisations may not be reliable.

There are three studies that appear to be comparative, although the precise design is not clear for any of them.1–3

Fifteen publications are described as trials but without a comparator group (Phase I/II pilot studies), with sample sizes ranging from 5 to 121.4–18

Eighty-seven publications report case series;19–105 eight have over 100 patients,26–28,33,61,87,94,105 but not all of these contain patients with only head and neck cancer; some studies report multiple cancer site series. Eleven publications report on case series, with between 50 and 100 patients, and 56 report less than 50 patients. For 12 publications it is not clear what the sample size is.19,39,40,48,56,57,6

0,64,68,82,85,99 Many of these publications are by the same authors and appear to be updated series of patients, or duplicate reports published in different journals. Therefore, these publications may double count patients to a certain degree.

Nineteen publications report fewer than 10 patients,106–124 seven of which are single case reports.108,110,112,115,120,121,124

A further five publications remain uncategorised.125–129

ReferencesObservational comparative studies1. Inoue H. [Voice evaluation after photodynamic

therapy for laryngeal cancer.] Otolaryngol Head Neck Surg 1997;69:407–10.

2. Lofgren LA, Hallgren S, Nilsson E, Westerborn A, Nilsson C, Reizenstein J. Photodynamic therapy for recurrent nasopharyngeal cancer. Arch Otolaryngol Head Neck Surg 1995;121:997–1002.

3. Smucler R, Vlk P. Combination of laser induced interstitial thermotherapy and photodynamic therapy in the treatment of neck cancer. Lasers Surg Med 2006;39:S18.

Experimental non-comparative studies4. Biel MA. Photodynamic therapy as an adjuvant

intraoperative treatment of recurrent head and neck carcinomas. Arch Otolaryngol Head Neck Surg 1996;122:1261–5.


6. Calzavara F, Tomio L, Norberto L, Peracchia A, Corti L, Zorat PL, et al. Photodynamic therapy in the treatment of malignant tumours of the upper aerodigestive tract. Lasers Med Sci 1989;4:279–84.

7. Carruth JA, McKenzie AL. Preliminary report of a pilot study of photoradiation therapy for the treatment of superficial malignancies of the skin, head and neck. Eur J Surg Oncol 1985;11:47–50.

8. Carruth JAS, Barrett JM, Barnes DWH, Buchanan RB, Sansom JM. A trial of photodynamic therapy for the treatment of tumors of the skin and head and neck, and the results of an experimental-study to determine the interrelationships between the tissue effects of ionizing radiation and photodynamic therapy. SPIE 1993;1616:14–19.

9. Feyh J. Photodynamic therapy of head and neck tumors. Adv Otorhinolaryngol 1995;49:53–7.

10. Feyh J. Photodynamic treatment for cancers of the head and neck. J Photochem Photobiol B 1996;36:175–7.

11. Grossweiner LI, Hill JH, Lobraico RV. Photodynamic therapy of head and neck squamous cell carcinoma: optical dosimetry and clinical trial. Photochem Photobiol 1987;46:911–17.

12. Hopper C, Kubler A, Lewis H, Tan IB, Putnam G. mTHPC-mediated photodynamic therapy for early oral squamous cell carcinoma. Int J Cancer 2004;111:138–46.

13. Lou PJ, Jager HR, Jones L, Theodossy T, Bown SG, Hopper C. Interstitial photodynamic therapy

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as salvage treatment for recurrent head and neck cancer. Br J Cancer 2004;91:441–6.

14. Rauschning W, Tan IB, Dolivet G. Photodynamic therapy (PDT) with mTHPC in the palliation of advanced head and neck cancer in patients who have failed prior therapies and are unsuitable for radiotherapy, surgery or systemic chemotherapy. J Clin Oncol 2004;22:5596.


16. Schweitzer VG. Photodynamic therapy: 1994 treatment of benign and malignant upper aerodigestive tract disease. SPIE 1995;2371:403–17.

17. Schweitzer VG, Dougherty TJ. Hematoporphyrin-mediated photodynamic therapy for treatment of head and neck cancer: clinical update 1996. SPIE 1996;2675:47–66.

18. Suhr MA, Hopper C, MacRobert AJ, Speight PM, Kubler AC, Kunz L. [Clinical pilot study of interstitial photodynamic therapy for treatment of advanced head and neck tumors.] Mund Kiefer Gesichtschir 2001;5:277–82.

Case series (10 or more patients)19. Bagnato VS, Kurachi C, Ferreira J, Marcassa

LG, Sibata CH, Allison RR. PDT experience in Brazil: a regional profile. Photodiagn Photodyn Ther 2005;2:107–18.

20. Biel MA. Photodynamic therapy and the treatment of neoplastic diseases of the larynx, oral cavity, pharynx and tracheobronchial tree. SPIE 1993;1881:10–19.

21. Biel MA. Photodynamic therapy and the treatment of neoplastic diseases of the larynx. Laryngoscope 1994;104:399–403.

22. Biel MA. Photodynamic therapy of head and neck cancers. Semin Surg Oncol 1995;11:355–9.

23. Biel MA. Photodynamic therapy and the treatment of neoplastic diseases of the larynx. SPIE 1995;2395:239–44.

24. Biel MA. Photodynamic therapy and the treatment of malignancies of the head and neck. SPIE 1995;2392:55–62.

25. Biel MA. Photodynamic therapy and the treatment of head and neck cancers. J Clin Laser Med Surg 1996;14:239–44.

26. Biel MA. Photodynamic therapy and the treatment of head and neck neoplasia. Laryngoscope 1998;108:1259–68.

27. Biel MA, Dougherty TJ. Photodynamic therapy using photofrin and foscan and the treatment of malignancies of the head and neck. SPIE 1998;3247:25–30.

28. Bloznelyte L, Cepulis V, Ponomarev I, Dougherty TJ. Intra-arterial PDT and ordinary PDT in head and neck cancer. SPIE 1996;2675:76–9.

29. Cai WM. [Result and indication of photodynamic therapy in the treatment of malignant tumors: analysis of 165 patients.] Zhonghua Zhong Liu Za Zhi 1990;12:69–71.

30. Copper MP, Tan IB, Oppelaar H, Ruevekamp MC, Stewart FA. Meta-tetra(hydroxyphenyl)chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 2003;129:709–11.

31. Copper MP, Triesscheijn M, Tan IB, Ruevekamp MC, Stewart FA. Photodynamic therapy in the treatment of multiple primary tumours in the head and neck, located to the oral cavity and oropharynx. Clin Otolaryngol 2007;32:185–9.

32. Cuenca RE, Sibata CH, Downie GH, Brodish B, Camnitz P, Allison RR. Photodynamic therapy for head and neck neoplasia using Photofrinin. Ann Surg Oncol 2006;13:16.

33. D’Cruz AK, Robinson MH, Biel MA. mTHPC-mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: a multicenter study of 128 patients. Head Neck 2004;26:232–40.

34. de Haas ER, Sterenborg HJ, Neumann HA, Robinson DJ. The influence of light fractionation on the response of superficial skin cancer to aminolevulinic-acid photodynamic therapy. J Invest Dermatol 2006;126:S73.

35. Decorbiere S, Ouayoun M, Sequert C, Freche C, Chabolle F. Use of photodynamic therapy in the treatment of vocal cord carcinoma retrospective study 1986–1992: on 41 cases. Photodyn Ther Biomed Lasers 1992;1011:656–61.

36. Delbove H, de Corbiere S, Fugain C, Freche C, Chabolle F. [Photochemotherapy in the treatment of carcinoma of the vocal cords of early stage (Tis, T1).] Ann Otolaryngol Chir Cervicofac 1996;113:155–61.

37. Dilkes M, Bapat U. Foscan photodynamic therapy for early head and neck cancer. Otolaryngol Head Neck Surg 2004;131:74–5.



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38. Dilkes MG, Benjamin E, Ovaisi S, Banerjee AS. Treatment of primary mucosal head and neck squamous cell carcinoma using photodynamic therapy: results after 25 treated cases. J Laryngol Otol 2003;117:713–17.

39. Dilkes MG, DeJode ML, Gardiner Q, Kenyon GS, McKelvie P. Treatment of head and neck cancer with photodynamic therapy: results after one year. J Laryngol Otol 1995;109:1072–6.

40. Dilkes MG, DeJode ML, Rowntree-Taylor A, McGilligan JA, Kenyon GS, McKelvie P. m-THPC photodynamic therapy for head and neck cancer. Lasers Med Sci 1996;11:23–9.

41. Fan KF, Hopper C, Speight PM, Buonaccorsi G, MacRobert AJ, Bown SG. Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesions of the oral cavity. Cancer 1996;78:1374–83.

42. Fan KF, Hopper C, Speight PM, Buonaccorsi GA, Bown SG. Photodynamic therapy using mTHPC for malignant disease in the oral cavity. Int J Cancer 1997;73:25–32.

43. Feyh J, Bujia J, Kastenbauer E. [Photodynamic therapy with hematoporphyrin derivatives in cervico-facial basaliomas and epidermoid carcinoma in stage I and II.] Acta Otorrinolaringol Esp 1993;44:121–4.

44. Feyh J, Goetz A, Muller W, Konigsberger R, Kastenbauer E. Photodynamic therapy in head and neck surgery. J Photochem Photobiol B 1990;7:353–8.

45. Freche C, De Corbiere S. Use of photodynamic therapy in the treatment of vocal cord carcinoma. J Photochem Photobiol B 1990;6:291–6.

46. Frisch C, Vocks E, Herzog M, Vogt HJ, Borelli S. [Persistent photosensitivity after systemic photodynamic therapy.] Aktuelle Dermatol 1996;22:98–103.

47. Gluckman JL. Hematoporphyrin photodynamic therapy: is there truly a future in head and neck oncology? Reflections on a 5-year experience. Laryngoscope 1991;101:36–42.

48. Gluckman JL, Waner M, Shumrick K, Peerless S. Photodynamic therapy. A viable alternative to conventional therapy for early lesion of the upper aerodigestive tract? Arch Otolaryngol Head Neck Surg 1986;112:949–52.

49. Grant WE, Hopper C, Speight PM, Macrobert AJ, Bown SG. Photodynamic therapy of malignant and premalignant lesions in patients with ‘field cancerization’ of the oral cavity. J Laryngol Otol 1993;107:1140–5.


51. Herzog M. [Photodynamic laser therapy and fluorescence diagnosis in squamous epithelial cancer of the oral cavity.] Fortschr Kiefer Gesichtschir 1993;38:139–43.

52. Herzog M, Fellbaum C, Horch HH. [Initial clinical experiences with the photodynamic therapy (PDT) of oral cavity carcinomas.] Dtsch Zahn Mund Kieferheilkd Zentralbl 1992;80:141–3.

53. Herzog M, Fellbaum C, Wagnermanslau C, Horch HH. Clinical, MRI and histological results after photodynamic therapy (PDT) of oral-cancer. SPIE 1992;1645:52–5.

54. Hopper C, Fan K, Grant WE, Speight PM, Bown SG. Photodynamic therapy using 5-aminolaevulinic acid in oral malignancy and premalignancy. SPIE 1995;2371:254–5.

55. Jiang X. The application of laser and PDT to treatment recurrent cancer in the paranasal sinuses. SPIE 1993;1616:127–8.

56. Keller GS, Doiron DR, Fisher GU. Photodynamic therapy in otolaryngology: head and neck surgery. Arch Otolaryngol Head Neck Surg 1985;111:758–61.

57. Kulapaditharom B, Boonkitticharoen V. Photodynamic therapy in the treatment of head and neck cancers: a two-year experience. J Med Assoc Thai 1996;79:229–35.

58. Kulapaditharom B, Boonkitticharoen V. Photodynamic therapy for residual or recurrent cancer of the nasopharynx. J Med Assoc Thai 1999;82:1111–17.

59. Kulapaditharom B, Boonkitticharoen V. Photodynamic therapy in management of head and neck cancers and precancerous lesions. J Med Assoc Thai 2000;83:249–58.

60. Kurachi C, Cestari G, Bagnato VS. Photodynamic therapy in the treatment of oral lesions. J Dent Res 2003;82:217.


62. Li LB, Luo RC, Liao WJ, Zhang MJ, Liu XJ, Luo YL, et al. [PHOTOFRIN photodynamic therapy for treating laryngeal carcinoma and improving voice function.] Chin J Clin Rehab 2005;9:160–1.

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65. Marchiori C, Zorat PL, Canaviglia G. [Photodynamic therapy with hematoporphyrin and red light for the treatment of head and neck cancer.] Acta Otorhinolaryngol Ital 1985;35:289–94.


67. Monnier P, Savary M, Fontolliet C, Wagnieres G, Vandenbergh H, Chatelain A. Photodynamic therapy (PDT) of 25 early pharyngoesophageal carcinomas: results and complications. Dis Esophagus 1990;1:359–71.


69. Savary JF, Monnier P, Wagnieres G, Braichotte D, Fontolliet C, Vandenbergh H. Preliminary clinical-studies of photodynamic therapy with meso-tetrahydroxyphenyl chlorin (M-Thpc) as a photosensitizing agent for the treatment of early pharyngeal, esophageal and bronchial carcinomas. SPIE 1994;2078:330–40.

70. Schuller DE, McCaughan JS, Jr, Rock RP. Photodynamic therapy in head and neck cancer. Arch Otolaryngol Head Neck Surg 1985;111:351–5.

71. Schweitzer VG. Photodynamic therapy for treatment of head and neck cancer. Otolaryngol Head Neck Surg 1990;102:225–32.

72. Schweitzer VG. PHOTOFRIN-mediated photodynamic therapy for treatment of early stage oral cavity and laryngeal malignancies. Lasers Surg Med 2001;29:305–13.

73. Shubina AM, Kaplan MA, Kapinus VN, Spichenkova IS, Polkin VV. The photodynamic therapy of malignant neoplasms of oral cavity and lips. Laser Helsinki 2008, 13th International Congress of EMLA (European Medical Laser Association) in conjunction with

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74. Sieron A, Namyslowski G, Misiolek M, Adamek M, Kawczyk-Krupka A. Photodynamic therapy of premalignant lesions and local recurrence of laryngeal and hypopharyngeal cancers. Eur Arch Otorhinolaryngol 2001;258:349–52.

75. Sieron A, Namyslowski G, Misiolek M, Adamek M, Kawczyk-Krupka A. [Clinical response to photodynamic therapy in premalignant lesions and advanced head and neck carcinomas.] Otolaryngol Pol 2003;57:501–4.

76. Stranadko E, Skobelkin O. Experience of PDT of cancer with two Russian-produced photosensitizers. SPIE 1995;2392:93–105.

77. Stranadko EF, Garbusov MI, Markitchev NA, Riabov MV. Photodynamic therapy of recurrent tumours of oropharyngeal area as an out-patient procedure. SPIE 1997;3191:237–42.

78. Stranadko EF, Garbuzov MI, Zenger VG, Nasedkin AN, Markichev NA, Riabov MV, et al. [Photodynamic therapy of recurrent and residual oropharyngeal and laryngeal tumors.] Vestn Otorinolaringol 2001:36–9.

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80. Stranadko EF, Skobelkin OK, Markichev NA, Riabov MV. Photodynamic therapy of recurrent cancer of oral cavity, an alternative to conventional treatment. SPIE 1996;2924:292–7.

81. Stranadko EF, Skobelkin OK, Markichev NA, Riabov MV, Khorana BM, Junheng L, et al. Photodynamic therapy of recurrent cancer of oral cavity. SPIE 1996;2887:233–5.

82. Stranadko EF, Skobelkin OK, Vorozhtsov GN, Beshleul SE, Markitchev NA, Riabov MV. Photodynamic therapy of cancer, five-year clinical experience. SPIE 1997;3191:253–62.

83. Stranadko EF, Titova VA, Rjabov MV, Petrovsky VY. Photodynamic therapy of squamous-cellular cancer of head and neck. Laser Helsinki 2008, 13th International Congress of EMLA (European Medical Laser Association) in conjunction with EMLA Finland and MAL (Medical Acupuncture and Laser) in cooperation with ASLMS (American Society for Laser Medicine and Surgery), Helsinki, 2008.



185

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86. Sun ZQ. [Hematoporphyrin derivative (HPD) plus laser photodynamic therapy for nasopharyngeal carcinoma: analysis of 57 cases.] Zhonghua Zhong Liu Za Zhi 1990;12:120–2.

87. Sun ZQ. [Photodynamic therapy of nasopharyngeal carcinoma by argon or dye laser: an analysis of 137 cases.] Zhonghua Zhong Liu Za Zhi 1992;14:290–2.

88. Tan I, Dolivet G, Ceruse P, Vander Poorten V, Mahy P, Roest G, et al. Temoporfin-mediated photodynamic therapy in advanced, incurable head and neck squamous cell carcinoma: a prospective multicenter study [abstract from 2008 ASCO annual meeting]. J Clin Oncol 2008;26:17001.

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90. Titova VA, Kharchenko V, Dykhno Y, Petrovsky Y, Stranadko F, Kreinina M, et al. Photodynamic therapy and lazer intensed thermotherapy in locally advanced and recurrent oropharyngeal cancer multimodal treatment. Radiother Oncol 2007;82 (Suppl.1).

91. Tong MC, van Hasselt CA, Woo JK. Preliminary results of photodynamic therapy for recurrent nasopharyngeal carcinoma. Eur Arch Otorhinolaryngol 1996;253:189–92.

92. Troillet FX, Dumonceau JM, Margalith D, Dorta G, Ortner MA. [New techniques in diagnostic and interventional endoscopy.] Med Hyg 2004;62:218–22.

93. Vakouloskaia EG, Chental VV, Abdoullin NA, Kuvshinov YP, Tabolinovskaia TD, Edinak NJ, et al. Photodynamic therapy of head and neck tumors. SPIE 1996;2924:309–13.

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96. Vakulovskaya EG, Ungiadze GV, Tabolinovskaya TD. Photodynamic therapy of oral cancer and cancer of oropharynx with second-generation photosensitizers. Oral Oncol 2005;1(Suppl.):68.

97. Wang KH. [Interstitial photodynamic therapy of oral squamous cancers.] Zhonghua Zhong Liu Za Zhi 1988;10:473–5.

98. Wenig BL, Kurtzman DM, Grossweiner LI, Mafee MF, Harris DM, Lobraico RV, et al. Photodynamic therapy in the treatment of squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1990;116:1267–70.

99. Wile AG, Dahlman A, Burns RG, Berns MW. Laser photoradiation therapy of cancer following hematoporphyrin sensitization. Lasers Surg Med 1982;2:163–8.

100. Wile AG, Novotny J, Mason GR, Passy V, Berns MW. Photoradiation therapy of head and neck cancer. Prog Clin Biol Res 1984;170:681–91.

101. Yoshida T. Clinical research of photodynamic therapy in the head and neck cancer. Nippon Gan Chiryo Gakkai Shi 1994;30:247.

102. Yoshida T, Kato H, Okunaka T, Saeki T, Ohashi S, Okudaira T, et al. Photodynamic therapy for head and neck cancer. Diagn Ther Endosc 1996;3:41–51.

103. Zeng CY, Yang D, Wang KH, Cao QQ. Interstitial photodynamic therapy for cancers of cavum oris, skin and cervix. SPIE 1993;1616:102–7.

104. Zhao FY, Zhang KH, Jiang F, Wu MJ. Photodynamic therapy for treatment of cancers in oral and maxillofacial regions: a long-term follow-up study in 72 complete remission cases. Lasers Med Sci 1991;6:201–4.

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187

107. Biel MA. Photodynamic therapy as an adjuvant intraoperative treatment of recurrent head and neck carcinomas. SPIE 1995;2395:235–8.

108. Chen H-M, Chen C-T, Yang H, Lee M-I, Kuo MY-P, Kuo Y-S, et al. Successful treatment of an extensive verrucous carcinoma with topical 5-aminolevulinic acid-mediated photodynamic therapy. J Oral Pathol Med 2005;34:253–6.

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110. Feyh J, Goetz A, Martin F, Lumper W, Muller W, Brendel W, et al. [Photodynamic laser tumor therapy with a hematoporphyrin derivative in spinocellular carcinoma of the external ear.] Laryngorhinootologie 1989;68:563–5.

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114. Ofner JG, Bartl B, Konig S, Thumfart WF. Photodynamic therapy in selected cases at the ENT Clinic, Innsbruck: case reports. J Photochem Photobiol B 1996; 36:185–7.

115. Poate TW, Dilkes MG, Kenyon GS. Use of photodynamic therapy for the treatment of squamous cell carcinoma of the soft palate. Br J Oral Maxillofac Surg 1996;34:66–8.

116. Prabhakar J, Fan K, Hopper C, Bown SG. Interstitial photodynamic therapy in head and neck tumours. Eur J Surg Oncol 1998;24:348.

117. Schweitzer VG. Photodynamic therapy improves Kaposi’s sarcoma in AIDS patients. Am Fam Physician 1988;38:260.

118. Schweitzer VG. Photodynamic therapy for treatment of aids-related mucocutaneous Kaposi’s sarcoma. Photodyn Ther Biomed Lasers 1992;1011:49–64.

119. Schweitzer VG. Photodynamic therapy for treatment of AIDS-related mucocutaneous Kaposi’s sarcoma. SPIE 1992;1645:10–32.

120. Soudant J, Castro DJ, Fougeront B, Saxton RE. The use of photodynamic therapy and photochemotherapy with lasers for palliative treatment of head and neck carcinomas: an initial human case report. J Clin Laser Med Surg 1992;10:367–71.

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126. Bing Tan I, Dolivet G, Ceruse P, Vander Poorten V, Roest GJ, Rauschning W. Foscan–mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: a multicenter study [unpublished]. Dublin: Biolitec Pharma Ltd.

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Appendix 12

186



187

Appendix 13 Actinic keratosis data extraction

Appendix 13

188



189Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Bra

athe

n et

al

. (20

08)54

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry N

ot s

tate

d,

‘Eur

ope’

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

119

rand

omis

ed, 1

12

trea

ted

(384

lesi

ons)

Inte

rven

tion:

28

(1 h

r; 16

0 m

g/g)

Com

para

tor:

30

(3 h

r; 16

0 m

g/g)

2nd

Com

para

tor:

25

(1 h

r; 80

mg/

g)3r

d C

ompa

rato

r: 29

(3

hr;

80 m

g/g)

No.

of r

ecru

itin

g ce

ntre

s Ei

ght

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

at w

k 1

and

2, t

hen

at 2

, 3, 6

and

12

mth

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y Pr

imar

y A

KM

ain

elig

ibili

ty c

rite

ria

Patie

nts

of 1

8 yr

or

olde

r w

ith F

itzpa

tric

k sk

in t

ype

I, II

or II

with

pri

mar

y pr

evio

usly

unt

reat

ed,

non-

pigm

ente

d an

d no

n-in

filtr

atin

g A

K le

sion

s (u

p to

four

lesi

ons)

. Ext

ensi

ve

excl

usio

n cr

iteri

a w

ere

repo

rted

Pati

ent

char

acte

rist

ics

% M

ale:

56, a

ge n

ot

repo

rted

. The

maj

ority

of

patie

nts

had

thre

e or

few

er

lesi

ons;

mos

t w

ere

loca

ted

on t

he fa

ce/s

calp

and

wer

e th

in o

r m

oder

atel

y th

ick

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

MA

L–PD

T c

ompa

ring

in

cuba

tion

time

(1 h

r or

3 h

r) a

nd d

ose

(160

mg/

g or

80

mg/

g)In

terv

enti

on M

AL–

PDT

(1

hr +

160

mg/

g). M

ost

lesi

ons

wer

e pr

epar

ed u

sing

der

mal

cur

ette

to

rem

ove

scal

es a

nd c

rust

s. 1-

mm

-thi

ck la

yer

of

MA

L cr

eam

app

lied

to e

ach

lesi

on a

nd

to 5

mm

of s

urro

undi

ng a

rea.

Lesi

ons

cove

red

with

occ

lusi

ve d

ress

ing

for

spec

ified

incu

batio

n pe

riod

the

n w

iped

of

f with

sal

ine.

Les

ions

wer

e ill

umin

ated

w

ith r

ed la

mp

light

(w

avel

engt

h 57

0–67

0 nm

, int

ensi

ty 7

0 –

190

mW

/cm

2 )

to p

rovi

de t

otal

ligh

t do

se o

f 75

J/cm

2 . T

he m

ean

illum

inat

ion

time

was

aro

und

9.5

min

. Any

lesi

ons

with

out

CR

at

2 or

3

mth

wer

e gi

ven

2nd

PDT

tre

atm

ent.

Any

non

-CR

at

6 m

th o

ffere

d al

tern

ativ

e tr

eatm

ent

Com

para

tor

MA

L–PD

T

(3 h

r + 1

60 m

g/g)

as

abov

e2n

d co

mpa

rato

r M

AL–

PDT

(1

hr +

80

mg/

g) a

s ab

ove

3rd

com

para

tor

MA

L–PD

T

(3 h

r + 8

0 m

g/g)

as

abov

e

Mor

bidi

ty L

esio

n re

spon

se (

base

d on

11

0 pa

tient

s w

ith 3

80 le

sion

s, tw

o pa

tient

s w

ith fo

ur le

sion

s ex

clud

ed d

ue t

o w

rong

di

agno

sis)

. Ove

rall

lesi

on r

espo

nse

(not

cl

ear

if C

R)

85%

3 h

r + 1

60 m

g/g

76%

1

hr +

160

mg/

g 74

% 3

hr +

80

mg/

g 77

%

1 hr

+ 8

0 m

g/g.

Not

e: A

bout

one

-thi

rd o

f le

sion

s w

ere

not

debr

ided

as

per

prot

ocol

. Fo

r th

e 3

hr +

160

mg/

g gr

oup

CR

was

hi

gher

for

debr

ided

lesi

ons

(89%

) th

an n

on-

debr

ided

(78

%)

Lesi

on r

ecur

renc

e (e

valu

ated

in 9

7 pa

tient

s w

ith 2

99 le

sion

s th

at h

ad r

espo

nded

co

mpl

etel

y): T

he lo

wes

t re

curr

ence

rat

es

occu

rred

in t

he 3

hr +

160

mg/

g gr

oup

(11%

) co

mpa

red

with

bet

wee

n 26

% a

nd 4

5% fo

r th

e ot

her

grou

psPa

tient

s w

ho r

ecei

ved

two

PDT

ses

sion

s: Le

sion

rec

urre

nce

was

low

er fo

r th

e 1-

hr

and

3 hr

+ 1

60 m

g/g

grou

ps (

19%

and

17%

) th

an fo

r th

e 80

mg/

g gr

oups

(44

–45%

). Fo

r de

brid

ed le

sion

s in

the

3 h

r + 1

60 m

g/g

recu

rren

ce w

as 1

0% v

s 14

% fo

r no

n-de

brid

ed le

sion

sQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y C

osm

etic

out

com

e (a

sses

sed

by V

AS

scor

e at

12

mth

) w

as r

ated

at

betw

een

8.4

cm a

nd

9.3

cm b

y bo

th in

vest

igat

or a

nd p

atie

nts

indi

catin

g an

exc

elle

nt c

osm

etic

out

com

eA

Es

Mos

t AEs

wer

e m

ild in

tens

ity a

nd t

he

maj

ority

wer

e lo

cal. T

he m

ost

com

mon

ly

repo

rted

AE

was

ery

them

a w

ith a

med

ian

dura

tion

of 1

7 d.

Oth

er A

Es in

clud

ed s

kin

pain

, pru

ritis

, bur

ning

sen

satio

n on

ski

n,

oede

ma

and

supp

urat

ion.

Fou

r pa

tient

s ex

peri

ence

d SA

Es b

ut t

hese

wer

e no

t co

nsid

ered

to

be t

reat

men

t re

late

dTr

eatm

ent-

rela

ted

AE

%:

1 hr

+ 1

60 m

g/g,

98%

3 hr

+ 1

60 m

g/g,

99%

1 hr

+ 8

0m/g

, 98%

3 hr

+ 8

0 m

g/g,

96%

Aut

hors

’ con

clus

ions

PD

T u

sing

a

1-hr

incu

batio

n w

ith 1

60 m

g/g

MA

L cr

eam

may

hav

e po

tent

ial f

or t

reat

ing

rela

tivel

y m

ild A

K le

sion

s an

d of

fers

pr

actic

al a

dvan

tage

s, bu

t re

gula

r su

bstit

utio

n is

not

rec

omm

ende

dB

rief

stu

dy a

ppra

isal

As

the

auth

ors

ackn

owle

dge,

the

re w

ere

som

e im

port

ant

flaw

s in

the

des

ign

of t

his

stud

y, in

clud

ing

the

lack

of b

lindi

ng o

f ou

tcom

e as

sess

ors,

and

havi

ng r

espo

nse

rate

judg

emen

ts m

ade

clin

ical

ly r

athe

r th

an h

isto

logi

cally

. Alth

ough

the

mea

n in

cuba

tion

and

illum

inat

ion

times

wer

e co

nsis

tent

acc

ordi

ng t

o th

e pr

otoc

ol,

it w

as c

lear

tha

t a

larg

e pr

opor

tion

of

patie

nts

rece

ived

onl

y 1

PDT

ses

sion

(w

hen

2 ar

e re

com

men

ded)

and

ar

ound

one

-thi

rd o

f les

ions

had

not

be

en d

ebri

ded.

Giv

en t

hat

the

prot

ocol

do

es n

ot a

ppea

r to

hav

e be

en fo

llow

ed

clos

ely,

or h

as n

ot u

tilis

ed P

DT

opt

imal

ly,

thes

e re

sults

sho

uld

be c

onsi

dere

d w

ith

caut

ion.

No

p-va

lues

or

form

al t

ests

of

stat

istic

al s

igni

fican

ce a

ppea

r to

hav

e be

en c

arri

ed o

ut, m

akin

g it

diffi

cult

to

asse

ss t

he r

eal d

iffer

ence

s be

twee

n tr

eatm

ent

grou

ps

d, d

ay(s

); hr

, hou

r(s)

; mth

, mon

th(s

); w

k, w

eek(

s); y

r, ye

ar(s

).

Appendix 13

188



189

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Dra

giev

a et

al

. (20

04)42

Link

ed p

ublic

atio

ns16

1

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry S

witz

erla

ndLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 17

(34

lesi

onal

ar

eas

with

129

AK

; tw

o le

sion

al a

reas

pe

r pa

tient

wer

e ra

ndom

ised

for

trea

tmen

t)In

terv

entio

n: 1

7 le

sion

al a

reas

(62

AK

)C

ompa

rato

r: 17

le

sion

al a

reas

(67

AK

)N

o. o

f rec

ruit

ing

Cen

tres

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

1, 4

, 8 a

nd 1

6 w

k af

ter

2nd

trea

tmen

t. A

Es

also

rec

orde

d at

the

se

times

and

bef

ore

and

afte

r ill

umin

atio

n

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on

and

hist

olog

y M

ild t

o m

oder

ate

AK

Mai

n el

igib

ility

cri

teri

a M

ale

and

fem

ale

orga

n tr

ansp

lant

rec

ipie

nts

(18

or o

ver)

with

mild

to

mod

erat

e A

K (

confi

rmed

by

4-m

m p

unch

bio

psy

from

thi

ckes

t re

gion

). Pa

tient

s w

ith p

orph

yria

or

kno

wn

alle

rgy

to

com

poun

ds o

r ex

cipi

ents

of

the

cre

am w

ere

excl

uded

Pati

ent

char

acte

rist

ics

% M

ale:

76A

ge r

ange

: 44–

76 yr

Mea

n ag

e: 61

yrM

ost

lesi

ons

wer

e lo

cate

d on

the

face

or

scal

p. Le

sion

s w

ere

eith

er

untr

eate

d or

had

rec

eive

d pr

evio

us in

effe

ctiv

e tr

eatm

ent

over

1 m

th a

goC

onco

mit

ant

trea

tmen

t 1

g of

ora

l pa

race

tam

ol 1

hr

befo

re

illum

inat

ion

and

a fa

n w

as

used

on

the

affe

cted

are

a

Tria

l tre

atm

ents

MA

L–PD

T v

s PD

T

with

pla

cebo

cre

am (

with

in-p

artic

ipan

t co

mpa

riso

n)In

terv

enti

on M

AL–

PDT:

Tw

o co

nsec

utiv

e tr

eatm

ents

1 w

k ap

art,

perf

orm

ed o

n ar

eas

of m

axim

um s

ize

4 x

4 cm

. Sup

erfic

ial c

uret

tage

follo

wed

by

app

licat

ion

of 1

-mm

-thi

ck M

AL

crea

m

then

cov

ered

with

an

occl

usiv

e dr

essi

ng

for

3 hr

. Afte

r re

mov

al o

f dre

ssin

g an

d cl

eani

ng o

f are

a us

ing

salin

e so

lutio

n,

PDT

was

del

iver

ed a

t 80

mW

/cm

2 (7

5 J/c

m2 )

by

a no

n-co

here

nt li

ght

sour

ce

(em

issi

on s

pect

rum

600

–730

nm

)C

ompa

rato

r PD

T w

ith p

lace

bo c

ream

: A

s fo

r M

AL

but

with

pla

cebo

cre

am

Mor

bidi

ty W

eek

16: F

or t

he M

AL–

PDT

gr

oup

ther

e w

as C

R o

f 13/

17 le

sion

al a

reas

(9

5% C

I 9 t

o 16

) an

d PR

in 3

/17.

The

re

was

no

redu

ctio

n in

siz

e or

num

ber

of A

K

in 1

/17

MA

L–PD

T t

reat

ed a

rea

and

in a

ll pl

aceb

o-tr

eate

d ar

eas.

Ove

rall

lesi

on C

R r

ate

for

MA

L–PD

T w

as 5

6/62

and

for

plac

ebo

0/67

(p

= 0.

0003

)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot

asse

ssed

AE

s Fo

r th

e M

AL–

PDT

gro

up d

isco

mfo

rt

(usi

ng t

he V

AS

scal

e) w

as m

ild in

11/

17 a

nd

mod

erat

e in

6/1

7 (1

st il

lum

inat

ion)

– a

nd

mild

in 6

/17,

mod

erat

e in

9/1

7 an

d se

vere

in

2/1

7 (2

nd il

lum

inat

ion)

. Mild

to

mod

erat

e in

tens

ity A

Es fo

r th

e M

AL–

PDT

gro

up

incl

uded

ert

hyem

a, oe

dem

a an

d cr

ustin

g. Fo

r pl

aceb

o tr

eate

d ar

eas

disc

omfo

rt w

as m

ild

in a

ll ca

ses

Aut

hors

’ con

clus

ions

PD

T w

ith

met

hyl a

min

olev

ulin

ate

is s

afe

and

effe

ctiv

e fo

r AK

in t

rans

plan

t re

cipi

ents

. It

may

als

o re

duce

the

ris

k of

tr

ansf

orm

atio

n of

AK

s to

inva

sive

, and

po

tent

ially

fata

l, SC

CB

rief

stu

dy a

ppra

isal

Thi

s st

udy

was

ge

nera

lly o

f hig

h qu

ality

in m

etho

ds a

nd

repo

rtin

g. A

s th

e po

pula

tion

recr

uite

d w

ere

imm

unos

uppr

esse

d tr

ansp

lant

re

cipi

ents

the

res

ults

may

not

be

gene

ralis

able

to

othe

r po

pula

tions

Appendix 13

190



191Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Eri

cson

et a

l. (2

004)

43

Dat

a so

urce

Ful

l pub

lishe

d pa

per

Cou

ntry

Sw

eden

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

40 (

37 a

naly

sed)

Inte

rven

tion:

Nin

e (b

road

fil

ter,

50 m

W/c

m2 )

Com

para

tor:

10 (

broa

d fil

ter,

75 m

W/c

m2 )

2nd

Com

para

tor:

Nin

e (n

arro

w fi

lter,

30 m

W/c

m2 )

3rd

Com

para

tor:

Nin

e (n

arro

w fi

lter,

45 m

W/c

m2 )

No.

of r

ecru

itin

g ce

ntre

s M

ultic

entr

eFo

llow

-up

peri

od a

nd

Freq

uenc

y 7

wk

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty c

rite

ria

Clin

ical

ly t

ypic

al A

K; e

ither

on

e A

K le

sion

, min

imum

di

amet

er o

f 20

mm

, or

thre

e le

sion

s w

ithin

are

a ex

ceed

ing

25 cm

2

Pati

ent

char

acte

rist

ics

% M

ale:

80M

ean

age:

71 yr

Lesi

ons

wer

e lo

cate

d on

th

e fa

ce, s

calp

, nec

k an

d up

per

ches

tC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

ALA

–PD

T

50 m

W/c

m2 (

broa

d fil

ter)

vs A

LA–P

DT

75

mW

/cm

2 (br

oad

filte

r) v

s ALA

–PD

T

30 m

W/c

m2 (

narr

ow fi

lter)

vs A

LA–

PDT

45

mW

/cm

2 (na

rrow

filte

r). T

otal

do

se 1

00 J/

cm2 (

all t

reat

men

ts)

Inte

rven

tion

ALA

–PD

T: C

rust

s an

d sc

ales

wer

e re

mov

ed t

hen

20%

A

LA c

ream

was

app

lied

usin

g an

oc

clus

ive

band

age

and

rem

oved

afte

r 3

hr. T

he P

hoto

Dem

arca

tion

Syst

em

1, P

roto

type

5, w

as u

sed

to d

eliv

er

50 m

W/c

m2 ,

tota

l dos

e 10

0 J/c

m2 .

Fluo

resc

ence

imag

ing

reco

rdin

gs (

365

and

405

nm, 0

.5 m

W/c

m2 )

too

k pl

ace

befo

re t

reat

men

t, du

ring

tre

atm

ent

(afte

r 5,

10,

20

and

40 J/

cm2 )

and

afte

r fin

ishi

ng t

reat

men

t (1

00 J/

cm2 )

Com

para

tor A

LA–P

DT

with

75

mW

/cm

2 (br

oad

filte

r); o

ther

tr

eatm

ent

deta

ils a

s be

fore

2nd

com

para

tor A

LA–P

DT

with

30

mW

/cm

2 (na

rrow

filte

r); o

ther

tr

eatm

ent

deta

ils a

s be

fore

3rd

com

para

tor A

LA–P

DT

with

45

mW

/cm

2 (na

rrow

filte

r); o

ther

tr

eatm

ent

deta

ils a

s be

fore

Mor

bidi

ty T

here

was

a s

igni

fican

t co

rrel

atio

n be

twee

n flu

ence

rat

e an

d tr

eatm

ent

outc

ome

(p <

0.0

2);

the

high

est

num

ber

of p

atie

nts

with

com

plet

e re

mis

sion

was

in t

he

30 m

W/c

m2 (

narr

ow fi

lter)

gro

up (

8/9

patie

nts)

. The

re w

as a

non

-sig

nific

ant

tren

d to

war

ds a

sm

alle

r pr

opor

tion

of r

emai

ning

AK

for

the

narr

ow fi

lter

(p =

0.0

7). N

o si

gnifi

cant

diff

eren

ce w

as

foun

d be

twee

n 45

mW

/cm

2 (na

rrow

) an

d 50

mW

(br

oad)

gro

ups

impl

ying

pr

efer

able

tre

atm

ent

outc

ome

was

at

trib

utab

le t

o flu

ence

rat

e no

t sp

ectr

al e

mis

sion

QoL

and

ret

urn

to n

orm

al

acti

vity

Not

ass

esse

dA

Es T

here

was

no

sign

ifica

nt

corr

elat

ion

betw

een

fluen

ce r

ate

and

VAS

scor

e. T

he V

AS

valu

e in

crea

sed

up

to a

pea

k af

ter

a cu

mul

ativ

e lig

ht d

ose

of 2

0 J/c

m2

Aut

hors

’ con

clus

ions

Ph

otob

leac

hing

rat

e an

d pr

imar

y tr

eatm

ent

outc

omes

are

dep

ende

nt

on fl

uenc

e ra

te. A

low

flue

nce

rate

(3

0 m

W/c

m2 )

see

ms

pref

erab

le w

hen

perf

orm

ing

PDT

of A

K u

sing

non

-co

here

nt li

ght

sour

ces

Bri

ef s

tudy

app

rais

al T

he d

etai

ls o

f th

is s

mal

l tri

al w

ere

poor

ly r

epor

ted

ther

efor

e th

e re

liabi

lity

of t

he

conc

lusi

ons

is u

ncle

ar; h

owev

er, t

he

auth

ors

ackn

owle

dge

that

a la

rger

R

CT

is r

equi

red

Appendix 13

190



191

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Fow

ler

and

Zax

(2

002)

44

Link

ed p

ublic

atio

ns16

2,16

3

Dat

a so

urce

Ful

l pub

lishe

d pa

per. A

sum

mar

y of

res

ults

of

2 t

rial

s w

ith id

entic

al

trea

tmen

t pr

otoc

ols.

Res

ults

fo

r m

ost

outc

omes

wer

e on

ly

avai

labl

e as

com

bine

d da

ta.

Furt

her

data

wer

e ob

tain

ed

from

dru

gs.c

om16

2

Cou

ntry

Not

sta

ted

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

Rep

orte

d as

bei

ng 2

43,

acro

ss t

wo

tria

ls –

116

in

tria

l ALA

-018

, and

125

in t

rial

A

LA-0

19 (

whi

ch t

otal

s 24

1)In

terv

entio

n: A

LA-0

18: 8

7 A

LA-0

19: 9

3C

ompa

rato

r: A

LA-0

18: 2

9 A

LA-0

19: 3

2N

o. o

f rec

ruit

ing

cent

res

Mul

ticen

tre

Follo

w-u

p pe

riod

and

fr

eque

ncy

1, 4

, 8, a

nd 1

2 w

k, th

en F

U a

t in

terv

als

of

appr

oxim

atel

y 3

to 6

mth

, up

to 4

8 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty

crit

eria

Pat

ient

s w

ith

4–15

gra

de I

or II

AK

s on

the

face

or

scal

p. Ex

clud

ed p

atie

nts

had

a hi

stor

y of

cut

aneo

us

phot

osen

sitis

atio

n,

porp

hyri

a, hy

pers

ensi

tivity

to

por

phyr

ins,

phot

oder

mat

osis

or

inhe

rite

d or

acq

uire

d co

agul

atio

n de

fect

sPa

tien

t ch

arac

teri

stic

s%

Mal

e: 90

Age

ran

ge: 3

4–89

yrT

he n

umbe

r of

tre

ated

le

sion

s pe

r pa

tient

ran

ged

from

4 t

o 15

Trea

ted

area

s w

ere

the

face

or

scal

p, bu

t no

t bo

th

in t

he s

ame

patie

ntC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

ALA

–PD

T

vs P

DT

with

pla

cebo

cre

amIn

terv

enti

on A

LA–P

DT:

To

pica

l 20%

ALA

and

10

J/cm

2 of

vis

ible

blu

e lig

ht (

from

th

e BL

U-U

illu

min

ator

, for

10

00 s)

wer

e ap

plie

d. L

esio

ns

that

had

not

cle

ared

wer

e re

-tre

ated

at

8 w

k an

d al

l pa

tient

s w

ere

re-e

valu

ated

at

12 w

k. A

fter

12-w

k lo

ng-t

erm

le

sion

rec

urre

nce

was

bas

ed

on c

ompl

ete

char

t re

view

(in

clud

ing

lesi

on p

hoto

grap

hs

and

trea

tmen

t du

ring

mos

t re

cent

pat

ient

vis

its a

t w

k 36

–48)

Com

para

tor

Not

des

crib

ed

Mor

bidi

tyAt

wk

8, C

R ra

te (1

00%

), by

no.

of p

atie

nts:

ALA

-018

: 60/

87 (

69%

) ALA

–PD

T v

s 4/

29 (

14%

) pl

aceb

oA

LA-0

19: 5

9/93

(63

%) A

LA–P

DT

vs

4/32

(13

%)

plac

ebo

At w

k 8,

> 7

5% c

lear

ance

rate

, by

no. o

f pat

ient

s:A

LA-0

18: 6

8/87

(78

%) A

LA–P

DT

vs

6/29

(21

%)

plac

ebo

ALA

-019

: 71/

93(7

6%) A

LA–P

DT

vs

8/32

(25

%)

plac

ebo

Whe

n re

sults

for

the

two

tria

ls w

ere

pool

ed, t

he C

R r

ate,

for

num

ber

of le

sion

s, w

as:

Lesi

on g

rade

I: 6

66/7

56 (

88%

) ALA

–PD

T v

s 12

2/30

2 (4

0%)

plac

ebo

Lesi

on g

rade

II: 4

95/6

32 (

78%

) ALA

–PD

T v

s 52

/199

(26

%)

plac

ebo

34%

of p

atie

nts

wer

e re

-tre

ated

at

8 w

kA

t w

k 12

CR

rat

e w

as 1

29/1

80 (

72%

) in

the

ALA

–PD

T g

roup

vs

7/6

1(11

%)

in p

lace

bo t

reat

ed p

atie

nts.

A r

espo

nse

rate

of

leas

t 75

% w

as r

epor

ted

in 1

58/1

80 (

88%

) of

ALA

–PD

T p

atie

nts

vs 1

2/61

(20%

) pl

aceb

o-tr

eate

d pa

tient

s. T

he c

lear

ance

rat

e w

as

high

er fo

r fa

cial

lesi

ons

than

sca

lp le

sion

sA

t 4

yr a

fter

PDT,

of 3

2 le

sion

s in

four

pat

ient

s (P

DT

gro

up),

69%

(22

) re

mai

ned

clea

red,

9%

(3)

wer

e ‘re

curr

ent’

and

22%

(7)

w

ere

‘unc

erta

in’.

Furt

her

resu

lts w

ere

repo

rted

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

For A

LA–P

DT

cos

met

ic

resp

onse

was

rat

ed a

s ‘go

od’ t

o ‘e

xcel

lent

’ by

inve

stig

ator

s in

92

% o

f les

ions

; pat

ient

s ra

ted

cosm

etic

res

pons

e as

‘goo

d’ t

o ‘e

xcel

lent

’ in

94%

AK

lesi

ons;

85%

of p

atie

nts

prev

ious

ly t

reat

ed

with

5-F

U o

r cr

yoth

erap

y in

dica

ted

a pr

efer

ence

for A

LA–P

DT

fo

r fu

ture

man

agem

ent

AE

s Se

vere

stin

ging

and

/or

burn

ing

was

rep

orte

d by

at

leas

t 50

% o

f PD

T p

atie

nts;

less

tha

n 3%

sto

pped

tre

atm

ent.

In 9

9%

of P

DT

pat

ient

s, so

me

or a

ll le

sion

s w

ere

eryt

hem

atou

s sh

ortly

af

ter

trea

tmen

t vs

79%

in t

he p

lace

bo g

roup

. In

35%

of P

DT

pa

tient

s so

me

or a

ll le

sion

s w

ere

oede

mat

ous

vs 0

% in

the

pl

aceb

o gr

oup.

Both

typ

es o

f AE

reso

lved

or

impr

oved

by

4 w

k. M

ore

ALA

pat

ient

s al

so r

epor

ted

post

PDT

itch

ing

(26%

vs

7%)

Seve

n pa

tient

s ha

d an

SA

E –

all w

ere

deem

ed r

emot

ely,

or n

ot

rela

ted

to, t

reat

men

t

Aut

hors

’ co

nclu

sion

s The

ex

celle

nt s

hort

- an

d lo

ng-t

erm

co

smet

ic r

esul

ts,

low

rec

urre

nce

rate

and

hig

h ra

te

of p

atie

nt a

nd

phys

icia

n sa

tisfa

ctio

n as

soci

ated

with

A

LA–P

DT

indi

cate

de

finite

adv

anta

ges

over

oth

er e

xist

ing

trea

tmen

t m

odal

ities

fo

r AK

Bri

ef s

tudy

ap

prai

sal F

ew

met

hodo

logi

cal

deta

ils w

ere

repo

rted

, an

d de

tails

of t

he

stud

y po

pula

tion

wer

e un

clea

r. T

he s

ourc

es o

f in

form

atio

n ap

pear

ed

cont

radi

ctor

y in

re

port

ing

that

FU

bo

th c

ease

d at

12

mth

, and

als

o co

ntin

ued

for

4 yr

. T

he 4

-yr

resu

lts w

ere

pres

ente

d fo

r ju

st

four

pat

ient

s an

d th

is, c

oupl

ed w

ith

the

lack

of a

clin

ical

ly

rele

vant

com

pari

son

trea

tmen

t, fu

rthe

r qu

estio

ns t

he

relia

bilit

y of

the

au

thor

s’ c

oncl

usio

ns.

(Att

empt

s w

ere

mad

e to

con

tact

aut

hors

fo

r fu

rthe

r de

tails

.)

Appendix 13

192



193Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Fr

eem

an (

2003

)45

Link

ed

publ

icat

ions

164,

165

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry

Aus

tral

iaLa

ngua

ge E

nglis

hSt

udy

desi

gn

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

204

Inte

rven

tion:

88

(360

AK

s) (

activ

e PD

T)

Com

para

tor:

23

(74

AK

s) (

plac

ebo

PDT

)2n

d C

ompa

rato

r: 89

(42

1 A

Ks)

(c

ryot

hera

py)

No.

of

recr

uiti

ng

cent

res

Nin

eFo

llow

-up

peri

od a

nd

freq

uenc

y FU

of

3 m

th (

afte

r a

run-

in p

erio

d of

up

to

2 w

k)

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y M

ild t

o m

oder

ate

non-

pigm

ente

d A

KM

ain

elig

ibili

ty c

rite

ria

Patie

nts

with

mild

to

mod

erat

e no

n-pi

gmen

ted

AK

of

the

face

or

scal

p su

itabl

e fo

r cr

yoth

erap

y (w

ith t

he

larg

est

diam

eter

of e

ach

lesi

on

at le

ast

5 m

m)

Pati

ent

char

acte

rist

ics

% M

ale:

56 a

ctiv

e PD

T; 7

0 pl

aceb

o PD

T; 6

1 cr

yoth

erap

yM

ean

age:

64A

ge r

ange

: 33–

89 yr

Can

cer

stag

e:G

rade

I: 2

09 a

ctiv

e PD

T; 3

5 pl

aceb

o PD

T; 2

32 c

ryot

hera

pyG

rade

II: 1

51 a

ctiv

e PD

T; 3

9 pl

aceb

o PD

T; 4

5 cr

yoth

erap

y. A

ll pa

tient

s w

ere

Cau

casi

an,

mos

t ha

d Fi

tzpa

tric

k sk

in t

ype

I or

IIC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

MA

L–PD

T v

s PD

T

with

pla

cebo

cre

am v

s co

nven

tiona

l cr

yoth

erap

yIn

terv

enti

on M

AL–

PDT:

Sca

les

and

crus

ts w

ere

rem

oved

and

lesi

on

surf

ace

roug

hene

d w

ith a

cur

ette

. MA

L cr

eam

(16

0 m

g/g)

was

app

lied

(1 m

m

thic

knes

s) u

nder

occ

lusi

on fo

r 3

hr

then

PD

T w

ith r

ed li

ght

(570

–670

nm

), in

tens

ities

of 5

0–25

0 m

W/c

m2 ,

tota

l do

se 7

5 J/c

m2 .

2 id

entic

al la

mps

(C

urel

ight

, Pho

tocu

re A

SA, O

slo)

ill

umin

ated

fiel

ds w

ith m

axim

um 5

.5cm

di

amet

er, m

ean

expo

sure

tim

e 10

min

w

ith a

max

imum

of s

ix t

reat

men

t si

tes

(map

ped

with

ace

tate

she

ets

and

AK

s m

arke

d) p

er p

atie

nt. A

nato

mic

al

land

mar

ks a

nd p

olar

oid

phot

ogra

phy

also

use

d. T

his

PDT

pro

cedu

re w

as

repe

ated

afte

r 7

dC

ompa

rato

r PD

T w

ith p

lace

bo:

As

for

MA

L–PD

T b

ut w

ith c

olou

r-m

atch

ed c

ream

bas

e in

stea

d of

MA

L2n

d co

mpa

rato

r C

ryot

hera

py: A

Ks

wer

e ou

tline

d an

d le

sion

s w

ere

froz

en

unifo

rmly

with

a 1

- to

2-m

m r

im. T

he

loca

lly a

ccep

ted

regi

men

was

use

d, i.

e.

the

prot

ocol

spe

cifie

d a

sing

le-t

imed

fr

eeze

–tha

w c

ycle

with

no

exac

t fr

eeze

tim

e (t

he t

ime

from

form

atio

n of

an

ice

ball

to c

omm

ence

men

t of

tha

win

g).

Lesi

ons

with

a m

ean

diam

eter

less

th

an 1

0 m

m h

ad a

mea

n (S

D)

free

ze

time

of 0

.12

s (0

.13)

; 10-

to

20-m

m

lesi

ons

0.16

s (0

.15)

and

mor

e th

an 2

0-m

m le

sion

s 0.

26 s

(0.1

1)

Mor

bidi

ty L

esio

n re

spon

se r

ate

was

sig

nific

antly

hi

gher

(91

%, 2

67/2

95)

in t

he M

AL–

PDT

gro

up,

than

the

pla

cebo

-PD

T g

roup

(30

%, 1

8/61

) an

d th

e cr

yoth

erap

y gr

oup

(68%

, 278

/407

), p

< 0.

001

for

both

. Res

pons

e ra

tes

wer

e hi

gher

in t

he t

hin

lesi

ons

than

the

mod

erat

ely

thic

k le

sion

s w

ith

MA

L–PD

T; in

the

cry

othe

rapy

gro

up, r

espo

nse

rate

s w

ere

high

er fo

r th

icke

r le

sion

sQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y A

si

gnifi

cant

ly h

ighe

r pr

opor

tion

of M

AL–

PDT

pa

tient

s gr

aded

ove

rall

cosm

etic

out

com

e as

ex

celle

nt t

han

with

cry

othe

rapy

pat

ient

s (8

3%

vs 5

1% a

s as

sess

ed b

y in

vest

igat

or, p

< 0

.001

; 76%

vs

56%

as

asse

ssed

by

the

patie

nt, p

= 0

.013

). H

ypop

igm

enta

tion

was

pre

sent

in 5

% M

AL–

PDT

tre

ated

site

s vs

29%

cry

othe

rapy

site

s. H

yper

pigm

enta

tion,

sca

r fo

rmat

ion

or t

issu

e de

fect

s w

ere

pres

ent

in le

ss t

han

6% o

f tot

al

lesi

on s

ites.

MA

L–PD

T p

atie

nt s

atis

fact

ion

was

ra

ted

bett

er t

han

prev

ious

tre

atm

ent

in 6

1%,

equa

l in

24%

and

wor

se in

15%

. Pla

cebo

-PD

T

patie

nt s

atis

fact

ion

was

rat

ed b

ette

r th

an p

revi

ous

trea

tmen

t (c

ryot

hera

py, s

urge

ry o

r 5-

FU)

in 2

1%,

equa

l in

14%

and

wor

se in

64%

AE

s N

o sy

stem

ic A

Es w

ere

repo

rted

. The

mos

t co

mm

on A

Es w

ere

loca

l rea

ctio

ns (

74%

). 73

%

patie

nts

expe

rien

ced

at le

ast

1 lo

cal A

E af

ter

the

1st

PDT

ses

sion

and

66%

afte

r th

e 2n

d PD

T

sess

ion;

35%

afte

r cr

yoth

erap

y; 30

% a

fter

the

1st

and

27%

afte

r th

e 2n

d pl

aceb

o PD

T. M

ost

of t

he

AEs

in t

he M

AL–

PDT

gro

up w

ere

mild

(48

%)

or

mod

erat

e (4

0%)

inte

nsity

. Oth

er r

epor

ted

AEs

co

mm

on w

ith M

AL–

PDT

wer

e: bu

rnin

g se

nsat

ion,

st

ingi

ng, p

ainf

ul s

kin

(46%

), er

ythe

ma

(23.

9%),

oede

ma

(8.5

%),

skin

pee

ling

(5.1

%),

blis

ters

(3.

4%),

itchi

ng (

5.1%

) an

d cr

ustin

g (2

.3%

). M

edia

n du

ratio

n w

as 1

wk

or le

ss (

all e

vent

s). 1

MA

L–PD

T p

atie

nt

disc

ontin

ued

due

to t

he b

urni

ng s

ensa

tion

Aut

hors

’ con

clus

ions

PD

T

with

MA

L–PD

T is

an

exce

llent

tr

eatm

ent

optio

n, p

artic

ular

ly fo

r pa

tient

s w

ith w

ides

prea

d da

mag

e or

AK

lesi

ons

in c

osm

etic

ally

se

nsiti

ve a

reas

Bri

ef s

tudy

app

rais

al

Gen

eral

ly a

wel

l-con

duct

ed

and

repo

rted

stu

dy; a

lthou

gh

the

conc

lusi

ons

appe

ar li

kely

to

be r

elia

ble,

it s

houl

d be

not

ed

that

cry

othe

rapy

was

del

iver

ed

usin

g ‘lo

cally

acc

epte

d re

gim

ens’

al

low

ing

clin

ical

var

iatio

n be

twee

n th

e ni

ne c

entr

es

s, se

cond

(s).

Appendix 13

192



193Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Gup

ta (

2004

)35

Dat

a so

urce

Abs

trac

tC

ount

ry C

anad

aLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 50

Inte

rven

tion:

25

Com

para

tor:

25N

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU a

t w

k 4,

8,

12

and

26

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty c

rite

ria

Part

icip

ants

with

5–2

0 le

sion

s of

mod

erat

e to

se

vere

AK

s w

ere

elig

ible

Pati

ent

char

acte

rist

ics

Not

sta

ted

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

ALA

–PD

T v

s 5-

FUIn

terv

enti

on A

LA–P

DT:

Incu

batio

n w

ith

ALA

for

45–6

0 m

in b

efor

e ill

umin

atio

n w

ith a

Blu

e Li

ght

PDT

Illu

min

ator

(40

0–45

0 nm

). Tre

atm

ent

repe

ated

at

wk

8 if

ther

e w

as le

ss t

han

a 75

% r

educ

tion

in

AK

s. N

o fu

rthe

r de

tails

rep

orte

dC

ompa

rato

r 5-

FU: A

pplic

atio

n of

5-F

U

to t

he fa

ce o

r sc

alp

twic

e da

ily fo

r 2–

4 w

k as

tol

erat

ed

Mor

bidi

ty N

ot a

sses

sed

QoL

and

ret

urn

to n

orm

al

acti

vity

Not

ass

esse

dA

Es A

t 1

wk

FU A

LA–P

DT

pa

tient

s sh

owed

few

sig

ns o

f ir

rita

tion

(ery

them

a, sc

alin

g an

d cr

ustin

g); 5

-FU

pat

ient

s ex

hibi

ted

mod

erat

e to

sev

ere

eryt

hem

a

Aut

hors

’ con

clus

ions

If s

hort

-dur

atio

n A

LA–P

DT

is s

how

n to

be

as e

ffect

ive

as

5% 5

-FU

at

wk

12 a

nd 2

6 th

en it

may

be

a su

itabl

e tr

eatm

ent

alte

rnat

ive

for

subj

ects

w

ith m

ultip

le m

oder

ate

to s

ever

e A

Ks

Bri

ef s

tudy

app

rais

al A

s th

ere

wer

e fe

w

deta

ils a

vaila

ble

in t

he a

bstr

act,

the

effic

acy

of t

he t

reat

men

ts w

as n

ot d

escr

ibed

an

d th

e st

udy

is n

ot y

et c

ompl

ete,

the

re

liabi

lity

of t

he a

utho

r’s c

oncl

usio

n is

un

clea

r. (A

ttem

pts

wer

e m

ade

to c

onta

ct

the

stud

y au

thor

.)

Appendix 13

194



195Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

H

ausc

hild

et a

l. (2

008)

,60 T

rial

A

K03

Link

ed

publ

icat

ions

166

Dat

a so

urce

Fu

ll pu

blis

hed

pape

rC

ount

ry

Ger

man

yLa

ngua

ge

Engl

ish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 10

3 (5

87

lesi

ons)

Inte

rven

tion:

69

Com

para

tor:

34N

o. o

f re

crui

ting

ce

ntre

s 29

(u

ncle

ar w

heth

er

this

was

for

each

tr

ial)

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU

afte

r 12

wk

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd h

isto

logy

A

KM

ain

elig

ibili

ty c

rite

ria

Cau

casi

an

mal

es a

nd fe

mal

es (

at le

ast

18 y

r ol

d) w

ith s

kin

type

s I–

IV w

ere

elig

ible

for

incl

usio

n. A

K le

sion

s ha

d to

be

mild

to

mod

erat

e (C

ockr

ell

defin

ition

) with

a m

axim

um d

iam

eter

of

1.8

cm a

nd in

terl

esio

nal d

ista

nce

of a

t le

ast

1 cm

. The

follo

win

g w

ere

excl

uded

: wom

en o

f chi

ld-

bear

ing

pote

ntia

l, no

n-re

spon

ders

to

pre

viou

s PD

T, pa

tient

s w

ith

part

icul

ar d

erm

atol

ogic

al c

ondi

tions

, po

rphy

ria,

dem

entia

or

clin

ical

ly

rele

vant

imm

unos

uppr

essi

on, t

opic

al

trea

tmen

t th

at m

ay a

ffect

res

pons

e 4

wk

befo

re a

nd d

urin

g th

e st

udy

(var

ious

cri

teri

a), t

reat

men

t w

ith

cyto

stat

ics

or r

adia

tion

3 m

th p

rior

to

/dur

ing

stud

y, an

d in

tole

ranc

e to

in

gred

ient

s of

ALA

Pati

ent

char

acte

rist

ics

% M

ale:

82M

ean

Age

: ALA

70.

4; P

lace

bo 7

1.4

Age

Ran

ge: 5

1–89

yrSk

in T

ype:

I 9%

; II 8

3%; I

II 1%

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

ALA

–PD

T p

atch

vs

pla

cebo

PD

T p

atch

Inte

rven

tion

ALA

–PD

T: 3

–6

patc

hes

(4 cm

2 ) c

onta

inin

g 8

mg

of

5-A

LA w

as a

pplie

d to

lesi

ons

with

out

prep

arat

ion.

One

pat

ch p

er le

sion

. A

fter

4 h,

illu

min

atio

n w

ith r

ed li

ght

(37

J/cm

2 , 63

0 ±

3nm

) w

ith a

n LE

D

sour

ce. P

atie

nts

wer

e in

stru

cted

to

prot

ect

lesi

ons

from

ligh

t fo

r 48

h

afte

r th

erap

yC

ompa

rato

r Pl

aceb

o-PD

T: A

s fo

r A

LA–P

DT

but

with

pla

cebo

on

the

patc

hes

Mor

bidi

ty C

CC

R (

lesi

ons)

was

82%

(3

16/3

84)

for A

LA–P

DT

vs

19%

(34

/179

) fo

r pl

aceb

o, p

< 0

.000

1. C

orre

spon

ding

cl

eara

nce

rate

s on

a p

atie

nt b

asis

wer

e 62

% (

41/6

6) v

s 6%

(2/

33),

p <

0.00

01Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y T

here

was

no

diffe

renc

e be

twee

n PD

T

or p

lace

bo in

the

cos

met

ic a

sses

smen

t of

‘cle

ared

lesi

ons’

(pa

tient

ass

essm

ent

p =

0.35

; inv

estig

ator

ass

essm

ent

0.54

). Pi

gmen

tatio

n st

atus

cla

ssed

as ‘

norm

al’

in t

he A

LA–P

DT

gro

ups

wer

e 91

% v

s 12

%. T

here

was

no

stat

istic

al d

iffer

ence

fr

om t

hose

tre

ated

with

pla

cebo

-PD

T

(p =

0.9

5). 9

5% o

f ALA

–PD

T p

atie

nts

wer

e ve

ry s

atis

fied

or s

atis

fied

with

the

ov

eral

l cos

met

ic o

utco

me

vs 4

4% w

ith

plac

ebo-

PDT.

Patie

nt s

atis

fact

ion

with

ov

eral

l out

com

e w

as g

reat

er w

ith P

DT

(p

< 0

.000

1)A

Es

One

AE

was

des

crib

ed a

s re

latin

g to

th

erap

y (t

rans

ient

dis

colo

ratio

n of

the

ski

n w

ith A

LA)

Tran

sien

t sk

in d

isco

lora

tion

in o

ne p

atie

nt

was

rel

ated

to

ALA

tre

atm

ent.

ALA

pa

tient

s ha

d m

ore

over

all l

ocal

rea

ctio

ns

whe

n tr

eatm

ent

was

app

lied

(mos

tly

itchi

ng, 4

2% v

s 13

%; t

he 1

3% p

lace

bo fi

gure

ap

pear

s to

be

pool

ed fr

om t

he 2

tri

als)

Aut

hors

’ con

clus

ions

ALA

–PD

T is

an

eas

y to

han

dle

one-

step

pro

cedu

re

for

ther

apy

of is

olat

ed m

ild t

o m

oder

ate

AK

lesi

ons.

Com

pare

d w

ith c

urre

nt P

DT

pro

cedu

res,

pre-

trea

tmen

t (e

.g. c

uret

tage

) is

not

ne

eded

and

han

dlin

g is

con

side

rabl

y fa

cilit

ated

. ALA

–PD

T le

ads

to e

ffica

cy

rate

s su

peri

or t

o pl

aceb

oB

rief

stu

dy a

ppra

isal

Thi

s st

udy

appe

ared

to

be g

ener

ally

wel

l co

nduc

ted;

how

ever

, it

was

unc

lear

ho

w m

any

cent

res

wer

e us

ed a

nd t

he

repo

rtin

g of

res

ults

was

som

etim

es

uncl

ear

CC

CR

, Com

plet

e cl

inic

al c

lear

ance

rat

e.

Appendix 13

194



195

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Hau

schi

ld e

t al.

(200

8),60

Tri

al

AK

04Li

nked

pu

blic

atio

ns16

6

Dat

a so

urce

Fu

ll pu

blis

hed

pape

rC

ount

ry

Ger

man

yLa

ngua

ge

Engl

ish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 34

9 (1

950

lesi

ons)

Inte

rven

tion:

148

Com

para

tor:

149

(cry

osur

gery

)2n

d C

ompa

rato

r: 49

(pl

aceb

o)N

o. o

f re

crui

ting

ce

ntre

s 29

(u

ncle

ar w

heth

er

this

was

for

each

tr

ial)

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU

afte

r 12

wk

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd h

isto

logy

AK

Mai

n el

igib

ility

cri

teri

a C

auca

sian

m

ales

and

fem

ales

(at

leas

t 18

yr

old)

w

ith s

kin

type

s I–

IV w

ere

elig

ible

for

incl

usio

n. A

K le

sion

s ha

d to

be

mild

to

mod

erat

e (C

ockr

ell d

efini

tion)

with

a

max

imum

dia

met

er o

f 1.8

cm a

nd

inte

rles

iona

l dis

tanc

e of

at

leas

t 1

cm.

The

follo

win

g w

ere

excl

uded

: wom

en o

f ch

ild-b

eari

ng p

oten

tial,

non-

resp

onde

rs

to p

revi

ous

PDT,

patie

nts

with

pa

rtic

ular

der

mat

olog

ical

con

ditio

ns,

porp

hyri

a, de

men

tia o

r cl

inic

ally

rel

evan

t im

mun

osup

pres

sion

, top

ical

tre

atm

ent

that

may

affe

ct r

espo

nse

4 w

k be

fore

an

d du

ring

the

stu

dy (

vari

ous

crite

ria)

, tr

eatm

ent

with

cyt

osta

tics

or r

adia

tion

3 m

th p

rior

to/

duri

ng s

tudy

and

in

tole

ranc

e to

ingr

edie

nts

of p

lace

bo o

r kn

own

reac

tions

to

cryo

ther

apy

Pati

ent

char

acte

rist

ics

% M

ale:

72M

ean

age:

PDT

70,

cry

osur

gery

71,

pl

aceb

o 72

Age

ran

ge: 4

1–94

yrSk

in t

ype:

I 18%

, II 6

6%, I

II 15

%, I

V 1

%C

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

ALA

–PD

T p

atch

vs

cryo

surg

ery

vs

Plac

ebo

PDT

pat

chIn

terv

enti

on A

LA–P

DT

pat

ch:

4–8

patc

hes

(4 cm

2 ) c

onta

inin

g 8

mg

of 5

-ALA

wer

e ap

plie

d to

le

sion

s w

ithou

t pr

epar

atio

n,

one

patc

h pe

r le

sion

. Afte

r 4

hr, i

llum

inat

ion

with

red

ligh

t (3

7 J/c

m2 ,

630

± 3

nm)

with

O

mni

lux

(11

cent

res)

. Pat

ient

s w

ere

inst

ruct

ed t

o pr

otec

t le

sion

s fr

om li

ght

for

48 h

r af

ter

ther

apy

Com

para

tor

cryo

surg

ery:

A s

tand

ardi

sed

prot

ocol

was

us

ed. O

pen

spra

ying

pro

cedu

re

with

liqu

id n

itrog

en in

1 c

ycle

w

as u

sed

(with

siz

e C

noz

zles

) an

d fr

eeze

tim

e (o

f 5–1

0 s)

st

arte

d af

ter

ice

ball

form

atio

n2n

d co

mpa

rato

r Pl

aceb

o PD

T p

atch

: As

for A

LA–P

DT

bu

t w

ith p

lace

bo o

n th

e pa

tche

s

Mor

bidi

ty T

he c

ompl

ete

clin

ical

cle

aran

ce r

ates

(le

sion

s) w

ere

89%

(66

4/75

0) fo

r ALA

–PD

T, 77

%

(530

/692

) fo

r cr

yosu

rger

y an

d 29

% (

75/2

59)

for

plac

ebo.

PD

T w

as s

igni

fican

tly b

ette

r th

an p

lace

bo

PDT

(p

< 0.

001)

and

cry

osur

gery

(p

= 0.

007)

. C

lear

ance

rat

es (

patie

nts)

wer

e A

LA–P

DT

67%

(8

6/12

9), c

ryos

urge

ry 5

2% (

66/1

26)

and

plac

ebo

12%

(5

/43)

. PD

T w

as s

igni

fican

tly b

ette

r th

an p

lace

bo a

nd

cryo

surg

ery

(p <

0.0

01 fo

r bo

th)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Patie

nts’

an

d in

vest

igat

ors’

ass

essm

ent

of c

osm

etic

out

com

e of

cle

ared

lesi

ons

was

sig

nific

antly

bet

ter

for A

LA–

PDT

tha

n cr

yosu

rger

y (p

< 0

.001

). 95

% o

f ALA

–PD

T

patie

nts

wer

e ve

ry s

atis

fied

or s

atis

fied

with

the

ov

eral

l cos

met

ic o

utco

me

vs 8

2% w

ith c

ryos

urge

ry.

It ap

pear

s to

be

repo

rted

tha

t ALA

pat

ient

s w

ere

sign

ifica

ntly

mor

e sa

tisfie

d th

an p

lace

bo

and

cryo

surg

ery

(p <

0.0

001)

. Pig

men

tatio

n st

atus

cl

asse

d as

‘nor

mal

’ in

the

ALA

–PD

T g

roup

s w

as

88%

. Hyp

opig

men

tatio

n w

as s

een

in 3

3% o

f les

ions

w

ith c

ryos

urge

ry. H

yper

pigm

enta

tion

was

see

n in

9%

PD

T p

atie

nts

vs 4

% p

lace

bo. P

igm

enta

tion

stat

us

was

sig

nific

antly

diff

eren

t be

twee

n A

LA–P

DT

and

cr

yosu

rger

y (p

< 0

.001

) bu

t th

e di

ffere

nce

betw

een

ALA

–PD

T a

nd p

lace

bo w

as n

ot s

igni

fican

t (p

= 0

.87)

AE

s Thr

ee p

er c

ent

in t

he A

LA a

nd c

ryos

urge

ry

arm

s an

d 2%

pla

cebo

rep

orte

d an

AE

rela

ted

to

ther

apy.

99%

of A

LA p

atie

nts

expe

rien

ced

an a

dver

se

reac

tion

at s

ome

stag

e of

tre

atm

ent

(pla

cebo

dat

a w

as p

oole

d w

ith t

rial

AK

03)

Aut

hors

’ con

clus

ions

A

LA–P

DT

is a

n ea

sy t

o ha

ndle

one

-ste

p pr

oced

ure

for

ther

apy

of is

olat

ed m

ild

to m

oder

ate

AK

lesi

ons.

Com

pare

d w

ith c

urre

nt P

DT

pr

oced

ures

, pre

-tre

atm

ent

is n

ot n

eede

d an

d ha

ndlin

g is

con

side

rabl

y fa

cilit

ated

. A

sin

gle

PDT

tre

atm

ent

resu

lts in

effi

cacy

rat

es b

eing

st

atis

tical

ly s

igni

fican

tly

supe

rior

to

plac

ebo

and

cryo

surg

ery

Bri

ef s

tudy

app

rais

al T

he

stud

y ap

pear

s to

be

gene

rally

w

ell c

ondu

cted

but

rep

ortin

g of

som

e of

the

met

hodo

logy

an

d re

sults

was

unc

lear

Appendix 13

196



197Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Hau

schi

ld

et a

l. (20

08)55

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry G

erm

any

Lang

uage

Eng

lish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 14

9: 1

46

patie

nts

com

plet

ed

stud

y, of

whi

ch 1

40

(520

lesi

ons)

wer

e in

the

per

pro

toco

l po

pula

tion

Inte

rven

tion:

34

(128

lesi

ons)

0.5

-hr

incu

batio

nC

ompa

rato

r: 38

(1

38 le

sion

s) 1

-hr

incu

batio

n2n

d C

ompa

rato

r: 34

(12

4 le

sion

s)

2-hr

incu

batio

n3r

d C

ompa

rato

r: 34

(13

0 le

sion

s)

4-hr

incu

batio

nN

o. o

f rec

ruit

ing

cent

res

12Fo

llow

-up

peri

od

and

freq

uenc

y 4

and

8 w

k af

ter

trea

tmen

t

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd h

isto

logy

AK

(m

ild t

o m

oder

ate)

Mai

n el

igib

ility

cri

teri

a C

auca

sian

m

ales

or

fem

ales

age

d at

leas

t 18

yr

with

his

tolo

gica

lly c

onfir

med

mild

to

mod

erat

e A

K. L

esio

ns w

ere

requ

ired

to

have

max

imum

dia

met

er o

f 1.8

cm a

nd

inte

rles

iona

l dis

tanc

e of

at

leas

t 1

cm.

Patie

nts

with

der

mat

olog

ical

con

ditio

ns

likel

y to

impa

ct o

n re

sults

wer

e ex

clud

ed. F

urth

er e

ligib

ility

cri

teri

a w

ere

repo

rted

Pati

ent

char

acte

rist

ics

% M

ale:

74A

ge r

ange

: 39–

91 yr

acr

oss

grou

psM

ean

age:

72 yr

, 72

yr, 7

0 yr

, 70

yr,

resp

ectiv

ely,

for

the

four

tre

atm

ent

grou

psM

ost

lesi

ons

wer

e lo

cate

d on

the

sca

lp

or fo

rehe

ad in

all

grou

ps, s

ever

ity w

as

fair

ly e

venl

y sp

lit b

etw

een

mild

and

m

oder

ate.

Mea

n le

sion

dia

met

er w

as

sim

ilar

acro

ss g

roup

s at

aro

und

8–9

cmC

onco

mit

ant

trea

tmen

t A

ny

othe

r to

pica

l tre

atm

ent

able

to

affe

ct

AK

not

per

mitt

ed 4

wk

prio

r to

and

du

ring

stu

dy. N

o ur

ea a

nd s

alic

ylic

aci

d-co

ntai

ning

pre

para

tions

per

mitt

ed 2

wk

prio

r an

d du

ring

stu

dy

Tria

l tre

atm

ents

Pat

ch c

onta

inin

g A

LA (

PD

P 50

6 A

) ap

plie

d to

lesi

ons

for

0.5,

1, 2

or

4 hr

fo

llow

ed b

y ill

umin

atio

n w

ith r

ed li

ght

Inte

rven

tion

PD

T p

atch

+ 0

.5-h

r in

cuba

tion:

Be

twee

n th

ree

and

four

lesi

ons

per

patie

nt

wer

e tr

eate

d us

ing

a PD

T p

atch

(on

e pa

tch

per

lesi

on)

cont

aini

ng 8

mg

of A

LA. P

atch

is

ligh

tpro

of t

here

fore

pro

vide

s oc

clus

ive

prot

ectio

n. A

fter

patc

h w

as r

emov

ed, l

esio

n ill

umin

ated

with

red

ligh

t (d

ose

37 J/

cm2 ,

wav

elen

gth

arou

nd 6

30 n

m).

Furt

her

PDT

pa

ram

eter

s w

ere

not

repo

rted

Com

para

tor

PDT

pat

ch +

1-h

r in

cuba

tion:

se

e ab

ove

2nd

com

para

tor

PDT

pat

ch +

2-h

r in

cuba

tion:

see

abo

ve3r

d co

mpa

rato

r PD

T p

atch

+ 4

-hr

incu

batio

n: s

ee a

bove

Mor

bidi

ty T

he m

ajor

ity o

f les

ions

sh

owed

cle

aran

ce 8

wk

afte

r PD

T a

nd

the

4-hr

incu

batio

n gr

oup

show

ed t

he

best

res

pons

e –

estim

ated

86%

cle

aran

ce

rate

and

thi

s w

as ‘s

tatis

tical

ly s

elec

ted

as

the

best

tre

atm

ent’.

All

but

1 of

the

12

cent

res

foun

d si

mila

r re

sults

(de

tails

not

re

port

ed).

In s

ome

patie

nts,

lesi

ons

that

ap

pear

ed ‘c

lear

ed’ a

t w

k 4

then

wor

sene

d by

wk

8 –

this

effe

ct w

as m

ost

appa

rent

in

the

0.5

-hr

grou

p, an

d w

as n

ot p

rese

nt

in t

he 4

-hr

grou

pQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot a

sses

sed

AE

s Fi

ve p

atie

nts

repo

rted

AE

cons

ider

ed t

o be

rel

ated

to

the

stud

y tr

eatm

ent:

head

ache

, mod

erat

e ep

ista

xis

and

mild

incr

ease

of a

lani

ne t

rans

amin

ase.

Lo

cal r

eact

ions

dur

ing

appl

icat

ion

and

incu

batio

n in

clud

ed b

urni

ng, p

ruri

tis a

nd

eryt

hem

a –

all b

ut o

ne c

ase

was

rat

ed

as m

ild o

r m

oder

ate.

Loc

al r

eact

ions

du

ring

illu

min

atio

n ap

pear

ed t

o be

do

se d

epen

dent

and

ran

ged

from

26%

in

the

0.5

-hr

grou

p to

66%

in t

he 4

-hr

grou

p. M

ost

freq

uent

rea

ctio

ns w

ere

pain

, bur

ning

and

pru

ritis

. One

pat

ient

’s tr

eatm

ent

was

inte

rrup

ted

due

to

seve

re p

ain.

Alm

ost

all p

atie

nts

had

loca

l re

actio

ns a

fter

trea

tmen

t, w

ith e

ryth

ema,

scab

bing

, des

quam

atio

n, b

urni

ng a

nd

prur

itis

bein

g co

mm

on. P

atie

nts

with

cl

eara

nce

expe

rien

ced

loca

l rea

ctio

ns t

o a

grea

ter

exte

nt t

han

patie

nts

with

out

clea

ranc

e

Aut

hors

’ con

clus

ions

PD

P 5

06 A

-PD

T p

atch

es

are

suita

ble

for

the

trea

tmen

t of

up

to e

ight

A

K le

sion

s of

mild

to

mod

erat

e in

tens

ity o

n th

e he

ad a

nd fa

ce, a

nd

4-hr

app

licat

ion

resu

lts

in e

xcel

lent

out

com

es.

Furt

her

Phas

e III

tri

als

are

requ

ired

to c

onfir

m

thes

e ou

tcom

esB

rief

stu

dy a

ppra

isal

T

his

stud

y w

as r

elat

ivel

y po

orly

rep

orte

d m

akin

g it

diffi

cult

to

asse

ss t

he r

elia

bilit

y of

the

met

hodo

logy

or

res

ults

. The

use

of

mul

tiple

cen

tres

in a

sm

all t

rial

rai

ses

the

poss

ibili

ty o

f cen

tre-

effe

cts

on t

reat

men

t an

d ou

tcom

es. P

atie

nts

wer

e on

ly fo

llow

ed u

p fo

r 8

wk.

No

stat

istic

al t

est

resu

lts w

ere

repo

rted

; th

eref

ore

it is

diffi

cult

to b

e co

nfide

nt in

the

co

nclu

sion

s of

effi

cacy

Appendix 13

196



197Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Jeffe

s et

al

. (19

98)41

Dat

a so

urce

A

bstr

act

Cou

ntry

USA

Lang

uage

Eng

lish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 36

Inte

rven

tion:

36

Com

para

tor:

36N

o. o

f rec

ruit

ing

cent

res

Not

st

ated

mul

ticen

tre

Follo

w-u

p pe

riod

and

fr

eque

ncy

8 an

d 16

wk

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on

and

hist

olog

y A

KM

ain

elig

ibili

ty

crit

eria

Pat

ient

s w

ith fo

ur A

Ks

on

the

face

and

sca

lpPa

tien

t ch

arac

teri

stic

s N

ot s

tate

dC

onco

mit

ant

trea

tmen

t N

ot

stat

ed

Tria

l tre

atm

ents

ALA

–PD

T v

s PD

T w

ith

plac

ebo

(with

in-p

artic

ipan

t co

mpa

riso

n)In

terv

enti

on A

LA–P

DT:

Tw

o A

Ks

wer

e tr

eate

d w

ith 2

0% A

LA s

olut

ion

(Lev

ulan

) an

d af

ter

14-

to 1

8-hr

exp

osed

to

blue

(n

on-la

ser)

ligh

t at

dos

es o

f 2, 5

and

10

J/cm

2 . Pa

tient

s w

ere

re-t

reat

ed a

t 8

wk

if ne

cess

ary.

Furt

her

PDT

par

amet

ers

wer

e no

t re

port

edC

ompa

rato

r Pl

aceb

o PD

T: A

s ab

ove

exce

pt p

lace

bo c

ontr

ol w

as u

sed

in p

lace

of

ALA

sol

utio

n

Mor

bidi

ty A

t 8

wk,

66%

of A

Ks

trea

ted

with

ALA

had

a C

R v

s 17

% w

ith p

lace

bo

(p <

0.0

01).

At

16 w

k. C

R w

as s

een

in 5

6/66

(8

5%)

of A

LA–P

DT

pat

ient

s (n

o re

sults

re

port

ed fo

r pl

aceb

o). A

Ks

trea

ted

with

A

LA–P

DT

at

5 or

10

J/cm

2 of l

ight

res

ulte

d in

a s

igni

fican

tly b

ette

r re

spon

se t

han

the

corr

espo

ndin

g pl

aceb

o gr

oup,

alth

ough

th

ere

was

no

sign

ifica

nt d

iffer

ence

bet

wee

n th

e gr

oups

at

2 J/c

m2

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

as

sess

edA

Es T

he a

utho

rs r

epor

ted

that

hy

perp

igm

enta

tion

was

see

n in

11%

of

AK

s tr

eate

d w

ith A

LA–P

DT,

whi

ch w

as

not

diffe

rent

from

the

pla

cebo

gro

up.

The

tre

atm

ent

was

wel

l tol

erat

ed a

nd n

o pa

tient

s w

ithdr

ew d

ue t

o an

AE

Aut

hors

’ con

clus

ions

The

aut

hors

did

no

t re

port

any

con

clus

ions

Bri

ef s

tudy

app

rais

al L

ittle

use

ful

evid

ence

cou

ld b

e re

trie

ved

from

thi

s ab

stra

ct w

hich

pro

vide

d ve

ry fe

w

met

hodo

logi

cal o

r re

sult

deta

ils, a

nd

invo

lved

a fa

irly

sm

all s

ampl

e fo

llow

ed u

p fo

r 16

wk

Appendix 13

198



199Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Kau

fman

n et

al

. (20

08)46

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ries

Aus

tral

ia,

Belg

ium

, Ger

man

y, U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 12

1 (1

343

lesi

ons)

Inte

rven

tion:

121

(69

1 le

sion

s)C

ompa

rato

r: 12

1 (6

52

lesi

ons)

No.

of r

ecru

itin

g ce

ntre

s 24

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

at w

k 12

and

24.

A

dditi

onal

tel

epho

ne

calls

wer

e m

ade

at w

k 1

and

13 w

hen

patie

nts

wer

e re

-tre

ated

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on

and

hist

olog

y N

on-

hype

rker

atot

ic A

KM

ain

elig

ibili

ty c

rite

ria

Mal

es a

nd n

on-p

regn

ant

wom

en a

ged

18 o

r ov

er,

with

a c

linic

al d

iagn

osis

of

non-

hype

rker

atot

ic A

K, o

f m

ild o

r m

oder

ate

thic

knes

s, on

loca

tions

oth

er t

han

the

face

or

scal

p, w

ere

elig

ible

fo

r in

clus

ion.

Pat

ient

s ha

d to

ha

ve a

t le

ast

four

com

para

ble

sym

met

rica

l AK

s, of

sim

ilar

seve

rity

and

tot

al n

umbe

r on

bot

h si

des

of t

he b

ody.

Furt

her

elig

ibili

ty c

rite

ria

wer

e re

port

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 65

Age

ran

ge: 3

8–89

yrM

ean

age:

68.9

yrC

ance

r st

age:

Gra

de I,

687

; gr

ade

II, 6

56Pa

tient

s ha

d (a

mea

n of

) si

x le

sion

s pe

r si

de. F

urth

er

patie

nt c

hara

cter

istic

s w

ere

repo

rted

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

MA

L–PD

T

vs c

ryot

hera

py (

with

in-

part

icip

ant

com

pari

son)

Inte

rven

tion

MA

L–PD

T:

Afte

r sc

rapi

ng o

f les

ions

, a

1-m

m la

yer

of 1

60-m

g/g

MA

L cr

eam

was

app

lied

to

each

lesi

on (

incl

udin

g 5

mm

of

sur

roun

ding

tis

sue)

for

3 hr

(un

der

occl

usio

n). A

fter

salin

e cl

eans

ing,

a st

anda

rd

LED

lam

p ill

umin

ated

lesi

ons

with

nar

row

ban

d re

d lig

ht (

aver

age

630

nm, d

ose

37 J/

cm2 ,

mea

n tim

e 8

min

36

s). L

esio

ns w

ith a

non

-CR

w

ere

re-t

reat

ed a

fter

12 w

kC

ompa

rato

r C

ryot

hera

py:

Dou

ble

free

ze–t

haw

cr

yoth

erap

y us

ing

liqui

d ni

trog

en s

pray

app

lied

with

a

1- t

o 2-

mm

froz

en r

im

outs

ide

the

lesi

on o

utlin

e.

Tim

ing

of fr

eeze

–tha

w

appl

icat

ion

was

as

per

usua

l pr

actic

e of

eac

h ce

ntre

(m

ean

time

20 s

± 14

s)

Mor

bidi

ty A

t w

k 24

the

mea

n re

duct

ion

in le

sion

cou

nt fr

om

base

line

was

78%

for

MA

L–PD

T a

nd 8

8% fo

r cr

yoth

erap

y (p

er-p

roto

col p

opul

atio

n) (

p =

0.00

2), 9

5% C

I of t

he b

ilate

ral

diffe

renc

e (M

AL–

PDT

/cry

othe

rapy

) w

as b

etw

een

–16.

6% a

nd

3.9%

. IT

T (

last

obs

erva

tion

carr

ied

forw

ard)

ana

lysi

s co

nfirm

ed

this

(75

% r

educ

tion

with

MA

L–PD

T v

s 87

% w

ith c

ryot

hera

py,

p <

0.00

1). 7

6% (

455)

of l

esio

ns w

ere

cure

d w

ith M

AL–

PDT

vs

88%

(49

0) w

ith c

ryot

hera

py. T

he d

iffer

ence

was

sim

ilar

for

mild

- an

d m

oder

ate-

thic

knes

s le

sion

sQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y In

vest

igat

or-a

sses

sed

cosm

etic

out

com

e w

as s

igni

fican

tly b

ette

r fo

r M

AL–

PDT

tha

n cr

yoth

erap

y (p

< 0

.001

). In

the

MA

L–PD

T g

roup

, 79%

of l

esio

ns

had

an e

xcel

lent

cos

met

ic o

utco

me,

19%

goo

d, 3

% fa

ir a

nd 0

%

poor

(co

mpa

red

with

56%

exc

elle

nt, 3

6% g

ood,

8%

fair

and

0.

9% p

oor

with

cry

othe

rapy

). A

fter

24 w

k, 50

% o

f pat

ient

s pr

efer

red

MA

L–PD

T in

ter

ms

of c

osm

etic

out

com

e co

mpa

red

with

22%

for

cryo

ther

apy

(p <

0.0

01).

28%

had

no

pref

eren

ce

(ITT

ana

lysi

s). P

atie

nts

pref

erre

d M

AL–

PDT

to

cryo

ther

apy

for

all q

uest

ions

in t

he p

atie

nt q

uest

ionn

aire

(be

twee

n 12

% a

nd

58%

of d

iffer

ence

). The

diff

eren

ces

wer

e m

arke

d ap

art

from

ef

fect

iven

ess

of t

reat

men

t (3

9% fa

vour

ed M

AL–

PDT

vs

26%

cr

yoth

erap

y, no

t si

gnifi

cant

). Pa

tient

s pr

efer

red

MA

L–PD

T in

te

rms

of c

omfo

rt (

60%

vs

10%

, p <

0.0

01),

proc

edur

e (4

9%

vs 2

8%, p

= 0

.05)

and

hea

ling

(64%

vs

6%, p

< 0

.001

). O

vera

ll pa

tient

sat

isfa

ctio

n fa

vour

ed M

AL–

PDT

(49

% v

s 20

%, p

< 0

.001

). If

re-t

reat

men

t w

as r

equi

red

59%

wou

ld p

refe

r M

AL–

PDT

ove

r cr

yoth

erap

y (2

5%, p

< 0

.001

)A

Es T

here

wer

e 63

% p

atie

nts

with

99

AEs

with

cry

othe

rapy

vs

45%

pat

ient

s w

ith 6

7 A

Es w

ith M

AL–

PDT.

Mos

t w

ere

derm

atol

ogic

al a

nd r

elat

ed t

o tr

eatm

ent.

The

mos

t co

mm

only

re

port

ed A

E fo

r M

AL–

PDT

was

pho

tose

nsiti

vity

rea

ctio

n (4

3% o

f pat

ient

s w

ith 6

3 A

Es)

and

cold

exp

osur

e in

jury

for

cryo

ther

apy

(62%

pat

ient

s w

ith 9

5 A

Es).

Mos

t w

ere

of m

ild

inte

nsity

. Tw

o pa

tient

s in

the

cry

othe

rapy

gro

up r

epor

ted

seve

re c

old

expo

sure

inju

ry

Aut

hors

’ con

clus

ions

M

AL–

PDT

sho

wed

in

feri

or e

ffica

cy fo

r tr

eatm

ent

of n

on-fa

ce/

scal

p A

K c

ompa

red

with

cr

yoth

erap

y. H

owev

er,

both

tre

atm

ents

sho

wed

hi

gh e

ffica

cy, a

nd M

AL–

PDT

con

veye

d th

e ad

vant

ages

of b

ette

r co

smes

is a

nd h

ighe

r pa

tient

pre

fere

nce

Bri

ef s

tudy

app

rais

al

The

stu

dy w

as q

uite

w

ell c

ondu

cted

, but

it

was

ope

n in

des

ign

and

ther

efor

e th

ere

was

po

tent

ial f

or in

vest

igat

or/

patie

nt b

ias.

The

po

ssib

ility

of i

nstit

utio

nal

diffe

renc

es a

nd/o

r pr

otoc

ol d

evia

tion

(24

cent

res

in fo

ur c

ount

ries

) af

fect

ing

the

relia

bilit

y of

res

ults

was

illu

stra

ted

by t

he w

ide

vari

atio

n of

fr

eeze

–tha

w t

imin

gs u

sed

for

cryo

ther

apy

Appendix 13

198



199Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Kur

wa

et a

l. (1

999)

47

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 17

Inte

rven

tion:

17

Com

para

tor:

17N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

an

d fr

eque

ncy

1 w

k, 4

wk

and

6 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty c

rite

ria

It ap

pear

ed t

hat

patie

nts

with

a

long

his

tory

of A

Ks

affe

ctin

g th

e fo

rear

ms

and

hand

s w

ere

elig

ible

for

incl

usio

nPa

tien

t ch

arac

teri

stic

s%

Mal

e: 47

Age

ran

ge: 5

3–79

yrC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

ALA

–PD

T

vs 5

-FU

(w

ithin

-par

ticip

ant

com

pari

son)

Inte

rven

tion

ALA

–PD

T:

Thi

ck s

urfa

ce s

cale

was

re

mov

ed if

pre

sent

the

n 20

%

5-A

LA w

as a

pplie

d to

pica

lly

and

cove

red

in a

ligh

t-im

perm

eabl

e dr

essi

ng fo

r 4

hr.

PDT

was

adm

inis

tere

d w

ith

a ha

loge

n la

mp

(580

–740

nm

, 15

0 J/c

m2 ,

mea

n flu

ence

rat

e 80

mW

/cm

2 )C

ompa

rato

r 5-

FU c

ream

(5

%)

was

app

lied

topi

cally

tw

ice

a da

y to

one

han

d fo

r 3

wk

by t

horo

ugh

mas

sage

Mor

bidi

ty T

he m

ean

lesi

onal

are

a be

fore

tre

atm

ent

for

PDT

was

132

2 m

m2 a

nd 6

mth

afte

r tr

eatm

ent

was

291

mm

2 (a

red

uctio

n of

73%

, 95%

CI 6

1% t

o 84

%).

For

5-FU

, mea

n le

sion

al a

rea

was

139

0 m

m2 b

efor

e tr

eatm

ent

and

297m

m2

afte

r (a

red

uctio

n of

70%

, 95%

CI 6

1% t

o 80

%). T

here

was

no

stat

istic

ally

sig

nific

ant

diffe

renc

e in

red

uctio

n of

lesi

onal

are

a be

twee

n PD

T a

nd 5

-FU

at

6 m

th (p

= 0

.72)

. No

patie

nts

wer

e co

mpl

etel

y cl

eare

d of

AK

s w

ith e

ither

tre

atm

ent

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

ass

esse

dA

Es A

ll pa

tient

s ex

peri

ence

d m

ild t

o m

oder

ate

pain

at

PDT

si

tes.

In w

k 1,

PD

T s

ites

wer

e si

gnifi

cant

ly m

ore

pain

ful t

han

5-FU

site

s, bu

t th

is d

iffer

ence

was

abs

ent

in w

k 2

and

reve

rsed

in

wk

4. T

here

was

no

sign

ifica

nt d

iffer

ence

bet

wee

n tr

eatm

ents

ov

eral

l ove

r th

e 4-

wk

peri

od. D

aily

sym

ptom

dia

ries

wer

e co

mpl

eted

by

11 p

atie

nts.

In w

k 1,

PD

T s

ites

wer

e si

gnifi

cant

ly

mor

e er

ythe

mat

ous

than

5-F

U s

ites

but

this

diff

eren

ce w

as

abse

nt in

wk

2 an

d re

vers

ed in

wk

3 an

d 4.

The

re w

as n

o si

gnifi

cant

diff

eren

ce b

etw

een

trea

tmen

ts o

vera

ll ov

er t

he

4-w

k pe

riod

. The

re w

as n

o bl

iste

ring

, ulc

erat

ion,

sca

rrin

g or

ph

otos

ensi

tivity

rea

ctio

n af

ter

eith

er t

reat

men

t m

etho

d. O

ne

patie

nt e

xper

ienc

ed c

onta

ct s

ensi

tivity

to

5-FU

Aut

hors

’ con

clus

ions

O

ne t

reat

men

t w

ith

PDT

usi

ng t

opic

al

5-A

LA a

ppea

rs t

o be

as

effe

ctiv

e an

d w

ell

tole

rate

d as

3 w

k of

tw

ice-

daily

top

ical

5-F

U,

a ch

eap

and

wid

ely

avai

labl

e al

tern

ativ

eA

ppra

isal

Thi

s st

udy

appe

ared

to

be

too

smal

l to

dete

ct

sign

ifica

nt t

reat

men

t ef

fect

s. T

he m

etho

ds

and

resu

lts w

ere

not

clea

rly

repo

rted

and

m

easu

res

to r

educ

e bi

as (

e.g.

rand

omis

atio

n,

blin

ding

and

allo

catio

n co

ncea

lmen

t) w

ere

not

repo

rted

at

all

so t

he r

elia

bilit

y of

th

e co

nclu

sion

s is

qu

estio

nabl

e

Appendix 13

200



201Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Leg

at e

t al. (

2006

)36

Dat

a so

urce

Abs

trac

tC

ount

ry A

ustr

iaLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 22

(m

ean

num

ber A

Ks

47,

rang

e 17

–89)

Inte

rven

tion:

22

(no.

of A

K n

ot

repo

rted

)C

ompa

rato

r: 22

(no

. of A

K n

ot

repo

rted

)2n

d C

ompa

rato

r: si

x (n

o. o

f AK

no

t re

port

ed)

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od a

nd

freq

uenc

y FU

at

4, 1

2 an

d 24

wk

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty c

rite

ria

Not

sta

ted

Pati

ent

char

acte

rist

ics

% M

ale:

100

Age

ran

ge: 5

9–84

yrM

edia

n ag

e: 75

yrPa

tient

s ha

d m

ultip

le A

Ks

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

PD

T w

ith fr

actio

nate

d ill

umin

atio

n vs

PD

T w

ith u

nfra

ctio

nate

d ill

umin

atio

n. W

ithin

-par

ticip

ant

com

pari

son,

bu

t si

x pa

tient

s ha

d PD

T w

ith fr

actio

nate

d ill

umin

atio

n vs

alte

rnat

ive

frac

tiona

ted

illum

inat

ion,

due

to

seve

re p

ain

afte

r 1s

t fr

actio

nate

d do

seIn

terv

enti

on P

DT

with

unf

ract

iona

ted

illum

inat

ion:

Fol

low

ing

appl

icat

ion

of M

AL

crea

m fo

r 3

hr, r

ed li

ght

illum

inat

ion

(pea

k em

issi

on 6

35 n

m)

of a

sin

gle

dose

of 3

7 J/c

m2

was

app

lied

Com

para

tor

PDT

with

frac

tiona

ted

illum

inat

ion:

As

for

PDT

with

unf

ract

iona

ted

illum

inat

ion

exce

pt P

DT

was

giv

en in

tw

o do

ses

of 1

8.5

J/cm

2 div

ided

by

a da

rk in

terv

al

of 1

5 m

in2n

d co

mpa

rato

r PD

T w

ith a

ltern

ativ

e fr

actio

nate

d ill

umin

atio

n: A

s fo

r PD

T w

ith

unfr

actio

nate

d ill

umin

atio

n ex

cept

with

thr

ee

dose

s of

12.

3 J/c

m2 ,

with

tw

o da

rk in

terv

als

of

5 m

in

Mor

bidi

ty T

he m

ean

num

ber

of A

K

at w

k 4,

12

and

24 w

as r

educ

ed b

y 65

, 60

and

48%

with

unf

ract

iona

ted

PDT

and

56,

53,

and

50%

with

fr

actio

nate

d PD

T r

espe

ctiv

ely

(diff

eren

ce n

ot s

igni

fican

t, n =

14)

. Si

mila

r re

sults

see

n fo

r al

tern

ativ

e fr

actio

nate

d PD

T g

roup

QoL

and

ret

urn

to n

orm

al

acti

vity

Not

ass

esse

dA

Es

PDT

indu

ced

pain

(VA

S sc

ore)

w

as 6

.7 (

SE 0

.5)

for

unfr

actio

nate

d PD

T a

nd 6

.0 (

0.5)

for

frac

tiona

ted

PDT

(n =

14,

p =

0.0

2). T

here

was

no

sig

nific

ant

diffe

renc

e in

pai

n be

twee

n fr

actio

nate

d an

d al

tern

ativ

e fr

actio

nate

d pa

tient

s [8

.0 (

0.7)

vs

8.2

(0.3

) re

spec

tivel

y]

Aut

hors

’ con

clus

ions

PD

T w

ith fr

actio

nate

d an

d un

frac

tiona

ted

illum

inat

ion

wer

e si

mila

rly

effe

ctiv

e in

re

duci

ng A

Ks.

How

ever

, pai

n se

nsat

ion

duri

ng P

DT

was

si

gnifi

cant

ly le

ss in

tens

e w

ith

stan

dard

frac

tiona

ted

than

un

frac

tiona

ted

illum

inat

ion

Bri

ef s

tudy

app

rais

al F

ew

met

hodo

logi

cal d

etai

ls w

ere

prov

ided

in t

he a

bstr

act

and

the

resu

lts o

f thi

s sm

all s

tudy

m

ay n

ot b

e ge

nera

lisab

le

Appendix 13

200



201Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mol

oney

et a

l. (2

007)

37

Dat

a so

urce

Abs

trac

tC

ount

ry N

ot s

tate

dLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 16

Inte

rven

tion:

16

Com

para

tor:

16N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

1 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on

and

hist

olog

y A

KM

ain

elig

ibili

ty

crit

eria

Not

sta

ted

Pati

ent

char

acte

rist

ics

% M

ale:

100

Age

ran

ge: 5

9–87

yrA

ll pa

tient

s ha

d A

Ks

on t

he s

calp

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

MA

L–PD

T v

s ALA

–PD

TIn

terv

enti

on M

AL–

PDT:

MA

L cr

eam

w

as a

pplie

d fo

r 3

hr. F

urth

er P

DT

pa

ram

eter

s w

ere

not

repo

rted

Com

para

tor A

LA–P

DT:

20%

ALA

cr

eam

was

app

lied

for

5 hr

. Fur

ther

PD

T

para

met

ers

wer

e no

t re

port

ed

Mor

bidi

ty A

K c

ount

s re

duce

d by

5.

6 ±

3.2

(MA

L) v

s 6.

2 ±

1.9

(ALA

) (p

= 0

.588

) (n

= 1

5)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot a

sses

sed

AE

s All

patie

nts

(n =

15)

exp

erie

nced

pa

in, w

hich

was

of g

reat

er in

tens

ity o

n th

e A

LA t

reat

ed s

ide

at a

ll tim

e po

ints

: 3

min

, p =

0.1

51; 6

min

, p =

0.0

85; 1

2 m

in,

p =

0.01

2; 1

6 m

in, p

= 0

.029

. The

re w

as

also

long

er d

urat

ion

of d

isco

mfo

rt p

ost

trea

tmen

t w

ith A

LA (

p =

0.04

4)

Aut

hors

’ con

clus

ions

Bot

h A

LA a

nd

MA

L–PD

T r

esul

t in

sig

nific

ant

redu

ctio

n in

sca

lp A

Ks.

The

re is

no

sign

ifica

nt

diffe

renc

e in

effi

cacy

. How

ever

, ALA

is

mor

e pa

infu

l tha

n M

AL–

PDT

in t

he

trea

tmen

t of

ext

ensi

ve s

calp

AK

sB

rief

stu

dy a

ppra

isal

The

abs

trac

t pr

ovid

ed fe

w m

etho

dolo

gica

l det

ails

an

d in

volv

ed a

sm

all s

ampl

e, fo

llow

ed u

p fo

r on

ly 1

mth

, so

the

relia

bilit

y of

the

co

nclu

sion

s is

unc

lear

Appendix 13

202



203Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mor

ton

et a

l. (20

06)48

Link

ed

publ

icat

ions

167,

168

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ries

Ir

elan

d, U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

119

(150

1 le

sion

s)In

terv

entio

n: 1

19

(758

lesi

ons)

C

ompa

rato

r: 11

9 (7

43 le

sion

s)N

o. o

f re

crui

ting

ce

ntre

s 25

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU

at w

k 12

and

24

. Add

ition

al

tele

phon

e FU

was

pe

rfor

med

at

wk

1 an

d 13

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on

and

hist

olog

y N

on-

hype

rker

atot

ic A

KM

ain

elig

ibili

ty c

rite

ria

Mal

es a

nd fe

mal

es o

ver

18 yr

(16

yr in

Sco

tland

) w

ith c

linic

al d

iagn

osis

of

(at

leas

t th

ree)

non

-hy

perk

erat

otic

AK

on

the

face

and

/or

scal

p (o

f sim

ilar

seve

rity

and

nu

mbe

r on

bot

h si

des)

w

ere

elig

ible

for

incl

usio

n.

Patie

nts

that

rec

eive

d to

pica

l tre

atm

ent

with

in

the

prev

ious

3 m

th, r

egul

ar

UV

the

rapy

, pat

ient

s w

ith t

hick

or

pigm

ente

d le

sion

s or

por

phyr

ia w

ere

excl

uded

Pati

ent

char

acte

rist

ics

% M

ale:

91A

ge r

ange

: 54–

93 yr

Mea

n ag

e: 75

yrM

ean

no. o

f les

ions

per

si

de: s

ixM

edia

n le

sion

dia

met

er:

7 m

mFu

rthe

r pa

tient

ch

arac

teri

stic

s w

ere

repo

rted

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

MA

L–PD

T v

s cr

yoth

erap

y (w

ithin

-par

ticip

ant

com

pari

son)

Inte

rven

tion

MA

L–PD

T: A

fter

scra

ping

of

lesi

ons,

a 1-

mm

laye

r of

M

AL

160

mg/

g cr

eam

was

ap

plie

d (in

clud

ing

5 m

m

of s

urro

undi

ng t

issu

e) fo

r 3

hr (

unde

r oc

clus

ion)

. Fo

llow

ing

salin

e cl

eans

ing,

lesi

ons

wer

e ill

umin

ated

w

ith n

arro

wba

nd li

ght

(app

roxi

mat

ely

630

nm,

dose

37

J/cm

2 ) u

sing

a

stan

dard

LED

ligh

t so

urce

. Mea

n ill

umin

atio

n tim

e w

as 8

min

41

s. Le

sion

s w

ith a

non

-CR

w

ere

re-t

reat

ed a

t 12

wk

Com

para

tor

Dou

ble

free

ze–t

haw

cry

othe

rapy

: Li

quid

nitr

ogen

spr

ay

appl

ied

to a

chie

ve a

1-

to

2-m

m fr

ozen

rim

aro

und

the

mar

ked

outli

ne o

f th

e le

sion

. Mea

n fr

eezi

ng

time

was

16

s (±

7 s)

Mor

bidi

ty A

t w

k 12

lesi

on r

educ

tion

with

MA

L–PD

T w

as 8

7%

vs 7

6% (p

< 0

.001

). R

educ

tion

in le

sion

cou

nt a

t w

k 24

was

89%

w

ith M

AL–

PDT

vs

86%

with

cry

othe

rapy

(p

= 0.

2, n

= 1

08).

At

wk

12 C

R w

as 8

3% w

ith M

AL–

PDT

vs

72%

with

cry

othe

rapy

. At

wk

24 it

was

86%

(65

0/75

8) w

ith M

AL–

PDT

vs

83%

(61

3/74

3)

with

cry

othe

rapy

. 21%

of l

esio

ns w

ith C

R a

t w

k 24

had

nee

ded

re-t

reat

men

t w

ith c

ryot

hera

py a

t w

k 12

vs

10%

with

MA

L–PD

T, re

sults

wer

e in

depe

nden

t of

initi

al s

ever

ity g

rade

or

loca

tion

(ITT

po

pula

tion)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Ove

rall

part

icip

ant

pref

eren

ce (

i.e. c

osm

etic

out

com

e, e

ffica

cy, a

nd s

kin

disc

omfo

rt)

was

49%

for

MA

L–PD

T v

s 21

% fo

r cr

yoth

erap

y (p

< 0

.001

, IT

T

anal

ysis

). R

esul

ts r

epor

ted

for

per-

prot

ocol

pop

ulat

ion

wer

e 45

%

vs 1

0%, p

< 0

.001

. Inv

estig

ator

pre

fere

nce

for

cosm

etic

out

com

e w

as 4

3% fo

r M

AL–

PDT

vs

12%

for

cryo

ther

apy,

p <

0.00

1, a

nd

for

over

all p

refe

renc

e w

as 5

2% v

s 16

%, p

< 0

.001

. Mos

t su

bjec

ts

wer

e ‘s

atis

fied’

to

‘ver

y sa

tisfie

d’ w

ith M

AL–

PDT

(co

mpa

red

with

cry

othe

rapy

and

pre

viou

s ot

her A

K t

reat

men

ts)

for

7/11

qu

estio

ns o

f a s

atis

fact

ion

ques

tionn

aire

. Mor

e th

an 9

0% w

ere

satis

fied

with

MA

L–PD

T in

ter

ms

of e

ffect

iven

ess

of t

reat

men

t, sc

arri

ng, s

kin

colo

ur a

nd a

ppea

ranc

e at

1-

and

3-m

th F

U.

Cry

othe

rapy

was

pre

ferr

ed fo

r tim

e ta

ken

over

tre

atm

ent

(92%

) co

mpa

red

to 7

8% fo

r M

AL–

PDT.

65%

wou

ld p

refe

r to

be

re-

trea

ted

with

MA

L–PD

T v

s 32

% w

ith c

ryot

hera

py (

n = 1

08)

AE

s Sk

in d

isco

mfo

rt V

AS

scor

es (

mea

n) w

ere

5.2

with

MA

L–PD

T v

s 4.

9 w

ith c

ryot

hera

py (

p =

0.24

) af

ter

1st

trea

tmen

t. Fo

r re

-tre

ated

lesi

ons,

mea

n VA

S sc

ores

wer

e 3.

7 vs

4.4

. Pat

ient

s pr

efer

red

cryo

ther

apy

in t

erm

s of

ski

n di

scom

fort

afte

r 1s

t tr

eatm

ent

(45%

vs

33%

, no

pref

eren

ce 2

2%, p

= 0

.07)

, but

the

re

was

no

diffe

renc

e fo

r re

-tre

ated

lesi

ons.

Skin

-rel

ated

AEs

wer

e re

port

ed b

y 62

% M

AL–

PDT

pat

ient

s vs

72%

for

cryo

ther

apy.

The

re w

as o

ne d

isco

ntin

uatio

n w

ith M

AL–

PDT

due

to

a lo

cal

reac

tion.

Mos

t sk

in-r

elat

ed A

Es w

ere

mild

to

mod

erat

e an

d tr

ansi

ent

Aut

hors

’ con

clus

ions

Whe

n tr

eate

d w

ith b

oth

MA

L–PD

T a

nd

cryo

ther

apy,

patie

nts

sign

ifica

ntly

pr

efer

MA

L–PD

T t

reat

men

t fo

r A

K. M

AL–

PDT

is a

n at

trac

tive

trea

tmen

t op

tion

for A

K, w

ith

com

para

ble

effic

acy

and

supe

rior

co

smet

ic o

utco

mes

com

pare

d w

ith

doub

le fr

eeze

–tha

w c

ryot

hera

pyB

rief

stu

dy a

ppra

isal

Thi

s st

udy

was

gen

eral

ly w

ell c

ondu

cted

and

re

port

ed; h

owev

er, i

t w

as a

n op

en-

labe

l tri

al, w

hich

can

lead

to

bias

in

favo

ur o

f a p

artic

ular

tre

atm

ent.

The

pos

sibi

lity

of in

stitu

tiona

l di

ffere

nces

and

/or

prot

ocol

de

viat

ion

(25

cent

res

in t

wo

coun

trie

s) a

ffect

ing

the

relia

bilit

y of

res

ults

was

illu

stra

ted

by t

he

vari

atio

n of

free

zing

tim

es u

sed

for

cryo

ther

apy

UV,

ultr

avio

let.

Appendix 13

202



203Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Par

iser

et a

l. (2

003)

49

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 80

(50

2 le

sion

s)In

terv

entio

n 42

(26

0 le

sion

)C

ompa

rato

r: 38

(24

2 le

sion

s)N

o. o

f rec

ruit

ing

cent

res

Five

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU w

as a

t 3

mth

. AEs

wer

e as

sess

ed

duri

ng, i

mm

edia

tely

af

ter

PDT,

at w

k 2

and

3 m

th a

fter

the

2nd

PDT

tr

eatm

ent

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y M

ild a

nd m

oder

ate

AK

Mai

n el

igib

ility

cri

teri

a M

ales

and

fem

ales

ove

r 18

yr w

ith 4

–10

prev

ious

ly

untr

eate

d m

ild t

o m

oder

ate

non-

pigm

ente

d A

K o

n th

e fa

ce a

nd s

calp

(at

leas

t 3

mm

di

amet

er)

wer

e el

igib

le fo

r in

clus

ion.

Fur

ther

elig

ibili

ty

crite

ria

wer

e re

port

edPa

tien

t ch

arac

teri

stic

s %

M

ale:

88A

ge r

ange

: 31–

84 yr

Mea

n ag

e: M

AL–

PDT

64;

pl

aceb

o PD

T 6

7T

he m

ajor

ity o

f les

ions

w

ere

mild

and

loca

ted

on

the

face

. Mos

t pa

tient

s w

ere

Fitz

patr

ick

skin

typ

e I o

r II

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

MA

L–PD

T

vs P

DT

with

pla

cebo

cre

amIn

terv

enti

on M

AL–

PDT:

Sc

ales

and

cru

sts

wer

e re

mov

ed u

sing

a c

uret

te M

AL

crea

m (

160

mg/

g) w

as a

pplie

d (1

-mm

thi

ckne

ss a

nd 5

mm

ar

ound

lesi

on)

for

mea

n 3

hr

unde

r oc

clus

ion.

Cre

am w

as

was

hed

off u

sing

a 0

.9%

sal

ine

solu

tion,

the

n a

non-

cohe

rent

re

d lig

ht w

as a

pplie

d: 5

70–

670

nm, d

ose

75 J/

cm2 ,

mea

n in

tens

ity 1

55 m

W/c

m2 (

rang

e 50

–200

mW

/cm

2 ). T

reat

men

t w

as r

epea

ted

afte

r 1

wk

Com

para

tor

PDT

with

pl

aceb

o cr

eam

: As

for

MA

L–PD

T b

ut w

ith p

lace

bo c

ream

Mor

bidi

ty F

or t

he M

AL–

PDT

gro

up, p

atie

nt r

espo

nse

was

32/

39 (

82%

) vs

8/3

8(21

%)

in p

lace

bo, t

reat

men

t di

ffere

nce

–61%

(p

= 0.

001)

For

the

MA

L–PD

T g

roup

le

sion

res

pons

e ra

te w

as 2

09/2

36 (

89%

) vs

92/

241

(38%

) fo

r pl

aceb

o. R

espo

nse

rate

was

sim

ilar

for

mild

an

d m

oder

ate

lesi

ons

in t

he M

AL

grou

p (9

0% a

nd 8

4%,

resp

ectiv

ely)

; pla

cebo

res

pons

e w

as h

ighe

r in

the

mild

le

sion

s (4

4% a

nd 2

5%)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Inve

stig

ator

as

sess

ed c

osm

etic

out

com

e in

the

MA

L–PD

T g

roup

w

as ‘e

xcel

lent

’ or ‘

good

’ in

31/3

2 (9

7%)

patie

nts

and

whe

n as

sess

ed b

y pa

tient

s th

is w

as 2

9/32

(91

%). T

he

outc

ome

was

not

rat

ed ‘p

oor’

by

eith

er in

vest

igat

or

or p

atie

nt. 7

3% o

f 32

patie

nts

pref

erre

d M

AL–

PDT

to

prev

ious

tre

atm

ents

(5-

FU, c

ryot

hera

py, s

urge

ry)

AE

s 38

(90

%)

MA

L–PD

T p

atie

nts

had

an A

E vs

22

(58%

) in

pla

cebo

. One

MA

L–PD

T p

atie

nt d

isco

ntin

ued

due

to A

E. C

omm

on lo

cal A

Es w

ere:

burn

ing

sens

atio

n of

the

ski

n (2

7 M

AL

patie

nts

vs 4

); er

ythe

ma

(22

vs 8

); cr

ustin

g (1

6 vs

6);

pain

on

the

skin

(10

vs

0); b

liste

rs (

8 vs

2);

skin

oed

ema

(6 v

s 1)

; stin

ging

ski

n (6

vs

1) a

nd

skin

ulc

erat

ion

(5 v

s 0)

. Mor

e de

tails

in p

aper

Aut

hors

’ con

clus

ions

PD

T

usin

g to

pica

l MA

L w

as a

saf

e an

d ef

fect

ive

trea

tmen

t fo

r A

K w

ith e

xcel

lent

cos

met

ic

outc

ome.

It is

a p

rom

isin

g tr

eatm

ent

that

cou

ld b

enefi

t fr

om fu

rthe

r st

udy

Bri

ef s

tudy

app

rais

al

Thi

s st

udy

appe

ared

to

be

gene

rally

wel

l con

duct

ed

Appendix 13

204



205Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Par

iser

et a

l. (2

008)

56

Link

ed p

ublic

atio

ns16

9

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 10

0 (7

23 le

sion

s)

(four

pat

ient

s w

ere

trea

ted

as ‘t

rain

ing’

po

pula

tion)

Inte

rven

tion:

49

(363

le

sion

s)C

ompa

rato

r: 47

(36

0 le

sion

s)N

o. o

f rec

ruit

ing

cent

res

Eigh

tFo

llow

-up

peri

od

and

freq

uenc

y FU

3 m

th a

fter

last

tr

eatm

ent

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd h

isto

logy

AK

Mai

n el

igib

ility

cri

teri

a Pr

evio

usly

un

trea

ted

mal

es a

nd n

on-p

regn

ant/

non-

lact

atin

g fe

mal

es w

ith a

dequ

ate

cont

race

ptio

n du

ring

and

1 m

th a

fter

trea

tmen

t th

at w

ere

at le

ast

18 yr

old

with

4–

10 n

on-p

igm

ente

d, n

on-h

yper

kera

totic

gr

ade

I or

II le

sion

s on

the

face

and

sca

lp

(at

leas

t 3-

mm

dia

met

er)

wer

e el

igib

le

for

incl

usio

n. E

xclu

sion

cri

teri

a w

ere

exte

nsiv

e bu

t in

clud

ed: i

mm

unos

uppr

essi

on,

porp

hyri

a, al

lerg

y to

MA

L or

sim

ilar,

alle

rgy

to n

ut p

rodu

cts

or p

rote

in a

ntig

ens,

regu

lar

UV

the

rapy

or

trea

tmen

t of

face

and

sca

lp

with

loca

l the

rapy

in p

revi

ous

30 d

, top

ical

th

erap

y in

pre

viou

s 3

mth

Pati

ent

char

acte

rist

ics

% M

ale:

82M

ean

age:

MA

L–PD

T 6

6.1;

Pla

cebo

PD

T

66.7

Age

ran

ge: 4

3–89

yrSk

in t

ype:

I 23%

; II 5

0%; I

II/IV

27%

Gra

de o

f les

ions

: Gra

de I

73%

; gra

de II

27%

The

maj

ority

of l

esio

ns w

ere

thin

(gr

ade

I) an

d lo

cate

d on

the

face

. Abo

ut 5

0% o

f pa

tient

s ha

d be

twee

n 8

and

10 le

sion

s in

to

tal

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

MA

L–PD

T v

s Pl

aceb

o PD

TIn

terv

enti

on M

AL–

PDT:

Pr

epar

atio

n of

lesi

ons

by

rem

oval

of s

cale

s an

d cr

usts

by

der

mal

cur

ette

, the

n ap

plic

atio

n of

1-m

m-t

hick

M

AL

crea

m t

o le

sion

and

su

rrou

ndin

g 5

mm

ski

n.

Occ

lusi

ve d

ress

ing

appl

ied

for

at le

ast

3 hr

(pe

rmitt

ed r

ange

2.

5–4

hr)

and

avoi

danc

e of

ex

posu

re t

o su

nlig

ht, b

righ

t in

door

ligh

t an

d ex

trem

e co

ld. A

rea

then

illu

min

ated

(a

vera

ge d

urat

ion,

8 m

in)

with

red

LED

(to

tal d

ose

37 J/

cm2 ,

5–8

cm fr

om s

kin)

. T

his

proc

edur

e w

as r

epea

ted

afte

r 1

wk

Com

para

tor

Plac

ebo

PDT:

A

s fo

r M

AL–

PDT

but

with

pl

aceb

o cr

eam

Mor

bidi

ty L

esio

n C

R r

ate

was

86%

fo

r M

AL–

PDT

vs

52%

for

plac

ebo,

OR

6.

9 (9

5% C

I 4.7

to

10.3

, p <

0.0

001)

. Pa

tient

CR

rat

e w

as 5

9% (

29/4

9)

for

MA

L–PD

T v

s 15

% (

7/47

) fo

r pl

aceb

o, O

R 1

3.2

(95%

CI 4

.1 t

o 43

.1,

p <

0.00

01).

3 m

th a

fter

trea

tmen

t 31

%

(15/

49)

MA

L–PD

T p

atie

nts

had

42

new

lesi

ons

vs 2

6% (

12/4

7) p

lace

bo-

PDT

pat

ient

s w

ith 3

4 ne

w le

sion

s. Fo

ur M

AL–

PDT

pat

ient

s ha

d at

leas

t fiv

e ne

w le

sion

s vs

tw

o pl

aceb

o. In

the

M

AL–

PDT

gro

up 6

7% o

f new

lesi

ons

wer

e on

the

face

vs

50%

pla

cebo

(p

= 0

.16)

, no

diffe

renc

e be

twee

n lo

catio

n of

new

lesi

ons

(p =

0.1

6)Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty N

ot a

sses

sed

AE

s Any

AE/

any

loca

l AE

was

re

port

ed b

y 98

% (

52/5

3) in

the

MA

L–PD

T g

roup

. 45%

(22

/47)

rep

orte

d an

y A

E in

pla

cebo

gro

up, 4

5% (

21/4

7)

repo

rted

any

loca

l AE.

In t

he M

AL

grou

p 32

% w

ere

mild

(vs

38%

), 49

%

wer

e m

oder

ate

(vs

6%)

and

17%

wer

e se

vere

(vs

0%

). C

omm

only

rep

orte

d lo

cal A

Es fo

r th

e M

AL–

PDT

(n =

53)

(v

s pl

aceb

o, n

= 4

7) p

atie

nts

wer

e: er

ythe

ma

(77

vs 1

5%),

skin

bur

ning

se

nsat

ion

(72

vs 1

1%),

pain

of s

kin

(60

vs 2

1%),

prur

itis

(23

vs 1

1%),

skin

oe

dem

a (2

8 vs

2%

), sc

ab (

26 v

s 0%

), sk

in d

isco

mfo

rt (

23 v

s 2%

), bl

iste

r (1

5 vs

0%

) an

d sk

in e

xfol

iatio

n (1

1 vs

4%

)

Aut

hors

’ con

clus

ions

Giv

en t

hat

MA

L–PD

T h

as p

rove

d ex

celle

nt

cosm

etic

out

com

es, s

uper

ior

to

conv

entio

nal t

hera

py, t

his

sugg

ests

a

role

for

MA

L–PD

T u

sing

a r

ed L

ED

light

sou

rce

in p

atie

nts

with

mul

tiple

(u

p to

eig

ht) A

K le

sion

sB

rief

stu

dy a

ppra

isal

Thi

s st

udy

appe

ared

to

be g

ener

ally

wel

l co

nduc

ted

and

expl

ored

cen

tre-

effe

cts

on t

he r

esul

ts, a

lthou

gh fu

rthe

r de

tails

of t

he P

DT

ligh

t tr

eatm

ent

wou

ld h

ave

been

use

ful

d, d

ay(s

).

Appendix 13

204



205

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Pui

zina

-Ivic

et

al. (

2008

)57

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry C

roat

iaLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 36

Inte

rven

tion:

Fr

actio

nate

d ill

umin

atio

n: 1

6C

ompa

rato

r: Si

ngle

ill

umin

atio

n: 2

0N

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

and

fr

eque

ncy

24 w

k

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty c

rite

ria

Prev

ious

his

tolo

gica

lly

confi

rmed

dia

gnos

is o

f AK

Pati

ent

char

acte

rist

ics

Not

sta

ted

Tria

l tre

atm

ents

ALA

–PD

T w

ith 1

6-hr

incu

batio

n an

d tw

o lig

ht fr

actio

ns v

s ALA

–PD

T w

ith 5

-hr

incu

batio

n an

d a

sing

le

illum

inat

ion

Inte

rven

tion

ALA

–PD

T w

ith 1

6-hr

incu

batio

n an

d tw

o lig

ht

frac

tions

: Thi

ck c

rust

s w

ere

1st

rem

oved

with

oin

tmen

ts

(and

wet

dre

ssin

gs).

Afte

r cl

eani

ng t

he a

rea

with

a s

alin

e so

lutio

n, t

he 2

0% A

LA c

ream

was

app

lied

to a

thi

ckne

ss o

f ap

prox

imat

ely

1 m

m, c

over

ing

the

trea

ted

area

, and

1 cm

of

the

sur

roun

ding

ski

n. T

he a

rea

was

cov

ered

by

occl

usiv

e dr

essi

ng. A

lum

iniu

m fo

il w

as p

lace

d on

top

in o

rder

to

prot

ect

skin

from

am

bien

t lig

ht. T

here

was

the

n a

16-h

r in

cuba

tion

peri

od b

efor

e re

d lig

ht (

635

nm)

was

app

lied.

The

to

tal o

f 100

J/cm

2 was

del

iver

ed in

2 d

oses

of 5

0 J/c

m2 w

ith

a flu

ence

inte

nsity

of 3

0 m

W/c

m2 . T

here

was

a 2

-hr

brea

k be

twee

n ill

umin

atio

ns. S

pray

ing

of w

ater

and

coo

ling

with

fa

n w

as c

arri

ed o

ut t

o m

inim

ise

pain

sen

satio

ns. A

fter

the

trea

tmen

ts s

unbl

ock

oint

men

ts w

ere

reco

mm

ende

d fo

r th

e ne

xt fe

w d

ays

in a

dditi

on t

o su

n pr

otec

tion

mea

sure

s. Bi

opsi

es

wer

e pe

rfor

med

24

wk

afte

r ill

umin

atio

n in

pat

ient

s w

ith

fluor

esce

nce

dete

cted

afte

r 4

hrC

ompa

rato

r PD

T w

ith 5

-hr

incu

batio

n w

ith A

LA c

ream

and

si

ngle

ligh

t fr

actio

n: P

repa

ratio

n fo

r ill

umin

atio

n w

as a

s fo

r th

e in

terv

entio

n gr

oup.

The

re w

as t

hen

a 5-

hr in

cuba

tion

peri

od

befo

re r

ed li

ght

(635

nm

) w

as a

pplie

d. 1

00 J/

cm2 w

as d

eliv

ered

in

1 d

ose,

with

a fl

uenc

e in

tens

ity o

f 30

mW

/cm

2 . Sp

rayi

ng o

f w

ater

and

coo

ling

with

fans

, and

sun

pro

tect

ion

mea

sure

s w

ere

as fo

r th

e in

terv

entio

n gr

oup.

Biop

sies

wer

e pe

rfor

med

24

wk

afte

r ill

umin

atio

n in

pat

ient

s w

hom

fluo

resc

ence

afte

r 3-

hr in

cuba

tion

with

ALA

was

det

ecte

d

Mor

bidi

ty A

t 24

wk,

resi

dual

tum

our

was

fo

und

in 1

5 of

20

(75%

) bi

opsi

ed p

atie

nts

in

the

sing

le il

lum

inat

ion,

sh

orte

r-in

cuba

tion

grou

p. Tr

eatm

ent

was

re

peat

ed. A

t 24

wk,

ther

e w

as p

ersi

sten

ce

of t

umou

r in

2 o

f 16

(13%

) bi

opsi

ed p

atie

nts

in t

he fr

actio

nate

d,

long

er-in

cuba

tion

grou

pQ

oL a

nd r

etur

n to

no

rmal

act

ivit

y N

ot

asse

ssed

AE

s N

ot a

sses

sed

Aut

hors

’ con

clus

ions

PD

T

deliv

ered

as

frac

tiona

ted

illum

inat

ion

with

16

hr o

f in

cuba

tion

sepa

rate

d by

a 2

-hr

dark

inte

rval

sig

nific

antly

impr

oves

th

erap

eutic

out

com

e in

tum

our

erad

icat

ion

Bri

ef s

tudy

app

rais

al T

his

tria

l had

onl

y a

smal

l num

ber

of p

atie

nts.

Proc

edur

es o

f ra

ndom

isat

ion

and

blin

ding

of

out

com

e as

sess

ors

wer

e un

clea

r. N

o pa

tient

det

ails

w

ere

prov

ided

. Alth

ough

the

gr

oup

rece

ivin

g fr

actio

nate

d ill

umin

atio

n ha

d be

tter

out

com

es,

the

rela

tive

cont

ribu

tion

of t

he

long

er in

cuba

tion

time

and

the

frac

tiona

ted

deliv

ery

are

uncl

ear.

It is

als

o un

clea

r if

ther

e w

ere

any

AEs

Appendix 13

206



207Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sot

irio

u et

al

. (20

09)61

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry G

reec

eLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l 30

(256

le

sion

s)In

terv

entio

n 30

(13

3 le

sion

s)C

ompa

rato

r 30

(12

3 le

sion

s)N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

an

d fr

eque

ncy

Follo

wed

up

at 1

an

d 6

mth

afte

r tr

eatm

ent;

if gi

ven

a 2n

d tr

eatm

ent

then

cy

cle

final

FU

was

at

6 m

th a

fter

last

tr

eatm

ent

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y N

on-

hype

rker

atot

ic A

KM

ain

elig

ibili

ty

crit

eria

Clin

ical

di

agno

sis

of n

on-

hype

rker

atot

ic g

rade

I (

mild

) an

d gr

ade

II (m

oder

ate)

AK

on

dors

a of

han

ds a

nd fo

rear

ms.

Each

pat

ient

req

uire

d to

hav

e at

leas

t th

ree

lesi

ons

of c

ompa

rabl

e se

veri

ty o

n ea

ch s

ide

of

body

(to

tal o

f six

lesi

ons

min

imum

). Ex

clus

ion

crite

ria

wer

e an

y ot

her

derm

atol

ogic

al

dise

ases

or

cond

ition

s in

tr

eatm

ent

area

or

with

in

3 cm

, top

ical

tre

atm

ents

fo

r AK

with

in p

revi

ous

2 m

th, a

nd a

ny in

vasi

ve

tum

ours

in t

he

trea

tmen

t ar

eaPa

tien

t ch

arac

teri

stic

s%

Mal

e: 83

Mea

n ag

e: 64

yrA

ge r

ange

: 49–

79 yr

Seve

rity

of l

esio

ns:

Gra

de I:

54%

(PD

T),

54%

(Im

iqui

mod

); gr

ade

II: 4

6% (

PDT

), 46

%

(Imiq

uim

od)

Con

com

itan

t tr

eatm

ent

Non

e

Tria

l tre

atm

ents

ALA

–PD

T

vs Im

iqui

mod

5%

intr

aind

ivid

ual

righ

t/le

ft co

mpa

riso

nIn

terv

enti

on A

LA–P

DT:

lesi

ons

prep

ared

by

rem

ovin

g cr

usts

and

cu

rett

age,

whe

re le

sion

s w

ere

not

prep

ared

the

se w

ere

all

grad

e I.

20%

5-A

LA c

ream

app

lied

to le

sion

s an

d 5-

mm

sur

roun

ding

sk

in a

nd le

ft fo

r 4

hr. I

llum

inat

ion

imm

edia

tely

follo

win

g re

mov

al o

f dr

essi

ng u

sing

non

-coh

eren

t re

d lig

ht s

ourc

e, li

ght

dose

75

J/cm

2 , an

d flu

ence

rat

e of

75

mW

/cm

2 . Pa

tient

s gi

ven

two

PDT

ses

sion

s on

sam

e da

y, 1s

t se

ssio

n ta

rget

ing

the

hand

and

low

er fo

rear

m,

2nd

trea

ting

uppe

r tw

o-th

irds

of t

he fo

rear

m. T

wo

com

plet

e PD

T t

reat

men

ts w

ere

deliv

ered

to

all

area

s 15

d a

part

. Pai

n m

anag

emen

t du

ring

tre

atm

ent

incl

uded

use

of a

fan

and/

or

cool

ing

spra

ysC

ompa

rato

r Im

iqui

mod

: tr

eatm

ent

base

d on

app

rove

d do

sage

reg

ime

for

the

head

. Pa

tient

s ap

plie

d 50

0 m

g of

im

iqui

mod

5%

cre

am d

aily

for

3 d/

wk

prio

r to

sle

ep, c

ream

le

ft on

ski

n fo

r at

leas

t 8

hr.

Thi

s tr

eatm

ent

cont

inue

d fo

r 4

wk

(cou

rse

1). F

ollo

win

g a

4-w

k po

st-t

reat

men

t pe

riod

fo

r ob

serv

atio

n, a

ny p

atie

nts

with

lesi

ons

rem

aini

ng r

epea

ted

the

proc

ess

for

a fu

rthe

r 4

wk

(cou

rse

2)

Mor

bidi

ty 1

mth

: PD

T C

R r

ates

wer

e si

gnifi

cant

ly b

ette

r ov

eral

l and

for

grad

e I a

nd g

rade

II le

sion

s. C

R fo

r PD

T

70%

(87

/124

) an

d 18

% (

21/1

15)

for

imiq

uim

od (

p <

0.05

). G

rade

I le

sion

CR

was

75%

for

PDT

(50

/67)

and

34%

(2

1/61

) fo

r im

iqui

mod

(p

< 0.

05).

Gra

de II

CR

for

PDT

w

as 6

5% (

37/5

7), n

o gr

ade

II le

sion

s ac

hiev

ed C

R w

ith

imiq

uim

od (

0/54

). 6

mth

: The

CR

was

65%

(81

/124

) fo

r PD

T a

nd 5

6% (

64/1

15)

for

imiq

uim

od, b

ut t

he d

iffer

ence

w

as n

ot s

tatis

tical

ly s

igni

fican

t (p

> 0

.05)

. The

re w

as a

lso

no

sign

ifica

nt d

iffer

ence

for

grad

e I l

esio

ns, 7

2% (

48/6

7, P

DT

) vs

72%

(44

/61,

imiq

uim

od).

CR

wer

e si

gnifi

cant

ly h

ighe

r fo

r gr

ade

II le

sion

s in

the

PD

T t

reat

men

t ar

eas

(58%

, 33/

57)

than

with

imiq

uim

od (

37%

, 20/

54, p

< 0

.05)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Cos

met

ic o

utco

me

was

ass

esse

d by

the

inve

stig

ator

s 6

mth

afte

r tr

eatm

ent

acco

rdin

g to

sca

rrin

g, at

roph

y, er

ythe

ma

and

pigm

ent

chan

ge. O

utco

mes

wer

e gr

aded

as

exce

llent

, goo

d, fa

ir o

r po

or. N

o si

gnifi

cant

diff

eren

ces

betw

een

the

grou

ps w

ere

obse

rved

; exc

elle

nt o

utco

mes

wer

e 85

% in

PD

T a

nd 7

5%

for

imiq

uim

od. A

pat

ient

-com

plet

ed q

uest

ionn

aire

at

6 m

th

asse

ssed

tre

atm

ent

pref

eren

ces.

The

PD

T p

roce

dure

was

pr

efer

red

by 6

9% o

f pat

ient

s, 55

% fa

vour

ed P

DT

in t

erm

s of

ef

ficac

y an

d 70

% w

ould

pre

fer

PDT

for

futu

re t

reat

men

tsA

Es

No

unex

pect

ed s

afet

y is

sues

wer

e re

cord

ed. P

DT

re

actio

ns d

urin

g tr

eatm

ent:

stin

ging

(83

%),

burn

ing

(100

%),

pain

(10

0%),

mod

erat

e er

ythe

ma

(100

%),

oede

ma

(67%

), bl

iste

ring

(27

%).

Rea

ctio

ns w

ere

wel

l tol

erat

ed, n

o fu

rthe

r tr

eatm

ent

was

req

uire

d an

d al

l res

olve

d w

ithin

7–1

5 d.

Im

iqui

mod

rea

ctio

ns w

ere

mos

t co

mm

only

app

licat

ion

site

rel

ated

: itc

hing

(21

%),

burn

ing

(11%

), pa

in (

4%).

Loca

l sk

in r

eact

ions

in t

he t

reat

men

t ar

ea w

ere

mos

tly m

ild t

o m

oder

ate

and

wel

l tol

erat

ed, a

nd m

ore

inte

nse

duri

ng

cour

se 1

tha

n co

urse

2: e

ryth

ema

(93%

), cr

ustin

g (1

1%),

scal

ing

(11%

), er

osio

ns/u

lcer

atio

ns (

7%),

oede

ma

(7%

)

Aut

hors

’ con

clus

ions

ALA

–PD

T a

nd im

iqui

mod

5%

cre

am

are

com

para

ble

trea

tmen

ts fo

r up

per

extr

emity

AK

. ALA

–PD

T

shou

ld b

e co

nsid

ered

as

a 1s

t-lin

e th

erap

y fo

r bo

th g

rade

I an

d gr

ade

II A

K o

f the

ext

rem

ities

Bri

ef s

tudy

app

rais

al A

lthou

gh

this

tri

al u

sed

an in

trai

ndiv

idua

l ra

ndom

isat

ion

desi

gn fo

r tr

eatm

ent,

it fa

iled

to r

epor

t on

as

pect

s of

met

hods

(in

clud

ing

rand

omis

atio

n) a

nd d

id n

ot u

se

an IT

T a

naly

sis

Out

com

e as

sess

ors

wer

e no

t bl

inde

d an

d on

ly in

vest

igat

or-

asse

ssed

cos

met

ic o

utco

mes

w

ere

repo

rted

. The

res

ults

su

gges

t th

ere

may

be

little

di

ffere

nce

betw

een

PDT

and

im

iqui

mod

for

grad

e I l

esio

ns, b

ut

PDT

may

be

bett

er fo

r gr

ade

IIT

hese

res

ults

can

be

cons

ider

ed

mod

erat

ely

relia

ble,

but

un

cert

aint

ies

do e

xist

abo

ut t

he

choi

ce o

f sta

tistic

al t

echn

ique

s us

ed, t

he in

cons

iste

nt r

epor

ting

of s

ome

resu

lts, a

nd t

he s

ampl

e si

ze (

as t

he a

utho

rs a

ssum

ed

that

lesi

ons

with

in p

atie

nts

wer

e in

depe

nden

t)

Appendix 13

206



207

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sm

ith e

t al.

(200

3)50

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of

part

icip

ants

Tota

l: 36

Inte

rven

tion

12

(ALA

with

blu

e lig

ht)

Com

para

tor:

12

(ALA

with

lase

r lig

ht)

2nd

Com

para

tor:

12

(5-F

U)

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od

and

freq

uenc

y FU

at

end

of t

reat

men

t, 2

wk

and

4 w

k

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty c

rite

ria

It ap

pear

ed t

hat

Cau

casi

an

patie

nts

with

a m

inim

um o

f fo

ur n

on-h

yper

kera

totic

AK

of

the

face

or

scal

p w

ere

elig

ible

for

incl

usio

nPa

tien

t ch

arac

teri

stic

s%

Mal

e: 81

Mea

n ag

e: A

LA w

ith b

lue

light

, 58.

9; A

LA w

ith la

ser

light

61.

0; 5

-FU

64.

3M

ean

no. o

f les

ions

: 6–7

per

pa

tient

Con

com

itan

t tr

eatm

ent

Patie

nts

with

mor

e dr

amat

ic

cuta

neou

s re

activ

ity (

6/11

5-

FU a

nd 1

/12

PDT-

lase

r pa

tient

s) w

ere

trea

ted

with

di

lute

ace

tic a

cid

soak

s an

d to

pica

l low

pot

ency

co

rtic

oste

roid

(2–

3 tim

es

daily

)

Tria

l tre

atm

ents

Bro

ad a

rea

ALA

–PD

T w

ith b

lue

light

vs

broa

d ar

ea A

LA–P

DT

with

la

ser

light

vs

5-FU

Inte

rven

tion

ALA

–PD

T

(blu

e lig

ht):

Follo

win

g to

pica

l ap

plic

atio

n of

ALA

for

1 hr

to

a br

oad

area

, illu

min

atio

n w

ith

blue

-ligh

t PD

T fo

r 10

00 s.

Tw

o tr

eatm

ents

30

d ap

art

wer

e ap

plie

dC

ompa

rato

r A

LA–P

DT

(w

ith la

ser)

: Fol

low

ing

broa

d ar

ea t

opic

al A

LA a

pplic

atio

n fo

r 1

hr, p

ulse

d dy

e la

ser

was

ad

min

iste

red

(595

nm

, 75

J/cm

2 w

ith 1

0-m

s pu

lse

dura

tion

usin

g a

10-m

m s

pot

size

, 10

% o

verl

ap o

f eac

h la

ser

impa

ct a

nd t

wo

pass

es a

cros

s tr

eatm

ent

area

). Pa

tient

s re

ceiv

ed t

wo

trea

tmen

ts 3

0 d

apar

t2n

d co

mpa

rato

r 5-

FU: 5

%

fluor

oura

cil c

ream

app

lied

once

or

twic

e da

ily fo

r 4

wk

Mor

bidi

ty 7

5% o

r m

ore

lesi

ons

wer

e cl

eare

d in

9/1

2 PD

T-bl

ue li

ght

patie

nts

vs 5

/12

PDT-

lase

r vs

9/1

1 5-

FU.

100%

of l

esio

ns w

ere

clea

red

in 6

/12

PDT-

blue

ligh

t pa

tient

s vs

1/1

2 PD

T-la

ser

vs 6

/11

5-FU

. The

cum

ulat

ive

clea

ranc

e ra

te (

or in

divi

dual

AK

lesi

on r

ate)

was

80%

(P

DT-

blue

ligh

t), 5

0% (

PDT-

lase

r) a

nd 7

9% (

5-FU

)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y A

ll th

ree

trea

tmen

ts s

how

ed im

prov

emen

t in

glo

bal r

espo

nse,

ta

ctile

rou

ghne

ss a

nd m

ottle

d hy

perp

igm

enta

tion;

th

e 5-

FU a

nd P

DT-

blue

ligh

t gr

oups

ten

ded

tow

ards

m

ore

bene

fit fo

r ta

ctile

rou

ghne

ss, w

here

as t

he 5

-FU

an

d PD

T-la

ser

grou

ps fa

vour

ed p

igm

enta

tion.

PD

T-bl

ue li

ght

was

the

onl

y gr

oup

in w

hich

the

sig

ns o

f ph

otoa

gein

g co

mpl

etel

y re

solv

ed b

ased

on

the

glob

al

resp

onse

sco

re (

two

patie

nts)

. Non

e of

the

tre

atm

ents

w

orse

ned

sign

s of

pho

toag

eing

AE

s Fo

ur P

DT-

blue

ligh

t an

d 3

PDT-

lase

r pa

tient

s re

port

ed m

ild o

r m

oder

ate

stin

ging

dire

ctly

afte

r th

erap

y bu

t no

t at

sub

sequ

ent

FU. E

ryth

ema

was

the

m

ost

pron

ounc

ed A

E; 5

-FU

pat

ient

s ha

d th

e gr

eate

st

aver

age

incr

ease

and

sho

wed

res

idua

l ery

them

a at

4

wk.

Cru

stin

g an

d er

osio

ns w

ere

only

see

n w

ith 5

-FU

. T

here

was

one

dis

cont

inua

tion

in t

he 5

-FU

gro

up d

ue

to a

sev

ere

confl

uent

ery

them

atou

s re

actio

n

Aut

hors

’ con

clus

ions

Bro

ad

area

PD

T t

reat

men

t w

ith A

LA p

lus

activ

atio

n w

ith b

lue

light

app

ears

to

be

as e

ffect

ive

as 5

-FU

in t

he

trea

tmen

t of

AK

. ALA

plu

s la

ser

light

is

som

ewha

t le

ss e

ffect

ive

than

the

ab

ove

ther

apie

sB

rief

stu

dy a

ppra

isal

Thi

s w

as a

sm

all s

tudy

with

poo

rly

repo

rted

m

etho

dolo

gy. A

dditi

onal

tre

atm

ent

was

giv

en t

o pa

tient

s th

at h

ad s

ever

e re

actio

ns, w

hich

may

hav

e be

en a

co

nfou

ndin

g fa

ctor

. The

rel

iabi

lity

of

the

resu

lts is

the

refo

re u

ncer

tain

Appendix 13

208



209Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sze

imie

s et

al.

(200

7)38

Link

ed p

ublic

atio

ns17

0–17

3

Dat

a so

urce

Abs

trac

tC

ount

ry N

ot s

tate

dLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 25

(23

8 le

sion

s)In

terv

entio

n: N

ot s

tate

dC

ompa

rato

r: N

ot s

tate

dN

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU a

t 2

wk

and

3 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on

and

hist

olog

y A

KM

ain

elig

ibili

ty

crit

eria

Not

sta

ted

Pati

ent

char

acte

rist

ics

% M

ale:

68M

ean

age:

73 yr

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

MA

L–PD

T w

ith V

PL

vs M

AL–

PDT

with

LED

ligh

t (w

ithin

-pa

rtic

ipan

t co

mpa

riso

n)In

terv

enti

on P

DT-

VPL

: MA

L cr

eam

w

as a

pplie

d to

tar

get

area

for

3 hr

. One

si

de r

ecei

ved

VPL

at

80 J/

cm2 (

doub

le

puls

ed a

t 40

J/cm

2 ) w

ith a

pul

se t

rain

of

15

impu

lses

, eac

h of

5-m

s du

ratio

n,

usin

g a

610–

950

nm fi

ltere

d ha

nd p

iece

. T

he o

ppos

ite s

ide

rece

ived

LED

ligh

t (3

7 J/c

m2 f

or 1

2 m

in)

Com

para

tor

PDT-

LED

: See

abo

ve

Mor

bidi

ty In

filtr

atio

n an

d ke

rato

ses

scor

e: N

o si

gnifi

cant

di

ffere

nce

betw

een

LED

0.8

6 (0

.71)

and

VPL

1.0

5 (0

.74)

, p

= 0.

292

QoL

and

ret

urn

to n

orm

al

acti

vity

No

sign

ifica

nt d

iffer

ence

s in

pat

ient

sat

isfa

ctio

n be

twee

n tr

eatm

ents

(p

= 0.

425)

AE

s Pa

in a

sses

smen

t (V

AS)

im

med

iate

ly a

fter

PDT

sho

wed

si

gnifi

cant

ly lo

wer

pai

n le

vels

for

the

VPL

sid

e (4

.3 v

s 6.

4)

Aut

hors

’ con

clus

ions

The

use

of V

PL

is a

n ef

ficie

nt a

nd u

sefu

l alte

rnat

ive

in t

he

phot

odyn

amic

tre

atm

ent

of A

K, w

here

ot

herw

ise

pain

dev

elop

men

t ca

n be

a li

miti

ng

fact

or fo

r th

e pe

rfor

man

ce o

f PD

TB

rief

stu

dy a

ppra

isal

Min

imal

rep

ortin

g of

bo

th m

etho

ds a

nd r

esul

ts m

eans

litt

le c

an b

e de

duce

d fr

om t

his

conf

eren

ce a

bstr

act

VPL

, var

iabl

e pu

lsed

ligh

t.

Appendix 13

208



209Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sze

imie

s et

al

. (20

02)51

Link

ed

publ

icat

ions

174,

175

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ries

Aus

tria

, G

erm

any,

Italy,

Sw

itzer

land

, the

N

ethe

rlan

dsLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 20

2 (7

32

lesi

ons)

Inte

rven

tion:

102

(3

84 le

sion

s)C

ompa

rato

r: 10

0 (3

48 le

sion

s)N

o. o

f rec

ruit

ing

cent

res

13Fo

llow

-up

peri

od

and

freq

uenc

y A

t 2

wk

and

3 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty c

rite

ria

Patie

nts

> 18

yr o

ld, w

ith u

p to

10

AK

lesi

ons

suita

ble

for

cryo

ther

apy

and

no t

reat

men

t w

ithin

the

last

4 w

k w

hen

elig

ible

. Dia

gnos

is w

as b

ased

on

clin

ical

ass

essm

ent

(and

hi

stol

ogy

whe

re n

eede

d).

Patie

nts

rece

ivin

g re

gula

r U

V t

hera

py a

nd p

atie

nts

with

pig

men

ted

lesi

ons

or

porp

hyri

a w

ere

excl

uded

Pati

ent

char

acte

rist

ics

% M

ale:

61A

ge r

ange

: 42–

89 yr

Mea

n ag

e: 71

yr (

PDT

), 72

yr

(cry

othe

rapy

)58

% o

f pat

ient

s ha

d 1–

3 le

sion

s, 33

% h

ad 4

–7 le

sion

s, an

d 9%

had

8–1

0 le

sion

s. Le

sion

s w

ere

mos

tly o

f thi

n (4

0%)

or m

oder

ate

(52%

) gr

ade,

and

mos

t w

ere

loca

ted

on t

he fa

ce (

63%

) or

sca

lp

(28%

)C

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

MA

L–PD

T v

s C

ryot

hera

pyIn

terv

enti

on M

AL–

PDT:

Loo

se

crus

ts w

ere

rem

oved

usi

ng a

cu

rett

e an

d th

e su

rfac

e ge

ntly

ro

ughe

ned.

MA

L cr

eam

(16

0 m

g/g)

w

as a

pplie

d as

a 1

-mm

-thi

ck la

yer

and

to 5

mm

of s

urro

undi

ng n

orm

al

tissu

e. T

he a

rea

was

cov

ered

with

an

occ

lusi

ve d

ress

ing

for

3 hr

, afte

r w

hich

the

cre

am w

as w

ashe

d of

f w

ith a

sal

ine

solu

tion,

follo

wed

by

illum

inat

ion

with

non

-coh

eren

t re

d lig

ht (

570–

670

nm)

with

a t

otal

lig

ht d

ose

of 7

5 J/c

m2 a

nd a

ligh

t in

tens

ity o

f 70–

200

mW

/cm

2 . The

m

ean

illum

inat

ion

time

was

11

min

. U

p to

10

lesi

ons

wer

e tr

eate

d at

th

e sa

me

sess

ion.

The

pro

cedu

re

was

rep

eate

d af

ter

1 w

k in

lesi

ons

not

on t

he fa

ce o

r sc

alp

(8%

of

patie

nts)

Com

para

tor

Cry

othe

rapy

: pr

epar

atio

n w

ith s

uper

ficia

l cu

rett

age,

follo

wed

by

cryo

ther

apy

with

liqu

id n

itrog

en s

pray

to

achi

eve

a 1-

to

2-m

m fr

ozen

rim

ou

tsid

e th

e m

arke

d le

sion

out

line.

T

he m

ean

tota

l fre

ezin

g tim

e w

as

24 s.

The

free

zing

pro

cedu

re w

as

perf

orm

ed in

tw

o cy

cles

dur

ing

the

sing

le t

reat

men

t se

ssio

n

Mor

bidi

ty T

he o

vera

ll C

R r

ate

was

69%

(25

2/36

7) fo

r PD

T v

s 75

%

(250

/332

) fo

r cr

yoth

erap

y. H

ighe

r re

spon

se r

ates

wer

e ob

serv

ed in

gra

de

I (th

in)

lesi

ons

than

in t

hick

er le

sion

s. G

rade

I fa

cial

lesi

ons

show

ed t

he b

est

resp

onse

reg

ardl

ess

of in

terv

entio

n ar

mQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y C

osm

etic

out

com

e w

as s

igni

fican

tly

bett

er in

PD

T g

roup

(p

= 0.

035)

, whe

re

96%

of i

nves

tigat

ors

and

98%

of p

atie

nts

grad

ed o

utco

me

as e

xcel

lent

or

good

(v

s 81

% a

nd 9

1%, r

espe

ctiv

ely,

for

cryo

ther

apy

grou

p). I

n th

e PD

T g

roup

, of

the

43

prev

ious

ly t

reat

ed p

atie

nts

(var

ious

tre

atm

ents

suc

h as

cry

othe

rapy

an

d 5-

FU)

32 r

ated

PD

T a

s be

tter

, 10

as

equa

l, an

d on

e w

orse

tha

n th

e pr

evio

us

trea

tmen

tA

Es

Loca

l AEs

wer

e re

port

ed b

y 44

(4

3%)

of P

DT

pat

ient

s vs

26

(26%

) of

cr

yoth

erap

y pa

tient

s. T

he c

omm

ones

t w

ere

burn

ing

sens

atio

n (P

DT

32%

vs

cryo

ther

apy

9%),

skin

pai

n (1

0% v

s 13

%)

and

crus

ting

(5%

vs

6%). T

hree

pa

tient

s st

oppe

d tr

eatm

ent

due

to lo

cal

reac

tions

– o

ne P

DT

(bu

rnin

g) a

nd t

wo

cryo

ther

apy

(pai

n)

Aut

hors

’ con

clus

ions

PD

T fo

r tr

eatin

g A

K

has

a si

mila

r re

spon

se r

ate

to c

ryot

hera

py,

but

with

sup

erio

r co

smet

ic r

esul

ts a

nd h

igh

patie

nt s

atis

fact

ion

Bri

ef s

tudy

app

rais

al In

rel

atio

n to

CR

, th

e au

thor

s’ c

oncl

usio

ns a

ppea

red

only

to

rela

te t

o th

in fa

cial

lesi

ons,

with

unc

erta

inty

su

rrou

ndin

g ot

her

resu

lts (

whi

ch fr

eque

ntly

la

cked

p-v

alue

s). C

osm

etic

out

com

e an

d sa

tisfa

ctio

n re

sults

wer

e ba

sed

on s

mal

ler

patie

nt n

umbe

rs. T

he s

tudy

was

not

blin

ded

whi

ch c

oupl

ed w

ith t

he r

eal p

ossi

bilit

y of

inst

itutio

nal d

iffer

ence

s an

d pr

otoc

ol

devi

atio

n (1

3 ce

ntre

s in

five

cou

ntri

es)

cast

s fu

rthe

r do

ubt

on t

he r

elia

bilit

y of

the

res

ults

Appendix 13

210



211Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sze

imie

s et

al. (

2009

)58

Link

ed

publ

icat

ions

169

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ries

G

erm

any,

USA

Lang

uage

Eng

lish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 13

1In

terv

entio

n:

57 (

plus

16

not

rand

omis

ed –

incl

uded

onl

y in

A

E an

alys

is)

Com

para

tor:

58N

o. o

f rec

ruit

ing

cent

res

10Fo

llow

-up

peri

od a

nd

freq

uenc

y FU

3

mth

afte

r la

st

trea

tmen

t

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd h

isto

logy

A

KM

ain

elig

ibili

ty c

rite

ria

Mal

es a

nd

non-

preg

nant

, non

-lact

atin

g w

omen

ag

ed o

ver

18 yr

with

4–1

0 pr

evio

usly

un

trea

ted,

non

-pig

men

ted,

non

-hy

perk

erat

otic

gra

de I

or II

lesi

ons

on t

he fa

ce a

nd s

calp

(at

leas

t 3-

mm

di

amet

er)

wer

e el

igib

le fo

r in

clus

ion.

Ex

clus

ion

crite

ria

wer

e ex

tens

ive

and

incl

uded

: im

mun

osup

pres

sion

, po

rphy

ria,

alle

rgy

to M

AL

or s

imila

r, hy

pers

ensi

tivity

to

nut

prod

ucts

or

oth

er p

rote

in a

ntig

ens,

regu

lar

UV

tre

atm

ent

of fa

ce o

r sc

alp

in

prev

ious

30

d, t

opic

al t

hera

py in

pr

evio

us 3

mth

Pati

ent

char

acte

rist

ics

% M

ale:

79M

ean

age:

MA

L–PD

T 6

9.5;

Pla

cebo

PD

T 6

7.0

Age

ran

ge: 4

1–90

yr s

kin

type

: I

19%

; II 4

4%; I

II/IV

27%

; IV

10%

le

sion

s: gr

ade

I (th

in)

41%

; gra

de II

(m

oder

ate)

59%

The

maj

ority

of l

esio

ns w

ere

loca

ted

on t

he fa

ce o

r sc

alp,

patie

nts

had

a m

edia

n of

sev

en le

sion

s ea

ch a

nd

the

med

ian

max

imum

dia

met

er w

as

9 m

mC

onco

mit

ant

trea

tmen

t 22

pa

tient

s (1

4 M

AL,

8 p

lace

bo)

rece

ived

ora

l ana

lges

ic t

reat

men

t or

fe

ntan

yl p

atch

es

Tria

l tre

atm

ents

MA

L–PD

T v

s Pl

aceb

o PD

TIn

terv

enti

on M

AL–

PDT:

Afte

r de

brid

emen

t of

lesi

ons,

1-m

m-

thic

k M

AL

crea

m (

160

mg/

g)

was

app

lied

to e

ach

lesi

on a

nd

5-m

m s

urro

undi

ng s

kin

for

3 hr

(p

erm

itted

ran

ge 2

.5–4

hr)

und

er

occl

usio

n. L

esio

ns w

ere

clea

ned

with

a s

alin

e so

lutio

n, t

hen

illum

inat

ed w

ith n

on-c

oher

ent

LED

red

ligh

t (a

vera

ge d

urat

ion

9 m

in, m

ean

dose

37

J/cm

2 , m

ean

inte

nsity

74

mW

/cm

2 , ra

nge

56–

83 m

W/c

m2 )

with

the

ligh

t so

urce

ke

pt a

t 5–

8 cm

from

ski

n. B

reak

s in

illu

min

atio

n w

ere

allo

wed

pr

ovid

ed t

hat

trea

tmen

t w

as

com

plet

ed w

ithin

4 h

of o

cclu

sion

. T

his

proc

ess

was

rep

eate

d af

ter

1 w

kC

ompa

rato

r Pl

aceb

o PD

T: A

s fo

r M

AL–

PDT

but

with

pla

cebo

cr

eam

Mor

bidi

ty L

esio

n re

spon

se r

ate

was

83%

(34

8/41

8)

with

MA

L vs

29%

(11

9/41

4) fo

r pl

aceb

o, O

R 1

3.8

(9.5

to

19.9

, p <

0.0

01).

Patie

nt C

R r

ate

with

MA

L w

as 6

8% (

39/5

7) v

s 7%

(4/

59)

for

plac

ebo,

OR

39.

5 (1

0.5

to 1

49.2

, p <

0.0

01).

At

3 m

th a

fter

trea

tmen

t, de

velo

pmen

t of

new

lesi

ons

was

18%

(10

/56)

in

MA

L pa

tient

s vs

34%

(20

/58)

for

plac

ebo,

p =

0.0

4.

73%

wer

e on

the

sca

lp in

the

MA

L gr

oup

vs 5

9%.

Res

pons

e ra

tes

wer

e hi

gher

for

smal

l les

ions

(3

–10

mm

) on

the

face

but

bet

ter

for

larg

e le

sion

s (>

20

mm

) on

the

sca

lpQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot a

sses

sed

AE

s 85

% (

62/7

3) M

AL

patie

nts

repo

rted

AEs

vs

60%

(3

5/58

) an

d m

ost

wer

e as

soci

ated

with

tre

atm

ent

site

(31

2/36

8 an

d 56

/89,

res

pect

ivel

y). T

he m

ost

com

mon

ly r

epor

ted

loca

l AEs

with

MA

L w

ere

pain

of

the

ski

n 55

% (

40/7

3) v

s 22

% (

13/5

8), e

ryth

ema

52%

(38

/73)

vs

5% (

3/58

), an

d sk

in b

urni

ng s

ensa

tion

36%

(26

/73)

vs

12%

(21

/58)

. In

the

plac

ebo

grou

p al

l but

six

loca

l AEs

wer

e m

ild; m

ost

MA

L A

Es w

ere

mild

to

mod

erat

e. N

inet

een

MA

L pa

tient

s ha

d se

vere

lo

cal A

Es c

onsi

dere

d tr

eatm

ent

rela

ted:

pai

n of

the

sk

in 1

3, e

ryth

ema

six,

ski

n bu

rnin

g se

nsat

ion

five,

sk

in e

xfol

iatio

n fo

ur, s

cab

one,

ski

n sw

ellin

g on

e an

d fa

ce s

wel

ling

one.

The

re w

ere

also

six

non

-loca

l AEs

: di

zzin

ess

and

incr

ease

d pe

rspi

ratio

n, e

yelid

oed

ema

(thr

ee r

epor

ts)

and

head

ache

(on

e re

port

). Tw

o M

AL

patie

nts

disc

ontin

ued

due

to s

ever

e sk

in p

ain

Aut

hors

’ con

clus

ions

To

pica

l MA

L–PD

T u

sing

an

LED

is a

n ef

fect

ive

trea

tmen

t fo

r m

ultip

le A

Ks

Bri

ef s

tudy

app

rais

al

Gen

eral

ly a

wel

l-con

duct

ed

tria

l tha

t co

nsid

ered

cen

tre

effe

cts

on t

he r

esul

ts;

how

ever

, a s

ubgr

oup

anal

ysis

of

pat

ient

s th

at r

ecei

ved

addi

tiona

l pai

nkill

ers

may

ha

ve b

een

usef

ul

Appendix 13

210



211Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Ta

rste

dt e

t al.

(200

5)52

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry S

wed

enLa

ngua

ge

Engl

ish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 21

1 (4

13

lesi

ons)

Inte

rven

tion:

105

(1

98 le

sion

s)C

ompa

rato

r: 10

6 (2

15 le

sion

s)N

o. o

f re

crui

ting

ce

ntre

s 21

Follo

w-u

p pe

riod

and

fr

eque

ncy

At

3 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd h

isto

logy

A

K (

grad

e I o

r II)

Mai

n el

igib

ility

cri

teri

a Pa

tient

s ag

ed a

t le

ast

18 yr

with

up

to 1

0 cl

inic

ally

dia

gnos

ed A

K le

sion

s on

the

fa

ce a

nd/o

r sc

alp,

whi

ch w

ere

mild

(g

rade

I) o

r m

oder

ate

(gra

de II

) an

d no

n-pi

gmen

ted,

wer

e el

igib

lePa

tien

t ch

arac

teri

stic

s%

Mal

e: 39

Mea

n ag

e: 69

yr s

ingl

e-se

ssio

n gr

oup,

68 yr

2-s

essi

on g

roup

Aro

und

one-

half

of t

he p

atie

nts

had

rece

ived

pri

or t

reat

men

t fo

r AK

. M

ean

lesi

on d

iam

eter

was

aro

und

10 m

m. T

he m

ajor

ity o

f pat

ient

s (7

6–83

% in

bot

h gr

oups

) ha

d 1

or 2

le

sion

s, an

d 90

% o

f les

ions

wer

e on

th

e fa

ce, w

ith t

he r

est

bein

g on

the

sc

alp.

Furt

her

char

acte

rist

ics

wer

e re

port

edC

onco

mit

ant

trea

tmen

t Lo

cal

anae

sthe

tic if

nee

ded

duri

ng

trea

tmen

t

Tria

l tre

atm

ents

MA

L–PD

T

sing

le s

essi

on v

s M

AL–

PDT

2

sess

ions

(1

wk

apar

t)In

terv

enti

on M

AL–

PDT

sin

gle

sess

ion:

Any

lesi

on c

rust

was

re

mov

ed u

sing

a c

uret

te o

r sc

alpe

l (w

ithou

t an

aest

hetic

) an

d a

1-m

m-t

hick

laye

r of

MA

L (M

etvi

x,

160

mg/

g) w

as a

pplie

d to

eac

h le

sion

and

5 m

m o

f sur

roun

ding

tis

sue

and

cove

red

with

an

occl

usiv

e dr

essi

ng fo

r m

ean

of

3 hr

. The

dre

ssin

g w

as r

emov

ed

and

the

crea

m w

ashe

d of

f with

0.

9% s

alin

e so

lutio

n im

med

iate

ly

befo

re il

lum

inat

ion,

for

mea

n of

8

min

, with

red

LED

ligh

t (p

eak

wav

elen

gth

634

± 3

nm, l

ight

dos

e 37

J/cm

2 , ir

radi

ance

50

mW

/cm

2 at

50 m

m fr

om s

kin)

. Re-

trea

tmen

t if

ther

e w

as a

non

-CR

afte

r 3

mth

Com

para

tor

MA

L–PD

T t

wo

sess

ions

: See

abo

ve, b

ut t

wo

trea

tmen

t se

ssio

ns, 1

wk

apar

t

Mor

bidi

ty A

naly

ses

base

d on

400

lesi

ons

(198

sin

gle

sess

ion;

202

dou

ble

sess

ion

MA

L–PD

T). T

he le

sion

C

R r

ates

wer

e si

mila

r (8

1% s

ingl

e tr

eatm

ent

vs 8

7%

2 tr

eatm

ents

). A

furt

her

22 le

sion

s sh

owed

a C

R

afte

r re

-tre

atm

ent

(incr

easi

ng t

he C

R fo

r th

e si

ngle

tr

eatm

ent

grou

p to

92%

). Si

ngle

and

tw

o-tr

eatm

ent

sche

dule

s ha

d si

mila

r C

Rs

for

thin

lesi

ons

(93%

vs

89%

), bu

t no

t fo

r m

oder

atel

y th

ick

lesi

ons

(70%

vs

84%

), al

thou

gh a

gain

thi

s im

prov

ed a

fter

re-t

reat

men

t (8

8%)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Cos

met

ic

outc

ome

was

rat

ed a

s ex

celle

nt fo

r ea

ch o

f fou

r pa

ram

eter

s in

> 7

5% o

f les

ions

in e

ach

grou

p. 66

%

of s

ingl

e tr

eatm

ent

patie

nts,

who

had

pre

viou

sly

been

tre

ated

with

cry

othe

rapy

, pre

ferr

ed P

DT

to

cryo

ther

apy

vs 5

8% in

the

tw

o-tr

eatm

ent

grou

pA

Es A

Es w

ere

repo

rted

in 4

2 si

ngle

-tre

atm

ent

patie

nts

and

in 5

3 tw

o-tr

eatm

ent

patie

nts.

Mos

t lo

cal A

Es w

ere

of m

ild t

o m

oder

ate

inte

nsity

and

of

rela

tivel

y sh

ort

dura

tion.

Bur

ning

of s

kin

occu

rred

in

15%

of s

ingl

e tr

eatm

ent

patie

nts

vs 1

9% o

f the

tr

eatm

ent

grou

p, w

here

as p

ain

occu

rred

in 9

% a

nd

18%

of p

atie

nts,

resp

ectiv

ely.

One

pat

ient

ran

dom

ised

to

tw

o se

ssio

ns d

isco

ntin

ued

due

to m

oder

ate

eryt

hem

a (w

hich

res

olve

d co

mpl

etel

y)

Aut

hors

’ con

clus

ions

Si

ngle

MA

L–PD

T t

reat

men

t is

as

effe

ctiv

e as

a t

wo-

trea

tmen

t sc

hedu

le fo

r th

in A

K le

sion

s. R

epea

ted

trea

tmen

t is

rec

omm

ende

d fo

r th

icke

r or

non

-re

spon

ding

lesi

ons

Bri

ef s

tudy

app

rais

al

Alth

ough

thi

s st

udy

appe

ars

to h

ave

been

qui

te w

ell

cond

ucte

d, it

was

unc

lear

w

heth

er t

he o

utco

me

asse

ssor

s w

ere

blin

ded

to t

reat

men

t al

loca

tion.

21

cen

tres

rec

ruite

d th

e 21

1 pa

tient

s (a

roun

d fiv

e pa

rtic

ipan

ts p

er c

entr

e on

ave

rage

) in

crea

sing

the

po

ssib

ility

tha

t pr

otoc

ol

devi

atio

n an

d in

stitu

tiona

l di

ffere

nces

wou

ld a

ffect

re

sults

. p-v

alue

s w

ere

not

repo

rted

Appendix 13

212



213Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Tou

ma

et a

l. (2

003)

39

Dat

a so

urce

Abs

trac

tC

ount

ry U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 18

Inte

rven

tion:

Not

sta

ted

Com

para

tor:

Not

sta

ted

2nd

Com

para

tor:

Not

st

ated

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od a

nd

freq

uenc

y D

ay 1

, the

n at

1

wk,

and

1 an

d 5

mth

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on

and

hist

olog

y N

on-

hype

rtro

phic

AK

Mai

n el

igib

ility

cr

iter

ia P

atie

nts

with

at

leas

t fo

ur n

on-

hype

rtro

phic

AK

and

di

ffuse

pho

toda

mag

ePa

tien

t ch

arac

teri

stic

s N

ot

stat

edC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

ALA

–PD

T, 1-

hr

incu

batio

n vs

2-h

r in

cuba

tion

vs 3

-hr

incu

batio

nIn

terv

enti

on 1

-hr

incu

batio

n: P

re-

trea

tmen

t w

ith 4

0% u

rea

crea

m

(pen

etra

tion

enha

ncer

) an

d xy

loca

ine

HC

L 3%

(pa

in c

ontr

ol)

follo

wed

by

20%

ALA

–PD

T w

ith 4

17-n

m b

lue

light

. Fu

rthe

r PD

T p

aram

eter

s w

ere

not

repo

rted

Com

para

tor

2 hr

incu

batio

n: S

ee a

bove

2nd

com

para

tor

3-hr

incu

batio

n: S

ee

abov

e

Mor

bidi

ty R

esul

ts n

ot b

roke

n do

wn

by t

reat

men

t gr

oup,

but

it w

as r

epor

ted

that

the

re w

as n

o ef

fect

of A

LA

incu

batio

n tim

e or

ure

a cr

eam

on

any

of t

he m

easu

red

outc

omes

. At

1 m

th,

90%

of A

Ks

had

clea

red

(ana

lysi

s on

17

patie

nts)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Patie

nt s

atis

fact

ion

with

cos

met

ic r

esul

ts

was

rep

orte

d as

mod

erat

ely

high

, and

all

patie

nts

com

men

ted

on im

prov

ed s

kin

text

ure

AE

s Ph

otot

oxic

rea

ctio

ns w

ere

wel

l to

lera

ted

Aut

hors

’ con

clus

ions

Sho

rt

incu

batio

n (1

–3 h

r) b

road

are

a A

LA–P

DT

ap

pear

s as

effe

ctiv

e in

era

dica

ting

AK

s as

the

long

incu

batio

n ap

plic

atio

n, w

ith

tole

rabl

e ph

otot

oxic

ityB

rief

stu

dy a

ppra

isal

Litt

le

info

rmat

ion

on m

etho

ds a

nd v

ery

limite

d re

sults

pre

sent

ed fo

r th

is v

ery

smal

l stu

dy. T

he c

oncl

usio

ns a

ppea

r in

appr

opri

ate

if th

ey w

ere

base

d on

the

st

udy

resu

lts, a

s sh

ort

incu

batio

n ap

pear

s to

be

defin

ed a

s 1–

3 hr

, yet

no

grou

p re

ceiv

ed lo

ng in

cuba

tion

trea

tmen

t

Appendix 13

212



213Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

W

ennb

erg

et a

l. (2

008)

59

Link

ed

publ

icat

ions

176–

178

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry N

ot

stat

ed, ‘E

urop

e’La

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of

part

icip

ants

Tota

l: 81

(88

9 le

sion

s, 90

% A

K)

Inte

rven

tion:

476

le

sion

sC

ompa

rato

r: 41

3 le

sion

sN

o. o

f rec

ruit

ing

cent

res

11Fo

llow

-up

peri

od

and

freq

uenc

y 3,

9, 1

5, 2

1 an

d 27

mth

afte

r in

itial

tr

eatm

ent

Trea

tmen

t in

tent

ion

Cur

ativ

e.

Thi

s tr

ial a

imed

to

trea

t ex

istin

g le

sion

s an

d al

so p

reve

nt r

ecur

renc

e.

Onl

y re

spon

se r

ates

and

cos

met

ic

outc

omes

hav

e be

en r

epor

ted

here

Type

(s)

of le

sion

and

his

tolo

gy

AK

(so

me

BCC

and

SC

C in

situ

in

clud

ed b

ut d

ata

not

repo

rted

)M

ain

elig

ibili

ty c

rite

ria

Org

an

tran

spla

nt r

ecip

ient

s w

ho h

ad

rece

ived

imm

unos

uppr

essi

ve

ther

apy

for

mor

e th

an 3

yr a

nd h

ad

betw

een

two

and

10 le

sion

s in

tw

o sy

mm

etri

cal 5

0-cm

2 con

tral

ater

al

area

s on

the

face

, sca

lp, n

eck,

trun

k or

ex

trem

ities

. All

patie

nts

wer

e re

quire

d to

hav

e re

ceiv

ed a

t le

ast

one

prev

ious

tr

eatm

ent

for

the

lesi

ons.

Excl

usio

n cr

iteri

a w

ere

repo

rted

Pati

ent

char

acte

rist

ics

% M

ale:

68A

ge r

ange

: 30–

78 yr

Med

ian

age:

57 yr

Mos

t pa

tient

s ha

d Fi

tzpa

tric

k sk

in

type

s I–

III, o

rgan

tra

nspl

anta

tion

occu

rred

bet

wee

n 3

and

34 yr

pr

evio

usly

(m

edia

n 16

yr)

with

the

m

ajor

ity m

ore

than

10

yr p

rior

to

trea

tmen

t. Se

lect

ed t

reat

men

t ar

eas

wer

e m

ostly

on

the

face

, sca

lp o

r ex

trem

ities

. AK

s w

ere

mos

tly g

rade

I or

II a

nd a

lmos

t al

l wer

e ≤

10 m

m in

di

amet

erC

onco

mit

ant

trea

tmen

t N

ot

stat

ed

Tria

l tre

atm

ents

MA

L–PD

T v

s in

vest

igat

or’s

choi

ce o

f tre

atm

ent

(with

in-p

artic

ipan

t co

mpa

riso

n)In

terv

enti

on M

AL–

PDT:

2

trea

tmen

ts w

ere

give

n, 1

wk

apar

t (b

asel

ine

and

1 w

k af

ter

rand

omis

atio

n). A

dditi

onal

sin

gle

trea

tmen

ts w

ere

give

n at

3, 9

and

15

mth

for

a to

tal o

f five

tre

atm

ents

. A

ny v

isib

le le

sion

s at

21

and

27 m

th

wer

e tr

eate

d at

the

inve

stig

ator

s’

disc

retio

n. L

esio

ns w

ere

prep

ared

us

ing

a sm

all c

uret

te t

o de

brid

e th

e ar

ea. M

AL

160

mg/

g cr

eam

app

lied

in

1-m

m la

yer

to 5

0-cm

2 tre

atm

ent

area

an

d co

vere

d fo

r 3

hr w

ith a

n oc

clus

ive

dres

sing

. Exc

ess

crea

m w

as r

emov

ed

with

sal

ine

and

the

area

illu

min

ated

w

ith n

on-c

oher

ent

red

light

from

a

lam

p (6

30 n

m, l

ight

dos

e 37

J/cm

2 ).

Patie

nts’

eye

s w

ere

prot

ecte

d du

ring

tr

eatm

ent.

Fans

and

col

d w

ater

sp

rayi

ng w

ere

used

for

all p

atie

nts

to

min

imis

e pa

inC

ompa

rato

r C

ontr

ol a

rea

was

tr

eate

d at

the

inve

stig

ator

’s di

scre

tion

utili

sing

any

sui

tabl

e th

erap

y in

ac

cord

ance

with

nor

mal

clin

ical

pr

actic

e EX

CEP

T 5

-FU

cre

am o

r im

iqui

mod

cre

am. T

reat

men

t w

as

carr

ied

out

at b

asel

ine

and

3, 9

and

15

mth

late

r. Any

vis

ible

lesi

ons

at 2

1 or

27

mth

wer

e tr

eate

d ac

cord

ing

to

the

inve

stig

ator

’s pr

efer

ence

. Con

trol

tr

eatm

ents

util

ised

: cry

othe

rapy

(83

%)

cure

ttag

e an

d ca

uter

y (4

%)

lase

r th

erap

y (2

%)

surg

ery

(1%

)

Mor

bidi

ty T

his

tria

l aim

ed t

o tr

eat

exis

ting

lesi

ons

and

also

pre

vent

re

curr

ence

. Onl

y re

spon

se r

ates

an

d co

smet

ic o

utco

mes

hav

e be

en

repo

rted

her

e. L

esio

n C

R r

ate

at

3 m

th: M

AL–

PDT

77%

and

con

trol

74

% (

no p

-val

ue r

epor

ted)

. Les

ion

resp

onse

rat

e at

15

mth

: MA

L–PD

T

88%

and

con

trol

89%

Rec

urre

nce

rate

s fo

r le

sion

s th

at

wer

e pr

esen

t at

bas

elin

e an

d ra

ted

as C

R b

y 3

mth

wer

e si

mila

r in

bot

h gr

oups

(PD

T 2

4% a

nd 2

0% c

ontr

ol)

with

no

sign

ifica

nt d

iffer

ence

QoL

and

ret

urn

to n

orm

al

acti

vity

Cos

met

ic o

utco

mes

wer

e ra

ted

by t

he in

vest

igat

or o

n a

3-po

int

scal

e. O

vera

ll M

AL–

PDT

res

ulte

d in

mor

e fa

vour

able

out

com

es

than

the

con

trol

tre

atm

ents

for

hypo

pigm

enta

tion

(p <

0.0

01).

At

15 m

th, m

ore

hypo

pigm

enta

tion

was

rep

orte

d in

the

con

trol

gro

up

and

obvi

ous

hypo

pigm

enta

tion

was

0%

(M

AL–

PDT

) vs

25%

(co

ntro

l).

No

sign

ifica

nt d

iffer

ence

was

foun

d be

twee

n gr

oups

for

scar

form

atio

nA

Es

Loca

l AEs

ass

ocia

ted

with

M

AL–

PDT

wer

e re

port

ed b

y 75

% o

f pa

tient

s al

thou

gh m

ost

wer

e tr

ansi

ent

and

reso

lved

with

in 1

wk

(ery

them

a, pa

in a

nd c

rust

ing)

. 6%

of p

atie

nts

disc

ontin

ued

MA

L–PD

T d

ue t

o pa

in;

pain

was

judg

ed a

s se

vere

in 1

7 ou

t of

420

tre

atm

ent

sess

ions

but

mos

t re

port

ed w

ere

of m

oder

ate

pain

. 48

% o

f pat

ient

s re

port

ed A

Es in

the

co

ntro

l are

a in

clud

ing

pain

, ery

them

a, cr

ustin

g or

blis

teri

ng o

f mild

to

mod

erat

e in

tens

ity

Aut

hors

’ con

clus

ions

Tre

atin

g fie

ld c

ance

risa

tion

in o

rgan

tra

nspl

ant

reci

pien

ts w

ith t

opic

al M

AL–

PDT

is

effi

caci

ous

and

gene

rally

wel

l to

lera

ted

(furt

her

conc

lusi

ons

rela

ting

to p

reve

ntio

n of

AK

rep

orte

d)B

rief

stu

dy a

ppra

isal

Thi

s st

udy

was

pri

mar

ily in

tend

ed

to e

valu

ate

prop

hyla

ctic

PD

T in

im

mun

osup

pres

sed

patie

nts

and

this

sh

ould

be

born

e in

min

d. F

ew d

etai

ls

wer

e pr

ovid

ed a

bout

con

ceal

men

t of

allo

catio

n, a

nd b

lindi

ng w

as n

ot

used

. The

con

trol

tre

atm

ent

was

not

pr

edefi

ned

and

inte

rcen

tre

diffe

renc

es

are

likel

y to

hav

e im

pact

ed o

n th

e re

sults

(of

whi

ch fe

w fi

gure

s w

ere

prov

ided

). A

s a

com

para

tive

stud

y, th

e re

sults

sho

uld

be c

onsi

dere

d w

ith

caut

ion

and

may

not

be

relia

ble

Appendix 13

214 Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Wie

gell

et

al. (

2008

)53

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry D

enm

ark

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

30 (

29

trea

ted)

Inte

rven

tion:

30

(29

trea

ted)

C

ompa

rato

r: 30

(29

tr

eate

d)N

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

at 1

–3 d

(A

Es)

and

3 m

th (

CR

)

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd

hist

olog

y A

KM

ain

elig

ibili

ty c

rite

ria

Patie

nts

with

AK

s sy

mm

etri

cally

di

stri

bute

d on

the

face

or

scal

p. Pr

egna

nt o

r la

ctat

ing

wom

en

wer

e ex

clud

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 79

Age

ran

ge: 6

3–90

yrM

ean

age:

78 yr

Mos

t le

sion

s w

ere

grad

e I,

with

ar

ound

a t

hird

gra

de II

and

ver

y sm

all n

umbe

r w

ere

grad

e III

Con

com

itan

t tr

eatm

ent

Suns

cree

n fo

r ex

pose

d ar

eas

not

cove

red

by t

reat

men

t

Tria

l tre

atm

ents

MA

L–PD

T w

ith

dayl

ight

vs

MA

L–PD

T w

ith r

ed L

ED

(with

in-p

artic

ipan

t co

mpa

riso

n)In

terv

enti

on P

DT

with

day

light

: Bef

ore

trea

tmen

t, le

sion

s w

ere

coun

ted,

gra

ded,

m

appe

d, a

nd p

hoto

grap

hed.

AK

lesi

ons

of fa

ce o

r sc

alp

wer

e m

arke

d in

to t

wo

sym

met

rica

l tre

atm

ent

area

s (~

80 cm

2

each

) an

d sc

ales

and

hyp

erke

rato

ses

wer

e re

mov

ed u

sing

a c

uret

te. A

roun

d 1

g of

MA

L cr

eam

was

app

lied

to e

ach

area

and

cov

ered

with

a d

ress

ing

and

light

-impe

rmea

ble

lead

rub

ber.

Follo

win

g 30

min

indo

ors,

the

dayl

ight

are

a ha

d th

e dr

essi

ng r

emov

ed a

nd p

atie

nts

spen

t 2.

5 hr

out

side

in d

aylig

ht (

mea

n ef

fect

ive

tota

l dos

e 43

J/cm

2 , m

ean

effe

ctiv

e re

d lig

ht d

ose

1.9

J/cm

2 , pa

tient

s tr

eate

d in

pe

riod

bet

wee

n Ju

ly a

nd S

epte

mbe

r),

befo

re r

etur

ning

to

have

MA

L cr

eam

from

bo

th t

reat

men

t ar

eas

rem

oved

. The

are

a ra

ndom

ised

to

red

LED

ligh

t w

as t

reat

ed

with

a li

ght

dose

of 3

7 J/c

m2 (

effe

ctiv

e re

d lig

ht d

ose

1.2

J/cm

2 , pe

ak ir

radi

ance

at

632

nm

) af

ter

cove

ring

the

day

light

tr

eatm

ent

area

with

ligh

t-im

perm

eabl

e ru

bber

Com

para

tor

PDT

with

red

LED

: See

ab

ove

Mor

bidi

ty A

t 3

mth

the

abs

olut

e de

crea

se in

the

m

ean

num

ber

of le

sion

s co

mpa

red

to b

asel

ine

was

8.0

(71

%)

in t

he L

ED a

reas

vs

8.4

(79%

) in

the

da

ylig

ht a

reas

(p

= 0.

13 fo

r pe

rcen

tage

, p =

0.5

0 fo

r m

ean

num

ber)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Eigh

teen

pa

tient

s (6

2%)

pref

erre

d th

e da

ylig

ht t

reat

men

t, fo

ur (

14%

) LE

D t

reat

men

t, an

d si

x (2

1%)

had

no

pref

eren

ceA

Es A

naly

ses

base

d on

24

patie

nts:

The

day

light

are

as

wer

e si

gnifi

cant

ly le

ss p

ainf

ul o

n a

10-p

oint

VA

S sc

ale

than

the

LED

are

as (

mea

n m

axim

al p

ain

scor

e, 2

.0

for

dayl

ight

vs

6.7

for

LED

, p <

0.0

001)

. In

the

LED

lig

ht g

roup

, 15

patie

nts

need

ed c

old

wat

er s

pray

to

mak

e pa

in t

oler

able

, and

one

-hal

f of t

hese

pat

ient

s ne

eded

one

or

two

brea

ks d

urin

g ill

umin

atio

n. In

tw

o pa

tient

s th

is w

as n

ot e

noug

h, s

o tr

eatm

ents

wer

e st

oppe

d af

ter

one-

third

of i

llum

inat

ion

time.

Pai

n sc

ores

6 h

r af

ter

LED

tre

atm

ent

wer

e no

t si

gnifi

cant

ly

diffe

rent

(m

ean

max

imal

sco

re o

f 1 fo

r da

ylig

ht v

s 1.

3 fo

r LE

D, p

= 0

.14)

. Bot

h ar

eas

deve

lope

d er

ythe

ma

and

crus

ting

afte

r tr

eatm

ent.

The

se A

Es w

ere

mos

t se

vere

in t

he d

aylig

ht a

rea

in 1

0 pa

tient

s (4

2%),

in

the

LED

are

a in

five

pat

ient

s (2

1%)

and

ther

e w

as n

o di

ffere

nce

betw

een

the

area

s in

nin

e pa

tient

s (3

8%)

Aut

hors

’ co

nclu

sion

s C

ontin

uous

act

ivat

ion

PDT

usi

ng d

aylig

ht

expo

sure

was

as

effe

ctiv

e as

, and

be

tter

tol

erat

ed t

han,

co

nven

tiona

l PD

TB

rief

stu

dy

appr

aisa

l Thi

s w

as

a ge

nera

lly w

ell

cond

ucte

d bu

t sm

all

stud

y an

d th

e re

sults

ap

pear

like

ly t

o be

re

liabl

e. It

sho

uld

be n

oted

tho

ugh

that

six

pat

ient

s ha

d pr

evio

usly

rec

eive

d PD

T in

the

tre

ated

ar

eas

(alth

ough

mor

e th

an 1

yr b

efor

e th

e st

udy)

, and

tha

t th

e LE

D il

lum

inat

ion

time

was

not

cle

arly

sta

ted



215

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Wie

gell

et a

l. (20

08)40

Dat

a so

urce

Abs

trac

tC

ount

ry D

enm

ark

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

29In

terv

entio

n: 2

9C

ompa

rato

r: 29

No.

of r

ecru

itin

g ce

ntre

s N

ot

stat

edFo

llow

-up

peri

od a

nd

freq

uenc

y FU

at

3 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on a

nd h

isto

logy

A

KM

ain

elig

ibili

ty c

rite

ria

Patie

nts

with

AK

of t

he fa

ce a

nd s

calp

Pati

ent

char

acte

rist

ics

Not

sta

ted

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

PD

T w

ith

8% M

AL

vs P

DT

with

16%

MA

L (w

ithin

-par

ticip

ant

com

pari

son)

Inte

rven

tion

PD

T 8

% M

AL:

Pa

tient

s w

ere

give

n bo

th

trea

tmen

ts, r

ando

mis

ed t

o tw

o sy

mm

etri

c ar

eas,

one

area

was

gi

ven

8% M

AL

crea

m a

nd t

he

othe

r 16

% M

AL

crea

m. P

atie

nts

wer

e se

nt h

ome

and

inst

ruct

ed

to s

pend

as

muc

h tim

e as

po

ssib

le o

utsi

de, i

n da

ylig

ht.

Patie

nts

spen

t an

ave

rage

of

210

min

out

door

s (r

ange

62

–372

min

). Li

ght

expo

sure

was

m

easu

red

usin

g an

ele

ctro

nic

dosi

met

er w

atch

Com

para

tor

PDT

16%

MA

L:

See

abov

e

Mor

bidi

ty A

t 3

mth

, the

re w

as

no s

igni

fican

t di

ffere

nce

in C

R

rate

(77

% in

16%

are

a vs

80%

in

8% a

rea)

, p =

0.3

7Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty N

ot a

sses

sed

AE

s Er

ythe

ma

and

crus

ting

occu

rred

in b

oth

trea

tmen

ts (a

nd

wer

e si

mila

r to

infla

mm

atio

n se

en a

fter

conv

entio

nal P

DT

). Pa

in d

iari

es w

ere

used

but

not

re

port

ed b

y in

terv

entio

n ar

m

Aut

hors

’ con

clus

ions

PD

T

usin

g da

ylig

ht a

ctiv

atio

n w

ill

mak

e A

K t

reat

men

t m

ore

time

and

cost

-effe

ctiv

e, a

nd m

ore

conv

enie

nt fo

r th

e pa

tient

Bri

ef s

tudy

app

rais

al T

he

auth

ors

com

pare

d ov

eral

l pai

n sc

ores

, and

AEs

in a

sm

all s

ampl

e,

with

tho

se s

een

in c

onve

ntio

nal

PDT,

but

usin

g a

com

para

tor

trea

tmen

t of

con

vent

iona

l PD

T

in t

his

stud

y w

ould

hav

e be

en

muc

h m

ore

info

rmat

ive.

Thi

s ab

stra

ct a

lso

feat

ured

min

imal

re

port

ing

of m

etho

ds a

nd r

esul

ts



217



217

Appendix 14 Bowen’s disease data extraction

Appendix 14

218



219Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

de

Haa

s et

al

. (20

07)69

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry T

he

Net

herl

ands

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

40 (

50 B

owen

’s di

seas

e pa

tche

s)In

terv

entio

n: 2

5 le

sion

s (p

artic

ipan

t no

. no

t st

ated

)C

ompa

rato

r: 25

le

sion

s (p

artic

ipan

t no

. no

t st

ated

)N

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

4 w

k, th

en a

t 3

mth

inte

rval

s up

to

28 m

th

Type

(s)

of le

sion

an

d hi

stol

ogy

Bow

en’s

dise

ase

Mai

n el

igib

ility

cr

iter

ia N

ot s

tate

dPa

tien

t ch

arac

teri

stic

s%

Mal

e: 43

Age

ran

ge: 4

9–91

yr

Mea

n ag

e: 74

yrM

ean

lesi

on d

iam

eter

: 14

.5 m

m (

rang

e 5–

40 m

m)

Loca

tions

: Tru

nk 1

2,

low

er le

g 11

, han

d 8,

ear

7, u

pper

leg

4,

chee

k an

d/or

nos

e 3,

ey

elid

2, a

rm 1

, fro

ntal

an

d/or

tem

pora

l are

a 1,

sca

lp 1

The

sam

ple

incl

uded

se

ven

orga

n re

cipi

ents

Con

com

itan

t tr

eatm

ent

Lido

cain

e,

2% w

ithou

t ad

rena

line

was

use

d if

patie

nts

requ

ired

it

Tria

l tre

atm

ents

ALA

–PD

T u

sing

a

sing

le il

lum

inat

ion

vs A

LA–P

DT

with

a

twof

old

illum

inat

ion

Inte

rven

tion

Sin

gle

Illum

inat

ion:

Sur

face

sc

ale

or c

rust

s w

ere

rem

oved

. 20%

ALA

, lo

cally

pro

duce

d, w

as a

pplie

d to

pica

lly a

nd

left

in p

lace

for

4 hr

with

a m

argi

n of

1 cm

. A

dio

de la

ser

and

light

em

ittin

g di

ode

prov

ided

illu

min

atio

n at

a w

avel

engt

h of

63

0 nm

, 4 h

r af

ter A

LA a

pplic

atio

n at

a

dose

of 7

5 J/c

m2

Furt

her

PDT

par

amet

ers

wer

e no

t re

port

edC

ompa

rato

r Tw

ofol

d ill

umin

atio

n: A

s fo

r si

ngle

illu

min

atio

n ex

cept

pat

ches

w

ere

light

tre

ated

4 a

nd 6

hr

afte

r ALA

ap

plic

atio

n at

dos

es o

f 20

and

80 J/

cm2 ,

resp

ectiv

ely,

sepa

rate

d by

a 2

-hr

dark

in

terv

al. E

ach

illum

inat

ion

was

del

iver

ed a

t 50

mW

/cm

2

Mor

bidi

ty In

the

sin

gle

illum

inat

ion

grou

p, C

R w

as s

een

in 2

2 pa

tche

s (8

0%)

at 1

2 m

th. I

n th

e tw

ofol

d-ill

umin

atio

n gr

oup

CR

was

see

n in

22

patc

hes

(88%

) (N

S). P

atie

nts

repo

rted

a 3

-wk

max

imum

he

alin

g tim

e, w

hich

was

not

diff

eren

t be

twee

n tr

eatm

ents

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

ass

esse

dA

Es A

ll pa

tient

s in

bot

h gr

oups

ex

peri

ence

d so

me

disc

omfo

rt d

urin

g tr

eatm

ent

but

all fi

nish

ed t

hera

py. N

o SA

Es w

ere

seen

in e

ither

gro

up. I

n th

e si

ngle

-illu

min

atio

n gr

oup

none

of t

he

patie

nts

com

plai

ned

of p

ain

duri

ng

trea

tmen

t. In

the

tw

ofol

d-ill

umin

atio

n gr

oup

five

patie

nts

com

plai

ned

abou

t pa

in

in t

he t

reat

men

t of

six

pat

ches

. Lid

ocai

ne

with

out

adre

nalin

e w

as u

sed

in fo

ur

patc

hes

Aut

hors

’ con

clus

ions

ALA

–PD

T

may

offe

r th

e be

st t

reat

men

t op

tion

for

Bow

en’s

dise

ase.

Thi

s st

udy

show

s th

e po

tent

ial o

f lig

ht fr

actio

natio

n fo

r en

hanc

ing

the

resp

onse

of t

he d

isea

se t

o A

LA–P

DT

and

illu

stra

tes

the

need

for

a la

rger

, sui

tabl

y po

wer

ed t

rial

to

dete

rmin

e if

the

effe

ct is

sta

tistic

ally

sig

nific

ant

Bri

ef s

tudy

app

rais

al T

his

was

a

smal

l tri

al w

ith u

ncle

ar m

etho

ds o

f ra

ndom

isat

ion

and

blin

ding

. Tre

atm

ent

met

hods

wer

e re

port

ed b

ut n

ot a

ll ou

tcom

es w

ere

deta

iled.

Thi

s st

udy

show

s th

e po

tent

ial o

f PD

T a

nd it

s en

hanc

emen

t th

roug

h lig

ht fr

actio

natio

n bu

t w

ould

nee

d co

nfirm

atio

n, a

s th

e au

thor

s st

ate,

in a

n ad

equa

tely

pow

ered

tri

al

Appendix 14

218



219

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Lui

et a

l. (20

04)68

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ries

Can

ada,

USA

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

Not

sta

ted

by

diag

nosi

s (3

4 le

sion

s)In

terv

entio

n: N

ot s

tate

d by

dia

gnos

is (

27 le

sion

s)C

ompa

rato

r: N

ot s

tate

d by

dia

gnos

is (

one

lesi

on)

2nd

Com

para

tor:

Not

st

ated

by

diag

nosi

s (s

ix

lesi

ons)

No.

of r

ecru

itin

g ce

ntre

s Fo

urFo

llow

-up

peri

od a

nd

freq

uenc

y 6

wk,

and

3, 6

, 12

, 18

and

24 m

th

Type

(s)

of le

sion

and

hi

stol

ogy

Supe

rfici

al

BCC

, 277

lesi

ons

(66%

); nB

CC

, 93

lesi

ons

(22%

); Bo

wen

’s di

seas

e,

34 le

sion

s (8

%);

BCC

un

spec

ified

17

lesi

ons

(4%

)M

ain

elig

ibili

ty

crit

eria

Pat

ient

s w

ith

at le

ast

two

biop

sy-

prov

en s

uper

ficia

l or

nBC

C o

r Bo

wen

’s le

sion

sPa

tien

t ch

arac

teri

stic

s N

ot

stat

ed fo

r Bo

wen

’s gr

oup

Con

com

itan

t tr

eatm

ent

Ora

l an

alge

sics

for

pain

Tria

l tre

atm

ents

PD

T a

t 60

J/cm

2 vs

PDT

at

120

J/cm

2 vs

PDT

at

180

J/cm

2

Inte

rven

tion

PD

T a

t 60

J/cm

2 : 10

min

intr

aven

ous

infu

sion

of

14 m

g/m

2 ver

tepo

rfin

follo

wed

1–3

hr

late

r by

exp

osur

e to

60

J/cm

2 of

red

light

(68

8 ±

10 n

m)

from

a n

on-

ther

mal

LED

pan

el. T

he e

xpos

ed a

rea

had

a m

argi

n of

3–4

mm

aro

und

the

lesi

on. T

he ir

radi

ance

del

iver

ed w

as

200

± 40

mW

/cm

2 . Tum

ours

re-

trea

ted

at

3 m

th if

nec

essa

ry (

with

dos

e in

crea

sed

to 1

8 m

g/m

2 )C

ompa

rato

r PD

T a

t 12

0 J/c

m2 :

See

abov

e2n

d co

mpa

rato

r PD

T a

t 18

0 J/c

m2 :

See

abov

e

Mor

bidi

ty A

t 6

mth

, the

hi

stop

atho

logi

cal r

espo

nse

(i.e.

no

resi

dual

tum

our)

was

85%

at

60 J/

cm2 ,

100%

at

120

J/cm

2 , an

d 50

% a

t 18

0 J/c

m2

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Ass

esse

d bu

t no

t re

port

ed fo

r Bo

wen

’s gr

oup

AE

s Ass

esse

d bu

t no

t re

port

ed fo

r Bo

wen

’s gr

oup

Aut

hors

’ con

clus

ions

A s

ingl

e co

urse

of

ver

tepo

rfin

PDT

sho

wed

tre

atm

ent

bene

fit fo

r pa

tient

s w

ith m

ultip

le n

on-

mel

anom

a sk

in c

ance

rsB

rief

stu

dy a

ppra

isal

The

re w

as a

la

ck o

f inf

orm

atio

n on

issu

es s

uch

as

blin

ding

and

allo

catio

n co

ncea

lmen

t, an

d th

e au

thor

s di

d no

t pr

esen

t m

any

resu

lts a

nd p

opul

atio

n de

tails

by

diag

nosi

s. It

is t

here

fore

diffi

cult

to

mak

e an

y re

liabl

e co

nclu

sion

s ab

out

the

effic

acy

of v

erte

porfi

n in

pat

ient

s w

ith

Bow

en’s

dise

ase,

par

ticul

arly

as

they

fo

rmed

a s

mal

l pro

port

ion

of t

he o

vera

ll nu

mbe

r of

lesi

ons

Appendix 14

220



221Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mor

ton

et a

l. (2

000)

70

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 19

(70

lesi

ons)

ra

ndom

ised

16

(61

lesi

ons)

follo

wed

up

Inte

rven

tion:

32

lesi

ons

(no

of p

atie

nts

not

spec

ified

)C

ompa

rato

r: 29

lesi

ons

(no

of p

atie

nts

not

spec

ified

)N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

an

d fr

eque

ncy

Afte

r cl

eara

nce,

all

patie

nts

wer

e re

view

ed a

t m

onth

ly

inte

rval

s, up

to

12 m

th

Type

(s)

of le

sion

and

hi

stol

ogy

Bow

en’s

dise

ase

Mai

n el

igib

ility

cri

teri

a Bi

opsy

-pro

ven

dise

ase

with

indi

vidu

al le

sion

s of

≤2

1 m

m in

dia

met

er. N

o le

sion

had

bee

n pr

evio

usly

tr

eate

dPa

tien

t ch

arac

teri

stic

s A

ge r

ange

: 50–

87 yr

Mea

n ag

e: 73

yrN

o. o

f les

ions

per

pat

ient

va

ried

bet

wee

n on

e an

d si

x (m

edia

n th

ree)

Con

com

itan

t tr

eatm

ent

Loca

l an

aest

hetic

(1%

pla

in

lidoc

aine

by

intr

ader

mal

in

ject

ion)

was

offe

red

duri

ng P

DT

tre

atm

ent

Tria

l tre

atm

ents

ALA

–PD

T w

ith r

ed li

ght

vs A

LA–P

DT

with

gre

en li

ght

Inte

rven

tion

Red

ligh

t: Su

rfac

e cr

usts

wer

e re

mov

ed a

nd t

he s

urfa

ce w

as g

ently

abr

aded

. To

pica

l ALA

in a

n oi

l-in-

wat

er e

mul

sion

was

ap

plie

d to

the

lesi

ons

4 h

pre-

illum

inat

ion.

A

ppro

xim

atel

y 50

mg/

cm2 o

f cre

am

was

app

lied

to c

over

the

ent

ire fi

eld

of

illum

inat

ion,

incl

udin

g a

clin

ical

ly d

isea

se-fr

ee

mar

gin

of a

t le

ast

4 m

m. T

he c

ream

was

kep

t in

pla

ce u

nder

an

occl

usiv

e dr

essi

ngA

‘Pat

erso

n’ la

mp

with

300

W x

enon

sho

rt

arc

plas

ma

disc

harg

e w

as a

djus

ted

usin

g ap

prop

riat

e fil

ters

to

630

± 15

nm

for

red

light

. At

a flu

ence

rat

e of

86

mW

/cm

2 les

ions

re

ceiv

ed 1

25 J/

cm2 o

f red

ligh

tA

rep

eat

trea

tmen

t w

as g

iven

afte

r 2

mth

if

nece

ssar

yC

ompa

rato

r As

for

red

light

exc

ept

a w

avel

engt

h of

540

± 1

5 nm

was

use

d to

de

liver

62.

5 J/c

m2 o

f lig

ht

Mor

bidi

ty In

the

red

ligh

t gr

oup

24 le

sion

s cl

eare

d fo

llow

ing

one

trea

tmen

t an

d a

furt

her

six

afte

r a

repe

at t

reat

men

t gi

ving

an

initi

al

resp

onse

rat

e of

94%

. Eig

htee

n le

sion

s tr

eate

d us

ing

gree

n lig

ht c

lear

ed a

fter

one

trea

tmen

t w

ith a

furt

her

thre

e cl

eari

ng o

n re

peat

giv

ing

an

initi

al r

espo

nse

of 7

2%. D

iffer

ence

in r

espo

nse

was

sta

tistic

ally

sig

nific

ant

(p =

0.0

02).

A h

igh

recu

rren

ce r

ate

was

obs

erve

d in

the

gre

en li

ght

grou

p w

ith s

even

rec

urre

nces

in c

ompa

riso

n w

ith t

wo

lesi

ons

rela

psin

g af

ter

PDT

with

red

lig

ht. O

R fo

r re

curr

ence

= 0

.13

(95%

CI 0

.04

to

0.48

)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

o cl

inic

ally

obv

ious

sca

rs w

ere

evid

ent

at 1

yr in

ei

ther

gro

upA

Es

No

ulce

ratio

n or

infe

ctio

n co

mpl

icat

ing

ther

apy

and

no p

hoto

sens

itivi

ty r

eact

ions

wer

e do

cum

ente

d af

ter

PDT

tre

atm

ent

in e

ither

gr

oup.

No

sign

ifica

nt d

iffer

ence

in p

ain

was

see

n be

twee

n th

e tr

eatm

ent

grou

ps. N

o re

d lig

ht

patie

nts

need

ed a

naes

thes

ia w

here

as t

wo

lesi

ons

(one

pat

ient

) tr

eate

d in

the

gre

en li

ght

grou

p ne

eded

ana

esth

esia

Twel

ve p

atie

nts

rece

ived

bot

h ty

pes

of li

ght.

Four

st

ated

tha

t gr

een

light

was

the

mos

t pa

infu

l, si

x th

at r

ed li

ght

was

the

mos

t pa

infu

l, w

hile

tw

o pa

tient

s co

uld

not

dist

ingu

ish

betw

een

the

light

us

ed

Aut

hors

’ con

clus

ions

G

reen

ligh

t is

less

ef

fect

ive

than

red

ligh

t in

th

e tr

eatm

ent

of B

owen

’s di

seas

e by

ALA

–PD

TB

rief

stu

dy a

ppra

isal

A

sm

all s

tudy

, with

un

clea

r m

etho

ds o

f ra

ndom

isat

ion,

allo

catio

n co

ncea

lmen

t an

d bl

indi

ng

of o

utco

me

asse

ssor

s

Appendix 14

220



221Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mor

ton

et a

l. (1

996)

71

Link

ed p

ublic

atio

ns17

9

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 19

(40

lesi

ons)

In

terv

entio

n: 2

0 le

sion

s, pa

rtic

ipan

t no

. not

st

ated

Com

para

tor:

20 le

sion

s, pa

rtic

ipan

t no

. not

st

ated

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od

and

freq

uenc

y 2

d an

d 10

d fo

r AEs

. 2-m

onth

ly

inte

rval

s fo

r cl

inic

al

resp

onse

. Fol

low

ing

clea

ranc

e, 2

-mon

thly

in

terv

als

for

12 m

th fo

r re

curr

ence

and

late

AEs

Mai

n el

igib

ility

cr

iter

ia H

isto

logi

cal

confi

rmat

ion

of

Bow

en’s

with

in

divi

dual

lesi

ons

≤ 21

mm

in d

iam

eter

. N

o le

sion

had

bee

n pr

evio

usly

tre

ated

Pati

ent

char

acte

rist

ics

% M

ale:

16A

ge r

ange

: 62–

88 yr

Mea

n ag

e: 76

yrLo

catio

n an

d no

. of

lesi

ons:

legs

33,

face

fiv

e, h

and

two

Con

com

itan

t tr

eatm

ent

Patie

nts

wer

e of

fere

d lo

cal

anae

sthe

tic (

1%

plai

n lid

ocai

ne b

y in

trad

erm

al in

ject

ion)

du

ring

tre

atm

ent

Tria

l tre

atm

ents

PD

T w

ith A

LA v

s C

ryot

hera

pyIn

terv

enti

on P

DT:

Sur

face

cru

sts

wer

e re

mov

ed a

nd t

he s

urfa

ce g

ently

abr

aded

pri

or

to a

pplic

atio

n w

ith t

opic

al 5

-ALA

in a

n oi

l-in-

wat

er e

mul

sion

20%

. App

roxi

mat

ely

50 m

g/cm

2 of

crea

m w

as a

pplie

d to

cov

er t

he e

ntire

irra

diat

ion

field

incl

udin

g th

e cl

inic

ally

dis

ease

-free

mar

gin.

T

he c

ream

was

kep

t in

pla

ce u

nder

an

occl

usiv

e dr

essi

ngFo

ur h

ours

late

r le

sion

s w

ere

illum

inat

ed w

ith a

pr

otot

ype

lam

p. T

he la

mp

inco

rpor

ated

a 3

00 W

xe

non

shor

t ar

c pl

asm

a di

scha

rge

prod

ucin

g a

cont

inuo

us w

ave

broa

dban

d fla

t sp

ectr

al o

utpu

t ac

ross

the

ent

ire v

isib

le s

pect

rum

. Usi

ng fi

lters

, th

e sp

ectr

al o

utpu

t of

the

lam

p w

as a

djus

ted

to

a 30

-nm

ban

dwid

th, a

bout

630

nm

. To

broa

den

the

trea

tmen

t fie

ld a

nd t

o pr

oduc

e un

iform

ir

radi

atio

n of

the

lesi

ons,

a 25

-mm

col

limat

ing

lens

was

att

ache

d to

the

5-m

m fi

bre

bund

le.

Allo

win

g at

leas

t a

10%

mar

gin

arou

nd le

sion

s in

th

e fie

ld o

f irr

adia

tion

perm

itted

the

tre

atm

ent

of le

sion

s ≤

21 m

m in

dia

met

er, a

t a

fluen

ce r

ate

of 7

0 m

W/c

m2 a

nd a

tre

atm

ent

time

of 3

0 m

in,

lesi

ons

rece

ived

125

J/cm

2 . Fo

llow

ing

ther

apy,

3-m

m p

unch

bio

psie

s w

ere

perf

orm

ed in

lesi

ons

whe

re t

here

was

dou

bt o

ver

clin

ical

cle

aran

ce o

r re

curr

ence

. Rep

eat

trea

tmen

ts w

ere

adm

inis

tere

d if

lesi

ons

pers

iste

dC

ompa

rato

r C

ryot

hera

py: L

iqui

d ni

trog

en

was

app

lied

to le

sion

s vi

a a

hand

-hel

d C

ry-A

c sp

ray.

Afte

r in

itial

ice

field

form

atio

n, t

he fr

eeze

w

as m

aint

aine

d fo

r 20

s. A

sin

gle

free

ze–t

haw

cy

cle

tech

niqu

e w

as u

sed

with

a 2

–3 m

m r

im o

f cl

inic

ally

hea

lthy

tissu

e in

clud

ed in

the

tre

atm

ent

field

. Fol

low

ing

ther

apy,

3-m

m p

unch

bio

psie

s w

ere

perf

orm

ed in

lesi

ons

whe

re t

here

was

do

ubt

over

clin

ical

cle

aran

ce o

r re

curr

ence

. R

epea

t tr

eatm

ents

wer

e ad

min

iste

red

if le

sion

s pe

rsis

ted

Mor

bidi

tyC

lear

ance

afte

r on

e tr

eatm

ent:

PDT,

15 o

f 20

lesi

ons;

cryo

ther

apy,

10 o

f 20

lesi

ons

Cle

aran

ce a

fter

two

trea

tmen

ts: P

DT,

five

rem

aini

ng le

sion

s; cr

yoth

erap

y, si

x le

sion

s T

he r

emai

ning

four

lesi

ons

in t

he c

ryot

hera

py

grou

p re

quire

d a

third

tre

atm

ent.

The

re w

as

no s

igni

fican

t di

ffere

nce

betw

een

the

two

trea

tmen

ts in

cle

aran

ce r

ates

. How

ever

, by

chan

ce le

sion

s tr

eate

d by

PD

T w

ere

over

all

larg

er t

han

thos

e in

the

cry

othe

rapy

gro

up. I

n a

linea

r re

gres

sion

mod

el t

akin

g si

ze o

f les

ion

into

acc

ount

, the

pro

babi

lity

that

a le

sion

of a

ny

size

is c

ompl

etel

y cl

eare

d at

the

1st

tre

atm

ent

was

sig

nific

antly

gre

ater

with

PD

T t

han

with

cr

yoth

erap

y (p

< 0

.01)

. Rec

urre

nce

Rat

e du

ring

12

-mth

follo

win

g cl

inic

al c

lear

ance

: PD

T z

ero;

cr

yoth

erap

y tw

o (6

mth

and

8 m

th).

CR

rat

e w

as, t

here

fore

, 100

% fo

r PD

T a

nd 9

0% fo

r cr

yoth

erap

yQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y V

isib

le

scar

ring

12

mth

follo

win

g cl

eara

nce

(no.

of

lesi

ons)

: PD

T z

ero,

cry

othe

rapy

four

AE

s Pa

in d

urin

g tr

eatm

ent

(no.

of l

esio

ns):

PDT,

six

mild

and

five

mod

erat

e; c

ryot

hera

py, 1

2 m

ild

and

seve

n m

oder

ate

(p =

0.0

1). F

ree

from

pai

n 10

d fo

llow

ing

trea

tmen

t (n

o. o

f les

ions

): PD

T

15; c

ryot

hera

py 1

0A

ll si

x pa

tient

s w

ho r

ecei

ved

both

tre

atm

ents

, du

e to

hav

ing

mul

tiple

lesi

ons,

repo

rted

PD

T a

s le

ss p

ainf

ul. B

liste

ring

(no

. of l

esio

ns):

PDT

zer

o;

cryo

ther

apy

seve

n. U

lcer

atio

n (n

o. o

f les

ions

): PD

T z

ero;

cry

othe

rapy

five

. Sec

onda

ry in

fect

ion

(no.

of l

esio

ns):

PDT

zer

o; c

ryot

hera

py t

wo.

No

phot

osen

sitiv

ity r

eact

ions

occ

urre

d af

ter

PDT

Aut

hors

’ con

clus

ions

PD

T is

at

leas

t as

effe

ctiv

e as

cry

othe

rapy

in t

he

trea

tmen

t of

Bow

en’s

dise

ase

and

was

ass

ocia

ted

in t

his

stud

y w

ith fe

wer

AEs

an

d a

low

er r

ecur

renc

e ra

teB

rief

stu

dy a

ppra

isal

T

his

was

a s

mal

l tri

al u

sing

a

prot

otyp

e la

mp

as a

lig

ht s

ourc

e. R

esul

ts w

ere

repo

rted

by

lesi

on r

athe

r th

an b

y pa

tient

. By

chan

ce

lesi

ons

wer

e si

gnifi

cant

ly

larg

er in

the

PD

T g

roup

but

th

is w

as t

aken

into

acc

ount

w

hen

asse

ssin

g cl

eara

nce

rate

s. T

he r

esul

ts o

f the

tri

al

are

prom

isin

g bu

t w

ould

re

quire

con

firm

atio

n in

la

rger

tri

als

Appendix 14

222



223Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mor

ton

et a

l. (2

006)

73

Link

ed p

ublic

atio

ns18

0–18

4

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ries

Not

sta

ted,

11

Eur

opea

n co

untr

ies

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

229

rand

omis

ed,

225

trea

ted

(275

le

sion

s)In

terv

entio

n: 9

6 (1

24

lesi

ons)

Com

para

tor:

17 (

24

lesi

ons)

2nd

Com

para

tor:

82 (

91

lesi

ons)

3rd

Com

para

tor:

30 (

36

lesi

ons)

No.

of r

ecru

itin

g ce

ntre

s 40

Follo

w-u

p pe

riod

an

d fr

eque

ncy

3, 1

2 an

d 24

mth

afte

r la

st

trea

tmen

t

Type

(s)

of le

sion

and

hi

stol

ogy

Bow

en’s

dise

ase

Mai

n el

igib

ility

cri

teri

a In

clus

ion

crite

ria:

Patie

nts

18 yr

or

olde

r w

ith

hist

olog

ical

ly c

onfir

med

di

agno

sis

of S

CC

in s

itu

from

a b

iops

y sp

ecim

en

take

n w

ithin

the

last

5 m

th

and

with

no

evid

ence

of

any

chan

ge in

app

eara

nce

sugg

estiv

e of

lesi

on

prog

ress

ion

Lesi

ons

that

had

bee

n tr

eate

d w

ithin

the

pre

viou

s 3

mth

or

that

wer

e st

rong

ly

pigm

ente

d, le

ss t

han

6 m

m

or m

ore

than

40

mm

in

diam

eter

or

loca

ted

on t

he

geni

talia

wer

e ex

clud

edPa

tien

t ch

arac

teri

stic

s Fo

r th

e tr

eate

d pa

tient

s:%

Mal

e: 39

Age

ran

ge: 3

9–99

yrM

ean

age:

73 yr

Loca

tion

of le

sion

(no

. of

lesi

ons)

: fac

e (s

calp

) 68

, ne

ck, t

runk

34,

ext

rem

ities

17

3C

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

MA

L–PD

T v

s Pl

aceb

o PD

T

vs C

ryot

hera

py v

s 5-

FUIn

terv

enti

on M

AL–

PDT:

Les

ions

wer

e pr

epar

ed b

y ge

ntle

sur

face

deb

ride

men

t w

ith

a cu

rett

e. 1

60 m

g/g

of t

opic

al M

AL

crea

m w

as

appl

ied

to t

he le

sion

s. It

rem

aine

d on

the

ski

n fo

r 3

hr t

hen

was

was

hed

off w

ith 0

.9%

sal

ine

solu

tion

befo

re il

lum

inat

ion

with

non

-coh

eren

t re

d lig

ht. W

avel

engt

h w

as 5

70–6

70 n

m, l

ight

do

se w

as 7

5 J/c

m2 .

Mea

n ill

umin

atio

n tim

e w

as

10 m

in 3

7 s.

Trea

tmen

t w

as r

epea

ted

once

afte

r 1

wk

for

a co

mpl

ete

trea

tmen

t cy

cle.

Les

ions

w

ith a

PR

at

12 w

k w

ere

re-t

reat

edC

ompa

rato

r Pl

aceb

o cr

eam

: As

for

MA

L–PD

T. Le

sion

s w

ith a

PR

at

12 w

k w

ere

re-

trea

ted

2nd

com

para

tor

Cry

othe

rapy

: A h

andh

eld

liqui

d ni

trog

en s

pray

was

use

d in

a s

ingl

e fr

eeze

–tha

w c

ycle

. Afte

r an

initi

al ic

e fie

ld

form

atio

n w

ith a

2-m

m r

im o

f clin

ical

ly h

ealth

y tis

sue,

the

ice

field

was

mai

ntai

ned

for

a m

inim

um o

f 20

s. M

ean

tota

l fre

ezin

g tim

e w

as

25 s

Lesi

ons

with

a P

R a

t 12

wk

wer

e re

-tre

ated

3rd

com

para

tor

5-FU

: Top

ical

5%

5-F

U

crea

m w

as a

pplie

d fo

r 4

wk,

once

dai

ly d

urin

g th

e 1s

t w

eek,

and

twic

e da

ily t

here

afte

r. M

ean

num

ber

of a

pplic

atio

ns w

as 4

2 an

d 45

in t

he

1st

and

2nd

trea

tmen

ts, r

espe

ctiv

ely.

Lesi

ons

with

a P

R a

t 12

wk

wer

e re

-tre

ated

Mor

bidi

ty C

R r

ate

at 3

mth

: PD

T, 10

3/11

1 (9

3%);

Plac

ebo,

4/1

9 (2

1%);

Cry

othe

rapy

, 73/

85 (

86%

), an

d 5-

FU

24/2

9, (

83%

). 12

-mth

rec

urre

nce

rate

: PD

T, 15

%; P

lace

bo, n

ot s

tate

d;

Cry

othe

rapy

, 24%

and

5-F

U, 2

1%.

Estim

ated

sus

tain

ed C

R r

ate

at

12 m

th: P

DT,

80%

; Pla

cebo

, not

st

ated

; cry

othe

rapy

, 67%

; 5-F

U, 6

9%.

The

re w

as a

sta

tistic

ally

sig

nific

ant

diffe

renc

e be

twee

n M

AL–

PDT

an

d co

mbi

ned

stan

dard

the

rapy

(O

R =

1.7

3; 9

5% C

I 1.0

3 to

2.9

3).

MA

L–PD

T w

as s

igni

fican

tly d

iffer

ent

from

cry

othe

rapy

(O

R =

1.7

7 to

1.0

1,

3.12

). Es

timat

ed s

usta

ined

CR

rat

e at

24

mth

: PD

T, 68

%; p

lace

bo, 1

1%;

cryo

ther

apy,

60%

; 5-F

U, 5

9%Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty G

ood

or e

xcel

lent

cos

met

ic

outc

ome

at 3

mth

: PD

T, 77

/82

(94%

); cr

yoth

erap

y, 43

/65

(66%

); 5-

FU, 1

6/21

(7

6%). T

his

was

mai

ntai

ned

at 1

2 m

thA

Es

SAEs

: PD

T, 6%

, cry

othe

rapy

, 12%

. SA

Es (

incl

udin

g fo

ur d

eath

s) w

ere

repo

rted

. PD

T, fo

ur p

atie

nts;

plac

ebo

crea

m, t

wo

patie

nts;

cryo

ther

apy,

thre

e pa

tient

s

Aut

hors

’ con

clus

ions

MA

L–PD

T

is a

n ef

fect

ive

trea

tmen

t op

tion

for

Bow

en’s

dise

ase

with

exc

elle

nt

cosm

etic

out

com

eB

rief

stu

dy a

ppra

isal

The

au

thor

s’ c

oncl

usio

ns a

ppea

r ap

prop

riat

e, a

lthou

gh m

itiga

ting

fact

ors

incl

ude

the

fact

tha

t 11

%

of t

reat

ed le

sion

s w

ere

excl

uded

fr

om t

he p

er-p

roto

col p

opul

atio

n,

the

lack

of r

epor

ting

on m

etho

ds

of r

ando

mis

atio

n an

d al

loca

tion

conc

ealm

ent,

and

the

poss

ibili

ty

of in

stitu

tiona

l diff

eren

ces

and

prot

ocol

dev

iatio

n (4

0 ce

ntre

s in

11

cou

ntri

es)

affe

ctin

g re

sults

Appendix 14

222



223Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Pui

zina

-Iv

ic e

t al. (

2008

)57

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry C

roat

iaLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of

part

icip

ants

Tota

l: 15

Inte

rven

tion:

Nin

eC

ompa

rato

r: Si

xN

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

24 w

k

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

lesi

on

and

hist

olog

y Bo

wen

’s di

seas

eM

ain

elig

ibili

ty

crit

eria

Pre

viou

s hi

stol

ogic

ally

co

nfirm

ed d

iagn

osis

of

Bow

en’s

dise

ase

Pati

ent

char

acte

rist

ics

Not

st

ated

Tria

l tre

atm

ents

ALA

–PD

T w

ith 1

6-hr

incu

batio

n an

d tw

o lig

ht fr

actio

ns v

s ALA

–PD

T w

ith 5

-hr

incu

batio

n an

d a

sing

le

illum

inat

ion

Inte

rven

tion

ALA

–PD

T w

ith 1

6-hr

incu

batio

n an

d tw

o lig

ht

frac

tions

: Thi

ck c

rust

s w

ere

1st

rem

oved

with

oin

tmen

ts (

and

wet

dre

ssin

gs).

Afte

r cl

eani

ng t

he a

rea

with

a s

alin

e so

lutio

n, t

he

20%

ALA

cre

am w

as a

pplie

d to

a t

hick

ness

of a

ppro

xim

atel

y 1

mm

, cov

erin

g th

e tr

eate

d ar

ea a

nd 1

cm o

f the

sur

roun

ding

sk

in. T

he a

rea

was

cov

ered

by

occl

usiv

e dr

essi

ng. A

lum

iniu

m

foil

was

pla

ced

on t

op in

ord

er t

o pr

otec

t sk

in fr

om a

mbi

ent

light

. The

re w

as t

hen

a 16

-hr

incu

batio

n pe

riod

bef

ore

red

light

(6

35 n

m)

was

app

lied.

The

tot

al o

f 100

J/cm

2 was

del

iver

ed in

tw

o do

ses

of 5

0 J/c

m2 w

ith a

flue

nce

inte

nsity

of 3

0 m

W/c

m2 . T

here

w

as a

2-h

r br

eak

betw

een

illum

inat

ions

. Spr

ayin

g of

wat

er a

nd

cool

ing

with

fan

was

don

e to

min

imis

e pa

in s

ensa

tions

. Afte

r th

e tr

eatm

ents

sun

bloc

k oi

ntm

ents

wer

e re

com

men

ded

for

the

next

fe

w d

ays

in a

dditi

on t

o su

n pr

otec

tion

mea

sure

s. Bi

opsi

es w

ere

perf

orm

ed 2

4 w

k af

ter

illum

inat

ion

in p

atie

nts

with

fluo

resc

ence

de

tect

ed a

fter

4 hr

Com

para

tor

PDT

with

5 h

r in

cuba

tion

with

ALA

cre

am a

nd

sing

le li

ght

frac

tion:

Pre

para

tion

for

illum

inat

ion

was

as

for

the

inte

rven

tion

grou

p. T

here

was

the

n a

5-hr

incu

batio

n pe

riod

be

fore

red

ligh

t (6

35 n

m)

was

app

lied.

100

J/cm

2 was

del

iver

ed

in o

ne d

ose,

with

a fl

uenc

e in

tens

ity o

f 30

mW

/cm

2 . Sp

rayi

ng o

f w

ater

and

coo

ling

with

fans

, and

sun

pro

tect

ion

mea

sure

s w

ere

as fo

r th

e in

terv

entio

n gr

oup.

Biop

sies

wer

e pe

rfor

med

24

wk

afte

r ill

umin

atio

n in

pat

ient

s w

hom

fluo

resc

ence

afte

r 3-

hr

incu

batio

n w

ith A

LA w

as d

etec

ted

Mor

bidi

ty A

t 24

wk,

resi

dual

tum

our

was

fo

und

in fo

ur o

f six

(6

7%)

biop

sied

pat

ient

s in

the

sin

gle-

illum

inat

ion,

sh

orte

r-in

cuba

tion

grou

p. Tr

eatm

ent

was

re

peat

ed. A

t 24

wk,

ther

e w

as p

ersi

sten

ce o

f tu

mou

r in

tw

o of

nin

e (2

2%)

biop

sied

pat

ient

s in

the

frac

tiona

ted,

lo

nger

incu

batio

n gr

oup

QoL

and

ret

urn

to

norm

al a

ctiv

ity

Not

as

sess

edA

Es

Not

ass

esse

d

Aut

hors

’ con

clus

ions

PD

T d

eliv

ered

as

frac

tiona

ted

illum

inat

ion

with

16

hr

of in

cuba

tion

sepa

rate

d by

a 2

-hr

dark

inte

rval

sig

nific

antly

impr

oves

th

erap

eutic

out

com

e in

tum

our

erad

icat

ion

Bri

ef s

tudy

app

rais

al T

his

tria

l ha

d on

ly a

sm

all n

umbe

r of

pat

ient

s w

ith B

owen

’s di

seas

e. P

roce

dure

s of

ran

dom

isat

ion

and

blin

ding

of

outc

ome

asse

ssor

s w

ere

uncl

ear.

No

patie

nt d

etai

ls w

ere

prov

ided

. Alth

ough

th

e gr

oup

rece

ivin

g fr

actio

nate

d ill

umin

atio

n ha

d be

tter

out

com

es, t

he

rela

tive

cont

ribu

tion

of t

he lo

nger

in

cuba

tion

time

and

the

frac

tiona

ted

deliv

ery

are

uncl

ear.

It is

als

o un

clea

r if

ther

e w

ere

any

AEs

Appendix 14

224



225Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sal

im e

t al

. (20

03)72

Link

ed

Publ

icat

ions

185

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

40In

terv

entio

n: 2

0 (3

3 le

sion

s)C

ompa

rato

r: 20

(3

3 le

sion

s)N

o. o

f rec

ruit

ing

cent

res

Two

Follo

w-u

p pe

riod

an

d fr

eque

ncy

12 m

th

Type

(s)

of le

sion

and

hi

stol

ogy

Bow

en’s

dise

ase

Mai

n el

igib

ility

cr

iter

ia P

atie

nts

with

1–

3 le

sion

s of

pre

viou

sly

untr

eate

d, h

isto

logi

cally

pr

oven

Bow

en’s

dise

ase

mea

suri

ng 0

.5–4

cmPa

tien

t ch

arac

teri

stic

s%

Mal

e: 20

Age

ran

ge: 6

5–88

yr

Mea

n ag

e: 76

yrLe

sion

site

: Leg

s 58

, arm

s 4,

face

4Pa

tient

s ha

d be

twee

n on

e an

d th

ree

lesi

ons

and

wer

e of

ski

n ty

pes

I–III

Con

com

itan

t tr

eatm

ent

Loca

l an

aest

hetic

(1%

pla

in

lidoc

aine

by

intr

ader

mal

in

ject

ion)

was

offe

red

to p

atie

nts

expe

rien

cing

pa

in d

urin

g PD

T

trea

tmen

t

Tria

l tre

atm

ents

PD

T v

s 5-

FUIn

terv

enti

on 2

0% A

LA in

an

oil-

in-w

ater

em

ulsi

on w

as

appl

ied

to le

sion

s in

clud

ing

a 5-

mm

mar

gin

of c

linic

ally

no

rmal

ski

n 4-

hr b

efor

e PD

T. Ill

umin

atio

n w

as w

ith a

300

-W

xen

on la

mp

at a

dos

e of

100

J/cm

squ

ared

with

a

dens

ity o

f 50–

90 m

W/c

m

squa

red

narr

owba

nd r

ed li

ght

(630

± 1

5 nm

). The

tim

e of

ill

umin

atio

n w

as d

epen

dent

on

lesi

on s

ize

and

rang

ed fr

om

12 t

o 40

min

. All

patie

nts

wer

e re

view

ed a

t 6

wk

and

PDT

was

re

peat

ed if

req

uire

d. F

urth

er

PDT

par

amet

ers

wer

e no

t re

port

edC

ompa

rato

r 5-

FU (

Efud

ix)

was

app

lied

thin

ly t

o th

e le

sion

s in

itial

ly o

nce

daily

dur

ing

wk

1 an

d th

en t

wic

e da

ily (

wk

2–4)

. A

ll pa

tient

s w

ere

revi

ewed

at

6wk

and

5-FU

was

rep

eate

d if

requ

ired

Mor

bidi

ty 2

9 of

33

lesi

ons

(88%

) sh

owed

initi

al c

ompl

ete

clin

ical

cle

aran

ce w

ith P

DT

with

a P

R in

the

four

rem

aini

ng

lesi

ons.

22 o

f 33

lesi

ons

(67%

) ha

d co

mpl

ete

clin

ical

cle

aran

ce

afte

r 5-

FU a

nd s

ix h

ad P

R. F

ive

lesi

ons

wer

e w

ithdr

awn

prio

r to

com

plet

ion

of a

sin

gle

cycl

e of

5-F

U. A

fter

adju

stm

ent

for

the

influ

ence

of l

esio

n si

ze o

n re

spon

se, t

he d

iffer

ence

in

cle

aran

ce r

ates

was

NS.

At

12 m

th F

U t

here

wer

e tw

o re

curr

ence

s in

the

PD

T g

roup

(at

6 a

nd 7

mth

). The

re w

ere

six

recu

rren

ces

in t

he 5

-FU

gro

up (

at 5

, 7, 8

, 11

and

2 at

12

mth

). O

vera

ll cl

eara

nce

(at

12 m

th)

in t

he P

DT

gro

up w

as 2

7 of

33

lesi

ons

(82%

) vs

16

of 3

3 le

sion

s in

the

5-F

U g

roup

(48

%).

OR

= 4

.78

(95%

CI 1

.56

to 1

4.62

, p =

0.0

06)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

ass

esse

dA

Es T

hree

pat

ient

s w

ith fi

ve le

sion

s fr

om t

he 5

-FU

gro

up

deve

lope

d w

ides

prea

d de

rmat

itic

reac

tions

ove

r th

e tr

eate

d lim

bs a

nd w

ere

with

draw

n fr

om t

he s

tudy

. Ano

ther

pat

ient

w

ith t

wo

lesi

ons

from

the

5-F

U g

roup

had

wid

espr

ead

derm

atiti

c re

actio

ns b

ut e

lect

ed t

o co

ntin

ue t

he t

reat

men

t. In

the

5-F

U g

roup

, thr

ee le

sion

s ul

cera

ted

and

two

deve

lope

d pa

infu

l ero

sion

s on

com

plet

ion

of t

he t

reat

men

t cy

cle.

The

ul

cera

ted

lesi

ons

heal

ed le

avin

g pr

omin

ent

scar

ring

. The

re

wer

e no

rea

ctio

ns in

the

PD

T g

roup

and

no

clin

ical

ly o

bvio

us

scar

form

atio

n at

12

mth

at

any

PDT

tre

atm

ent

site

. 10

of 1

5 pa

tient

s in

the

5-F

U g

roup

and

14

of 1

9 in

the

PD

T g

roup

re

port

ed p

ain

duri

ng t

he t

reat

men

t cy

cle.

Dur

ing

PDT

pai

n w

as r

ated

‘mild

’ by

six

patie

nts,

‘mod

erat

e’ b

y si

x an

d ‘s

ever

e’

by t

wo.

Pai

n se

ttle

d fo

llow

ing

illum

inat

ion

in 4

pat

ient

s an

d pe

rsis

ted

to 2

4 hr

in fo

ur. M

ild d

isco

mfo

rt w

as r

epor

ted

by t

he

rem

aini

ng s

ix p

atie

nts

last

ing

7–42

d (

mea

n 14

). In

the

5-F

U

grou

p pa

in w

as r

ated

‘mild

’ by

six

patie

nts,

‘mod

erat

e’ b

y tw

o an

d ‘s

ever

e’ b

y tw

o. D

isco

mfo

rt p

ersi

sted

in t

he 5

-FU

gro

up

for

7–42

d (

mea

n 21

). In

ass

essm

ent

of in

tens

ity a

nd d

urat

ion

of p

ain,

mor

e pa

in w

as fo

und

in t

he 5

-FU

gro

up (

p =

0.01

). C

ompa

riso

n of

tot

al p

ain

over

tim

e re

veal

ed n

o st

atis

tical

ly

sign

ifica

nt d

iffer

ence

in t

he m

edia

n pa

in s

core

s be

twee

n th

e tw

o gr

oups

Aut

hors

’ con

clus

ions

Top

ical

A

LA–P

DT

is m

ore

effe

ctiv

e th

an

topi

cal 5

-FU

in t

he t

reat

men

t of

Bow

en’s

dise

ase

with

few

er

AEs

. ALA

sho

uld

be c

onsi

dere

d on

e of

the

1st

-line

the

rape

utic

op

tions

for

Bow

en’s

dise

ase

Bri

ef s

tudy

app

rais

al

Met

hods

of r

ando

mis

atio

n,

allo

catio

n co

ncea

lmen

t an

d bl

indi

ng o

f out

com

e as

sess

ors

wer

e no

t de

scri

bed.

Thi

s st

udy,

alth

ough

sm

all,

high

light

s th

e po

tent

ial o

f PD

T fo

r Bo

wen

’s di

seas

e bu

t re

sults

sho

uld

be

confi

rmed

in fu

rthe

r tr

ials

Appendix 14

224



225

Appendix 15 Basal cell carcinoma data extraction

Appendix 15

226



227Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Bas

sett

-Se

guin

et a

l. (20

08)79

Link

ed

publ

icat

ions

186–

190

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry N

ot s

tate

dLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

(b

etw

een-

part

icip

ant

com

pari

son)

No.

of p

arti

cipa

nts

Tota

l: 12

0 ra

ndom

ised

, 11

8 tr

eate

d (2

19

lesi

ons)

Inte

rven

tion:

60,

58

trea

ted

and

anal

ysed

(1

03 le

sion

s)C

ompa

rato

r: 58

, 57

trea

ted

and

anal

ysed

(9

8 le

sion

s)N

o. o

f rec

ruit

ing

cent

res

13 a

cros

s se

ven

Euro

pean

co

untr

ies

Follo

w-u

p pe

riod

an

d fr

eque

ncy

3 m

th, t

hen

at 1

, 2, 3

, 4

and

5 yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Pr

imar

y su

perfi

cial

BC

CM

ain

elig

ibili

ty

crit

eria

Pat

ient

s ag

ed

18 yr

or

olde

r w

ith

up t

o 10

pre

viou

sly

untr

eate

d pr

imar

y su

perfi

cial

BC

C

lesi

ons

suita

ble

for

cryo

ther

apy.

Dia

gnos

is

confi

rmed

usi

ng p

unch

bi

opsy

. Les

ions

had

to

have

dia

met

er >

6 m

m

but

< 15

mm

on

face

/sc

alp,

< 20

mm

on

neck

/ex

trem

ities

, or

< 30

mm

on

tru

nk. F

urth

er

elig

ibili

ty c

rite

ria

wer

e re

port

edPa

tien

t ch

arac

teri

stic

s N

ot

stat

edC

onco

mit

ant

trea

tmen

t C

onco

mita

nt

trea

tmen

t w

ith

imm

unos

uppr

essi

ve

med

icat

ion

was

pr

ohib

ited

Tria

l tre

atm

ents

MA

L–PD

T

vs C

ryot

hera

pyIn

terv

enti

on M

AL–

PDT:

A

sing

le t

reat

men

t w

as in

itial

ly

give

n. L

esio

ns w

ere

prep

ared

by

sur

face

deb

ride

men

t. M

AL

crea

m, 1

60 m

g/g,

was

ap

plie

d in

a la

yer

of 1

mm

to

the

lesi

on a

nd 5

mm

of

surr

ound

ing

tissu

e fo

r 3

hr. T

he

crea

m w

as w

ashe

d of

f usi

ng a

sa

line

solu

tion

and

the

trea

ted

area

was

the

n ill

umin

ated

w

ith n

on-c

oher

ent

red

light

(w

avel

engt

h 57

0–67

0 nm

) us

ing

a lig

ht d

ose

of 7

5 J/c

m.

In p

atie

nts

with

inco

mpl

ete

CR

at

3-m

th t

reat

men

t w

as

repe

ated

(tw

o co

nsec

utiv

e M

AL–

PDT

ses

sion

s 7

d ap

art)

Com

para

tor

Cry

othe

rapy

: C

ryot

hera

py w

as a

pplie

d in

tw

o fr

eeze

–tha

w c

ycle

s us

ing

liqui

d ni

trog

en s

pray

ap

plie

d to

the

lesi

on a

nd a

3-

mm

sur

roun

ding

are

a of

he

alth

y tis

sue.

Pro

cedu

re w

as

repe

ated

afte

r a

thaw

per

iod

of t

wo

to t

hree

tim

es t

he

free

ze d

urat

ion.

In p

atie

nts

with

an

inco

mpl

ete

resp

onse

at

3-m

th t

reat

men

t w

as

repe

ated

(do

uble

free

ze–t

haw

cr

yoth

erap

y)

Mor

bidi

ty3

mth

(11

5 pa

tient

s): L

esio

ns w

ith in

CR

afte

r 3

mth

wer

e 32

% in

th

e PD

T g

roup

and

30%

in t

he c

ryot

hera

py g

roup

. CR

rat

es d

id

not

diffe

r be

twee

n th

e gr

oups

(PD

T: 9

7% v

s cr

yoth

erap

y: 95

%,

p =

0.49

)12

mth

(10

5 pa

tient

s): F

ewer

lesi

ons

recu

rred

with

MA

L–PD

T

than

with

cry

othe

rapy

(8%

vs

16%

) M

ore

patie

nts

had

an

‘exc

elle

nt/g

ood’

cos

met

ic o

utco

me

with

MA

L–PD

T t

han

with

cr

yoth

erap

y at

3 a

nd 1

2 m

th36

mth

(10

7 pa

tient

s): P

ropo

rtio

n of

lesi

ons

in C

R w

as 6

6% fo

r M

AL–

PDT

and

67%

for

cryo

ther

apy

(NS)

. 74%

est

imat

ed C

R

rate

in b

oth

grou

ps a

ccor

ding

to

per-

prot

ocol

pop

ulat

ion.

The

le

sion

rec

urre

nce

rate

s in

lesi

ons

with

CR

3 m

th a

fter

the

last

tr

eatm

ent

wer

e 23

% fo

r M

AL–

PDT

and

20%

for

cryo

ther

apy

The

ove

rall

cosm

etic

out

com

e w

as r

ated

by

phys

icia

ns a

s ‘e

xcel

lent

’ or ‘

good

’ for

89%

of t

he M

AL–

PDT

pat

ient

s an

d 63

%

of t

he c

ryot

hera

py p

atie

nts

5 yr

: CR

rat

es d

id n

ot d

iffer

bet

wee

n th

e gr

oups

(PD

T: 7

5% v

s cr

yoth

erap

y: 74

%, p

= 0

.90)

. Cum

ulat

ive

recu

rren

ce r

ate

afte

r 5

yr w

as P

DT:

22%

and

cry

othe

rapy

: 20%

, p =

0.8

6Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y C

osm

etic

out

com

e w

as b

ette

r w

ith P

DT

at

both

3 m

th a

nd 5

yr 3

mth

: 30%

of P

DT

pa

tient

s ha

d an

‘exc

elle

nt’ o

utco

me

com

pare

d w

ith 4

% fo

r cr

yoth

erap

y (p

= 0

.000

5)5

yr: 6

0% o

f PD

T p

atie

nts

had

an ‘e

xcel

lent

’ out

com

e co

mpa

red

with

16%

for

cryo

ther

apy

(p =

0.0

0078

)A

ll co

smet

ic o

utco

mes

rat

ed b

y in

vest

igat

ors

usin

g a

4-po

int

scal

eA

Es A

Es w

ere

repo

rted

by

73%

(44

/60)

PD

T p

atie

nts

and

79%

(4

6/58

) cr

yoth

erap

y pa

tient

s. M

ost A

Es w

ere

loca

l and

tra

nsie

nt,

no p

atie

nts

disc

ontin

ued

as a

res

ult

of t

reat

men

t-re

late

d A

EsPa

in: 3

7% P

DT,

33%

cry

othe

rapy

Cru

stin

g: 35

% P

DT,

47%

cry

othe

rapy

Eryt

hem

a: 30

% P

DT,

21%

cry

othe

rapy

Mild

: 80%

PD

T 7

3% c

ryot

hera

pyM

oder

ate:

13%

PD

T, 25

% c

ryot

hera

pySe

vere

: 5%

PD

T, 1%

cry

othe

rapy

Aut

hors

’ con

clus

ions

Thi

s st

udy

dem

onst

rate

d th

at le

sion

re

curr

ence

rat

e w

ith M

AL–

PDT

tr

eatm

ent

was

com

para

ble

to

doub

le fr

eeze

tha

w c

ryot

hera

py

for

trea

tmen

t of

sup

erfic

ial B

CC

an

d pr

ovid

ed a

bet

ter

cosm

etic

ou

tcom

eB

rief

stu

dy a

ppra

isal

Ove

rall

this

tri

al w

as w

ell c

ondu

cted

cl

earl

y re

port

ed. T

he la

ck o

f a

pow

er c

alcu

latio

n m

eans

it

is u

ncle

ar if

the

re w

as

no d

iffer

ence

bet

wee

n th

e tr

eatm

ents

, or

if th

e st

udy

was

un

derp

ower

ed t

o de

tect

suc

h a

diffe

renc

e. T

his

tria

l did

incl

ude

a lo

ng t

erm

FU

of 5

yr a

s w

ell

as e

xam

inat

ion

of s

afet

y, ef

ficac

y an

d co

smet

ic o

utco

mes

Appendix 15

226



227Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Ber

roet

a et

al.

(200

7)87

Link

ed p

ublic

atio

ns19

1

Dat

a so

urce

Ful

l pub

lishe

d pa

per

(lett

er)

Cou

ntry

UK

Lang

uage

Eng

lish

Stud

y de

sign

RC

T

(bet

wee

n-pa

rtic

ipan

t co

mpa

riso

n)N

o. o

f par

tici

pant

sTo

tal:

31 (

40 le

sion

s)In

terv

entio

n: 1

8 (2

1 le

sion

s)C

ompa

rato

r: 13

(19

lesi

ons)

No.

of r

ecru

itin

g ce

ntre

s O

neFo

llow

-up

peri

od a

nd

freq

uenc

y FU

to

asse

ss

resp

onse

at

3, 6

and

12

mth

. FU

to

asse

ss p

ain

at 3

, 6, 2

4 an

d 48

hr

and

also

at

1 w

k

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y N

odul

ar B

CC

Mai

n el

igib

ility

cr

iter

ia N

on-

preg

nant

adu

lts (

18

or o

ver)

with

wel

l-de

fined

BC

Cs ≤

2cm

on

ana

tom

ical

ly n

on-

criti

cal s

ites

wer

e el

igib

lePa

tient

s w

ith

recu

rren

t BC

Cs,

or

BCC

s at

hig

h-ri

sk

site

s or

pat

ient

s w

ith

imm

unod

efici

ency

or

phot

osen

sitiv

ity w

ere

excl

uded

% M

ale:

100

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

ALA

–PD

T (

follo

win

g su

perfi

cial

cur

etta

ge)

vs E

xcis

ion

surg

ery

Inte

rven

tion

Initi

al 4

-mm

pun

ch

biop

sy t

o as

sess

tum

our

dept

h, fo

llow

ed

by s

uper

ficia

l cur

etta

ge (

with

out

anae

sthe

tic)

and

PDT

with

630

-nm

lase

r af

ter

20%

ALA

app

lied

for

6 hr

(un

der

occl

usio

n). I

rrad

ianc

e w

as 1

2 m

W/c

m2

and

tota

l dos

e 12

5 J/c

m2 .

PDT

rep

eate

d at

3 m

th if

res

idua

l BC

C w

as c

linic

ally

ev

iden

tC

ompa

rato

r Ex

cisi

on w

ith s

urgi

cal

mar

gins

as

reco

mm

ende

d by

the

Bri

tish

Ass

ocia

tion

of D

erm

atol

ogis

ts. S

calp

el

surg

ery

was

per

form

ed u

nder

infil

trat

ive

lidoc

aine

ana

esth

esia

but

sur

gica

l re-

exci

sion

s w

ere

not

cond

ucte

d

Mor

bidi

ty F

or t

he P

DT

gro

up 1

3/21

le

sion

s (6

2%)

wer

e cl

ear

at 1

yr

com

pare

d to

15/

19 le

sion

s (7

9%)

in t

he

surg

ery

grou

p, p

= 0.

24T

here

wer

e fiv

e pe

rsis

tent

BC

Cs

in

the

PDT

gro

up b

ut n

one

in t

he s

urge

ry

grou

p (n

s)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y T

here

was

no

diffe

renc

e in

mea

n sc

ar

seve

rity

(on

a 1

–4 s

cale

) be

twee

n th

e gr

oups

whe

n ju

dged

inde

pend

ently

by

10 n

on-m

edic

al m

en (

1.9

for

PDT

vs

2.1

for

surg

ery,

p =

0.42

) or

10

non-

med

ical

w

omen

(2.

2 fo

r PD

T v

s 2.

5 fo

r su

rger

y, p

= 0.

23)

AE

s M

edia

n pa

in s

core

s fo

r th

e 1s

t BC

C t

reat

ed (

scor

ed o

ut o

f 10)

bot

h du

ring

tre

atm

ent,

and

imm

edia

tely

afte

r tr

eatm

ent,

wer

e fiv

e fo

r th

e PD

T g

roup

, an

d 0

for

surg

ery

grou

p (p

= 0

.001

, and

p

= 0.

004,

res

pect

ivel

y). B

oth

grou

ps h

ad

a sc

ore

of z

ero

at la

ter

asse

ssm

ents

Aut

hors

’ con

clus

ions

The

re w

as n

o su

gges

tion

that

PD

T w

as, i

n ge

nera

l, be

tter

tha

n su

rger

y. PD

T a

ppea

rs m

ore

pain

ful t

han

surg

ery

for

low

-ris

k nB

CC

s. Su

rger

y re

mai

ns t

he 1

st t

reat

men

t ch

oice

for

nBC

Cs

Bri

ef s

tudy

app

rais

al T

his

smal

l pilo

t st

udy

was

gen

eral

ly o

f hig

h qu

ality

in it

s m

etho

ds a

nd r

epor

ting.

The

abs

ence

of

anae

sthe

tic fo

r th

e PD

T g

roup

bef

ore

cure

ttag

e m

ay e

xpla

in t

he d

iffer

ence

s in

pa

in s

core

s

Appendix 15

228



229Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

de

Haa

s et

al.

(200

6)83

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry T

he

Net

herl

ands

Lang

uage

Eng

lish

Stud

y de

sign

RC

T

(bet

wee

n-pa

rtic

ipan

t co

mpa

riso

n)N

o. o

f par

tici

pant

sTo

tal:

154

(505

lesi

ons)

Inte

rven

tion:

55

(262

le

sion

s)C

ompa

rato

r: 10

0 (2

43

lesi

ons)

No.

of r

ecru

itin

g ce

ntre

s O

neFo

llow

-up

peri

od a

nd

freq

uenc

y FU

four

tim

es

a ye

ar in

1st

yea

r, th

en

twic

e ye

arly.

Pat

ient

s te

ndin

g to

dev

elop

mor

e le

sion

s w

ere

seen

mor

e fr

eque

ntly.

Min

imum

FU

pe

riod

was

1 yr

, max

imum

FU

per

iod

was

5 yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Pr

imar

y su

perfi

cial

BC

CM

ain

elig

ibili

ty

crit

eria

Not

sta

ted

Pati

ent

char

acte

rist

ics A

ge

rang

e: 31

–83

yrM

ean

age:

57 yr

All

part

icip

ants

wer

e C

auca

sian

sC

onco

mit

ant

trea

tmen

t Pa

race

tam

ol, l

idoc

aine

(w

ithou

t ad

rena

line)

or

bup

ivac

aine

if

requ

ired

Tria

l tre

atm

ents

Fra

ctio

nate

d ill

umin

atio

n PD

T v

s si

ngle

-illu

min

atio

n PD

TIn

terv

enti

on F

ract

iona

ted

illum

inat

ion

PDT:

Cru

sts

and

scal

ing

wer

e ge

ntly

rem

oved

us

ing

a di

spos

able

cur

ette

bef

ore

ALA

ap

plic

atio

n. Il

lum

inat

ion

usin

g do

ses

of 2

0 an

d 80

J/cm

2 (at

50

mW

/cm

2 ) d

eliv

ered

4 a

nd 6

hr

afte

r ad

min

istr

atio

n of

20%

ALA

oin

tmen

t (c

onta

inin

g 2%

lido

cain

e) w

ith a

1-c

m m

argi

n.

One

of t

hree

diff

eren

t lig

ht s

ourc

es w

ere

used

on

each

lesi

on (

a 63

0-nm

dio

de la

ser,

coup

led

into

a 6

00-µ

m o

ptic

al fi

bre

and

usin

g a

com

bina

tion

of le

nses

for

unifo

rm fl

uenc

e ra

te;

a lig

ht-e

mitt

ing

diod

e 63

3 nm

with

a b

andw

idth

of

20

nm; o

r a

2nd

broa

dban

d so

urce

with

an

out

put

of b

etw

een

590

and

650

nm),

with

a

mar

gin

of a

t le

ast

5 m

m. A

ligh

t-pr

otec

tive

band

age

(incl

udin

g al

umin

ium

foil)

was

use

d to

pro

vide

the

2-h

r da

rk in

terv

al b

etw

een

frac

tions

. Par

ticip

ants

wer

e in

stru

cted

to

stay

ou

t of

the

col

dC

ompa

rato

r PD

T w

ith p

lace

bo c

ream

: Pa

tient

s re

ceiv

ed t

wo

cycl

es (

1 w

k ap

art)

of

pla

cebo

cre

am P

DT.

The

re w

as s

urfa

ce

debr

idem

ent

and

slig

ht le

sion

deb

ulki

ng p

rior

to

PD

T. BC

C w

ith p

artia

l clin

ical

res

pons

e at

3

mth

wer

e re

-tre

ated

. Fur

ther

par

amet

ers

wer

e no

t re

port

ed

Mor

bidi

ty C

R o

f les

ions

w

as s

igni

fican

tly g

reat

er u

sing

fr

actio

nate

d ill

umin

atio

n co

mpa

red

with

sin

gle

illum

inat

ion

(at

1 yr

, 97

% v

s 89

%, p

= 0

.002

). The

res

ults

w

ere

very

sim

ilar

whe

n an

alys

is

was

und

erta

ken

on a

sub

grou

p of

hi

stol

ogic

ally

pro

ven

BCC

s. 10

/262

(4

%)

lesi

ons

faile

d to

res

pond

, or

rec

urre

d, in

the

frac

tiona

ted-

illum

inat

ion

grou

p co

mpa

red

with

32/

243

(13%

) in

the

sin

gle-

illum

inat

ion

grou

p (p

= 0

.000

2).

The

re w

ere

no s

igni

fican

t di

ffere

nces

in r

espo

nse

rate

s, w

ithin

ea

ch il

lum

inat

ion

grou

p, fo

r th

e di

ffere

nt li

ght

sour

ces

used

QoL

and

ret

urn

to n

orm

al

acti

vity

Ass

esse

d bu

t no

t re

port

edA

Es

5/10

0 (5

%)

patie

nts

requ

ired

pain

rel

ief i

n th

e si

ngle

illu

min

atio

n gr

oup

com

pare

d to

15/

55 (

27%

) pa

tient

s in

the

frac

tiona

ted

illum

inat

ion

grou

p

Aut

hors

’ con

clus

ions

The

re is

a

sign

ifica

nt in

crea

se in

the

CR

rat

e of

PD

T u

sing

tw

o-lig

ht fr

actio

n ill

umin

atio

n sc

hem

e co

mpa

red

with

a s

ingl

e-ill

umin

atio

n sc

hem

eB

rief

stu

dy a

ppra

isal

Alth

ough

tr

eatm

ent

met

hods

wer

e ve

ry w

ell

desc

ribe

d, s

tudy

des

ign

deta

ils o

n is

sues

su

ch a

s ra

ndom

isat

ion,

blin

ding

, and

dr

opou

ts (

wer

e 15

4 or

155

pat

ient

s tr

eate

d?)

wer

e no

t pr

ovid

ed, m

akin

g it

diffi

cult

to a

sses

s th

e re

liabi

lity

of t

he

resu

lts

Appendix 15

228



229Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Fol

ey e

t al. (

2003

)77

Dat

a so

urce

Abs

trac

tC

ount

ry A

ustr

alia

Lang

uage

Eng

lish

Stud

y de

sign

RC

T (

betw

een-

part

icip

ant

com

pari

son)

No.

of p

arti

cipa

nts

Tota

l: 66

Inte

rven

tion:

33

Com

para

tor:

33N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

Not

cle

ar, b

ut

appe

ared

to

be a

t le

ast

6 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

e pa

tient

s w

ith h

isto

logi

cally

co

nfirm

ed n

BCC

Type

(s)

of c

ance

r an

d hi

stol

ogy

nBC

CM

ain

elig

ibili

ty

crit

eria

Pat

ient

s w

ith h

isto

logi

cally

co

nfirm

ed n

BCC

Pati

ent

char

acte

rist

ics

Not

st

ated

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

PD

T (

met

hyl

amin

olev

ulin

ate)

vs

PDT

(pl

aceb

o cr

eam

)In

terv

enti

on L

esio

ns 1

st p

repa

red

by d

ebri

dem

ent/

debu

lkin

g. PD

T w

ith

160

mg/

g of

met

hyl a

min

olev

ulin

ate

crea

m a

nd 3

hr

of r

ed li

ght

(570

–67

0 nm

) w

ith a

tot

al li

ght

dose

of

75 J/

cm2 . T

reat

men

t re

peat

ed a

fter

7 d.

Le

sion

s w

ith P

R a

t 3

mth

wer

e re

-tr

eate

d. F

urth

er P

DT

par

amet

ers

wer

e no

t re

port

edC

ompa

rato

r As

for

activ

e PD

T g

roup

, bu

t us

ing

plac

ebo

crea

m

Mor

bidi

ty A

t 6

mth

, his

tolo

gica

l ev

alua

tion

ther

e w

ere

no s

igns

of

mal

igna

ncy

in 7

3% o

f the

act

ive

PDT

gr

oup

vs 2

1% in

the

pla

cebo

PD

T g

roup

(p

< 0

.001

)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y C

osm

etic

out

com

e ra

ted

as e

xcel

lent

or

goo

d in

95%

of t

he a

ctiv

e PD

T

patie

nts

AE

s The

re w

ere

no t

reat

men

t-re

late

d se

riou

s or

sys

tem

ic A

Es.

Burn

ing,

stin

ging

, pai

n, a

nd e

ryth

ema

wer

e tr

ansi

ent,

and

grad

ed a

s m

ild o

r m

oder

ate

Aut

hors

’ con

clus

ions

PD

T is

a

good

alte

rnat

ive

to e

xist

ing

ther

apie

s, pa

rtic

ular

ly in

are

as w

here

an

exce

llent

co

smet

ic o

utco

me

is c

ruci

alB

rief

stu

dy a

ppra

isal

Lim

ited

repo

rtin

g of

met

hods

and

res

ults

mak

es

mea

ning

ful i

nter

pret

atio

n di

fficu

lt. N

o de

tails

wer

e re

port

ed o

n w

ho a

sses

sed

cosm

etic

out

com

es, a

nd w

heth

er

outc

ome

asse

ssor

s w

ere

blin

ded.

O

utco

mes

not

alw

ays

repo

rted

for

both

gro

ups,

or b

roke

n do

wn

by g

roup

nBC

C, n

odul

ar b

asal

cel

l car

cino

ma.

Appendix 15

230



231Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Kui

jper

s et

al

. (20

06)84

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry T

he

Net

herl

ands

Lang

uage

Eng

lish

Stud

y de

sign

RC

T

(bet

wee

n-pa

rtic

ipan

t co

mpa

riso

n)N

o. o

f par

tici

pant

sTo

tal:

43 B

CC

s in

39

patie

nts

Inte

rven

tion:

22

BCC

sC

ompa

rato

r: 21

BC

Cs

No.

of r

ecru

itin

g ce

ntre

s O

neFo

llow

-up

peri

od

and

freq

uenc

y 8

wk

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y N

odul

ar p

rim

ary

BCC

Mai

n el

igib

ility

cri

teri

a Pa

tient

s w

ith n

odul

ar p

rim

ary

BCC

loca

ted

anyw

here

on

skin

ex

cept

per

iocu

lar

area

and

hai

ry

scal

p, w

ith a

clin

ical

dia

met

er

smal

ler

than

20

mm

. Pig

men

ted

BCC

s an

d pa

tient

s w

ith m

ore

than

five

BC

Cs

wer

e ex

clud

ed,

as w

ere

patie

nts

with

por

phyr

ia,

cont

rain

dica

tions

to

surg

ery,

or

hype

rsen

sitiv

ity t

o da

ylig

ht o

r to

ei

ther

of t

he c

ream

sPa

tien

t ch

arac

teri

stic

s%

Mal

e: 62

Age

ran

ge: 3

9–87

yrM

ean

age:

68 yr

Mos

t tu

mou

rs w

ere

less

tha

n 10

mm

in d

iam

eter

Con

com

itan

t tr

eatm

ent

Topi

cal e

mol

lient

for

pain

Tria

l tre

atm

ents

PD

T w

ith

5-am

inol

evul

inat

e (A

LA–P

DT

) vs

PD

T

with

met

hyl a

min

olev

ulin

ate

(MA

L–PD

T)

Inte

rven

tion

ALA

–PD

T: A

ll tu

mou

r tis

sue

abov

e sk

in le

vel w

as r

emov

ed

by c

uret

tage

(w

ith e

thyl

chl

orid

e sp

ray

anae

sthe

tic). T

he v

isib

le t

umou

r, pl

us

5-m

m m

argi

n, w

as c

over

ed in

a la

yer

of 2

0% A

LA c

ream

(ar

ound

2 m

m

thic

k) a

nd p

olyu

reth

ane

and

opaq

ue

dres

sing

s w

ere

appl

ied.

Afte

r 3

hr

the

area

was

cle

aned

and

illu

min

ated

w

ith li

ght

of 6

00–7

30 n

m (

from

met

al

halo

gen

sour

ce)

with

an

inte

nsity

of

100

mW

/cm

2 giv

ing

a to

tal d

ose

of

75 J/

cm2 . A

fter

illum

inat

ion

the

area

w

as c

over

ed w

ith a

ligh

t pr

otec

tive

dres

sing

for

1 d

Proc

edur

e re

peat

ed a

fter

7 d

(but

w

ithou

t de

bulk

ing)

Com

para

tor

MA

L–PD

T:

Sam

e m

etho

ds a

s fo

r PD

T w

ith

5-am

inol

evul

inat

e gr

oup,

exce

pt 1

6%

met

hyl a

min

olev

ulin

ate

crea

m w

as

used

inst

ead

of 2

0% A

LA

Mor

bidi

ty T

here

was

no

stat

istic

ally

si

gnifi

cant

diff

eren

ce in

inco

mpl

ete

clea

ranc

e ra

tes

[6/2

2 (2

7%) A

LA v

s 6/

21 (

29%

) M

AL,

p =

0.9

2]Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty N

ot a

sses

sed

AE

s Ave

rage

inte

nsity

of p

ain

did

not

diffe

r si

gnifi

cant

ly b

etw

een

grou

ps (

1st

trea

tmen

t: VA

S = 4

.4 fo

r ALA

vs

2.8

for

MA

L, p

= 0

.09,

2nd

tre

atm

ent: V

AS =

4.8

fo

r ALA

vs

3.9

for

MA

L, p

= 0

.4),

nor

did

char

acte

r of

pai

n. M

ost

pain

was

de

scri

bed

as b

eing

bur

ning

or

stin

ging

Aut

hors

’ con

clus

ions

The

stu

dy

foun

d no

diff

eren

ce in

sho

rt-t

erm

ef

ficac

y be

twee

n A

LA–P

DT

and

M

AL–

PDT,

so b

oth

can

be e

qual

ly

reco

mm

ende

d as

pho

tose

nsiti

sers

Bri

ef s

tudy

app

rais

al T

his

pilo

t st

udy

blin

ded

both

pat

ient

s an

d ou

tcom

e as

sess

ors.

How

ever

, the

re

was

no

men

tion

of a

pow

er c

alcu

latio

n an

d th

e sa

mpl

e si

ze w

as v

ery

smal

l; a

larg

er s

tudy

wou

ld h

ave

been

mor

e in

form

ativ

e, p

artic

ular

ly o

n di

ffere

nces

in

pai

n sc

ores

Appendix 15

230



231Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Lui

et a

l. (20

04)68

Dat

a so

urce

Ful

l pub

lishe

d pa

per

Cou

ntri

es C

anad

a, U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

(be

twee

n-pa

rtic

ipan

t co

mpa

riso

n)N

o. o

f par

tici

pant

sTo

tal:

Not

sta

ted

by d

iagn

osis

(3

87 le

sion

s cl

assi

fied

as B

CC

)In

terv

entio

n: S

uper

ficia

l BC

C

120

lesi

ons;

nBC

C 4

7 le

sion

s; BC

C (

not

spec

ified

) ze

roC

ompa

rato

r: Su

perfi

cial

BC

C

77 le

sion

s; nB

CC

30

lesi

ons;

BCC

(no

t sp

ecifi

ed)

nine

2nd

Com

para

tor:

Supe

rfici

al

BCC

80

lesi

ons;

nBC

C 1

6 le

sion

s, BC

C (

not

spec

ified

) ei

ght

No.

of r

ecru

itin

g ce

ntre

s Fo

urFo

llow

-up

peri

od a

nd

freq

uenc

y FU

at

6 w

k, an

d 3,

6,

12,

18

and

24 m

th (

optio

nal

beyo

nd 6

mth

)

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Su

perfi

cial

BC

C, 2

77

lesi

ons

(66%

); nB

CC

, 93

lesi

ons

(22%

); Bo

wen

’s di

seas

e, 3

4 le

sion

s (8

%);

BCC

uns

peci

fied

17 le

sion

s (4

%)

Mai

n el

igib

ility

cri

teri

a Pa

tient

s w

ith a

t le

ast

two

biop

sy-

prov

en s

uper

ficia

l or

nBC

C o

r Bo

wen

’s le

sion

sPa

tien

t ch

arac

teri

stic

s N

ot

stat

ed fo

r BC

C o

nly

(stu

dy a

lso

incl

uded

SC

C)

but

over

all:

Ave

rage

tum

ours

tre

ated

per

pa

tient

= e

ight

Age

ran

ge: 2

2–79

yrM

ean

age:

55 yr

Mos

t pa

tient

s ha

d Fi

tzpa

tric

k sk

in

type

II o

r III

Con

com

itan

t tr

eatm

ent

Ora

l an

alge

sic

drug

s fo

r pa

in

Tria

l tre

atm

ents

PD

T a

t 60

J/cm

2 vs

PDT

at

120

J/cm

2 vs

PDT

at

180

J/cm

2

Inte

rven

tion

PD

T a

t 60

J/cm

2 : 10

m

in in

trav

enou

s in

fusi

on o

f 14

mg/

m2

vert

epor

fin, f

ollo

wed

1–3

hr

late

r by

exp

osur

e to

60

J/cm

2 of r

ed li

ght

(688

± 1

0 nm

) fr

om a

non

-the

rmal

LE

D p

anel

. The

exp

osed

are

a in

clud

ed

a m

argi

n of

3–4

mm

aro

und

the

lesi

on. T

he ir

radi

ance

del

iver

ed w

as

200

± 40

mW

/cm

2 . Tum

ours

re-

trea

ted

at 3

mth

if n

eces

sary

(w

ith d

ose

incr

ease

d to

18

mg/

m2 )

Com

para

tor

PDT

at

120

J/cm

2 : Se

e ab

ove

2nd

com

para

tor

PDT

at

180

J/cm

2 : Se

e ab

ove

Mor

bidi

ty A

t 6

mth

, the

hi

stop

atho

logi

cal r

espo

nse

(i.e.

no

resi

dual

tum

our)

was

: nBC

C: 7

6% a

t 60

J/cm

2 , 82

% a

t 12

0 J/c

m2 ,

and

100%

at

180

J/cm

2 ; su

perfi

cial

BC

C: 6

3%, 8

0%,

and

97%

; BC

C n

ot s

peci

fied:

0%

, 56%

an

d 75

%T

here

was

a t

rend

indi

catin

g a

bett

er

resp

onse

with

a h

ighe

r lig

ht d

ose

(p =

0.0

6)Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty R

epor

ted

by li

ght

dose

ra

ther

tha

n tu

mou

r ty

peA

Es

Rep

orte

d by

ligh

t do

se, r

athe

r th

an b

y tu

mou

r ty

pe

Aut

hors

’ con

clus

ions

A

sing

le c

ours

e of

ver

tepo

rfin

PDT

sho

wed

tre

atm

ent

bene

fit

for

patie

nts

with

mul

tiple

non

-m

elan

oma

skin

can

cers

Bri

ef s

tudy

app

rais

al N

o cl

inic

ally

rel

evan

t co

mpa

rato

r tr

eatm

ent

was

use

d, t

here

w

as a

lack

of i

nfor

mat

ion

on

issu

es s

uch

as b

lindi

ng a

nd

allo

catio

n co

ncea

lmen

t, an

d th

e au

thor

s di

d no

t pr

esen

t m

any

resu

lts a

nd p

opul

atio

n de

tails

by

dia

gnos

is. I

t is

the

refo

re

diffi

cult

to m

ake

any

relia

ble

conc

lusi

ons

abou

t th

e ef

ficac

y of

ver

tepo

rfin

in p

atie

nts

with

BC

C

Appendix 15

232



233Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mos

terd

et

al. (

2008

)86

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry T

he

Net

herl

ands

Lang

uage

Eng

lish

Stud

y de

sign

RC

T

(bet

wee

n-pa

rtic

ipan

t co

mpa

riso

n)N

o. o

f par

tici

pant

sTo

tal:

149

(173

lesi

ons

rand

omis

ed, 1

71

trea

ted)

Inte

rven

tion:

85

lesi

ons

Com

para

tor:

88 le

sion

sN

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

1–2

wk

for

surg

ery,

then

3, 6

, 12

and

18

mth

; 2, 3

, 4 a

nd 5

yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y nB

CC

Mai

n el

igib

ility

cri

teri

a Pr

evio

usly

unt

reat

ed p

rim

ary

nBC

C w

ith m

axim

um

diam

eter

of 2

0 m

m in

pa

tient

s of

18

yr o

r ol

der.

Preg

nanc

y, lif

e ex

pect

ancy

of

less

tha

n 5

yr a

nd u

se

of p

hoto

sens

itive

dru

gs

wer

e ex

clus

ion

crite

ria.

Tum

ours

wer

e ex

clud

ed

if re

curr

ent,

pigm

ente

d or

lo

cate

d on

hai

ry o

r co

ncav

e ar

eas.

Furt

her

deta

ils w

ere

repo

rted

Pati

ent

char

acte

rist

ics

% M

ale:

50M

ean

age:

65 yr

Mos

t tu

mou

rs w

ere

loca

ted

on t

he fo

rehe

ad/t

empl

e, b

ack

or n

ose

area

. Max

imum

mea

n tu

mou

r di

amet

er 9

.1 m

mC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

ALA

–PD

T v

s Su

rgic

al e

xcis

ion

Inte

rven

tion

ALA

–PD

T: P

artia

l tum

our

debu

lkin

g pe

rfor

med

und

er lo

cal a

naes

thet

ic 3

wk

prio

r to

PD

T

trea

tmen

t. 20

% A

LA c

ream

app

lied

to le

sion

incl

udin

g 5-

mm

sur

roun

ding

are

a an

d co

vere

d w

ith o

cclu

sive

dr

essi

ng fo

r 4

hr. L

esio

n th

en il

lum

inat

ed u

sing

a

broa

dban

d m

etal

-hal

ogen

ligh

t so

urce

for

15 m

in w

ith

inte

nsity

of 1

00 m

Wcm

2 and

dos

e of

75

J/cm

2 . Are

a w

as t

hen

cove

red

and

re-il

lum

inat

ed a

fter

60 m

in. T

his

prod

uced

a fr

actio

nate

d tr

eatm

ent

on t

he s

ame

day

with

a t

otal

ligh

t do

se o

f 150

J/cm

2 . A

ny in

com

plet

e re

spon

ses

or r

ecur

rent

tum

ours

wer

e re

-tre

ated

su

rgic

ally

Com

para

tor

Surg

ical

Exc

isio

n: L

ocal

ana

esth

etic

usi

ng

lidoc

aine

(1%

) w

ith a

dren

alin

e fo

llow

ed b

y ex

cisi

on o

f th

e tu

mou

r an

d a

3-m

m s

urro

undi

ng m

argi

n. C

losu

re

was

by

sutu

res

or t

rans

posi

tion/

tran

spla

ntat

ion

depe

ndin

g on

lesi

on lo

catio

n. S

ectio

ns o

f the

late

ral

and

deep

mar

gins

wer

e hi

stol

ogic

ally

exa

min

ed; i

f re

sidu

al t

umou

r w

as fo

und

then

thi

s w

as r

egar

ded

as

a tr

eatm

ent

failu

re a

nd r

e-ex

cisi

ons

wer

e pe

rfor

med

un

til m

argi

ns w

ere

free

from

tum

our

Mor

bidi

ty 3

mth

: 78

/83

(94%

) C

R in

PD

T

and

86/8

8 (9

8%)

in S

E pa

tient

s, p

= 0.

27Fa

ilure

rat

es: C

umul

ativ

e in

cide

nce

of fa

ilure

pr

obab

ility

at

3 yr

was

2.

3% fo

r SE

and

30.

3%

for

PDT

(p

< 0.

001)

QoL

and

ret

urn

to

norm

al a

ctiv

ity

Not

as

sess

edA

Es

No

seri

ous

com

plic

atio

ns w

ere

obse

rved

Aut

hors

’ con

clus

ions

Tre

atm

ent

of n

BCC

with

SE

is s

igni

fican

tly m

ore

effe

ctiv

e th

an t

reat

men

t w

ith A

LA–

PDT

afte

r de

bulk

ing.

PDT

sho

uld

not

ther

efor

e be

use

d as

a s

tand

ard

trea

tmen

t fo

r nB

CC

Bri

ef s

tudy

app

rais

al T

his

was

a

wel

l-con

duct

ed a

nd g

ener

ally

w

ell-r

epor

ted

stud

y, w

hich

dra

ws

appr

opri

ate

conc

lusi

ons

and

can

be

cons

ider

ed t

o be

rel

iabl

e. A

s th

e au

thor

s su

gges

t fu

rthe

r st

udie

s ar

e re

quire

d to

exp

lore

pos

sibl

e va

riat

ions

in

PD

T t

reat

men

t

Appendix 15

232



233Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Rho

des

et a

l. (2

007)

85

Link

ed

publ

icat

ions

192–

197

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ries

Not

sta

ted

‘Eur

opea

n ho

spita

ls’

Lang

uage

Eng

lish

Stud

y de

sign

RC

T

(bet

wee

n-pa

rtic

ipan

t co

mpa

riso

n)N

o. o

f par

tici

pant

sTo

tal:

103

rand

omis

ed

(101

tre

ated

)In

terv

entio

n: 5

3 (6

0 le

sion

s)C

ompa

rato

r: 50

(58

le

sion

s)N

o. o

f rec

ruit

ing

cent

res

13Fo

llow

-up

peri

od

and

freq

uenc

y 3

mth

, th

en a

t 1,

2, 3

, 4 a

nd

5 yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Pr

imar

y nB

CC

Mai

n el

igib

ility

cri

teri

a H

isto

logi

cally

con

firm

ed

nBC

C, p

revi

ously

un

trea

ted

in p

atie

nts

≥ 18

yr. P

atie

nts

with

mor

e th

an 1

0 le

sion

s, po

rphy

ria,

or G

orlin

syn

drom

e w

ere

excl

uded

. Fur

ther

ex

clus

ion

crite

ria

wer

e re

port

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 60

Age

ran

ge: 3

8–95

yrM

ean

age:

69 yr

(PD

T

grou

p), 6

7 yr

(su

rger

y gr

oup)

Aro

und

90%

of p

atie

nts

had

only

one

lesi

on, a

nd

arou

nd t

hree

-qua

rter

s of

le

sion

s w

ere

betw

een

5 an

d 14

mm

in d

iam

eter

. T

he m

ajor

ity o

f pat

ient

s w

ere

clas

sifie

d as

Fi

tzpa

tric

k sk

in t

ype

II or

III

, and

lesi

ons

wer

e m

ostly

on

the

face

/sca

lp/t

runk

an

d ne

ck

Tria

l tre

atm

ents

MA

L–PD

T v

s ex

cisi

on s

urge

ryIn

terv

enti

on S

urfa

ce s

cale

re

mov

ed u

sing

sca

lpel

or

cure

tte

(with

out a

naes

thes

ia).

The

n on

e or

tw

o PD

T c

ycle

s w

ith m

ethy

l am

inol

evul

inat

e (1

60 m

g/g)

, eac

h co

mpr

isin

g of

tw

o se

ssio

ns (

1 w

k ap

art)

. Cre

am w

as a

pplie

d 1

mm

thi

ck a

nd t

o 5

mm

of

sur

roun

ding

tis

sue,

the

n co

vere

d w

ith a

n oc

clus

ive

dres

sing

for

3 hr

. Cre

am

then

was

hed

off w

ith 0

.9%

sa

line

solu

tion

imm

edia

tely

be

fore

illu

min

atio

n w

ith

non-

cohe

rent

red

ligh

t (5

70–6

70 n

m, t

otal

flue

nce

75 J/

cm2 ,

fluen

ce r

ate

of 5

0 to

200

mW

/cm

2 ), m

ean

light

de

nsity

of 1

27 m

W/c

m2 f

rom

a

stan

dard

ligh

t so

urce

If no

t C

R b

y 3m

th, 2

nd

trea

tmen

t cy

cle

adm

inis

tere

d.

76%

of l

esio

ns t

reat

ed w

ith

one

cycl

e on

lyC

ompa

rato

r Si

mpl

e el

liptic

al e

xcis

ion

surg

ery

with

at

leas

t 5-

mm

mar

gins

. Lo

cal a

naes

thes

ia

Mor

talit

y Fo

ur p

atie

nts

in e

ach

grou

p di

ed d

urin

g FU

(al

l co

nsid

ered

to

be u

nrel

ated

to

trea

tmen

t)M

orbi

dity

At

3 m

th: 4

8 le

sion

s (9

1%, 5

0 pa

tient

s) in

the

PD

T

grou

p, an

d 51

lesi

ons

(98%

, 47

patie

nts)

in t

he s

urge

ry g

roup

, sh

owed

CR

, mea

n di

ff =

4.8%

, ns.

At

1 yr

: 44/

53 P

DT

lesi

ons

(83%

) ha

d C

R v

s 50

/52

(96%

) su

rger

y le

sion

s (p

= 0

.15)

. Rec

urre

nce

was

4%

in P

DT

gro

up v

s 0%

in s

urge

ry g

roup

. At

2 yr

: 32/

53 (

60%

) PD

T

lesi

ons

had

CR

vs

44/5

2 (8

5%)

surg

ery

lesi

ons.

By t

his

stag

e, 1

1 (2

1%)

of P

DT

lesi

ons

wer

e lo

st t

o FU

vs

six

(11%

) su

rger

y le

sion

s. R

ecur

renc

e w

as 9

% in

PD

T g

roup

vs

2% in

sur

gery

gro

up. A

t 36

mth

: CR

79%

in P

DT

gro

up v

s 96

% in

sur

gery

gro

up. R

ecur

renc

e w

as 1

0% in

PD

T g

roup

vs

2% in

sur

gery

gro

up. A

t 5

yr: C

R w

as

76%

in t

he P

DT

gro

up a

nd 9

6% in

the

sur

gery

gro

up (

per-

prot

ocol

po

pula

tion,

p =

0.0

1). T

here

was

rec

urre

nce

in 1

4% o

f les

ions

in

PDT

gro

up a

nd 4

% in

the

sur

gery

gro

up (

p =

0.09

). O

nly

one

lesi

on

(in t

he s

urge

ry g

roup

) re

curr

ed w

ithin

the

3-

to 5

-yr

FU p

erio

d.

In t

he P

DT

gro

up, t

here

was

no

evid

ence

tha

t th

e re

curr

ence

rat

e w

as h

ighe

r in

larg

er le

sion

sQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y C

osm

etic

out

com

e w

as

rate

d by

inve

stig

ator

as

bein

g: A

t 3m

th, e

xcel

lent

or

good

in

36/4

4 pa

tient

s (8

2%)

havi

ng P

DT

vs

15/4

5 pa

tient

s (3

3%)

havi

ng

surg

ery

(p <

0.0

01).

At

1 yr

, exc

elle

nt o

r go

od in

33

of 4

2 (7

9%)

PDT

pat

ient

s vs

17

of 4

5 (3

8%)

surg

ery

patie

nts

(p <

0.0

01).

At

2 yr

, ex

celle

nt o

r go

od in

24/

29 (

83%

) PD

T p

atie

nts

vs 1

6 of

39

(41%

) su

rger

y pa

tient

s (p

< 0

.001

). A

t 36

mth

, exc

elle

nt o

r go

od in

83%

of

PD

T p

atie

nts

vs 3

7% s

urge

ry p

atie

nts.

At

5yr,

exce

llent

or

good

in

27

of 3

1 (8

7%)

PDT

pat

ient

s vs

19

of 3

5 (5

4%)

surg

ery

patie

nts,

p =

0.00

7). P

atie

nts

also

rat

ed g

loba

l cos

met

ic o

utco

me

on a

4-

poin

t sc

ale

at 3

, 12

and

24 m

th. N

o si

gnifi

cant

diff

eren

ce a

t 3

mth

, at

12

mth

exc

elle

nt o

r go

od in

41/

42 (

98%

) fo

r PD

T p

atie

nts

vs

36/4

3 (8

4%)

for

surg

ery,

p =

0.03

. At

24 m

th, P

DT

pat

ient

s re

port

ed

28/2

9 (9

7%)

vs 2

7/36

(75

%)

for

surg

ery,

p =

0.04

AE

s M

ore

PDT

pat

ient

s re

port

ed A

Es [

27/5

2 (5

2%)

vs 1

4/49

(29%

), p

= 0.

03].

Mos

t AEs

wer

e tr

ansi

ent

loca

l rea

ctio

ns s

uch

as b

urni

ng

sens

atio

ns, s

kin

pain

, or

eryt

hem

a. O

ne P

DT

pat

ient

had

to

stop

tre

atm

ent

due

to a

sev

ere

burn

ing

sens

atio

n; t

hree

sur

gery

pa

tient

s ha

d sk

in in

fect

ions

Aut

hors

’ con

clus

ions

Lo

ng-t

erm

FU

indi

cate

s su

peri

or e

ffica

cy o

f su

rger

y to

PD

T. H

owev

er,

PDT

is a

lso

an e

ffect

ive

trea

tmen

t an

d ex

hibi

ts a

m

ore

favo

urab

le c

osm

etic

ou

tcom

eB

rief

stu

dy a

ppra

isal

T

his

gene

rally

wel

l-co

nduc

ted

tria

l, w

hich

ha

d a

long

FU

per

iod,

was

re

port

ed in

tw

o pa

pers

an

d fo

ur a

bstr

acts

. The

re

sults

are

like

ly t

o be

re

liabl

e, a

lthou

gh t

he

3-m

th C

R r

esul

ts d

id v

ary

slig

htly

bet

wee

n re

port

s

Appendix 15

234



235Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sch

leie

r et

al.

(200

7)81

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry G

erm

any

Lang

uage

Eng

lish

Stud

y de

sign

RC

T

(bet

wee

n-pa

rtic

ipan

t co

mpa

riso

n)N

o. o

f par

tici

pant

sTo

tal:

24 (

112

lesi

ons)

Inte

rven

tion:

13

Com

para

tor:

11N

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

2, 4

an

d 12

wk

and

6 m

th

afte

r pr

imar

y tr

eatm

ent

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Su

perfi

cial

BC

CM

ain

elig

ibili

ty

crit

eria

His

tolo

gica

lly

veri

fied

BCC

of t

he s

kin,

hi

stol

ogic

ally

pro

ven

supe

rfici

al B

CC

with

no

dee

p in

filtr

atio

n (<

2 m

m),

no m

orph

eic

and

pigm

ente

d BC

C a

nd

good

pat

ient

com

plia

nce.

Ex

clus

ion

crite

ria

wer

e: U

ncle

ar h

isto

logy

, cl

inic

ally

nBC

C, e

xpec

ted

poor

com

plia

nce

of

the

patie

nt, u

ntre

ated

di

abet

es m

ellit

us a

nd

preg

nanc

yPa

tien

t ch

arac

teri

stic

s%

Mal

e: 54

Age

ran

ge: 4

2–96

yrM

ean

age

74 yr

The

vas

t m

ajor

ity o

f the

tu

mou

rs w

ere

loca

ted

in

the

head

and

nec

k ar

ea.

The

ave

rage

dia

met

er

of t

he le

sion

s w

as 7

mm

(r

ange

3–1

2 m

m). T

hree

pa

tient

s w

ith G

GS

wer

e in

clud

ed in

the

stu

dyC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

ALA

-bas

ed P

DT

vs

mA

LA-b

ased

PD

TIn

terv

enti

on A

LA a

nd m

ALA

gel

s w

ere

prep

ared

less

tha

n 1h

r be

fore

tr

eatm

ent

by d

isso

lvin

g in

a c

old

(app

rox

4°C

) th

erm

o ge

l (Lu

trol

F-1

27)

up t

o a

conc

entr

atio

n of

10%

of A

LA (

mA

LA)/

ml

(w/v

). The

gel

was

app

lied

3 m

m b

eyon

d th

e vi

sibl

e m

argi

n of

the

tum

our

and

was

ap

prox

imat

ely

5 m

m t

hick

. The

are

a w

as

cove

red

with

pla

ster

and

pro

tect

ed fr

om

light

. 3 h

r la

ter,

resi

dues

wer

e re

mov

ed

and

tum

our

area

s ci

rcle

d w

ith a

blu

e sk

in

mar

ker. T

he le

sion

was

the

n ill

umin

ated

w

ith a

dio

de la

ser

equi

pped

with

a

mic

role

ns fi

bre.

The

pow

er d

ensi

ty w

as

0.1 W

/cm

2 and

the

ene

rgy

dens

ity w

as

120

J/cm

2 . A d

iam

eter

of t

he ir

radi

ated

ar

ea o

f app

roxi

mat

ely

10 m

m w

as

sele

cted

and

dis

tanc

e la

ser-

diffu

ser-

skin

co

rres

pond

ed t

o 15

mm

. The

pro

cedu

re

was

per

form

ed w

ith o

r w

ithou

t lo

cal

anae

sthe

sia

acco

rdin

g to

the

pai

n m

anag

emen

t ne

eds

of t

he p

atie

nt. I

n ca

ses

whe

re t

reat

men

t w

as o

nly

part

ially

su

cces

sful

, the

the

rapy

was

rep

eate

d af

ter

the

final

exa

min

atio

n (1

2th

wk)

. Fu

rthe

r PD

T p

aram

eter

s w

ere

not

repo

rted

Com

para

tor

See

‘Inte

rven

tion’

for

deta

ils

Mor

bidi

ty A

LA g

roup

: 44

of 7

2 BC

C

(61%

) sh

owed

a C

R 1

2 w

k af

ter

the

1st

trea

tmen

t vs

mA

LA g

roup

: 23

of 4

0 BC

C

(58%

) N

ST

here

was

no

stat

istic

ally

sig

nific

ant

diffe

renc

e in

par

tial s

ucce

sses

(re

duct

ion

of t

he d

iam

eter

of t

he B

CC

of a

t le

ast

50%

of t

he in

itial

tum

our

size

) be

twee

n th

e gr

oups

. Thr

ee t

umou

rs (

4%)

in t

he

ALA

gro

up a

nd o

ne B

CC

(3%

) di

d no

t re

spon

d to

tre

atm

ent

and

show

ed n

o re

duct

ion

in t

umou

r si

ze. T

hese

pat

ient

s w

ere

give

n su

rgic

al t

reat

men

t. Ei

ght

BCC

s in

the

ALA

gro

up a

nd fi

ve in

the

m

ALA

gro

up d

evel

oped

a r

ecur

renc

e du

ring

the

6-m

th p

erio

d. A

fter

a se

cond

PD

T, se

ven

lesi

ons

in t

he A

LA g

roup

and

se

ven

in t

he m

ALA

gro

up w

ere

trea

ted

succ

essf

ully

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

ass

esse

dA

Es

Dur

ing

illum

inat

ion,

eig

ht A

LA

patie

nts

and

five

mA

LA p

atie

nts

expe

rien

ced

mod

erat

ely

pain

ful

sens

atio

ns in

the

tre

ated

are

(1–

4 on

the

pa

in s

cale

). Tw

o pa

tient

s in

the

mA

LA

grou

p ha

d st

abbi

ng p

ain

sens

atio

ns

(leve

l 6–7

on

the

pain

sca

le)

duri

ng t

he

lase

r ap

plic

atio

n an

d ha

d to

be

trea

ted

with

loca

l ana

esth

etic

. Fiv

e pa

tient

s in

A

LA g

roup

and

tw

o in

mA

LA g

roup

felt

mod

erat

e pa

in s

ensa

tions

up

to t

he 3

rd

day

post

illu

min

atio

n (1

–3 o

n th

e pa

in

scal

e)

Aut

hors

’ con

clus

ions

The

the

rape

utic

ou

tcom

e of

thi

s pi

lot

stud

y sh

owed

no

diff

eren

ce b

etw

een

PDT

with

ALA

an

d m

ALA

. Thi

s pr

elim

inar

y re

sult

will

re

quire

con

firm

atio

n in

furt

her

rese

arch

Bri

ef s

tudy

app

rais

al T

his

was

a p

ilot

stud

y in

pre

para

tion

for

a la

rger

clin

ical

tr

ial. A

s su

ch, i

t is

like

ly t

o ha

ve b

een

unde

rpow

ered

to

dete

ct s

tatis

tical

ly

sign

ifica

nt d

iffer

ence

s fo

r at

leas

t so

me

of t

he o

utco

mes

inve

stig

ated

. Tre

atm

ent

met

hods

wer

e w

ell d

escr

ibed

but

st

udy

met

hods

, suc

h as

met

hods

of

rand

omis

atio

n, c

once

alm

ent

of a

lloca

tion

and

blin

ding

, wer

e no

t re

port

ed in

det

ail

GG

S, G

orlin

–Gol

tz s

yndr

ome.

Appendix 15

234



235Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sol

er e

t al.

(200

0)82

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry N

orw

ayLa

ngua

ge E

nglis

hSt

udy

desi

gn

RC

T (

betw

een-

part

icip

ant

com

pari

son)

No.

of

part

icip

ants

Tota

l: 83

(24

5 le

sion

s)In

terv

entio

n: 4

1 (1

11 le

sion

s)C

ompa

rato

r: 42

(1

34 le

sion

s)N

o. o

f rec

ruit

ing

cent

res

One

Fo

llow

-up

peri

od

and

freq

uenc

y FU

at

1 w

k, an

d 3

and

6 m

th. S

ome

part

icip

ants

als

o fo

llow

ed u

p af

ter

1 an

d 2

yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Su

perfi

cial

BC

CM

ain

elig

ibili

ty c

rite

ria

Patie

nts

with

his

tolo

gica

lly/

cyto

logi

cally

con

firm

ed

supe

rfici

al B

CC

with

th

ickn

ess

< 1

mm

, and

di

amet

er <

3 cm

. Pat

ient

s w

ith

few

er t

han

six

lesi

ons

Pati

ent

char

acte

rist

ics

% M

ale:

47

Mea

n ag

e: 62

yrA

ll C

auca

sian

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

PD

T-la

ser

vs P

DT-

broa

dban

d la

mp

Inte

rven

tion

PD

T-la

ser:

Pre-

trea

tmen

t w

ith d

ress

ing

soak

ed w

ith 9

9%

dim

ethy

lsul

phox

ide

for

15 m

in fo

llow

ed

by 2

0% A

LA c

ream

and

cov

erin

g w

ith

occl

usiv

e dr

essi

ng fo

r 3h

. Cre

am w

as

was

hed

off b

efor

e ex

posu

re t

o lig

ht

of 6

30 n

m fr

om a

cop

per

vapo

ur la

ser

pum

ping

a d

ye la

ser.

Irra

dian

ce o

f 12

0–15

0 m

W/c

m2 ,

and

a lig

ht d

ose

of

100–

150

J/cm

2 (m

edia

n do

se 1

00 J/

cm2 )

Com

para

tor

PDT-

broa

dban

d la

mp:

As

for

PDT-

lase

r ex

cept

ligh

t so

urce

was

a

150W

hal

ogen

bul

b br

oadb

and

lam

p, gi

ving

filte

red

light

of b

etw

een

570

and

740n

m. I

rrad

ianc

e w

as 1

00–1

80 m

W/c

m2

and

tota

l lig

ht d

ose

rang

ed fr

om 1

50–

200

J/cm

2 with

med

ian

light

dos

e of

20

0 J/c

m2 . T

otal

irra

dian

ce in

clud

ing

infr

a-re

d w

as 1

35–2

40 m

W/c

m2

Mor

bidi

ty O

vera

ll, th

ere

wer

e no

st

atis

tical

ly s

igni

fican

t di

ffere

nces

(p

= 0

.49)

in r

espo

nse

rate

s (c

ompl

ete,

pa

rtia

l, or

non

e) b

etw

een

the

grou

ps

[CR

was

95/

111

lesi

ons

(86%

) fo

r la

ser

vs 1

10/1

34 (

82%

) fo

r la

mp]

. Pat

ient

s w

ith C

R w

ere

follo

wed

up

beyo

nd

the

prot

ocol

6-m

th p

erio

d. D

ata

wer

e pr

esen

ted,

but

not

sta

tistic

ally

ana

lyse

d –

recu

rren

ce a

fter

2 yr

s oc

curr

ed in

fo

ur le

sion

s fo

r th

e la

ser

grou

p, an

d fiv

e le

sion

s fo

r th

e la

mp

grou

pQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y O

vera

ll th

ere

wer

e no

sta

tistic

ally

si

gnifi

cant

diff

eren

ces

in c

osm

etic

res

ults

(p

= 0

.075

). R

esul

ts w

ere

scor

ed a

s be

ing

exce

llent

or

good

in 8

0 le

sion

s (8

4%)

in

the

lase

r gr

oup

vs 1

02 le

sion

s (9

2%)

in

the

lam

p gr

oup

AE

s D

urin

g th

e 1s

t w

k af

ter

trea

tmen

t 68

% o

f the

lase

r gr

oup

and

74%

of t

he

lam

p gr

oup

patie

nts

repo

rted

som

e de

gree

of d

isco

mfo

rt (

e.g.

stin

ging

, itc

hing

, pai

n). T

here

wer

e no

sta

tistic

ally

si

gnifi

cant

diff

eren

ces

betw

een

the

grou

ps fo

r AEs

eith

er d

urin

g or

afte

r tr

eatm

ent.

No

SAEs

wer

e re

port

ed

duri

ng 6

-mth

FU

per

iod

Aut

hors

’ con

clus

ions

Top

ical

ALA

–PD

T w

ith a

bro

adba

nd h

alog

en li

ght

sour

ce g

ives

cur

e ra

tes

and

cosm

etic

ou

tcom

e si

mila

r to

tho

se o

btai

ned

with

a

lase

r so

urce

Bri

ef s

tudy

app

rais

al A

lthou

gh t

his

was

qui

te a

wel

l-con

duct

ed s

tudy

, the

re

wer

e st

ill is

sues

whi

ch q

uest

ion

the

relia

bilit

y of

its

resu

lts: t

he a

utho

rs

ackn

owle

dged

tha

t th

e op

timum

w

avel

engt

h fo

r ALA

–PD

T is

635

nm

, but

63

0 nm

was

use

d fo

r th

e la

ser

grou

p, fo

r re

ason

s of

pra

ctic

ality

; lig

ht d

oses

var

ied

betw

een

patie

nts

with

in a

tre

atm

ent

grou

p; a

nd t

he M

/F r

atio

diff

ered

su

bsta

ntia

lly b

etw

een

the

trea

tmen

t gr

oups

Appendix 15

236



237Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sze

imie

s et

al. (

2008

)80

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ries

A

ustr

alia

, Ger

man

y, Sw

itzer

land

, UK

Lang

uage

Eng

lish

Stud

y de

sign

R

CT

(be

twee

n-pa

rtic

ipan

t co

mpa

riso

n)N

o. o

f pa

rtic

ipan

tsTo

tal:

196

(182

an

alys

ed)

Inte

rven

tion:

100

Com

para

tor:

96N

o. o

f rec

ruit

ing

cent

res

27: 1

0 in

U

K, 1

0 in

Ger

man

y, tw

o in

Sw

itzer

land

, fiv

e in

Aus

tral

iaFo

llow

-up

peri

od

and

freq

uenc

y 3,

6

and

12 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Su

perfi

cial

BC

CM

ain

elig

ibili

ty c

rite

ria

Patie

nts

over

18

yr w

ith

hist

olog

ical

ly c

onfir

med

pr

imar

y sB

CC

sui

tabl

e fo

r si

mpl

e ex

cisi

on s

urge

ry.

Patie

nts

with

mor

e th

an fi

ve

lesi

ons,

lesi

ons

in t

he m

id-

face

are

a, le

sion

s sm

alle

r th

an 8

mm

or

larg

er t

han

20 m

m w

ere

excl

uded

(o

ther

cri

teri

a re

port

ed)

Pati

ent

char

acte

rist

ics

% M

ale:

67A

ge r

ange

: 31–

92 yr

Mea

n ag

e: 64

yrA

ll pa

tient

s w

ere

Cau

casi

an,

and

the

mea

n no

. of l

esio

ns

per

patie

nt w

as 1

.4 (

rang

e 1–

5). M

ost

lesi

ons

wer

e lo

cate

d on

the

tru

nk o

r ne

ckC

onco

mit

ant

trea

tmen

t co

ncur

rent

tre

atm

ent

on

the

lesi

on a

reas

was

not

pe

rmitt

ed

Tria

l tre

atm

ents

MA

L–PD

T v

s Su

rger

yIn

terv

enti

on M

AL–

PDT:

Pat

ient

s re

ceiv

ed t

wo

trea

tmen

t se

ssio

ns, 7

d

apar

t. Le

sion

s w

ere

prep

ared

pri

or t

o ea

ch s

essi

on if

dee

med

nec

essa

ry b

y re

mov

ing

crus

ts a

nd r

ough

enin

g th

e su

rfac

e. 1

60 m

g/g

of M

AL

crea

m w

as

appl

ied

1 m

m t

hick

to

the

lesi

on a

nd

surr

ound

5–1

0 m

m o

f ski

n an

d co

vere

d w

ith a

n oc

clus

ive

dres

sing

for

3 hr

. Cre

am

was

was

hed

off u

sing

sal

ine

solu

tion

and

the

area

exp

osed

to

red

light

from

a

larg

e-fie

ld L

ED s

ourc

e fo

r be

twee

n 7

and

10 m

in, t

otal

ligh

t do

se 3

7 J/c

m2 .

Min

i-des

k fa

ns w

ere

prov

ided

to

cool

the

ir

radi

atio

n si

tes

duri

ng li

ght

expo

sure

Com

para

tor

Surg

ery:

One

sim

ple

ellip

tical

exc

isio

n su

rger

y w

as p

erfo

rmed

ac

cord

ing

to t

he in

vest

igat

ors

rout

ine

prac

tice

with

an

estim

ated

3-m

m m

argi

n fr

om e

stim

ated

edg

e of

the

lesi

on

Mor

bidi

ty (

all p

er p

roto

col a

naly

ses)

3-m

th c

ompl

ete

lesi

on r

espo

nse:

118/

128

(92%

) fo

r PD

T v

s 11

7/11

8 (9

9%)

in

surg

ery

12-m

th le

sion

rec

urre

nce:

11/1

18 (

9%)

for

PDT

vs

0.11

7 (0

%)

for

surg

ery

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Cos

met

ic o

utco

me

asse

ssed

by

patie

nt

and

inve

stig

ator

, in

both

cas

es P

DT

tr

eatm

ent

was

judg

ed t

o be

sup

erio

r12

-mth

inve

stig

ator

rat

ed a

sses

smen

t: 77

/83

(93%

) for

PD

T a

nd 4

4/86

(51%

) for

su

rger

y w

ere

cons

ider

ed a

s a

‘suc

cess

’, p

< 0.

001

AE

s Tre

atm

ent-

rela

ted

AE

wer

e hi

gher

in

the

PD

T (

37%

) th

an s

urge

ry (

15%

) gr

oup.

Mos

t re

late

d A

Es w

ere

of m

ild

to m

oder

ate

seve

rity

and

wer

e m

ost

com

mon

ly p

hoto

sens

itivi

ty (

31%

) re

actio

n fo

r PD

T a

nd w

ound

infe

ctio

n (5

%)

for

surg

ery

patie

nts

11%

of P

DT

pat

ient

s w

ith r

elat

ed

AEs

req

uire

d tr

eatm

ent

whi

le 5

7% o

f su

rger

y pa

tient

s w

ith r

elat

ed A

Es n

eede

d tr

eatm

ent

No

SAEs

wer

e re

cord

ed t

hat

wer

e co

nsid

ered

to

be r

elat

ed t

o ei

ther

tr

eatm

ent

Aut

hors

’ con

clus

ions

MA

L–PD

T

has

high

leve

ls o

f effi

cacy

and

exc

elle

nt

cosm

etic

out

com

es w

hen

trea

ting

sBC

C a

nd s

houl

d be

con

side

red

as a

n al

tern

ativ

e to

sur

gery

Bri

ef s

tudy

app

rais

al T

his

was

a w

ell-

repo

rted

and

con

duct

ed t

rial

; how

ever

, lo

nger

-ter

m F

U w

ould

pro

vide

use

ful

outc

ome

data

on

the

recu

rren

ce r

ates

. It

was

not

cle

ar if

the

stu

dy w

as a

dequ

atel

y po

wer

ed t

o sh

ow e

quiv

alen

ce o

f tr

eatm

ents

. Giv

en t

hat

incl

uded

pat

ient

s w

ere

rest

rict

ed t

o th

ose

elig

ible

for

surg

ery,

as t

he a

utho

rs h

ave

high

light

ed it

se

ems

plau

sibl

e th

at P

DT

may

be

mor

e ef

fect

ive

than

sho

wn

here

Appendix 15

236



237Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Top

e et

al.

(200

4)78

Dat

a so

urce

Abs

trac

tC

ount

ry U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

(b

etw

een-

part

icip

ant

com

pari

son)

No.

of p

arti

cipa

nts

Tota

l: 65

(80

lesi

ons)

Inte

rven

tion:

33

patie

nts

(41

lesi

ons)

Com

para

tor:

32 p

atie

nts

(39

lesi

ons)

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

d bu

t de

scri

bed

as b

eing

m

ultic

entr

eFo

llow

-up

peri

od a

nd

freq

uenc

y N

ot c

lear

, bu

t ap

pear

ed t

o be

at

leas

t 6

mth

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y nB

CC

Mai

n el

igib

ility

cri

teri

a N

ot s

tate

dPa

tien

t ch

arac

teri

stic

s N

ot s

tate

dC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

MA

L–PD

T (

met

hyl

amin

olev

ulin

ate)

vs

PDT

(pl

aceb

o cr

eam

)In

terv

enti

on M

AL–

PDT:

Pat

ient

s re

ceiv

ed t

wo

cycl

es (

1 w

k ap

art)

of

met

hyl a

min

olev

ulin

ate

PDT.

The

re w

as

surf

ace

debr

idem

ent

and

slig

ht le

sion

de

bulk

ing

prio

r to

PD

T. BC

C w

ith

part

ial c

linic

al r

espo

nse

at 3

mth

wer

e re

-tre

ated

. Fur

ther

PD

T p

aram

eter

s w

ere

not

repo

rted

Com

para

tor A

s fo

r M

AL–

PDT

usi

ng

plac

ebo

crea

m

Mor

bidi

ty C

ompl

ete

clin

ical

res

pons

e w

as 8

0% (

33/4

1 le

sion

s) fo

r ac

tive

PDT

vs

51%

(20

/39

lesi

ons)

for

plac

ebo

PDT.

Com

plet

e hi

stol

ogic

al r

espo

nse

was

78%

(32

/41

lesi

ons)

vs

33%

(13

/39

lesi

ons)

, bot

h ap

pear

ed t

o be

at

p <

0.00

1Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y Fo

r si

tes

show

ing

com

plet

e cl

inic

al

resp

onse

, inve

stig

ator

-ass

esse

d co

smet

ic

outc

ome

was

exc

elle

nt o

r go

od in

93%

of

act

ive

PDT

vs

90%

of p

lace

bo P

DT

Patie

nt s

atis

fact

ion

with

PD

T c

ompa

red

with

pre

viou

s tr

eatm

ent

was

bet

ter

in

60%

of M

AL–

PDT

pat

ient

s, an

d 52

% in

pl

aceb

o PD

T p

atie

nts

AE

s The

re w

ere

no s

yste

mic

AEs

in

eith

er g

roup

. Loc

al A

Es: 9

1% in

the

ac

tive

grou

p vs

75%

in t

he p

lace

bo

grou

p. M

ild t

o m

oder

ate

eryt

hem

a, bu

rnin

g, st

ingi

ng, a

nd p

ain

foun

d in

bot

h gr

oups

. Pai

n oc

curr

ed fo

r a

med

ian

of 2

d in

act

ive

PDT

gro

up v

s 3–

6 d

in

plac

ebo

PDT

gro

up. A

ll SA

Es in

bot

h gr

oups

wer

e no

t re

late

d to

tre

atm

ent

Aut

hors

’ con

clus

ions

PD

T w

as

clin

ical

ly a

nd h

isto

logi

cally

sup

erio

r to

pl

aceb

o PD

T in

tre

atin

g nB

CC

Bri

ef s

tudy

app

rais

al V

ery

little

in

form

atio

n w

as a

vaila

ble

in t

his

abst

ract

. It

was

not

alw

ays

clea

r w

heth

er r

esul

ts w

ere

for

lesi

ons

or

indi

vidu

al p

atie

nts

Appendix 15

238



239Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Wan

g et

al.

(200

1)88

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry S

wed

enLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

(b

etw

een-

part

icip

ant

com

pari

son)

No.

of p

arti

cipa

nts

Tota

l: 88

Inte

rven

tion:

47

Com

para

tor:

41N

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

at 1

, 4, 8

and

12

wk,

and

at 1

yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y N

on-m

orph

oeic

BC

Cs

(sup

erfic

ial a

nd

nodu

lar)

Mai

n el

igib

ility

cri

teri

a Pa

tient

s ag

ed 2

0–90

, with

hi

stop

atho

logi

cally

ver

ified

BC

Cs

suita

ble

for

both

PD

T a

nd c

ryos

urge

ry, w

ere

elig

ible

. Exc

lusi

on c

rite

ria

(e.g

. pre

gnan

cy)

wer

e al

so

repo

rted

Pati

ent

char

acte

rist

ics

% M

ale:

50A

ge r

ange

: 42–

88 yr

The

re w

ere

39 p

atie

nts

with

sup

erfic

ial B

CC

s an

d 49

with

nBC

Cs.

54%

wer

e on

the

tru

nk, 2

8% o

n he

ad

and

neck

, 11%

on

legs

, and

7%

on

arm

sC

onco

mit

ant

trea

tmen

t Lo

cal a

naes

thet

ic a

vaila

ble

duri

ng p

roce

dure

s. U

se

of a

nalg

esic

dru

gs w

as

perm

itted

for

pain

rel

ief

duri

ng t

he w

eek

follo

win

g pr

oced

ures

Tria

l tre

atm

ents

ALA

–PD

T v

s C

ryot

hera

pyIn

terv

enti

on L

esio

ns w

ere

1st

prep

ared

(re

mov

al o

f str

atum

cor

neum

m

ater

ial u

sing

sca

lpel

/96%

alc

ohol

/is

oton

ic s

alin

e). 2

0% A

LA w

as t

hen

appl

ied

to le

sion

with

1-c

m m

argi

n, a

nd

cove

red

with

a t

hin

occl

usiv

e dr

essi

ng.

6 hr

afte

r ALA

, 635

-nm

ligh

t th

roug

h a

600-µ

m o

ptic

al fi

bre

(with

a c

lear

-cut

po

lishe

d en

d) fr

om a

Nd:

YAG

lase

r w

as

appl

ied.

The

sin

gle

light

dos

e w

as 6

0 J/c

m2 ,

and

the

mea

n flu

ence

rat

e 80

mW

/cm

2 . La

rger

lesi

ons

had

to b

e ill

umin

ated

with

m

ore

than

one

ligh

t so

urce

. Pat

ient

s w

ith p

ain

duri

ng li

ght

expo

sure

rec

eive

d w

ater

spr

ay a

t 15

–20°

C. A

dditi

onal

tr

eatm

ent

give

n if

ther

e w

as e

vide

nce

of r

esid

ual t

umou

r gr

owth

at

the

4, 8

or

12 w

k ex

amin

atio

nsC

ompa

rato

r Tre

atm

ent

with

a li

quid

ni

trog

en u

nit

usin

g a

spra

y te

chni

que.

Two

free

ze–t

haw

cyc

les

wer

e gi

ven,

and

the

ar

ea fr

ozen

for

25–3

0 s

each

tim

e, w

ith

a th

awin

g pe

riod

of 2

–4 m

in in

bet

wee

n.

Add

ition

al t

reat

men

t gi

ven

if th

ere

was

ev

iden

ce o

f res

idua

l tum

our

grow

th a

t th

e 4-

, 8-

or 1

2-w

k ex

amin

atio

ns

Mor

talit

y O

ne p

atie

nt d

ied

in e

ach

grou

p af

ter

the

3-m

th F

U. B

oth

deat

hs

wer

e un

rela

ted

to B

CC

and

its

trea

tmen

tM

orbi

dity

Mor

e pa

rtic

ipan

ts in

the

PD

T

grou

p ha

d to

be

re-t

reat

ed (

13/4

4, 3

0%)

com

pare

d w

ith t

he c

ryos

urge

ry g

roup

(1

/39,

3%

). The

rec

urre

nce

rate

at

1 yr

w

as h

ighe

r in

the

PD

T g

roup

(11

/44,

25%

vs

6/3

9, 1

5%),

thou

gh n

ot s

tatis

tical

ly

sign

ifica

nt (

and

the

PDT

gro

up h

ad fe

wer

cl

inic

ally

obv

ious

rec

urre

nces

). A

fter

1 w

k, th

e PD

T g

roup

had

a s

igni

fican

tly

shor

ter

heal

ing

time

in t

erm

s of

le

akag

e an

d oe

dem

a (p

< 0

.001

), bu

t no

t er

ythe

ma.

The

re w

as a

lso

a si

gnifi

cant

di

ffere

nce

in le

akag

e at

1 m

th, f

avou

ring

th

e PD

T g

roup

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

The

cos

met

ic o

utco

me

was

sig

nific

antly

be

tter

at

1 yr

in t

he P

DT

gro

up fo

r hy

popi

gmen

tatio

n, s

car

form

atio

n,

tissu

e de

fect

s (a

ll p

< 0.

001)

, and

hy

perp

igm

enta

tion

(p <

0.0

5)A

Es T

here

was

no

stat

istic

ally

si

gnifi

cant

diff

eren

ce in

mea

n pa

in

VAS

scor

es d

urin

g tr

eatm

ent

(PD

T

43 v

s cr

yosu

rger

y 32

). O

ne P

DT

pa

tient

req

uire

d lo

cal a

naes

thet

ic. O

ne

cryo

surg

ery

patie

nt d

evel

oped

a b

acte

rial

in

fect

ion

at t

he t

reat

men

t si

te. D

urin

g th

e 1s

t w

eek

post

tre

atm

ent

eigh

t PD

T

patie

nts

and

two

cryo

surg

ery

patie

nts

used

ana

lges

ic m

edic

atio

n (p

< 0

.05)

Aut

hors

’ con

clus

ions

ALA

–PD

T

is c

ompa

rabl

e w

ith c

ryos

urge

ry

as a

tre

atm

ent

mod

ality

for

BCC

s. R

etre

atm

ents

are

mor

e co

mm

on w

ith

PDT,

but

this

can

eas

ily b

e pe

rfor

med

du

e to

sho

rter

hea

ling

times

, les

s sc

arri

ng, a

nd b

ette

r co

smet

ic o

utco

me,

w

hich

follo

ws A

LA–P

DT

Bri

ef s

tudy

app

rais

al T

his

stud

y w

as

gene

rally

qui

te w

ell c

ondu

cted

and

the

re

sults

are

like

ly t

o be

rel

iabl

e. H

owev

er,

mor

e in

form

atio

n on

loss

es t

o FU

and

an

y sa

mpl

e si

ze c

alcu

latio

n us

ed, w

ould

ha

ve b

een

usef

ul

Appendix 15

238



239

Appendix 16 Barrett’s oesophagus data extraction

Appendix 16

240



241Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Ack

royd

et

al. (

2000

)95

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

K

Lang

uage

Eng

lish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 36

Inte

rven

tion:

18

Com

para

tor:

18N

o. o

f rec

ruit

ing

cent

res

Not

st

ated

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU a

t 1,

6, 1

2 an

d 24

mth

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y BO

– L

GD

Mai

n el

igib

ility

cri

teri

a Pa

tient

s w

ith L

GD

in

circ

umfe

rent

ial B

O o

f at

leas

t 3

cm in

leng

th, w

ho w

ere

rece

ivin

g om

epra

zole

wer

e el

igib

le. H

owev

er, h

isto

logi

cal

re-e

xam

inat

ion

afte

r bi

opsy

ha

d to

con

firm

the

dia

gnos

isPa

tien

t ch

arac

teri

stic

s%

Mal

e: 83

Age

ran

ge: 3

0–71

yrM

edia

n ag

e: 56

yrR

ange

of p

re-t

reat

men

t le

ngth

s of

Bar

rett

’s: 3

–15

cmC

onco

mit

ant

trea

tmen

t Pa

tient

s w

ere

give

n an

alge

sic

and

antie

met

ic d

rugs

as

requ

ired

follo

win

g tr

eatm

ent.

Patie

nts

wer

e al

so s

uppl

ied

with

ant

acid

s to

tak

e as

ne

eded

. Thr

ough

out

the

trea

tmen

t an

d FU

per

iod

patie

nts

wer

e m

aint

aine

d on

20

mg

omep

razo

le d

aily

Tria

l tre

atm

ents

ALA

–PD

T v

s Pl

aceb

o-PD

TIn

terv

enti

on P

atie

nts

dran

k 30

mg/

kg A

LA (

diss

olve

d in

50

ml o

f ora

nge

juic

e) fo

llow

ed 4

hr

late

r by

lase

r en

dosc

opy

(und

er in

trav

enou

s se

datio

n an

d an

alge

sia)

whe

n th

e ex

tent

of

Barr

ett’s

are

a w

as r

ecor

ded.

A c

oppe

r va

pour

lase

r de

liver

ed b

y a

fibre

with

a

diffu

ser

tip w

as u

sed

to d

eliv

er g

reen

lig

ht (

514

nm)

at a

pow

er d

ensi

ty o

f 12

0 m

W/c

m2 f

or 5

00 s

per

3-cm

leng

th.

All

patie

nts

had

two

sepa

rate

tre

atm

ents

(d

ista

l, th

en p

roxi

mal

, tot

al t

reat

men

t tim

e 10

00 s,

ene

rgy

dens

ity 6

0 J/c

m2 )

so

that

6 cm

of o

esop

hagu

s w

as t

reat

ed

(upp

er 6

cm o

f Bar

rett

’s m

ucos

a). T

his

repr

esen

ted

com

plet

e tr

eatm

ent

of

Barr

ett’s

epi

thel

ium

in o

ne-h

alf o

f the

pa

tient

s. Pa

tient

s re

mai

ned

in h

ospi

tal

until

dar

k, an

d w

ere

advi

sed

to a

void

br

ight

ligh

t fo

r 24

hr

Com

para

tor A

s fo

r ab

ove,

exc

ept

oran

ge ju

ice

alon

e w

as u

sed

as p

lace

bo

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty In

the

PD

T g

roup

16/

18

(89%

) sh

owed

mac

rosc

opic

evi

denc

e of

re

gres

sion

at

FU e

ndos

copy

, com

pare

d w

ith 2

/18

(11%

) in

the

pla

cebo

gro

up;

the

corr

espo

ndin

g m

edia

n re

duct

ion

in a

reas

wer

e 30

% fo

r PD

T v

s 0%

for

plac

ebo

(bot

h p

< 0.

001)

. All

regr

essi

on

case

s di

spla

yed

norm

al s

quam

ous

muc

osa

whe

n bi

opsi

ed. T

here

was

a r

educ

tion

in

prev

alen

ce o

f dys

plas

ia in

favo

ur o

f the

PD

T g

roup

(0/

18 v

s 12

/18,

p <

0.0

01).

Alth

ough

it w

as u

ncle

ar a

s to

whi

ch F

U

poin

t th

ese

resu

lts r

elat

e to

, the

aut

hors

di

d st

ate

that

the

effe

cts

of t

reat

men

t w

ere

mai

ntai

ned

for

up t

o 24

mth

AE

s All

PDT

pat

ient

s ex

peri

ence

d ch

est

pain

dur

ing

trea

tmen

t th

at p

ersi

sted

for

3–5

d, a

nd w

as a

ggra

vate

d by

sw

allo

win

g or

cou

ghin

g. O

ne p

atie

nt d

evel

oped

a

mild

ski

n ra

sh o

n ex

posu

re t

o su

nlig

ht

(res

olve

d w

ithin

48

hr).

No

patie

nts

com

plai

ned

of d

ysph

agia

. No

resu

lts

appe

ared

to

have

bee

n re

port

ed fo

r th

e pl

aceb

o gr

oup

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

ALA

–PD

T c

an

prov

ide

safe

and

effe

ctiv

e ab

latio

n of

low

-gr

ade

dysp

last

ic e

pith

eliu

mB

rief

stu

dy a

ppra

isal

Thi

s sm

all s

tudy

w

as g

ener

ally

wel

l con

duct

ed, a

nd t

he

resu

lts a

ppea

r re

liabl

e. H

owev

er, i

t sh

ould

be

not

ed t

hat

no r

esul

ts a

ppea

r to

hav

e be

en r

epor

ted

on A

Es in

the

pla

cebo

gr

oup,

and

it w

as u

ncle

ar t

o w

hich

FU

th

e m

ain

stud

y re

sults

rel

ate

BO, B

arre

tt’s

oeso

phag

us.

Appendix 16

240



241Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Ack

royd

et a

l. (1

996)

96

Dat

a so

urce

Abs

trac

tC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 28

Inte

rven

tion:

Not

sta

ted

Com

para

tor:

Not

sta

ted

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od a

nd

freq

uenc

y N

ot s

tate

d

Trea

tmen

t in

tent

ion

Cur

ativ

e (d

osin

g st

udy)

Type

(s)

of c

ance

r an

d hi

stol

ogy

Dys

plas

tic B

OM

ain

elig

ibili

ty

crit

eria

Not

sta

ted

Pati

ent

char

acte

rist

ics

Not

st

ated

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

ALA

–PD

T 3

0 m

g/kg

vs

ALA

–PD

T 5

0 m

g/kg

vs

plac

ebo

Inte

rven

tion

Ora

l ALA

at

30 o

r 50

mg/

kg, o

r pl

aceb

o, w

as fo

llow

ed 4

hr

late

r by

ligh

t ad

min

istr

atio

n. N

o fu

rthe

r pa

ram

eter

s w

ere

repo

rted

Com

para

tor

See

‘Inte

rven

tion’

2nd

com

para

tor

See

‘Inte

rven

tion’

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty N

ot a

sses

sed

AE

s In

the

30-

mg/

kg g

roup

, one

pat

ient

ha

d m

ild p

hoto

sens

itivi

ty, b

ut n

o ot

her

AEs

wer

e se

en. I

n th

e 50

-mg/

kg g

roup

, oe

soph

agea

l dis

com

fort

, hai

r lo

ss, a

nd

tran

sien

t di

stur

banc

e of

live

r fu

nctio

n te

st r

esul

ts w

ere

obse

rved

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

ALA

–PD

T

at 3

0 m

g/kg

sho

uld

prov

ide

optim

al

trea

tmen

t co

nditi

ons

in B

OB

rief

stu

dy a

ppra

isal

The

abs

ence

of

impo

rtan

t m

etho

dolo

gica

l, po

pula

tion,

an

d re

sult

deta

ils in

thi

s ab

stra

ct o

f a

smal

l stu

dy, m

eans

it is

diffi

cult

to

asse

ss t

he r

elia

bilit

y of

its

resu

lts

Appendix 16

242



243Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Hag

e et

al.

(200

4)97

Link

ed p

ublic

atio

ns19

8

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry T

he

Net

herl

ands

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

40In

terv

entio

n: P

DT

20

+ 1

00: 1

3C

ompa

rato

r: PD

T10

0: 1

32n

d C

ompa

rato

r: A

PC: 1

4N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

an

d fr

eque

ncy

6 w

k, 6,

12,

18

and

24 m

th

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Pa

tient

s w

ith B

O

with

out

dysp

lasi

a or

with

LG

DM

ain

elig

ibili

ty c

rite

ria

Patie

nts

18 yr

or

over

with

BO

w

ithou

t dy

spla

sia

or w

ith L

GD

on

his

tolo

gica

l exa

min

atio

n w

ere

elig

ible

. Pat

ient

s ha

d to

hav

e a

BO

leng

th o

f 2–5

cm a

nd s

peci

alis

ed

inte

stin

al m

etap

lasi

a. A

ll pa

tient

s w

ere

taki

ng P

PIs

for

at le

ast

6 m

th

befo

re t

reat

men

t. Ex

clus

ion

crite

ria

wer

e in

tole

ranc

e to

(re

peat

ed)

endo

scop

y, pr

egna

ncy,

acut

e po

rphy

ria

and

inte

rcur

rent

dis

ease

s pr

eclu

ding

sur

viva

l dur

ing

the

stud

y pe

riod

Pati

ent

char

acte

rist

ics

% M

ale:

78M

edia

n ag

e: 59

yrA

ge r

ange

: 41–

72 yr

M

ean

BO le

ngth

: 3 cm

(ra

nge

2–5

cm)

Dys

plas

ia: N

one

32; L

GD

ei

ght

Con

com

itan

t tr

eatm

ent

If co

mpl

ete

elim

inat

ion

of B

O w

as

not

achi

eved

by

the

desi

gnat

ed

trea

tmen

t at

6 w

k, th

e re

mai

ning

BO

was

abl

ated

by

addi

tiona

l APC

w

ith a

max

imum

of t

wo

sess

ions

at

4-w

k in

terv

als.

Patie

nts

wer

e tr

eate

d w

ith a

dai

ly d

ose

of a

t le

ast

40 m

g of

om

epra

zole

for

the

dura

tion

of t

he s

tudy

. Mea

n do

se

47.5

mg

(ran

ge 4

0–80

mg)

Tria

l tre

atm

ents

PD

T w

ith

frac

tiona

ted

dose

(20

+ 1

00) A

LA v

s PD

T w

ith s

ingl

e-do

se A

LA v

s APC

Inte

rven

tion

Fra

ctio

nate

d PD

T:

60 m

g/kg

ALA

was

dis

solv

ed in

20

ml

of o

rang

e ju

ice.

All

patie

nts

wer

e ke

pt in

a d

arke

ned

room

for

36 h

r. A

KT

P/53

2 dy

e la

ser

mod

ule

was

us

ed t

o de

liver

ligh

t at

a w

avel

engt

h of

630

nm

. PD

T w

as p

erfo

rmed

w

ith a

flue

nce

of 2

0 J/c

m2 a

t 1

hr

and

100

J/cm

2 at

4 hr

afte

r ALA

ad

min

istr

atio

n. L

ight

del

iver

y w

as

perf

orm

ed u

sing

an

infla

tabl

e ba

lloon

w

ith a

n in

flate

d di

amet

er o

f 2.5

cm.

Cal

cula

ted

tota

l flue

nce

rate

was

10

0 m

W/c

m2

Com

para

tor

Sing

le-d

ose

ALA

–PD

T:

As

for

frac

tiona

ted

PDT

with

the

ex

cept

ion

that

the

re w

as a

sin

gle

illum

inat

ion

of 1

00 J/

cm2 a

t 4

hr a

fter

ALA

adm

inis

trat

ion

2nd

com

para

tor

APC

: an

Arg

on

Beam

er 2

dev

ice,

APC

300

was

use

d w

ith a

gas

flow

rat

e of

2 l/

min

at

a po

wer

set

ting

of 6

5 W. T

he a

im w

as t

o ab

late

tw

o-th

irds

of t

he o

esop

hage

al

circ

umfe

renc

e of

BO

dur

ing

the

1st

sess

ion

and

in t

he fo

llow

ing

sess

ion

to

abla

te t

he r

emai

nder

. APC

invo

lved

a

max

imum

of t

wo

trea

tmen

t se

ssio

ns

per

patie

nt a

t 4-

wk

inte

rval

s

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty A

t 6

wk,

mea

n en

dosc

opic

BO

sur

face

red

uctio

n w

as 5

1% (

rang

e 20

–100

%)

in t

he s

ingl

e do

se P

DT

gr

oup,

86%

(ra

nge

0–10

0%)

in t

he

frac

tiona

ted

PDT

gro

up a

nd 9

3%

(ran

ge 4

0–10

0%)

in t

he A

PC g

roup

. T

his

was

sta

tistic

ally

sig

nific

ant

for

the

com

pari

son

betw

een

sing

le-d

ose

PDT

and

frac

tiona

ted

dose

PD

T a

nd

sing

le-d

ose

PDT

and

APC

. Diff

eren

ces

betw

een

frac

tiona

ted

dose

PD

T a

nd

APC

wer

e no

t si

gnifi

cant

. Rat

es o

f co

mpl

ete

abla

tion

wer

e ns

bet

wee

n th

e gr

oups

. 6-,

12-

and

18-m

th d

ata

not

extr

acte

d as

pat

ient

s w

ere

then

el

igib

le t

o re

ceiv

e A

PCA

Es

23 o

f 26

patie

nts

acro

ss t

he

two

PDT

gro

ups

and

five

of 1

4 in

the

A

PC g

roup

exp

erie

nced

pai

n du

ring

tr

eatm

ent

(p <

0.0

1). T

here

wer

e m

ore

case

s of

nau

sea

and

vom

iting

w

ith P

DT

(7

vs 0

in A

PC, p

< 0

.05)

an

d pa

tient

s ha

d m

ore

elev

ated

live

r en

zym

e re

sults

in t

ests

(20

vs

0,

p <

0.01

). D

iffer

ence

s in

ody

noph

agia

, fe

ver,

sudd

en d

eath

and

str

ictu

re

form

atio

n w

ere

not

sign

ifica

ntR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

APC

alo

ne

or A

LA–P

DT

in c

ombi

natio

n w

ith

APC

can

lead

to

com

plet

e re

vers

al o

f Ba

rret

t’s e

pith

eliu

m in

at

leas

t tw

o-th

irds

of p

atie

nts

whe

n ad

min

iste

red

in m

ultip

le t

reat

men

t se

ssio

ns. T

he

auth

ors

did

not

reco

mm

end

use

of

thes

e te

chni

ques

for

prop

hyla

ctic

ab

latio

n of

BO

Bri

ef s

tudy

app

rais

al T

his

was

a

smal

l tri

al a

nd t

he lo

w n

umbe

rs o

f pa

tient

s ac

ross

the

thr

ee g

roup

s m

ay

have

mea

nt t

here

was

insu

ffici

ent

pow

er t

o de

tect

tre

atm

ent

diffe

renc

es

whe

re t

hey

exis

ted.

A fu

rthe

r pr

oble

m

is t

hat

all p

atie

nts

who

did

not

re

spon

d ad

equa

tely

wer

e gi

ven

APC

, so

the

long

-ter

m e

ffect

of P

DT

alo

ne

is u

ncle

ar

Appendix 16

242



243Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Kel

ty e

t al

. (20

04)10

2

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

25

Inte

rven

tion:

Fiv

eC

ompa

rato

r: Fi

ve2n

d C

ompa

rato

r: Fi

ve3r

d C

ompa

rato

r: Fi

ve4t

h C

ompa

rato

r: Fi

veN

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

4 w

k

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y N

on-d

yspl

astic

BO

Mai

n el

igib

ility

cr

iter

ia P

atie

nts

alre

ady

part

icip

atin

g in

a la

rge

coho

rt

stud

y on

BO

with

bi

opsy

pro

ven

Barr

ett’s

epi

thel

ium

Pati

ent

char

acte

rist

ics

% M

ale:

80M

edia

n ag

e: 63

yr

Age

ran

ge: 3

1–81

yrM

edia

n le

ngth

of

Barr

ett’s

epi

thel

ium

w

as 4

cm (

rang

e 2–

15 cm

), no

pat

ient

s ha

d hi

gh o

r LG

D o

n bi

opsy

Con

com

itan

t tr

eatm

ent

40 m

g es

omep

razo

le d

aily

Tria

l tre

atm

ents

ALA

–PD

T a

t va

riou

s do

ses

(30

mg/

kg o

r 60

mg/

kg)

at 4

- or

6-

hr in

cuba

tion

times

or

with

frac

tiona

ted

illum

inat

ion

Inte

rven

tion

30

mg/

kg A

LA–P

DT,

light

de

liver

ed b

y en

dosc

opy

afte

r 4-

hr P

DT

pr

otoc

ol: A

LA d

isso

lved

in 5

0 m

l of o

rang

e ju

ice

and

take

n or

ally.

Pat

ient

s ke

pt in

dim

ly

lit r

oom

pri

or t

o tr

eatm

ent.

At

appr

opri

ate

time

patie

nts

unde

rwen

t en

dosc

opy

with

in

trav

enou

s se

datio

n, a

nalg

esia

and

an

antie

met

ic d

rug.

Ballo

on a

pplic

ator

was

pl

aced

ove

r a

guid

ewire

in t

he o

esop

hagu

s an

d po

sitio

n co

nfirm

ed e

ndos

copi

cally

. Ba

lloon

was

infla

ted

to a

roun

d 20

mm

Hg

and

light

del

iver

ed b

y a

5-cm

cyl

indr

ical

di

ffuse

r fib

re. R

ed li

ght

(635

nm

, 2W

di

ode

lase

r) w

as u

sed

at fl

uenc

e ra

te o

f 68

mW

/cm

2 for

a t

otal

dos

e of

85

J/cm

2 . Pa

tient

s re

cove

red

in a

dim

ly li

t ro

om,

disc

harg

ed w

ith o

ral a

nalg

esia

and

adv

ice

to

avoi

d br

ight

ligh

ts fo

r 24

hr

Com

para

tor

30 m

g/kg

ALA

–PD

T, lig

ht

deliv

ered

by

endo

scop

y af

ter

6 hr

2nd

com

para

tor

30 m

g/kg

ALA

–PD

T

repe

ated

at

2 hr

, lig

ht d

eliv

ered

by

endo

scop

y af

ter

4 hr

3rd

com

para

tor

60 m

g/kg

ALA

–PD

T, lig

ht

deliv

ered

by

endo

scop

y af

ter

4 hr

4th

com

para

tor

60 m

g/kg

ALA

–PD

T, lig

ht

deliv

ered

by

endo

scop

y af

ter

6 hr

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty A

t 1

mth

FU

all

patie

nts

show

ed a

red

uctio

n in

the

are

a of

Bar

rett

’s ep

ithel

ium

in t

he t

reat

ed a

rea,

med

ian

redu

ctio

n fo

r al

l 25

patie

nts

was

60%

. M

edia

n re

duct

ion

in a

rea

vari

ed b

etw

een

30%

and

60%

for

each

tre

atm

ent

grou

p. T

he g

reat

est

redu

ctio

ns w

ere

seen

in t

he

frac

tiona

ted

and

30 m

g/kg

gro

ups

(all

60%

), bu

t th

is d

iffer

ence

was

not

sta

tistic

ally

si

gnifi

cant

AE

s N

o m

ajor

AEs

– n

o pe

rfor

atio

ns o

r st

rict

ures

. Sig

nific

ant

N&

V o

ccur

red

in

32%

of p

atie

nts

who

req

uire

d fu

rthe

r an

ti-em

etic

tre

atm

ent.

N&

V w

as m

ore

com

mon

in

pat

ient

s w

ho r

ecei

ved

the

high

er d

ose

of A

LA. F

ive

patie

nts

had

a do

cum

ente

d ph

otos

ensi

tivity

rea

ctio

n –

all w

ere

mild

ca

ses

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

Low

dos

e A

LA–

PDT

app

ears

to

be a

saf

e pr

otoc

ol fo

r th

e ab

latio

n of

BO

. The

aut

hors

rec

omm

end

that

ALA

sho

uld

be g

iven

ora

lly a

s 30

mg/

kg

4- t

o 6-

hr b

efor

e ac

tivat

ion

and

coul

d be

ta

ken

at h

ome

Bri

ef s

tudy

app

rais

al T

his

was

a s

mal

l st

udy

that

aim

ed t

o es

tabl

ish

optim

um

dosa

ge r

egim

es. A

lthou

gh p

atie

nts

wer

e ra

ndom

ised

to

trea

tmen

t, no

info

rmat

ion

on b

lindi

ng o

r al

loca

tion

conc

ealm

ent

was

pro

vide

d. T

he s

ampl

e si

ze a

ppea

rs t

o ha

ve b

een

too

smal

l to

view

the

aut

hors

’ co

nclu

sion

s as

bei

ng r

elia

ble

Appendix 16

244



245Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Kel

ty e

t al.

(200

4)98

Link

ed

publ

icat

ions

199–

201

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 72

Inte

rven

tion:

35

(PD

T)

Com

para

tor:

37

(APC

)N

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

1 da

y, 4

wk

then

6, 1

2 an

d 24

mth

afte

r su

cces

sful

tre

atm

ent

or fi

ve s

essi

ons

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y BO

Mai

n el

igib

ility

cr

iter

ia P

atie

nts

wer

e in

vite

d to

ta

ke p

art

from

an

end

osco

pic

scre

enin

g pr

ogra

mm

e (o

ver

150

wer

e ap

proa

ched

). N

o fu

rthe

r de

tails

re

port

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 81

Age

ran

ge: 2

8–83

yr

Med

ian

age:

61 yr

All

patie

nts

had

biop

sy p

rove

n Ba

rret

t’s e

pith

eliu

m

(med

ian

leng

th o

f 4

cm, r

ange

2–1

5cm

). N

o pa

tient

s ha

d hi

gh

or L

GD

Con

com

itan

t tr

eatm

ent

40 m

g es

omep

razo

le d

aily,

w

ith o

ral a

nalg

esia

as

requ

ired

Tria

l tre

atm

ents

ALA

–PD

T v

s APC

Inte

rven

tion

ALA

–PD

T: 3

0 m

g/kg

of A

LA

diss

olve

d in

50

ml o

f ora

nge

juic

e ta

ken

oral

ly, p

atie

nt k

ept

in a

dim

roo

m p

rior

to

tre

atm

ent

(46

hr la

ter)

. End

osco

py w

as

carr

ied

out

(with

intr

aven

ous

seda

tion,

an

alge

sia

and

an a

ntie

met

ic)

and

a ba

lloon

ap

plic

ator

was

pla

ced

over

a g

uide

wire

(p

ositi

on c

onfir

med

end

osco

pica

lly)

and

infla

ted

to a

ppro

xim

atel

y 20

mm

Hg.

Ligh

t w

as d

eliv

ered

usi

ng a

cyl

indr

ical

diff

user

fib

re –

red

lase

r lig

ht (

635

nm 3

W)

at a

flu

ence

rat

e of

68

mW

/cm

2 and

tot

al li

ght

dose

of 8

5 J/c

m2 .

Patie

nts

wer

e di

scha

rged

an

d ad

vise

d to

avo

id b

righ

t lig

hts

for

24 h

r. Fo

llow

-up

at 4

wk

– if

resi

dual

Bar

rett

’s ep

ithel

ium

pat

ient

was

re-

trea

ted

until

re

-epi

thel

isat

ion

was

com

plet

e or

to

a m

axim

um o

f five

tre

atm

ents

Com

para

tor A

PC: e

ndos

copy

as

per

PDT

pr

otoc

ol. A

PC g

ener

ator

set

with

gas

flow

of

2 l/

min

and

pow

er s

ettin

g of

65 W

. APC

pr

obe

pass

ed d

own

biop

sy c

hann

el a

nd

posi

tione

d w

ith t

ip o

f pro

be 1

cm d

ista

l to

the

end

of t

he s

cope

. APC

per

form

ed in

a

linea

r fa

shio

n co

agul

atin

g st

rips

of t

issu

e ap

prox

imat

ely

2 m

m w

ide

at e

ach

pass

. O

ne-h

alf o

f the

affe

cted

circ

umfe

renc

e w

as

trea

ted

at a

ny o

ne s

ittin

g on

the

rat

iona

le

of r

educ

ing

chan

ces

of s

tric

ture

. Rep

eat

trea

tmen

t as

per

PD

T b

ut u

sing

APC

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty S

igni

fican

tly fe

wer

tre

atm

ents

w

ere

perf

orm

ed in

the

APC

gro

up (

med

ian

3) t

han

in t

he P

DT

gro

up (

med

ian

5),

p =

0.01

6. T

he m

edia

n nu

mbe

r of

tre

atm

ents

re

quire

d fo

r su

cces

sful

abl

atio

n w

as t

wo

in

the

PDT

gro

up a

nd t

hree

in t

he A

PC g

roup

, p

= 0.

189

Com

plet

e m

acro

scop

ic r

ever

sal o

f the

co

lum

nar

segm

ent

to s

quam

ous

epith

eliu

m

was

ach

ieve

d in

50%

of P

DT

pat

ient

s an

d 97

% o

f APC

pat

ient

s, p

< 0.

0001

AE

s M

ajor

sid

e ef

fect

s fo

r PD

T w

ere

min

imal

with

no

stri

ctur

es o

r pe

rfor

atio

ns.

Sign

ifica

nt N

&V

occ

urre

d in

32%

of

patie

nts

who

req

uire

d fu

rthe

r an

tiem

etic

tr

eatm

ent.

Five

pat

ient

s re

port

ed c

utan

eous

ph

otos

ensi

tivity

(m

ild e

ryth

ema

and

pain

). A

ll A

PC p

atie

nts

repo

rted

dis

com

fort

an

d 91

% r

epor

ted

tran

sien

t dy

spha

gia

and

odyn

opha

gia.

All

wer

e re

solv

ed w

ith

oral

ana

lges

ia o

ver

3 d.

No

oeso

phag

eal

perf

orat

ions

occ

urre

d, o

ne p

atie

nt

deve

lope

d dy

spha

gia

to s

olid

s an

d re

quire

d fo

ur d

ilata

tions

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

PD

T a

nd A

PC a

re

both

effe

ctiv

e fo

r ab

latin

g BO

. APC

app

ears

m

ore

effe

ctiv

e bu

t la

rger

stu

dies

sho

uld

asse

ss im

pact

on

carc

inom

a de

velo

pmen

tB

rief

stu

dy a

ppra

isal

Thi

s w

as a

re

lativ

ely

robu

st c

ompa

rativ

e tr

ial (

desp

ite

the

sam

ple

size

), w

hich

wou

ld a

lso

have

be

nefit

ed fr

om t

he u

se o

f blin

ded

outc

ome

asse

ssor

s. H

owev

er, t

his

stud

y, lik

e its

re

late

d do

sing

stu

dy10

2 was

of B

O p

atie

nts

with

out

dysp

lasi

a; su

ch p

atie

nts

are

ofte

n no

t tr

eate

d at

all,

so t

he r

esul

ts a

ppea

r to

be

of li

mite

d us

e in

rel

atio

n to

clin

ical

pr

actic

e

Appendix 16

244



245Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mac

kenz

ie e

t al.

(200

8)10

5

Link

ed p

ublic

atio

ns20

2–20

4

Dat

a so

urce

Ful

l pap

erC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 27

Inte

rven

tion

(ALA

w

ith r

ed li

ght)

: 14

Com

para

tor:

(ALA

with

gre

en

light

): 13

No.

of r

ecru

itin

g ce

ntre

s O

neFo

llow

-up

peri

od a

nd

freq

uenc

y 4

wk

then

eve

ry

3 m

th fo

r th

e 1s

t ye

ar t

hen

ever

y 6

mth

for

the

2nd

year

, th

en y

earl

y

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y BO

w

ith H

GD

Mai

n el

igib

ility

cr

iter

ia P

atie

nts

with

BO

with

HG

D.

Patie

nts

wer

e no

t al

low

ed t

o re

ceiv

e ch

emot

hera

py o

r ra

diot

hera

py w

ithin

1

mth

pri

or t

o PD

T. O

ther

exc

lusi

on

crite

ria

wer

e pr

ovid

edPa

tien

t ch

arac

teri

stic

s N

ot

stat

edC

onco

mit

ant

trea

tmen

t A

ll pa

tient

s re

ceiv

ed P

PIs.

Intr

aven

ous

fluid

s an

d an

tiem

etic

s w

ere

give

n pr

e-op

erat

ivel

y

Tria

l tre

atm

ents

ALA

–PD

T w

ith r

ed

light

vs A

LA–P

DT

with

gre

en li

ght

Inte

rven

tion

Phas

e 1

(eig

ht p

atie

nts)

ALA

with

red

ligh

t: at

635

nm

del

iver

ing

a do

se o

f 200

J/cm

2. L

aser

tre

atm

ent

was

app

lied

4 hr

afte

r or

al A

LA

adm

inis

trat

ion

(30

mg/

kg).

Patie

nts

rece

ived

up

to t

hree

tre

atm

ents

with

PD

T 1

mth

apa

rtPh

ase

2 (s

ix p

atie

nts)

As

abov

e bu

t w

ith 6

0 m

g/kg

ALA

Com

para

tor

Phas

e 1

(eig

ht p

atie

nts)

ALA

with

gre

en li

ght

at 5

12 n

m

othe

rwis

e as

for

inte

rven

tion

Phas

e 2

(five

pat

ient

s)A

s ab

ove

but

with

60

mg/

kg A

LA

Mor

talit

y N

ot a

sses

sed

Mor

bidi

tyPh

ase

14

of 1

6 pa

tient

s (2

5%)

had

HG

D

erad

icat

ed (

thre

e re

d lig

ht, o

ne g

reen

lig

ht)

The

tri

al w

as p

ause

d fo

llow

ing

inte

rim

an

alys

is. I

t th

en p

roce

eded

to

Phas

e 2

Phas

e 2

Six

of s

ix p

atie

nts

in t

he 6

0-m

g re

d lig

ht g

roup

had

suc

cess

ful t

reat

men

t, w

here

as o

ne o

f five

was

suc

cess

ful i

n th

e 60

-mg

gree

n lig

ht g

roup

(p

= 0.

01)

60-m

g A

LA r

ed li

ght

was

als

o m

ore

succ

essf

ul t

han

30-m

g A

LA r

ed li

ght

(p =

0.0

3) a

nd t

han

30 m

g A

LA g

reen

lig

ht (

p =

0.00

5)A

Es A

Es w

ere

not

all r

epor

ted

by

grou

p. A

ll pa

tient

s re

ceiv

ing

60 m

g PD

T s

how

ed m

inor

, sel

f-lim

iting

ab

norm

aliti

es in

the

res

ults

of t

heir

liv

er fu

nctio

n te

sts

Res

ourc

e us

eN

ot a

sses

sed

Aut

hors

’ con

clus

ions

PD

T w

ith

ALA

at

30 m

g/kg

with

gre

en o

r re

d la

ser

is in

effe

ctiv

e fo

r er

adic

atio

n of

H

GD

in B

O. A

LA a

t 60

mg/

kg a

ctiv

ated

by

100

0 J/c

m r

ed la

ser

light

has

hig

h ef

ficac

y fo

r H

GD

in B

OB

rief

stu

dy a

ppra

isal

Thi

s tr

ial,

alth

ough

sm

all,

was

abl

e to

sug

gest

a

grea

ter

effe

ctiv

enes

s w

ith 6

0 m

g re

d lig

ht. S

uch

findi

ngs

wou

ld n

eed

to b

e co

nfirm

ed in

larg

er t

rial

s an

d an

y A

Es

docu

men

ted

Appendix 16

246



247Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mac

kenz

ie

et a

l. (20

08)10

4

Dat

a so

urce

A

bstr

act

Cou

ntry

UK

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

40 r

ecru

ited

of a

pla

nned

66.

32

wer

e tr

eate

dIn

terv

entio

n: A

LA–

PDT:

16

Com

para

tor:

PDT

w

ith P

hoto

frin

: 16

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od

and

freq

uenc

y 6

wk,

4 m

th a

nd 1

yr

post

the

rapy

Trea

tmen

t in

tent

ion

Not

st

ated

Type

(s)

of c

ance

r an

d hi

stol

ogy

BO

with

HG

DM

ain

elig

ibili

ty

crit

eria

Pat

ient

s w

ith B

O w

ith

HG

D c

onfir

med

by

two

inde

pend

ent

path

olog

ists

wer

e el

igib

le fo

r th

e tr

ial.

Any

vis

ible

nod

ules

of

HG

D w

ere

rem

oved

an

d pa

tient

s on

ly

trea

ted

if re

sidu

al

HG

D w

as s

till

pres

ent

Pati

ent

char

acte

rist

ics

Not

st

ated

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

ALA

–PD

T v

s PD

T w

ith P

hoto

frin

Inte

rven

tion

60

mg/

kg A

LA

activ

ated

by

1178

J/cm

of r

ed

lase

r lig

htC

ompa

rato

r Ph

otof

rin

PDT

with

the

sta

ndar

d pr

otoc

ol o

r as

pre

viou

sly

show

n to

be

the

mos

t ef

fect

ive

(no

furt

her

deta

ils

give

n)

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty F

ive

patie

nts

are

unde

rgoi

ng r

epea

t th

erap

y (t

hree

Ph

otof

rin,

tw

o A

LA).

Rem

issi

on r

ates

ar

e 14

of 1

4 (1

00%

) in

the

ALA

–PD

T

grou

p an

d ni

ne o

f 14

(64%

) in

the

Ph

otof

rin

grou

p (p

< 0

.05)

AE

s St

rict

ures

dev

elop

ed in

six

of 1

6 pa

tient

s tr

eate

d w

ith P

hoto

frin

and

on

e of

16

trea

ted

with

ALA

(pr

obab

ly

not

rela

ted

to t

reat

men

t), p

< 0

.05.

Sk

in p

hoto

sens

itivi

ty d

evel

oped

in

seve

n of

16

patie

nts

trea

ted

with

Ph

otof

rin,

one

of w

hom

had

to

be

brie

fly a

dmitt

ed t

o ho

spita

l. N

o in

stan

ces

of p

hoto

sens

itisa

tion

wer

e fo

und

with

ALA

(p

< 0.

05). T

here

w

ere

no o

ther

sig

nific

ant

diffe

renc

es

betw

een

grou

ps r

egar

ding

sid

e ef

fect

sR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

The

pre

limin

ary

data

sug

gest

tha

t A

LA–P

DT

is b

oth

safe

r an

d po

tent

ially

mor

e ef

fect

ive

than

PD

T w

ith P

hoto

frin

but

FU

is s

hort

and

not

all

patie

nts

in t

he

tria

l hav

e be

en t

reat

ed a

s ye

tB

rief

stu

dy a

ppra

isal

Thi

s tr

ial w

as r

epor

ted

in a

bstr

act

form

onl

y so

full

deta

ils o

f the

met

hods

are

not

ava

ilabl

e. T

he

data

pre

sent

ed a

re p

rom

isin

g bu

t w

ould

nee

d co

nfirm

atio

n in

lo

nger

FU

and

with

all

the

plan

ned

patie

nts

trea

ted

Appendix 16

246



247

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mac

kenz

ie e

t al.

(200

7)10

3

Link

ed p

ublic

atio

ns20

5

Dat

a so

urce

Abs

trac

tC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 24

app

eare

d to

hav

e be

en r

ando

mis

ed t

o ei

ther

re

d or

gre

en li

ght

and

wer

e pa

rt o

f a la

rger

stu

dy o

f 72

patie

nts

Inte

rven

tion:

Hig

h-do

se A

LA

(60

mg/

kg)

with

hig

h-do

se r

ed

or g

reen

ligh

t (1

000

J/cm

) –

not

stat

edC

ompa

rato

r: H

igh-

dose

ALA

(6

0 m

g/kg

) w

ith lo

w-d

ose

red

light

(50

0–70

0 J/c

m)

– no

t st

ated

2nd

Com

para

tor:

Low

-dos

e A

LA (

30 m

g/kg

) w

ith h

igh-

dose

red

or

gree

n lig

ht

(100

0 J/c

m)

– no

t st

ated

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od a

nd

freq

uenc

y 36

mth

Trea

tmen

t in

tent

ion

Not

sta

ted

Type

(s)

of c

ance

r an

d hi

stol

ogy

BO w

ith

HG

DM

ain

elig

ibili

ty

crit

eria

Not

sta

ted

Pati

ent

char

acte

rist

ics

Not

st

ated

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

Hig

h-do

se A

LA

(60

mg/

kg)

with

Hig

h-do

se r

ed o

r gr

een

light

(10

00 J/

cm)

vs H

igh-

dose

A

LA (

60 m

g/kg

) w

ith lo

w-d

ose

red

light

(50

0–70

0 J/c

m)

vs L

ow-d

ose

ALA

(30

mg/

kg)

with

hig

h-do

se r

ed

or g

reen

ligh

t (1

000

J/cm

)In

terv

enti

on H

igh-

dose

ALA

(6

0 m

g/kg

) w

ith h

igh-

dose

red

or

gree

n lig

ht (

1000

J/cm

)C

ompa

rato

r H

igh-

dose

ALA

(6

0 m

g/kg

) w

ith lo

w-d

ose

red

light

(5

00–7

00 J/

cm)

2nd

com

para

tor

Low

-dos

e A

LA

(30

mg/

kg)

with

hig

h-do

se r

ed o

r gr

een

light

(10

00 J/

cm)

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty P

atie

nts

in t

he g

roup

rec

eivi

ng

Hig

h-do

se A

LA–P

DT

and

Hig

h-do

se r

ed

light

had

a s

igni

fican

t de

crea

se in

can

cer

risk

w

hen

com

pare

d w

ith t

he o

ther

tre

atm

ent

grou

ps a

t 36

mth

(24

% r

isk

vs 3

%). T

he

diffe

renc

e in

ade

noca

rcin

oma

rate

s w

ere

sign

ifica

nt w

hen

red

light

was

com

pare

d w

ith g

reen

(8%

vs

45%

, p <

0.0

5)A

Es

No

patie

nts

suffe

red

phot

osen

sitiv

ity

reac

tions

or

deve

lope

d oe

soph

agea

l st

rict

ures

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

The

dat

a fr

om t

his

tria

l sup

port

the

use

of

the

optim

al r

egim

en o

f ALA

in a

R

CT

of A

LA v

s Ph

otof

rin

PDT

Bri

ef s

tudy

app

rais

al T

his

smal

l st

udy

is r

epor

ted

in a

bstr

act

form

on

ly a

nd n

o fu

rthe

r pu

blic

atio

n is

av

aila

ble.

It is

, the

refo

re, d

ifficu

lt to

as

sess

the

qua

lity

of t

he t

rial

and

th

e re

liabi

lity

of t

he fi

ndin

gs

Appendix 16

248 Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

O

verh

olt

et a

l. (2

007)

99

Link

ed

publ

icat

ions

206–

209

Dat

a so

urce

Fu

ll pu

blis

hed

pape

rC

ount

ry N

ot

stat

edLa

ngua

ge

Engl

ish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 20

8 (6

1 in

lo

ng-t

erm

pha

se

grou

p)In

terv

entio

n:

PHO

PDT:

138

(4

8 in

long

-ter

m

phas

e gr

oup)

Com

para

tor:

OM

: 70

(13

in

long

ter

m p

hase

gr

oup)

No.

of

recr

uiti

ng

cent

res

30 (

in

four

unn

amed

co

untr

ies)

Follo

w-u

p pe

riod

and

fr

eque

ncy

Ever

y 3

mth

unt

il fo

ur c

onse

cutiv

e bi

opsy

res

ults

w

ere

nega

tive

for

HG

D, t

hen

bian

nual

ly u

ntil

5 yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y BO

with

H

GD

Mai

n el

igib

ility

cr

iter

ia P

atie

nts

wer

e el

igib

le if

the

y w

ere

diag

nose

d w

ith B

O

with

HG

D p

rove

n by

bi

opsy

and

be ≥

18yr

. Ex

clus

ion

crite

ria

wer

e: ca

ncer

oth

er t

han

non-

mel

anom

a sk

in c

ance

r w

ithin

the

last

5yr

; pri

or

PDT

to

the

oeso

phag

us,

oeso

phag

eal s

tric

ture

s un

resp

onsi

ve t

o di

lata

tion

and

furt

her

crite

ria

deta

iled

in fu

ll in

th

e pa

per

Pati

ent

char

acte

rist

ics

% M

ale:

85M

ean

age:

67 yr

Furt

her

patie

nt

char

acte

rist

ics

wer

e re

port

edC

onco

mit

ant

trea

tmen

t 9%

of

patie

nts

in th

e PH

OPD

T

grou

p un

derw

ent

an

oeso

phag

ecto

my

or

othe

r en

dosc

opic

ab

latio

n (3

%).

19%

of

the

pat

ient

s in

th

e O

M g

roup

had

PH

OPD

T t

reat

men

t, 10

% u

nder

wen

t an

oe

soph

agec

tom

y an

d 2.

9% h

ad a

noth

er

endo

scop

ic a

blat

ion

tech

niqu

e

Tria

l tre

atm

ents

PD

T

with

PH

OPD

T v

s O

M

alon

e In

terv

enti

on P

HO

PDT:

Pa

tient

s in

thi

s ar

m

rece

ived

a m

axim

um o

f th

ree

cour

ses

of P

DT

ove

r 5

yr s

epar

ated

by

at le

ast

3 m

th. O

ne c

ours

e of

PD

T

cons

iste

d of

a 2

-mg/

kg

PHO

inje

ctio

n fo

llow

ed

by o

ne la

ser

light

ses

sion

(6

30 n

m)

appl

ied

to t

he

oeso

phag

eal s

egm

ent

with

HG

D 4

0–50

hr

afte

r in

ject

ion.

The

ligh

t do

se

was

130

J/cm

of d

iffus

er

leng

th w

ith a

cen

trin

g ba

lloon

. A 2

nd li

ght

appl

icat

ion

of 5

0 J/c

m

with

out

the

cant

erin

g ba

lloon

cou

ld b

e gi

ven

96–1

20hr

afte

r PH

O

inje

ctio

n bu

t on

ly fo

r ar

eas

with

insu

ffici

ent

muc

osal

re

spon

se a

fter

the

1st

light

ap

plic

atio

n. A

max

imum

of

7 cm

of B

O w

as t

reat

ed

duri

ng o

ne c

ours

e of

PD

T. It

was

req

uire

d th

at t

he

entir

e le

ngth

of B

arre

tt’s

muc

osa

be t

reat

ed. P

atie

nts

also

rec

eive

d 20

mg

of O

M

twic

e da

ily. P

atie

nts

had

to

avoi

d ex

posu

re o

f eye

s an

d sk

in t

o di

rect

sun

light

and

hi

gh in

tens

ity li

ght

for

at

leas

t 30

d. T

hey

wer

e to

ld

to w

ear

dark

sun

glas

ses

for

a 30

-d p

erio

d w

hen

outd

oors

Com

para

tor

OM

: Pa

tient

s re

ceiv

ed 2

0 m

g O

M t

wic

e da

ily

Mor

talit

y Tw

o pa

tient

s in

the

PH

OPD

T a

nd o

ne p

atie

nt in

the

OM

gro

up d

ied

with

in t

he 1

st 2

yr fr

om e

vent

s un

rela

ted

to B

arre

tt’s

dise

ase.

No

deat

hs w

ere

rela

ted

to t

he t

reat

men

t. T

here

wer

e no

add

ition

al p

atie

nts

who

die

d ov

er t

he

cour

se o

f the

add

ition

al 3

yr o

f FU

Mor

bidi

ty T

he p

ropo

rtio

n of

res

pond

ers

(com

plet

e ab

latio

n of

HG

D)

was

si

gnifi

cant

ly h

ighe

r in

PH

OPD

T t

han

with

OM

(77

% v

s 39

%, p

< 0

.000

1). O

f the

om

epra

zole

alo

ne r

espo

nder

s th

ere

wer

e 26

% o

f the

PH

OPD

T a

nd 5

2% o

f th

e O

M p

atie

nts

who

ter

min

ated

the

tri

al w

ith e

ither

HG

D o

r ca

ncer

. Ana

lysi

s of

res

pond

ers

for

both

tre

atm

ent

grou

ps a

t 10

spe

cific

tim

e po

ints

sho

wed

a

prop

ortio

n of

res

pond

ers

alm

ost

twic

e as

larg

e in

PH

OPD

T c

ompa

red

with

OM

at

all a

sses

smen

t pe

riod

s (d

ata

not

show

n). T

here

was

a s

igni

fican

t di

ffere

nce

betw

een

the

med

ian

time

to C

R in

the

2 g

roup

s: PH

OPD

T, 11

3 d

and

OM

, 551

d, p

< 0

.000

1. O

ver

the

tria

l per

iod

10%

of P

HO

PDT

pat

ient

s ha

d H

GD

com

pare

d w

ith 3

1% o

f the

OM

pat

ient

sBy

the

end

of t

he 5

-yea

r FU

per

iod,

the

pro

babi

lity

of m

aint

aini

ng c

ompl

ete

abla

tion

of H

GD

was

48%

in P

HO

PDT

com

pare

d w

ith 4

% in

OM

, p <

0.0

001.

T

he m

edia

n du

ratio

n of

the

CR

was

44.

8 m

th in

the

PH

OPD

T g

roup

and

3.

2 m

th in

the

OM

gro

up. A

2-y

r re

spon

der

in t

he P

HO

PDT

gro

up h

ad a

90%

ch

ance

of m

aint

aini

ng t

he r

espo

nse

for

5 yr

com

pare

d w

ith 3

0% fo

r a

2-yr

re

spon

der

in t

he O

M g

roup

. Com

pari

son

betw

een

the

2 gr

oups

sho

wed

tha

t pa

tient

s in

the

PH

OPD

T g

roup

had

a s

igni

fican

t de

lay

in p

rogr

essi

on t

o ca

ncer

co

mpa

red

with

pat

ient

s in

the

OM

gro

up. I

n th

e PH

OPD

T g

roup

, 21

(15%

) pa

tient

s pr

ogre

ssed

to

canc

er fr

om d

48 t

o 17

93. I

n th

e O

M g

roup

, 20

(29%

) pa

tient

s pr

ogre

ssed

to

canc

er fr

om d

63 t

o 10

92. A

fter

5yr

of F

U, t

he r

ate

of

patie

nts

who

pro

gres

sed

to c

ance

r in

PH

OPD

T w

as s

igni

fican

tly lo

wer

tha

n in

O

M (

p =

0.02

7). T

here

was

no

sign

ifica

nt d

iffer

ence

in s

quam

ous

over

grow

th

betw

een

grou

ps w

hen

com

pare

d pe

r pa

tient

or

per

biop

sy o

r w

hen

the

aver

age

no. o

f bio

psie

s w

ith s

quam

ous

over

grow

th w

ere

com

pare

d pe

r pa

tient

. Sq

uam

ous

over

grow

th d

id n

ot o

bscu

re t

he m

ost

adva

nced

neo

plas

ia in

any

pa

tient

AE

s In

the

initi

al p

hase

of t

he t

rial

, the

mos

t co

mm

on A

Es w

ere

phot

osen

sitiv

ity (

69%

) an

d oe

soph

agea

l str

ictu

res

(36%

). A

ll ph

otos

ensi

tivity

ev

ents

wer

e re

solv

ed a

nd 9

4% o

f pat

ient

s w

ith s

tric

ture

s w

ere

stri

ctur

e fr

ee

duri

ng t

he c

ours

e of

the

initi

al p

hase

. Eve

nts

of s

ever

e in

tens

ity w

ere

sim

ilar

for

PHO

PDT

(16

%)

and

OM

(15

%)

with

65%

of t

he P

HO

PDT

gro

up b

eing

re

late

d to

the

tre

atm

ent

com

pare

d w

ith 2

% in

the

OM

gro

up. F

rom

yea

rs 2

to

5, t

here

wer

e no

SA

Es a

nd o

f tho

se A

Es r

epor

ted,

non

e w

as a

ttri

bute

d to

th

e tr

eatm

ents

. The

re w

ere

no p

hoto

sens

itivi

ty A

Es o

ccur

ring

dur

ing

the

long

te

rm p

hase

. Ful

l det

ails

of a

ll A

ES, b

oth

rela

ted

and

unre

late

d to

tre

atm

ent

are

avai

labl

e in

the

pap

erR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

T

his

tria

l sho

ws

that

PD

T w

ith P

hoto

frin

is a

cl

inic

ally

and

sta

tistic

ally

ef

fect

ive

ther

apy

in

prod

ucin

g lo

ng-t

erm

ab

latio

n of

HG

D a

nd

redu

cing

the

pot

entia

l im

pact

of c

ance

r co

mpa

red

with

OM

Bri

ef s

tudy

app

rais

al

Thi

s w

as a

RC

T w

ith

proc

edur

es fo

r bl

indi

ng

of o

utco

me

asse

ssor

s. O

utco

mes

wer

e de

fined

an

d ap

prop

riat

ely

asse

ssed

and

AEs

no

ted.

Lon

ger-

term

FU

w

as u

sed

to t

race

the

de

velo

pmen

t of

dys

plas

ia

and

prog

ress

ion

to

canc

er. T

he r

esul

ts o

f th

is t

rial

app

ear

to b

e re

liabl

e w

ith t

he c

avea

t be

ing

the

larg

e nu

mbe

r of

rec

ruiti

ng c

entr

es

(and

ver

y sm

all n

umbe

rs

of p

atie

nts

at s

ome

site

s) w

hich

may

hav

e re

sulte

d in

bet

wee

n-si

te d

iffer

ence

s, su

ch

as t

he d

eliv

ery

of t

he

inte

rven

tion

(e.g

. var

ying

ex

pert

ise

in d

eliv

erin

g PD

T),

whi

ch m

ay h

ave

affe

cted

the

ove

rall

resu

lts. T

he n

umbe

r re

crui

ted

at in

divi

dual

si

tes

rang

ed fr

om o

ne t

o 51

par

ticip

ants

OM

, om

epra

zole

; PH

OPD

T, Ph

otof

rin

and

omep

razo

le.



249Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

R

agun

ath

et a

l. (2

005)

100

Link

ed

publ

icat

ions

210

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

26In

terv

entio

n: P

DT:

13 C

ompa

rato

r: A

PC:

13 No.

of r

ecru

itin

g ce

ntre

s N

ot

stat

edFo

llow

-up

peri

od a

nd

freq

uenc

y 4

mth

an

d 12

mth

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y BO

with

LG

D o

r H

GD

Mai

n el

igib

ility

cri

teri

a Pa

tient

s w

ith B

O ≥

3 cm

and

LG

D o

r H

GD

w

ith h

isto

logi

cal d

iagn

osis

con

firm

ed

on b

iops

y no

mor

e th

an 3

mth

be

fore

stu

dy e

ntry

wer

e el

igib

le. T

he

follo

win

g w

ere

excl

uded

: pat

ient

s w

ith o

esop

hage

al m

alig

nanc

y of

an

y fo

rm, p

revi

ous

oeso

phag

eal

rese

ctio

n, p

revi

ous

muc

osal

ab

lativ

e th

erap

y or

end

osco

pic

muc

osal

res

ectio

n, p

atie

nts

with

pr

edom

inan

tly t

ongu

es r

athe

r th

an

circ

umfe

rent

ial B

arre

tt’s

oeso

phag

us,

patie

nts

with

por

phyr

ia o

r pa

tient

s in

tole

rant

to

endo

scop

y. Pa

tient

s pr

egna

nt, t

ryin

g to

get

pre

gnan

t or

no

t us

ing

cont

race

ptio

n w

ere

also

ex

clud

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 81

Med

ian

age:

60 yr

Age

ran

ge: 3

5–86

yrM

edia

n BO

leng

th: 4

cmD

yspl

asia

: HG

D, 3

(12%

), 23

(88%

)C

onco

mit

ant

trea

tmen

t A

fter

the

proc

edur

es, p

atie

nts

rece

ived

a

high

-dos

e PP

I, la

nsop

razo

le 6

0 m

g/d,

du

ring

the

tre

atm

ent

peri

od a

nd

wer

e th

en m

aint

aine

d on

30

mg/

d.

All

patie

nts

also

rec

eive

d tw

o ta

blet

s of

co-

coda

mol

, to

be t

aken

ev

ery

6 hr

as

pain

rel

ief f

or 2

4–48

hr

afte

r th

e tr

eatm

ent.

A fe

w p

atie

nts

also

rec

eive

d 1

g of

suc

ralfa

te e

very

6

hr fo

r re

tros

tern

al d

isco

mfo

rt a

nd

tran

sien

t dy

spha

gia

Tria

l tre

atm

ents

PD

T w

ith P

hoto

frin

vs A

PCIn

terv

enti

on 2

mg/

kg o

f Pho

tofr

in w

as in

ject

ed

intr

aven

ously

48

hr b

efor

e ill

umin

atio

n w

ith la

ser.

PDT

was

per

form

ed u

sing

630

-nm

red

lase

r lig

ht w

ith a

pow

er o

utpu

t of

840

mW

del

iver

ing

200

J/cm

thr

ough

an

endo

scop

ical

ly in

sert

ed

PDT

bal

loon

. End

osco

py w

as p

erfo

rmed

un

der

intr

aven

ous

seda

tion

with

mid

azol

am

5–15

mg

and

fent

anyl

50–

100 µ

g. In

trav

enou

s bu

scop

an w

as u

sed

as a

n an

timot

ility

age

nt.

A 3

-cm

win

dow

PD

T b

allo

on w

as in

sert

ed

over

a g

uide

wire

and

infla

ted

afte

r po

sitio

ning

, ad

jace

nt t

o th

e Ba

rret

t’s s

egm

ent.

The

lase

r fib

re

was

inse

rted

into

the

bal

loon

and

pos

ition

ed

to a

llow

uni

form

lase

r lig

ht d

istr

ibut

ion.

The

pr

oced

ure

was

rep

eate

d fo

r ev

ery

addi

tiona

l 3

cm o

f the

Bar

rett

’s se

gmen

t. Fu

rthe

r tr

eatm

ent

para

met

ers

wer

e de

scri

bed.

All

patie

nts

wer

e ad

mitt

ed t

o th

e ga

stro

ente

rolo

gy w

ard

and

nurs

ed in

a s

emi-d

ark

room

. The

war

d nu

rsin

g st

aff a

nd t

he p

atie

nts

wer

e gi

ven

inst

ruct

ions

an

d an

info

rmat

ion

leafl

et a

bout

avo

idin

g di

rect

su

nlig

ht a

nd b

righ

t in

door

ligh

ts fo

r 4–

8 w

kC

ompa

rato

r APC

: End

osco

py w

as p

erfo

rmed

un

der

intr

aven

ous

seda

tion

with

mid

azol

am

5–15

mg.

Afte

r as

sess

men

t of

the

Bar

rett

’s se

gmen

t, A

PC w

as p

erfo

rmed

usi

ng t

he E

RBE

IC

C 2

00 A

rgon

Bea

mer

. APC

was

app

lied

until

a

whi

te c

oagu

lum

app

eare

d at

a p

ower

set

ting

of

65 W

and

arg

on g

as fl

ow o

f 1.8

l/m

in. D

epen

ding

on

the

leng

th o

f the

Bar

rett

’s se

gmen

t an

d pa

tient

tol

erab

ility

, APC

was

car

ried

out

in o

ne

or m

ore

sess

ions

with

an

inte

rval

of 2

–4 w

k be

twee

n th

e se

ssio

ns. T

he t

reat

men

t go

al

was

com

plet

e ab

latio

n of

BO

and

dys

plas

ia

or a

max

imum

of s

ix s

essi

ons

whe

n co

mpl

ete

abla

tion

was

not

ach

ieve

d. F

urth

er d

etai

ls w

ere

prov

ided

in t

he p

aper

Mor

talit

y N

ot a

sses

sed

Mor

bidi

tyM

edia

n le

ngth

of B

O e

radi

cate

d at

4-m

th

FU: P

DT

57%

(3

cm);

APC

65%

(3

cm)

Med

ian

leng

th o

f BO

era

dica

ted

at

12-m

th F

U: P

DT

60%

(3

cm);

APC

56%

(2

.5 cm

)D

yspl

asia

era

dica

tion

at 4

mth

: PD

T 7

7%;

APC

62%

(p =

0.0

3)D

yspl

asia

era

dica

tion

at 1

2 m

th: P

DT

77

%; A

PC 6

7% N

SD

evel

opm

ent

of m

alig

nanc

y at

12

mth

: PD

T o

ne; A

PC z

ero

AE

s Se

vere

AEs

:PD

T: fo

ur o

f 13

(31%

), ph

otos

ensi

tivity

tw

o; o

esop

hage

al s

tric

ture

tw

oA

PC: t

hree

of 1

3 (2

3%),

Oes

opha

geal

st

rict

ure,

tw

o; s

ever

e ch

est

pain

, od

ynop

hagi

a an

d fe

ver

requ

irin

g ho

spita

l ad

mis

sion

, one

Res

ourc

e us

e A

cos

t-ef

fect

iven

ess

anal

ysis

was

con

duct

ed fr

om t

he

pers

pect

ive

of t

he U

K N

HS.

The

cos

t of

PD

T p

er p

atie

nt w

as c

alcu

late

d at

£28

04

and

that

of A

PC £

1341

. The

ICER

s w

ere

calc

ulat

ed b

ased

on

diffe

renc

es in

cos

t an

d ef

fect

s be

twee

n th

e tw

o pr

oced

ures

fo

r BO

leng

th e

radi

catio

n an

d dy

spla

sia

erad

icat

ion

at 4

and

12

mth

. At

4 m

th

APC

was

the

dom

inan

t st

rate

gy b

eing

le

ss e

xpen

sive

and

mor

e ef

fect

ive.

At

12 m

th t

he in

crem

enta

l cos

t ra

tio w

as

£266

, i.e

. it

wou

ld c

ost

an a

dditi

onal

£2

66 fo

r ev

ery

perc

enta

ge r

educ

tion

in

Barr

ett’s

usi

ng P

DT.

Full

deta

ils o

f the

co

st-e

ffect

iven

ess

anal

ysis

are

pro

vide

d in

th

e pa

per

Aut

hors

’ con

clus

ions

PD

T a

nd A

PC a

re e

qual

ly

effe

ctiv

e in

era

dica

ting

Barr

ett’s

muc

osa.

How

ever

, PD

T is

mor

e ef

fect

ive

in e

radi

catin

g dy

spla

sia.

Long

-ter

m F

U is

nee

ded

to

asse

ss c

ance

r pr

even

tion

and

the

dura

bilit

y of

the

ne

osqu

amou

s ep

ithel

ium

. T

hese

inte

rven

tions

can

not

be r

ecom

men

ded

as y

et fo

r ro

utin

e pr

actic

eB

rief

stu

dy a

ppra

isal

T

his

was

a s

mal

l tri

al

that

will

like

ly h

ave

been

un

derp

ower

ed t

o de

tect

tr

eatm

ent

diffe

renc

es fo

r al

l out

com

es. T

his

wou

ld

also

hav

e im

pact

ed o

n th

e co

st e

ffect

iven

ess

anal

ysis

, w

hich

acc

ompa

nied

thi

s tr

ial. T

reat

men

t pr

otoc

ols

are

wel

l des

crib

ed b

ut

stud

y m

etho

ds s

uch

as p

roce

dure

s fo

r ra

ndom

isat

ion

and

blin

ding

ar

e le

ss w

ell d

escr

ibed

. The

au

thor

s ad

vise

a la

rger

tri

al

and

also

hig

hlig

ht t

he n

eed

for

long

er-t

erm

FU

Appendix 16

250



251

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Zoe

pf e

t al.

(200

3)10

1

Dat

a so

urce

Abs

trac

tC

ount

ry G

erm

any

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

20In

terv

entio

n: P

DT

10

Com

para

tor:

APC

10

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od

and

freq

uenc

yPD

T: M

edia

n 27

mth

, ra

nge

12–4

2 m

thA

PC: M

edia

n 24

mth

, ra

nge

4–46

mth

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Lo

ng-

segm

ent

BOM

ain

elig

ibili

ty

crit

eria

Not

sta

ted

Pati

ent

char

acte

rist

ics

% M

ale:

65M

edia

n ag

e: 68

yrA

ge r

ange

: 44–

77 yr

PDT:

4/1

0 LG

D, 6

/10

HG

DA

PC: 5

/10

LGD

, 5/1

0N

o dy

spla

sia

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

PD

T v

s APC

Inte

rven

tion

PD

T: 6

0 m

g/kg

bw

of A

LA.

Cyl

indr

ical

diff

user

fibr

e in

the

cen

tre

of a

bal

loon

app

licat

or a

nd il

lum

inat

ed

usin

g a

diod

e la

ser

syst

em w

ith 1

50 J/

cm2 .

Num

ber

of t

reat

men

t se

ssio

ns w

as t

wo

(1–5

). Fu

rthe

r PD

T p

aram

eter

s w

ere

not

repo

rted

Com

para

tor A

PC: A

PC w

as a

pplie

d w

ith

a po

wer

of 7

0 W. T

he n

umbe

r of

tre

atm

ent

sess

ions

was

four

(2–

9)

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty R

educ

tion

of le

ngth

was

90%

fo

r PD

T (

rang

e 0–

100%

) an

d 90

% fo

r APC

(r

ange

50–

100%

)A

Es A

ll pa

tient

s w

ith P

DT

dev

elop

ed

naus

ea a

nd v

omiti

ng o

ver

a pe

riod

of

4 hr

afte

r tr

eatm

ent.

4/10

PD

T p

atie

nts

show

ed t

rans

ient

dys

phag

ia. N

o sk

in

phot

otox

ity w

as fo

und

afte

r PD

T. T

here

w

as n

o vo

miti

ng in

the

APC

gro

up

but

3/10

pat

ient

s de

velo

ped

tran

sien

t dy

spha

gia

and

one

med

iast

inal

em

phys

ema

and

trea

tmen

t ha

d to

be

inte

rrup

ted

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

Bot

h A

PC a

nd

PDT

can

abl

ate

BO b

ut fo

r APC

onl

y ha

lf as

man

y tr

eatm

ent

sess

ions

nee

ded

Bri

ef s

tudy

app

rais

al T

his

smal

l tri

al

was

rep

orte

d in

abs

trac

t on

ly a

nd n

o fu

rthe

r fu

ll pu

blic

atio

n w

as lo

cate

d. M

any

of t

he s

tudy

det

ails

and

met

hods

wer

e un

clea

r fr

om t

he a

bstr

act

and

the

qual

ity

of t

he t

rial

was

the

refo

re d

ifficu

lt to

as

sess

. Tre

atm

ent

grou

ps d

o no

t ap

pear

co

mpa

rabl

e in

ter

ms

of d

yspl

asia

bw, b

ody

wei

ght.

Appendix 16

250



251

Appendix 17 Oesophageal cancer data extraction

Appendix 17

252



253Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Can

to e

t al.

(200

5)10

7

Dat

a so

urce

Abs

trac

tC

ount

ry N

ot s

tate

dLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-

RC

TN

o. o

f par

tici

pant

sTo

tal:

80In

terv

entio

n: 5

8C

ompa

rato

r: 22

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

d,

mul

ticen

tre

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

at 4

–6 w

k, ev

ery

3 m

th

(yea

r 1)

, eve

ry 3

–6 m

th

(yea

r 2)

the

n ev

ery

6–12

mth

. EU

S an

d C

T s

cans

tak

en e

very

6

mth

(ye

ar 1

) th

en

ever

y 6–

12 m

th. M

ean

FU 3

1.2

mth

(6–

96)

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y T

1 oe

soph

agea

l can

cer

Mai

n el

igib

ility

cri

teri

a Pa

tient

s w

ith o

esop

hage

al S

CC

, ad

enoc

arci

nom

a of

the

oes

opha

gus,

EGJ s

tage

d as

T1

N0

M0

by E

US

or

CT

and

tha

t re

fuse

d, o

r w

ere

unfit

fo

r oe

soph

agec

tom

y, or

dec

lined

ra

diat

ion

ther

apy,

or d

eclin

ed

chem

orad

iatio

n th

erap

y w

ere

elig

ible

fo

r in

clus

ion

Pati

ent

char

acte

rist

ics

% M

ale:

70M

ean

age:

73 yr

Age

ran

ge: 4

3–91

yr; 7

4 Ba

rret

t’s

oeso

phag

eal c

arci

nom

as, t

wo

oeso

phag

eal s

quam

ous

cell

canc

ers,

four

oes

opha

goga

stri

c ju

nctio

n ad

enoc

arci

nom

asC

onco

mit

ant

trea

tmen

t N

ot

stat

ed

Tria

l tre

atm

ents

Bar

e fib

re P

s PD

T

alon

e vs

PD

T p

lus

EMR

Inte

rven

tion

PD

T a

lone

: Ps

infu

sion

(2

mg/

kg),

then

EG

D p

lus

PDT

(do

se

175–

300

J/cm

fibr

e, w

ith a

1.0

, 2.5

, 5

or 7

cm d

iffus

er fi

bre

with

out

a ba

lloon

cen

trin

g de

vice

)C

ompa

rato

r PD

T w

ith E

MR

: Le

sion

s w

ere

stag

ed a

nd r

emov

ed b

y EM

R b

efor

e PD

T fr

om 2

001

to 2

004

Mor

talit

y O

vera

ll an

d di

seas

e sp

ecifi

c 5-

yr s

urvi

val w

as 8

8% a

nd

100%

, res

pect

ivel

yM

orbi

dity

The

CR

rat

e w

as

89.7

% fo

r PD

T a

lone

vs

91.2

% fo

r PD

T +

EM

R (

p =

0.67

). N

ine

patie

nts

had

a 2n

d co

urse

for

abla

tion

of

HG

D o

r ca

ncer

. Fou

r pa

tient

s w

ith

new

HG

D in

res

idua

l Bar

rett

’s oe

soph

agea

l can

cers

of 9

–14

cm

wer

e tr

eate

d su

cces

sful

ly w

ith P

DT.

Five

(6.

2%)

subs

quam

ous

lesi

ons

diag

nose

d at

FU

with

HG

D/c

ance

r w

ere

trea

ted

succ

essf

ully

with

PD

T

(2),

chem

orad

iatio

n (1

) or

sur

gery

(2

)Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty N

ot a

sses

sed

AE

s Si

x pa

tient

s (7

.5%

) re

quire

d ho

spita

lisat

ion

for

naus

ea, v

omiti

ng,

dehy

drat

ion,

tra

nsie

nt d

ysph

agia

, bl

eedi

ng o

r pa

in);

nine

(11

.2%

) de

velo

ped

PDT-

rela

ted

stri

ctur

es.

The

re w

ere

no t

reat

men

t-re

late

d de

aths

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

Ps-

PDT

w

ithou

t a

ballo

on c

entr

ing

devi

ce,

with

or

with

out

EMR

, is

a sa

fe a

nd

high

ly e

ffect

ive

cura

tive

trea

tmen

t fo

r ea

rly

canc

er o

f the

oes

opha

gus/

EGJ

Bri

ef s

tudy

app

rais

al T

his

stud

y w

as a

vaila

ble

only

as

a sh

ort

abst

ract

, the

met

hodo

logy

was

not

cl

earl

y re

port

ed a

nd it

was

unc

lear

w

hich

res

ults

wer

e ap

plic

able

to

each

tre

atm

ent

grou

p. A

s a

non-

rand

omis

ed s

tudy

, the

aut

hors

’ co

nclu

sion

s m

ay b

e ov

erly

str

ong

and

shou

ld b

e re

gard

ed w

ith c

autio

n

CT,

com

pute

rise

d to

mog

raph

y; EG

D, o

esop

hago

gast

rodu

oden

osco

py; E

GJ,

oeso

phag

ogas

tric

junc

tion;

EM

R, e

ndos

copi

c m

ucos

al r

esec

tion;

EU

S, en

dosc

opic

ultr

asou

nd s

can;

HG

D,

high

-gra

de d

yspl

asia

; Ps,

porfi

mer

sod

ium

.

Appendix 17

252



253

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

G

rosj

ean

et a

l. (1

998)

108

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry

Switz

erla

ndLa

ngua

ge E

nglis

hSt

udy

desi

gn

Non

-RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

15 (

22

tum

ours

)In

terv

entio

n: 1

3 tu

mou

rs (

630

nm

PDT

)C

ompa

rato

r: N

ine

tum

ours

(51

4 nm

PD

T)

No.

of r

ecru

itin

g ce

ntre

s N

ot

stat

edFo

llow

-up

peri

od a

nd

freq

uenc

y FU

at

7–10

d, t

hen

3 m

th

afte

r tr

eatm

ent

and

twic

e pe

r ye

ar

ther

eafte

r

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Su

perfi

cial

oe

soph

agea

l and

br

onch

ial c

ance

rsM

ain

elig

ibili

ty

crit

eria

It a

ppea

red

that

men

and

wom

en

with

one

or

seve

ral

biop

sy-p

rove

n su

perfi

cial

SC

C

of t

he b

ronc

hi o

r oe

soph

agus

Pati

ent

char

acte

rist

ics

% M

ale:

80A

ge r

ange

: 46–

79 yr

Mea

n A

ge: 5

9.8

yrA

ll pa

tient

s ha

d pr

evio

usly

rec

eive

d ra

diot

hera

py a

nd/o

r su

rger

y fo

r pr

imar

y in

vasi

ve c

ance

r of

the

he

ad a

nd n

eck

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

PD

T a

t 63

0 nm

with

Ph

otof

rin

II vs

PD

T a

t 51

4 nm

with

Ph

otof

rin

IIIn

terv

enti

on P

DT

with

Pho

tofr

in

(630

nm

): A

fter

inje

ctio

n w

ith P

hoto

frin

II

(1 o

r 2

mg/

kg)

irra

diat

ion

with

630

nm

, 10

0 m

W/c

m2 (

tota

l dos

e 10

0 J/c

m2 )

arg

on

ion

pum

ped-

dye

lase

r un

der

gene

ral

anae

sthe

tic. M

icro

lens

and

/or

cylin

dric

al

light

dis

trib

utor

s w

ere

used

in t

he b

ronc

hi

and

180

or 2

40°

win

dow

ed c

ylin

dric

al li

ght

dist

ribu

tors

in t

he o

esop

hagu

s. Te

n tu

mou

rs

had

a dr

ug–l

ight

inte

rval

of 7

2 hr

, thr

ee

tum

ours

had

a d

rug–

light

inte

rval

of 1

hr.

If th

ere

was

less

tha

n C

R a

t 3-

mth

end

osco

py,

PDT

was

rep

eate

d. P

atie

nts

wer

e ad

vise

d to

av

oid

dire

ct s

unlig

ht fo

r 4–

6 w

k af

ter

drug

ad

min

istr

atio

nC

ompa

rato

r PD

T a

t 51

4 nm

: As

for

PDT

at

630

nm b

ut u

sing

514

nm

and

five

tu

mou

rs h

ad a

dru

g–lig

ht in

terv

al o

f 72

h,

four

tum

ours

had

a d

rug–

light

inte

rval

of

1 hr

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty C

R w

as s

een

in 9

/13

of t

he

supe

rfici

al t

umou

rs (

69%

) w

ith 6

30-n

m P

DT

vs

6/9

tum

ours

(67

%)

with

514

-nm

PD

T. In

the

630

-nm

PD

T g

roup

thr

ee t

umou

rs

show

ed a

PR

(vs

thr

ee in

524

-nm

gro

up)

and

one

tum

our

only

min

imal

ly r

educ

ed in

si

ze. I

n th

e oe

soph

agus

, bot

h w

avel

engt

hs

wer

e ef

fect

ive

in e

radi

catin

g in

situ

and

in

tram

ucos

al c

ance

r bu

t di

d bo

th c

ure

mor

e th

an h

alf o

f the

sub

muc

osal

tum

ours

. 2/1

0 tu

mou

rs t

reat

ed a

t a

drug

–lig

ht in

terv

al o

f 1

hr a

chie

ved

a C

RQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot

asse

ssed

AE

s N

o m

ajor

com

plic

atio

ns w

ere

obse

rved

in e

ither

tre

atm

ent

grou

p. T

hree

63

0-nm

PD

T p

atie

nts

repo

rted

che

st p

ains

w

ith a

ssoc

iate

d hi

gh-g

rade

feve

r fo

r 10

d

afte

r PD

T (

two

with

ple

ural

effu

sion

, the

3r

d w

ith e

ndos

copi

c ev

iden

ce o

f oed

ema

and

eryt

hem

a on

the

pos

teri

or w

all o

f the

tr

ache

a at

the

leve

l of t

he o

esop

hage

al

canc

er).

All

thre

e pa

tient

s re

cove

red

with

an

timic

robi

al t

hera

pyR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

PD

T w

ith 5

14-n

m

light

has

the

pot

entia

l to

cure

sup

erfic

ial

canc

er in

the

oes

opha

gus

and

bron

chi w

ith

the

sam

e pr

obab

ility

as

630-

nm P

DT.

In

the

oeso

phag

us, g

reen

ligh

t pr

even

ts d

eep

tissu

e da

mag

e, t

hus

redu

cing

the

ris

k of

pe

rfor

atio

nB

rief

stu

dy a

ppra

isal

The

num

bers

in

clud

ed in

thi

s st

udy

wer

e sm

all a

nd t

he

met

hods

wer

e no

t cl

earl

y re

port

ed –

pa

rtic

ular

ly in

ter

ms

of c

ompa

rabi

lity

of

the

two

grou

ps. T

he c

oncl

usio

ns m

ay n

ot

ther

efor

e be

rel

iabl

e. N

ote:

The

maj

ority

of

pat

ient

s in

thi

s tr

ial h

ad o

esop

hage

al

tum

ours

(14

/22)

, the

refo

re t

he r

esul

ts h

ave

been

incl

uded

in t

he o

esop

hage

al c

ance

r gr

oup

Appendix 17

254



255Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Hei

er e

t al

. (19

95)11

4

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

42In

terv

entio

n: 2

2C

ompa

rato

r: 20

No.

of r

ecru

itin

g ce

ntre

s N

ot

stat

edFo

llow

-up

peri

od

and

freq

uenc

y FU

at

1 w

k, th

en o

nce

per

mon

th. C

T

ever

y 3

mth

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y O

esop

hage

al c

ance

rM

ain

elig

ibili

ty c

rite

ria

Patie

nts

with

dys

phag

ia c

ause

d by

bio

psy-

prov

en o

esop

hage

al m

alig

nanc

y th

at

wer

e no

t su

itabl

e fo

r, ha

d re

fuse

d or

faile

d su

rger

y, ra

diot

hera

py

and

chem

othe

rapy

wer

e el

igib

le

for

incl

usio

n. P

rior

the

rapy

had

to

have

end

ed a

t le

ast

1 m

th b

efor

e en

rolm

ent.

Excl

usio

n cr

iteri

a w

ere:

trac

heal

invo

lvem

ent

by

bron

chos

copy

and

Kar

nofs

ky

perf

orm

ance

sta

tus

< 30

Pati

ent

char

acte

rist

ics

% M

ale:

62A

ge r

ange

: 42–

87 yr

Mea

n ag

e: 70

yr (P

DT

) 73y

r N

d:YA

GM

ean

Kar

nofs

ky s

tatu

s fo

r bo

th

grou

ps w

as a

roun

d 73

–74

Ove

rall,

60%

of t

umou

rs w

ere

squa

mou

s an

d 40

% w

ere

aden

ocar

cino

ma.

Mos

t pa

tient

s ha

d so

me

kind

of p

rior

the

rapy

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

PD

T w

ith D

HE

vs N

d:YA

G la

ser

Inte

rven

tion

PD

T: I

V D

HE

was

gi

ven

(2 m

g/kg

bw

), th

en il

lum

inat

ion

with

an

argo

n pu

mpe

d-dy

e la

ser.

630

± 2

nm (

300

J/cm

) re

d lig

ht w

as

deliv

ered

by

cylin

der-

diffu

sing

fibr

es,

and

tum

our

segm

ents

wer

e tr

eate

d se

quen

tially

in a

ret

rogr

ade

fash

ion.

Po

wer

den

sity

was

400

mW

/cm

fib

re t

ip. T

issu

e do

se w

as c

alcu

late

d fr

om li

ght

dose

del

iver

ed a

nd

surf

ace

area

exp

osed

, est

imat

ed

from

seg

men

tal l

umin

al d

iam

eter

. A

2nd

dose

cou

ld b

e gi

ven

if ne

cess

ary

(13

patie

nts)

. Pat

ient

s ad

vise

d to

re

stri

ct s

un e

xpos

ure

for

at le

ast

30 d

pos

t in

ject

ion.

If t

here

was

a

recu

rren

ce o

f tum

our

obst

ruct

ion

anot

her

cour

se o

f PD

T w

as g

iven

if

1 m

th h

ad e

laps

ed s

ince

DH

E in

ject

ion

Com

para

tor

Nd:

YAG

: Sta

ndar

d te

chni

que

was

use

d at

90 W

in a

re

trog

rade

fash

ion.

Las

er p

ulse

s w

ere

deliv

ered

thr

ough

qua

rtz

fibre

s (b

are

or c

oaxi

al a

ir fl

ow).

The

rapy

was

del

iver

ed e

very

2–4

d

until

lum

inal

pat

ency

was

ach

ieve

d.

Mos

t pa

tient

s re

quire

d tw

o se

ssio

ns

Mor

talit

y M

ean

surv

ival

was

not

si

gnifi

cant

ly d

iffer

ent

betw

een

PDT

and

Nd:

YAG

(14

5 vs

128

d,

p =

0.41

9)M

orbi

dity

At

1 m

th P

DT

was

as

soci

ated

with

a g

reat

er in

crea

se

in d

ieta

ry p

erfo

rman

ce (

p =

0.00

6),

Kar

nofs

ky p

erfo

rman

ce s

tatu

s (p

< 0

.001

) an

d oe

soph

agea

l gra

de

(p =

0.0

02)

com

pare

d w

ith N

d:YA

G.

Mea

n du

ratio

n of

res

pons

e w

ith

PDT

was

84

d vs

53

for

Nd:

YAG

, p

= 0.

008.

The

diff

eren

ce in

die

tary

le

vels

at

1 w

k an

d w

eigh

t ch

ange

be

twee

n tr

eatm

ent

grou

ps w

as n

s. C

R w

as s

een

in t

wo

PDT

pat

ient

s vs

one

QoL

and

ret

urn

to n

orm

al

acti

vity

Not

ass

esse

dA

Es

In t

he r

ando

mis

ed t

rial

pat

ient

s co

mpl

icat

ions

wer

e re

lativ

ely

few

: fist

ula

(one

PD

T p

atie

nt v

s tw

o), s

tric

ture

(ze

ro v

s tw

o), s

kin

phot

orea

ctio

n (fo

ur v

s ze

ro),

feve

r (fi

ve v

s on

e) a

nd lu

min

al p

lugg

ing

(five

vs

five)

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

PD

T c

an r

elie

ve

oeso

phag

eal o

bstr

uctio

n fr

om s

quam

ous

cell

and

aden

ocar

cino

ma

and

is a

n al

tern

ativ

e to

Nd:

YAG

the

rmal

nec

rosi

s w

ith a

long

er d

urat

ion

of r

espo

nse.

H

owev

er, P

DT

req

uire

s pa

tient

pre

caut

ions

to

min

imis

e sk

in p

hoto

reac

tions

Bri

ef s

tudy

app

rais

al T

his

was

a s

mal

l bu

t w

ell-c

ondu

cted

and

rep

orte

d st

udy

desp

ite t

he a

ppar

ent

lack

of b

lindi

ng o

f ou

tcom

e as

sess

ors.

The

ana

lyse

s ad

just

ed

for

conf

ound

ing

vari

able

s, an

d th

e si

gnifi

cant

ben

efits

in fa

vour

of P

DT

cou

ld

be c

onsi

dere

d as

pro

mis

ing

DH

E, d

ihae

mat

opor

phyr

in e

ther

s; ns

, not

sig

nific

ant.

Appendix 17

254



255

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Lec

leire

et a

l. (2

008)

111

Dat

a so

urce

Abs

trac

tC

ount

ry N

ot s

tate

dLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-R

CT

No.

of p

arti

cipa

nts

Tota

l: 35

(37

lesi

ons)

Inte

rven

tion:

21

(22

lesi

ons)

(p

rim

ary

inte

nt P

DT

)C

ompa

rato

r: 14

(15

le

sion

s) (

PDT

indi

cate

d af

ter

loca

l fai

lure

of C

RT)

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od a

nd

freq

uenc

y M

edia

n FU

15

mth

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Ea

rly

stag

e oe

soph

agea

l ca

ncer

Mai

n el

igib

ility

cr

iter

ia N

ot s

tate

dPa

tien

t ch

arac

teri

stic

s N

ot r

epor

ted

in

deta

il, pa

per

stat

es n

o si

gnifi

cant

diff

eren

ces

betw

een

grou

ps.

Med

ian

tum

our

leng

th 2

cmC

onco

mit

ant

trea

tmen

t N

ot

stat

ed

Tria

l tre

atm

ents

PD

T in

pat

ient

s tr

eate

d in

pri

mar

y in

tent

vs

PDT

in

patie

nts

trea

ted

with

PD

T a

fter

loca

l fa

ilure

of d

efini

tive

CRT

Inte

rven

tion

Pri

mar

y in

tent

PD

T:

Afte

r IV

Pho

tofr

in (

2 m

g/kg

), ill

umin

atio

n w

ith a

dye

lase

r be

twee

n 48

h. T

he

mea

n nu

mbe

r of

PD

T s

essi

ons

was

1.

18. C

ontr

ol e

ndos

copi

es w

ith r

outin

e bi

opsi

es w

ere

plan

ned

6–8

wk

afte

r PD

T. N

o fu

rthe

r de

tails

wer

e re

port

edC

ompa

rato

r PD

T a

fter

faile

d C

RT: A

s fo

r pr

imar

y in

tent

PD

T e

xcep

t m

ean

num

ber

of P

DT

ses

sion

s w

as 1

.33

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty 1

6/22

lesi

ons

(73%

) w

ere

succ

essf

ully

tre

ated

in t

he p

rim

ary

inte

nt g

roup

vs

8/15

(53

%)

afte

r fa

iled

CRT

, p =

0.3

. The

re w

as n

o di

ffere

nce

in

recu

rren

ce r

ate

betw

een

grou

ps (

9 vs

14

%, n

s)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot a

sses

sed

AE

s Se

vere

com

plic

atio

ns w

ere

10%

in

the

prim

ary

inte

nt P

DT

gro

up v

s 50

%

for

faile

d C

RT (

p =

0.01

5) (

two

stri

ctur

es

requ

irin

g en

dosc

opic

dila

tion

vs t

wo

perf

orat

ions

and

five

str

ictu

res

requ

irin

g di

latio

n re

spec

tivel

y). D

eath

rat

e di

rect

ly

rela

ted

to P

DT

was

0%

in p

rim

ary

inte

nt

patie

nts

vs 1

4% fo

r fa

iled

CRT

(ns

)R

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

PD

T w

hen

indi

cate

d as

a s

alva

ge t

hera

py in

pa

tient

s w

ith lo

cal f

ailu

re a

fter

CRT

fo

r oe

soph

agea

l can

cer

tend

ed t

o be

le

ss e

ffect

ive

than

whe

n in

dica

ted

as

a 1s

t-lin

e tr

eatm

ent.

Mor

eove

r, se

vere

co

mpl

icat

ions

, inc

ludi

ng d

eath

-rel

ated

pr

oced

ures

wer

e si

gnifi

cant

ly m

ore

freq

uent

in p

atie

nts

trea

ted

afte

r pr

ior

CRT

Bri

ef s

tudy

app

rais

al F

ew

met

hodo

logi

cal a

nd p

atie

nt d

etai

ls w

ere

repo

rted

in t

his

abst

ract

of a

sm

all s

tudy

so

the

rel

iabi

lity

of t

he c

oncl

usio

ns is

un

clea

r. The

aut

hors

app

ear

to h

ave

draw

n co

nclu

sion

s at

odd

s w

ith t

he

stat

istic

al t

est

resu

ltsTh

e au

thor

s’ co

nclu

sions

do

not f

ollo

w fr

om

the

resu

lts re

port

ed

CRT

, che

mor

adio

ther

apy;

ns, n

ot s

igni

fican

t.

Appendix 17

256



257Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Li

ghtd

ale

et a

l. (1

995)

112

Dat

a so

urce

Fu

ll pu

blis

hed

pape

rC

ount

ry U

SALa

ngua

ge

Engl

ish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 23

6 (2

18

trea

ted)

Inte

rven

tion:

11

8 (1

10

trea

ted)

Com

para

tor:

118

(108

tr

eate

d)N

o. o

f re

crui

ting

ce

ntre

s 24

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU

at 1

wk,

then

1,

2, 3

and

6 m

th

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y O

esop

hage

al c

arci

nom

aM

ain

elig

ibili

ty c

rite

ria

Patie

nts

with

a b

iops

y-pr

oven

oes

opha

geal

m

alig

nanc

y an

d th

at w

ere

too

debi

litat

ed fo

r, re

fuse

d, fa

iled

to

resp

ond

to o

r ha

d a

recu

rren

ce

follo

win

g ch

emot

hera

py, r

adia

tion

ther

apy

or s

urge

ry w

ere

elig

ible

for

incl

usio

n. A

lso

patie

nts

with

SC

C

or a

deno

carc

inom

a, an

d th

at w

ere

sym

ptom

atic

, had

mal

igna

ncy-

caus

ed

dysp

hagi

a to

sol

id fo

ods

and

a K

arno

fsky

sta

tus

of a

t le

ast

30%

wer

e el

igib

le. P

rior

the

rapy

was

req

uire

d to

be

term

inat

ed a

t le

ast

4 w

k be

fore

ra

ndom

isat

ion.

Bro

ncho

scop

y w

as

requ

ired

for

tum

ours

at

or a

bove

th

e le

vel o

f the

car

ina.

Patie

nts

with

in

volv

emen

t of

the

tra

cheo

bron

chia

l tr

ee a

nd t

hose

tha

t ha

d pr

ior

trea

tmen

t fo

r oe

soph

agea

l car

cino

ma

with

PD

T o

r N

d:YA

G la

ser

wer

e ex

clud

ed. C

oncu

rren

t ra

diat

ion

and

chem

othe

rapy

wer

e no

t pe

rmitt

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 72

Med

ian

age:

PDT

68

yr; N

d:YA

G 7

2 yr

Med

ian

Kar

nofs

ky p

erfo

rman

ce s

tatu

s: 80

%Pr

ior

ther

apy:

45%

Med

ian

tum

our

leng

th: P

DT

6 cm

; N

d:YA

G 5

cmA

deno

carc

inom

a 51

%, t

he r

est

had

SCC

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

PD

T v

s N

d:YA

G

lase

rIn

terv

enti

on P

DT:

40–

50 h

r af

ter

sing

le in

trav

enou

s in

ject

ion

with

Ps

(2

mg/

kg b

w),

illum

inat

ion

by

red

light

(63

0 nm

) pr

ovid

ed b

y a

cont

inuo

us w

ave

argo

n pu

mpe

d-dy

e la

ser

and

deliv

ered

via

an

optic

al

quar

tz fi

bre

with

a c

ylin

dric

al

diffu

sing

tip

(40

0 m

W/c

m, t

otal

dos

e 30

0 J/c

m).

Afte

r 2–

3 d

patie

nts

wer

e re

-end

osco

ped

to d

ebri

de t

he n

ecro

tic

tum

our

and

resi

dual

tum

our

coul

d be

tre

ated

with

a 2

nd a

pplic

atio

n of

la

ser

light

(sa

me

dose

). A

max

imum

of

thre

e co

urse

s at

1-m

th in

terv

als

was

pe

rmitt

edC

ompa

rato

r N

d:YA

G la

ser

ther

apy:

A la

ser

pow

er s

ettin

g of

15–

90 W

an

d pu

lse

dura

tion

of 0

.5–4

.0 s

was

us

ed (

deliv

ered

with

eith

er c

onta

ct

or n

on-c

onta

ct t

echn

ique

via

qua

rtz

fibre

s). E

ach

sess

ion

ende

d w

hen

the

endo

scop

ist

thou

ght

max

imum

ac

hiev

able

ben

efit

or m

axim

um p

atie

nt

tole

ranc

e w

as r

each

ed. R

epea

t se

ssio

ns

coul

d be

giv

en if

initi

al r

espo

nse

was

dee

med

insu

ffici

ent

(the

cou

rse

was

dee

med

com

plet

e w

hen

the

inve

stig

ator

bel

ieve

d dy

spha

gia

had

been

pal

liate

d or

furt

her

ther

apy

wou

ld b

e fu

tile)

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty D

ysph

agia

gra

des

sign

ifica

ntly

impr

oved

from

bas

elin

e at

1 w

k (P

DT

–0.

73 v

s N

d:YA

G

–0.9

0) a

nd 1

mth

(PD

T –

0.75

vs

Nd:

YAG

–0.

68)

with

bot

h tr

eatm

ents

(n

s di

ffere

nce

betw

een

trea

tmen

t gr

oups

). O

bjec

tive

tum

our

resp

onse

(r

espo

nder

s: pa

tient

s w

ith C

R o

r PR

) w

as 4

4% P

DT

vs

48%

Nd:

YAG

(ns

) at

1

wk

and

32%

PD

T v

s 20

% N

d:YA

G

at 1

mth

(p

< 0.

05).

Dat

a w

as o

btai

ned

from

80%

pat

ient

s at

1 w

k an

d 60

%

at 1

mth

. Sub

grou

p an

alys

es s

how

ed

ns d

iffer

ence

s be

twee

n gr

oups

but

th

ere

was

a t

rend

in fa

vour

of P

DT

fo

r ob

ject

ive

tum

our

resp

onse

rat

es

in t

he u

pper

and

low

er t

hird

of t

he

oeso

phag

us, t

umou

rs >

10

cm a

nd in

pa

tient

s th

at r

ecei

ved

prio

r th

erap

y. T

here

was

no

diffe

renc

e be

twee

n gr

oups

for

patie

nts

with

squ

amou

s ce

ll ca

ncer

and

ade

noca

rcin

oma

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

ass

esse

dA

Es

Sign

ifica

ntly

mor

e PD

T p

atie

nts

had

an A

E (9

2% v

s 82

%, p

< 0

.05)

. Su

nbur

n (1

9% P

DT

vs

0%),

naus

ea (

8%

vs 2

%),

feve

r (1

6% v

s 5%

) an

d pl

eura

l ef

fusi

on (

10%

vs

2%)

wer

e si

gnifi

cant

ly

grea

ter

for

PDT

and

oes

opha

geal

pe

rfor

atio

n gr

eate

r fo

r N

d:YA

G (

1%

vs 7

%) p

< 0

.05)

. All

PDT

pat

ient

s w

ere

phot

osen

sitiv

e fo

r 1–

2 m

th, n

one

seve

re. T

reat

men

t-re

late

d re

spir

ator

y in

suffi

cien

cy o

ccur

red

in 3

% P

DT

(vs

1%

). Se

vere

AEs

wer

e eq

ual o

vera

ll fo

r bo

th t

reat

men

tsR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

PD

T w

ith

porfi

mer

sol

utio

n ha

s ov

eral

l equ

al

effic

acy

to N

d:YA

G la

ser

ther

mal

ab

latio

n fo

r pa

lliat

ion

of d

ysph

agia

in

oes

opha

geal

can

cer,

and

equa

l or

bett

er o

bjec

tive

tum

our

resp

onse

ra

te. T

empo

rary

pho

tose

nsiti

vity

is a

lim

itatio

n, b

ut P

DT

is c

arri

ed o

ut w

ith

grea

ter

ease

and

is a

ssoc

iate

d w

ith

few

er a

cute

per

fora

tions

tha

n N

d:YA

G

lase

r th

erap

yB

rief

stu

dy a

ppra

isal

The

met

hods

w

ere

gene

rally

wel

l-des

crib

ed t

houg

h a

few

feat

ures

wer

e no

t re

port

ed.

It m

ay h

ave

been

use

ful t

o ga

uge

patie

nt/in

vest

igat

or o

pini

on o

f eas

e of

tre

atm

ent

and

impo

rtan

ce o

f ph

otos

ensi

tivity

to

QoL

to

info

rm t

he

conc

lusi

ons

ns, n

ot s

igni

fican

t.

Appendix 17

256



257Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mai

er e

t al.

(200

0)11

5

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry A

ustr

iaLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-

RC

TN

o. o

f par

tici

pant

sTo

tal:

52In

terv

entio

n: 2

3 (P

DT

)C

ompa

rato

r: 29

(PD

T

unde

r H

BO)

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od

and

freq

uenc

y FU

at

1 m

th, t

hen

ever

y 3

mth

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y A

dvan

ced

canc

er o

f the

upp

er

gast

roin

test

inal

tra

ctM

ain

elig

ibili

ty c

rite

ria

It ap

pear

ed

that

pat

ient

s w

ith a

dvan

ced

canc

er

of t

he u

pper

gas

troi

ntes

tinal

tra

ct

who

wer

e no

t el

igib

le fo

r re

sect

ion

trea

tmen

t du

e to

poo

r pe

rfor

man

ce

stat

us, f

unct

iona

l and

/or

anat

omic

in

oper

abili

ty, a

nd/o

r an

atom

ic

inop

erab

ility

, and

/or

refu

sing

sur

gery

w

ere

elig

ible

for

incl

usio

nPa

tien

t ch

arac

teri

stic

s%

Mal

e: 81

Age

ran

ge: 4

6–87

yrM

ean

age:

67.3

yrM

ost

patie

nts’

can

cers

wer

e ju

dged

to

be

stag

e III

, dys

phag

ia s

core

s va

ried

acr

oss

leve

ls 2

, 3 a

nd 4

and

no

sign

ifica

nt d

iffer

ence

s at

bas

elin

e w

ere

foun

d. T

umou

rs w

ere

SCC

in 2

5 ca

ses,

aden

ocar

cino

ma

in 2

5 ca

ses.

Furt

her

patie

nt c

hara

cter

istic

s w

ere

repo

rted

Con

com

itan

t tr

eatm

ent

Befo

re

PDT,

12 (

seve

n in

PD

T, fiv

e in

PD

T/

HBO

) pa

tient

s un

derw

ent

dila

tatio

n an

d re

trog

rade

Nd:

YAG

lase

r di

sobl

itera

tion

Tria

l tre

atm

ents

PD

T v

s PD

T

unde

r H

BOIn

terv

enti

on P

DT:

Pho

tosa

n-3

(2 m

g/kg

) w

as a

dmin

iste

red

intr

aven

ously

. Afte

r 48

hr,

PDT,

usin

g a

fibre

with

a 1

-cm

tip

rad

ial

light

-diff

usin

g cy

linde

r, w

as in

sert

ed

usin

g an

end

osco

pe. I

llum

inat

ion

dose

was

300

J/cm

of fi

bre,

630

nm

ap

plie

d by

a K

TP-

Nd:

YAG

lase

r. Tr

eatm

ent

was

und

er s

hort

-te

rm in

trav

enou

s an

aest

hesi

a. 2–

3 d

afte

r PD

T, en

dosc

opy

was

re

peat

ed, a

nd n

ecro

tic t

issu

e re

mov

ed m

echa

nica

lly if

nec

essa

ry.

Trea

tmen

t co

uld

be r

epea

ted

afte

r 3

mth

if n

eces

sary

but

mos

t pa

tient

s re

ceiv

ed o

ne s

essi

onC

ompa

rato

r PD

T u

nder

HBO

(P

DT

/HBO

): A

s fo

r PD

T b

ut

unde

r H

BO a

t a

leve

l of 2

ATA

in

a h

yper

bari

c ch

ambe

r. O

xyge

n w

as a

dmin

iste

red

with

the

Scu

ba

valv

e, t

rans

cuta

neou

s P o

2 lev

els

wer

e 50

0–75

0 m

mH

g. Be

fore

H

BO, p

atie

nts

had

an e

ar, n

ose

and

thro

at c

heck

-up

Mor

talit

y M

edia

n su

rviv

al a

fter

PDT

w

as 8

.7 m

th v

s 13

.8 m

th fo

r PD

T/

HBO

(p

= 0.

021)

Mor

bidi

ty A

t 3

mth

, dys

phag

ia s

core

ha

d de

crea

sed

in b

oth

grou

ps b

ut

ther

e w

as n

o si

gnifi

cant

diff

eren

ce

betw

een

trea

tmen

ts (

p =

0.43

). A

t 3

mth

, mea

n de

crea

se in

ste

nosi

s w

as

5.6

mm

in t

he P

DT

gro

up v

s 6.

3 m

m

PDT

/HBO

, p =

0.0

65. M

ean

decr

ease

in

tum

our

leng

th w

as 2

cm P

DT

vs

2.8

cm P

DT

/HBO

, p =

0.0

02Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty A

sem

i-sol

id d

iet

was

po

ssib

le in

all

patie

nts

afte

r PD

T o

r PD

T/H

BOA

Es

No

maj

or c

ompl

icat

ions

rel

ated

to

PD

T, H

BO a

nd p

hoto

sens

itisa

tion,

an

d no

bar

otra

uma

of t

he e

ar o

r lu

ng o

r su

nbur

n w

as o

bser

ved.

M

inor

com

plic

atio

ns in

clud

ed:

post

inte

rven

tiona

l ody

noph

agia

(e

ight

PD

T v

s ni

ne P

DT

/HBO

), fe

ver

up t

o 39°

(five

vs

nine

) an

d ch

est

pain

for

1 or

2 d

(fiv

e vs

nin

e). S

ix

oeso

phag

otra

chea

l fist

ulas

wer

e fo

und

in t

wo

case

s (P

DT

at

5 an

d 17

mth

) an

d fo

ur c

ases

(PD

T/H

BO

at 4

, 7, 1

4 an

d 24

mth

). St

entin

g w

ith

coat

ed, s

elf-e

xpan

dabl

e st

ents

was

pe

rfor

med

in o

ne P

DT

pat

ient

at

16 m

th a

nd t

wo

PDT

/HBO

pat

ient

s at

14

and

17 m

th. O

ne p

atie

nt h

ad

haem

orrh

age

of t

he t

umou

r 18

mth

af

ter

PDT

/HBO

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

Com

bine

d PD

T/H

BO r

epre

sent

s a

new

app

roac

h in

the

tre

atm

ent

of o

esop

hage

al a

nd

card

ial c

ance

r, w

hich

app

ears

to

have

en

hanc

ed t

he e

ffica

cy o

f PD

TB

rief

stu

dy a

ppra

isal

Thi

s w

as a

sm

all p

ilot

stud

y th

at, d

espi

te n

ot

bein

g ra

ndom

ised

, doe

s se

em t

o ha

ve

achi

eved

rea

sona

ble

com

pari

son

grou

ps. T

he a

utho

rs c

omm

ent

that

ra

ndom

isat

ion

was

not

pos

sibl

e du

e to

the

var

iabl

e av

aila

bilit

y of

the

ox

ygen

cha

mbe

r. The

con

clus

ions

ar

e re

ason

able

but

the

stu

dy w

ould

ha

ve b

enefi

ted

from

blin

ded

outc

ome

asse

ssor

s

ATA

, atm

osph

ere

abso

lute

.

Appendix 17

258



259Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mai

er e

t al.

(200

0)11

6

Link

ed p

ublic

atio

ns21

1

Dat

a so

urce

Ful

l pub

lishe

d pa

per

Cou

ntry

Aus

tria

Lang

uage

Eng

lish

Stud

y de

sign

Non

-RC

TN

o. o

f par

tici

pant

sTo

tal:

75In

terv

entio

n: 3

1C

ompa

rato

r: 44

No.

of r

ecru

itin

g ce

ntre

s O

neFo

llow

-up

peri

od a

nd

freq

uenc

y FU

afte

r 1

mth

, th

en e

very

3 m

th

Trea

tmen

t in

tent

ion

Not

st

ated

Type

(s)

of c

ance

r an

d hi

stol

ogy

Adv

ance

d oe

soph

agea

l car

cino

ma

Mai

n el

igib

ility

cri

teri

a Pa

tient

s th

at w

ere

not

elig

ible

fo

r re

sect

ion

trea

tmen

t du

e to

si

gnifi

cant

com

orbi

dity

wer

e in

clud

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 80

Mea

n ag

e: PD

T a

lone

, 67

yr;

PDT

/HBO

67.

5A

ge r

ange

: 46–

87 yr

Can

cer

stag

e: III

, 59;

IV, 1

6 D

ysph

agia

sc

ore:

leve

l 2, 2

3; le

vel 3

, 37

; lev

el 4

, 15.

40

SCC

, 35

aden

ocar

cino

ma

Furt

her

patie

nt c

hara

cter

istic

s w

ere

repo

rted

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

PD

T v

s PD

T/H

BOIn

terv

enti

on P

DT:

H

pD g

iven

intr

aven

ously

(2

mg/

kg)

and

cam

oufla

ge

skin

pro

tect

ion

used

for

2 w

k, th

en s

unbl

ock

for

10 w

k. PD

T g

iven

48

hr

afte

r se

nsiti

satio

n w

ith

a fib

re (

1-cm

tip

, rad

ial

light

diff

usin

g cy

linde

r)

inse

rted

thr

ough

the

bio

psy

chan

nel o

f the

end

osco

pe

(sev

eral

pla

cem

ents

wer

e ne

cess

ary)

. Lig

ht d

ose

was

30

0 J/c

m, 6

30 n

m a

pplie

d w

ith a

KT

P-N

d:YA

G la

ser

with

DY

E bo

x. T

reat

men

t gi

ven

unde

r sh

ort-

term

an

aest

hesi

a. En

dosc

opy

was

re

peat

ed 2

–3 d

afte

r PD

T

and

necr

otic

tis

sue

rem

oved

m

echa

nica

lly if

nec

essa

ry.

Prio

r to

PD

T, di

lata

tion

and

retr

ogra

de N

d:YA

G w

as

nece

ssar

y in

15

case

sC

ompa

rato

r PD

T/

HBO

: As

for

PDT

exc

ept

patie

nts

had

ear,

nose

an

d th

roat

che

ck-u

p, th

en

PDT

giv

en u

nder

HBO

(2

atm

osph

eres

) in

a w

alk-

in

hype

rbar

ic c

ham

ber

Mor

talit

y M

edia

n ov

eral

l sur

viva

l with

PD

T

was

7 m

th (

vs 1

2 m

th in

PD

T/H

BO g

roup

), p

= 0.

0098

. 12-

mth

sur

viva

l with

PD

T w

as

25%

vs

52%

with

PD

T/H

BOM

orbi

dity

At

3 m

th, s

teno

sis

decr

ease

d in

bo

th g

roup

s by

6 m

mIn

the

PD

T g

roup

med

ian

tum

our

leng

th

decr

ease

was

2 cm

vs

3 cm

in t

he P

DT

/HBO

gr

oup,

p =

0.00

02A

t 3-

mth

FU

(or

last

FU

in c

ase

of d

eath

)in

the

PD

T g

roup

dys

phag

ia s

core

cou

ld b

e lo

wer

ed b

y on

e le

vel i

n ei

ght

case

s (v

s ni

ne)

and

two

leve

ls in

23

case

s (v

s 33

) (a

nd in

th

e PD

T/H

BO g

roup

it c

ould

be

low

ered

by

thre

e le

vels

in t

wo

case

s); t

his

sign

ifica

ntly

fa

vour

ed P

DT

/HBO

(p

= 0.

0064

). N

o re

curr

ent

dysp

hagi

a w

as o

bser

ved

at 3

-mth

FU

for

eith

er g

roup

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

At

leas

t a

sem

i-sol

id d

iet

was

pos

sibl

e in

all

patie

nts

afte

r ei

ther

tre

atm

ent

AE

s The

re w

ere

no m

ajor

pos

tinte

rven

tiona

l co

mpl

icat

ions

or

skin

pho

tose

nsiti

satio

n re

late

d to

eith

er t

reat

men

t. N

o ba

rotr

aum

a w

as o

bser

ved.

Min

or c

ompl

icat

ions

incl

uded

: od

ynop

hagi

a (P

DT

gro

up 6

vs

PDT

/HBO

8)

; fev

er u

p to

39°

in t

he a

ftern

oon

of t

he

inte

rven

tiona

l day

, one

in P

DT

vs

thre

e in

PD

T/H

BO);

ches

t pa

in fo

r 1

or 2

d (

four

in

PDT

vs

seve

n in

PD

T/H

BO).

30-d

ay m

orta

lity

was

0%

. Six

oes

opha

gotr

ache

al fi

stul

as in

tw

o pa

tient

s w

ere

foun

d (P

DT,

two

case

s; PD

T/

HBO

four

cas

es)

Res

ourc

e us

e H

ospi

talis

atio

n in

bot

h gr

oups

was

3–9

d (

med

ian

4.9

d)

Aut

hors

’ con

clus

ions

Com

bine

d PD

T/H

BO r

epre

sent

s a

new

ap

proa

ch in

the

tre

atm

ent

of

oeso

phag

eal a

nd c

ardi

al c

ance

r w

hich

app

ears

to

have

enh

ance

d th

e ef

ficie

ncy

of P

DT

Bri

ef s

tudy

app

rais

al T

his

stud

y w

as n

ot r

ando

mis

ed (

and

so m

ay h

ave

been

sub

ject

to

bias

) an

d in

clud

ed a

fair

ly s

mal

l nu

mbe

r of

pat

ient

s. T

he a

utho

rs

did

thou

gh a

ckno

wle

dge

that

de

finiti

ve c

oncl

usio

ns c

ould

not

be

draw

n ba

sed

on t

hese

res

ults

. Thi

s pu

blic

atio

n ap

pear

s to

be

the

sam

e st

udy

as a

rep

ort

of a

pilo

t st

udy

211 ,

alth

ough

the

aut

hors

wer

e no

t ex

plic

it ab

out

this

Appendix 17

258



259Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mai

er e

t al.

(200

0)11

7

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry A

ustr

iaLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-

RC

TN

o. o

f par

tici

pant

sTo

tal:

119

Inte

rven

tion:

44

(PD

T a

nd

brac

hyra

diot

hera

py)

Com

para

tor:

75

(bra

chyr

adio

ther

apy)

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od

and

freq

uenc

y FU

at

1 m

th, t

hen

ever

y 3

mth

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y A

dvan

ced

oeso

phag

eal c

arci

nom

aM

ain

elig

ibili

ty c

rite

ria

Patie

nts

who

wer

e no

t el

igib

le fo

r re

sect

ion

due

to t

umou

r in

volv

emen

t of

th

e ad

jace

nt t

issu

e, p

oor

perf

orm

ance

sta

tus

plus

in

oper

able

sta

tus

as a

res

ult

of c

omor

bidi

ty, r

efus

al o

f su

rgic

al in

terv

entio

n, o

r a

com

bina

tion

of t

hese

, wer

e in

clud

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 81

Mea

n A

ge: M

en, 6

7 yr

; w

omen

65

yrA

ge R

ange

: 27–

93 yr

Can

cer

stag

e: III

, 80;

IV

, 39.

68

SCC

and

51

aden

ocar

cino

ma

Furt

her

patie

nt

char

acte

rist

ics

wer

e re

port

edC

onco

mit

ant

trea

tmen

t Pr

ior

to t

hera

py 2

1 pa

tient

s re

quire

d in

itial

dila

tatio

n an

d tu

mou

r ob

liter

atio

n w

ith N

d:YA

G

Tria

l tre

atm

ents

PD

T a

nd b

rach

ythe

rapy

vs

bra

chyt

hera

py a

lone

Inte

rven

tion

PD

T a

nd b

rach

ythe

rapy

: In

trav

enou

s ha

emat

opor

phyr

in w

as

adm

inis

tere

d (m

ean

1.5

inje

ctio

ns/p

atie

nt)

(2 m

g/kg

), af

ter

48 h

r PD

T t

reat

men

t us

ing

a fib

re w

ith 2

-cm

rad

ial l

ight

-diff

usin

g cy

linde

r in

sert

ed t

hrou

gh b

iops

y ch

anne

l of

an e

ndos

cope

(do

se 3

00 J/

cm fi

bre,

630

nm

ap

plie

d by

a K

TP-

Nd:

YAG

lase

r w

ith D

YE-

box)

. 2–3

d a

fter

PDT,

endo

scop

y re

peat

ed

and

necr

otic

tis

sue

rem

oved

. End

osco

py

was

per

form

ed a

fter

1 m

th, t

hen

ever

y 3

mth

. PD

T w

as n

ot r

epea

ted

with

in 3

mth

. Ir

idiu

m-1

92 b

rach

yrad

ioth

erap

y w

as g

iven

by

inse

rtio

n of

the

afte

rloa

ding

cat

hete

r. 5

Gy

per

sess

ion

was

giv

en, p

atie

nts

rece

ived

on

e to

four

ses

sion

s in

tot

al d

epen

ding

on

endo

scop

ic fi

ndin

gs a

nd d

ysph

agia

, with

3–

7 d

betw

een

sess

ions

. Thi

s pr

oces

s w

as

carr

ied

out

unde

r sh

ort-

term

intr

aven

ous

anae

sthe

sia,

com

bine

d w

ith t

opic

al

anae

sthe

sia

with

sup

port

ed b

reat

hing

. In

25

patie

nts

with

Kar

nofs

ky s

core

of >

80

(fair

co

nditi

on)

trea

tmen

t w

as c

ompl

eted

by

exte

rnal

bea

m ir

radi

atio

n us

ing

the

mul

tiple

fie

ld t

echn

ique

to

deliv

er m

ean

dose

of

44 G

yC

ompa

rato

r B

rach

ythe

rapy

: Iri

dium

-192

br

achy

radi

othe

rapy

was

giv

en b

y in

sert

ion

of t

he a

fterl

oadi

ng c

athe

ter.

5 G

y pe

r se

ssio

n w

as g

iven

, pat

ient

s re

ceiv

ed o

ne t

o fo

ur

sess

ions

in t

otal

dep

endi

ng o

n en

dosc

opic

fin

ding

s an

d dy

spha

gia,

with

3–7

d b

etw

een

sess

ions

. Thi

s pr

oces

s w

as d

one

unde

r sh

ort-

term

intr

aven

ous

anae

sthe

sia,

com

bine

d w

ith

topi

cal a

naes

thes

ia w

ith s

uppo

rted

bre

athi

ng.

In 1

7 pa

tient

s w

ith K

arno

fsky

sco

re o

f > 8

0 (fa

ir c

ondi

tion)

tre

atm

ent

was

com

plet

ed b

y ex

tern

al b

eam

irra

diat

ion

usin

g th

e m

ultip

le

field

tec

hniq

ue t

o de

liver

mea

n do

se o

f 44

Gy

Mor

talit

y M

ean

surv

ival

was

5.6

mth

for

brac

hyth

erap

y; 7.

7 m

th b

rach

ythe

rapy

and

ex

tern

al b

eam

irra

diat

ion;

6.3

mth

PD

T

brac

hyth

erap

y; 13

mth

PD

T, br

achy

ther

apy

and

exte

rnal

bea

m ir

radi

atio

n. T

here

was

a

sign

ifica

nt d

iffer

ence

with

PD

T*

(p =

0.0

129)

an

d ex

tern

al b

eam

irra

diat

ion*

(p

= 0.

0001

). T

his

was

bia

sed,

as

grou

ps w

ithou

t ex

tern

al

beam

irra

diat

ion

cont

aine

d pa

tient

s th

at

died

bef

ore

ente

ring

the

irra

diat

ion

regi

men

. (A

utho

rs’ c

omm

ent.)

*It

was

unc

lear

whi

ch p

atie

nt g

roup

s th

ese

resu

lts r

efer

red

toM

orbi

dity

Dys

phag

ia s

core

impr

oved

in

all

patie

nts

by o

ne t

o th

ree

leve

ls a

nd

was

sig

nific

antly

gre

ater

in t

he P

DT

gro

up

(p =

0.0

003)

. The

mea

n in

crea

se in

ope

ning

di

amet

er o

f tum

our-

rela

ted

sten

osis

was

si

gnifi

cant

ly g

reat

er in

the

PD

T g

roup

with

or

with

out

exte

rnal

bea

m ir

radi

atio

n th

an in

ei

ther

of t

he b

rach

ythe

rapy

con

ditio

nsQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y T

here

wer

e no

sig

nific

ant

diffe

renc

es

betw

een

the

two

grou

ps in

ter

ms

of

Kar

nofs

ky p

erfo

rman

ce s

tatu

s sc

ores

at

3 m

th, p

= 0

.28

AE

s M

ajor

com

plic

atio

ns o

ccur

red

in 9

%

(11/

119)

of p

atie

nts,

incl

udin

g oe

soph

agea

l pe

rfor

atio

n af

ter

brac

hyth

erap

y, se

vere

ha

emor

rhag

ing

3 d

afte

r PD

T, sp

onta

neou

s pe

rfor

atio

n of

dis

tal o

esop

hagu

s w

ith

oeso

phag

omed

iast

inop

leur

al fi

stul

a an

d co

ncur

rent

ple

ural

em

phys

ema

5 m

th

afte

r PD

T, tr

ache

o-oe

soph

agea

l or

trac

heob

ronc

hial

fist

ula.

Due

to

stri

ctur

es,

dila

tion

was

nec

essa

ry a

fter

PDT

(fo

ur

patie

nts)

and

Nd:

YAG

(45

pat

ient

s). A

fter

PDT

28

patie

nts

repo

rted

ody

noph

agia

for

2–5

dR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

PD

T h

as

been

sho

wn

to b

e an

effe

ctiv

e pa

lliat

ive

trea

tmen

t of

adv

ance

d oe

soph

agea

l can

cer.

How

ever

, pr

oper

pat

ient

sel

ectio

n is

ne

cess

ary

to p

reve

nt s

erio

us

com

plic

atio

nsB

rief

stu

dy a

ppra

isal

A

size

able

pro

port

ion

of p

atie

nts

in e

ach

grou

p w

ere

pre-

trea

ted

with

Nd:

YAG

, whi

ch d

id n

ot

appe

ar t

o be

acc

ount

ed fo

r in

th

e an

alys

is. T

his

tria

l app

ears

to

hav

e co

ntai

ned

four

sep

arat

e ar

ms,

alth

ough

thi

s w

as p

oorl

y de

scri

bed.

Pat

ient

s in

goo

d/fa

ir c

ondi

tion

rece

ived

a s

light

ly

diffe

rent

tre

atm

ent

prot

ocol

. T

hese

lim

itatio

ns m

ake

it di

fficu

lt to

eva

luat

e re

liabi

lity

of t

he

auth

ors’

con

clus

ions

Appendix 17

260



261Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mai

er e

t al

. (20

01)11

8

Link

ed

publ

icat

ions

120

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry A

ustr

iaLa

ngua

ge E

nglis

hSt

udy

desi

gn

Non

-RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

49In

terv

entio

n: 2

2 (A

LA–P

DT

)C

ompa

rato

r: 27

(P

hoto

san-

PDT

)N

o. o

f rec

ruit

ing

cent

res

Not

st

ated

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

at 1

mth

, the

n ev

ery

3 m

th

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y A

dvan

ced

oeso

phag

eal c

ance

rM

ain

elig

ibili

ty

crit

eria

Pat

ient

s th

at

wer

e no

t el

igib

le fo

r re

sect

ion

trea

tmen

t du

e to

poo

r pe

rfor

man

ce

stat

us, f

unct

iona

l and

/or

anat

omic

al in

oper

abili

ty,

and/

or r

efus

ing

surg

ery

wer

e in

clud

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 78

Age

ran

ge: 4

6–88

yrM

ean

age:

ALA

, 69

yr;

Phot

osan

68

yrC

ance

r st

age:

III, 1

7; IV

32

. Dys

phag

ia s

core

va

ried

with

mos

t in

leve

l 2

or 3

but

no

sign

ifica

nt

diffe

renc

esO

vera

ll th

ere

wer

e 13

SC

C, 1

4 ad

enoc

arci

nom

aFu

rthe

r pa

tient

ch

arac

teri

stic

s w

ere

repo

rted

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

ALA

- PD

T v

s PD

T w

ith

Phot

osan

(H

pD).

Both

per

form

ed w

ith

addi

tiona

l hyp

erba

ric

oxyg

enat

ion

Inte

rven

tion

ALA

–PD

T: D

iagn

ostic

w

ork-

up w

as p

erfo

rmed

usi

ng b

ariu

m

oeso

phag

ogra

m, o

esop

hago

gast

rosc

opy,

bron

chos

copy

and

CT

sca

ns. O

ral

adm

inis

trat

ion

of A

LA (

60 m

g/kg

) th

en s

kin

prot

ectio

n by

cam

oufla

ge fo

r 24

hr.

6–8

hr

afte

r ALA

, PD

T w

as c

arri

ed o

ut u

sing

a fi

bre

with

2-c

m t

ip r

adia

l lig

ht-d

iffus

ing

cylin

der,

inse

rted

thr

ough

the

bio

psy

chan

nel o

f the

en

dosc

ope.

Lig

ht d

ose

was

300

J/cm

fibr

e an

d 63

0-nm

ligh

t w

as a

pplie

d by

KT

P-N

d:

YAG

lase

r ha

ving

a D

YE

mod

ule.

Add

ition

al

hype

rbar

ic o

xyge

natio

n w

as a

pplie

d (a

fter

an e

ar, n

ose

and

thro

at c

heck

-up)

at

leve

l 2 A

TA u

sing

a S

cuba

val

ve s

yste

m.

Trea

tmen

t w

as p

erfo

rmed

und

er s

hort

-ter

m

intr

aven

ous

anae

sthe

sia.

Endo

scop

y w

as

perf

orm

ed 2

–3 d

afte

r PD

T a

nd n

ecro

tic

tissu

e re

mov

ed. E

ndos

copy

was

the

n pe

rfor

med

afte

r 1

mth

, the

n ev

ery

3 m

th.

Incr

ease

d tu

mou

r le

ngth

and

dys

phag

ia a

t FU

indi

cate

d fu

rthe

r PD

T t

reat

men

t. N

o tr

eatm

ent

was

rep

eate

d w

ithin

3 m

th a

fter

the

1st

PDT

ses

sion

Com

para

tor

Phot

osan

-PD

T: A

s fo

r ALA

–PD

T e

xcep

t in

trav

enou

s ad

min

istr

atio

n of

Ph

otos

an (

2 m

g/kg

), 48

hr

befo

re P

DT

Mor

talit

y M

edia

n su

rviv

al fo

r A

LA g

roup

was

8 m

th v

s 9m

th,

p =

0.44

(K

apla

n–M

eier

sur

viva

l cu

rve

in p

aper

)M

orbi

dity

At

1 m

th, t

here

was

si

gnifi

cant

ly m

ore

impr

ovem

ent

in t

he A

LA g

roup

tha

n th

e Ph

otos

an g

roup

for

the

follo

win

g ou

tcom

es: d

ysph

agia

(p

= 0.

02),

tum

our

sten

osis

(p =

0.0

0000

) an

d tu

mou

r le

ngth

(p =

0.0

0001

4)Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty K

arno

vsky

Per

form

ance

st

atus

impr

oved

by

23%

for

ALA

vs

44%

for

Phot

osan

, not

si

gnifi

cant

(p

= 0.

12)

AE

s N

o ba

rotr

aum

a of

th

e ea

r w

as o

bser

ved.

No

sunb

urn

occu

rred

in e

ither

gr

oup.

The

re w

ere

no m

ajor

A

Es. 3

0-da

y m

orta

lity

was

0%

. M

inor

com

plic

atio

ns w

ere:

post

inte

rven

tiona

l ody

noph

agia

(n

ine

in A

LA g

roup

vs

13);

feve

r up

to

39°

in t

he a

ftern

oon

of t

he

inte

rven

tiona

l day

(fiv

e vs

eig

ht);

ches

t pa

in fo

r 1

or 2

d (

nine

vs

13).

Afte

r ALA

adm

inis

trat

ion

all

patie

nts

expe

rien

ced

naus

eaR

esou

rce

use

Hos

pita

lisat

ion

was

4–6

d in

bot

h tr

eatm

ent

grou

ps

Aut

hors

’ con

clus

ions

Des

pite

the

lim

itatio

ns

of a

non

-ran

dom

ised

stu

dy, p

hoto

sens

itisa

tion

with

Pho

tosa

n se

ems

to b

e m

ore

effe

ctiv

e in

PD

T o

f adv

ance

d oe

soph

agea

l car

cino

ma

com

pare

d w

ith A

LAB

rief

stu

dy a

ppra

isal

The

con

clus

ions

tha

t co

uld

be d

raw

n w

ere

limite

d as

thi

s w

as a

sm

all,

non-

rand

omis

ed s

tudy

. Bas

elin

e ch

arac

teri

stic

s w

ere

larg

ely

sim

ilar

apar

t fr

om M

sta

ge a

nd t

he

auth

ors’

cau

tious

con

clus

ions

app

ear

relia

ble.

T

his

stud

y ap

pear

s to

hav

e be

en p

ublis

hed

twic

e (s

ee r

ef. 1

20)

with

Pho

tosa

n be

ing

desc

ribe

d as

HpD

. The

pat

ient

s, tr

eatm

ents

and

res

ults

ap

pear

to

be id

entic

al, t

here

fore

onl

y on

e st

udy

has

been

dat

a ex

trac

ted

ATA

, atm

osph

ere

abso

lute

.

Appendix 17

260



261Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sav

ary

et a

l. (1

998)

109

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry S

witz

erla

ndLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-

RC

TN

o. o

f par

tici

pant

sTo

tal:

24 (

31 t

umou

rs)

Inte

rven

tion:

Nin

e tu

mou

rs (

HpD

-PD

T)

Com

para

tor:

Eigh

t tu

mou

rs (

Phot

ofri

n II-

PDT

)2n

d C

ompa

rato

r: Tw

o tu

mou

rs (

mT

HPC

-PD

T, 0.

15 m

g/kg

with

652

nm

)3r

d C

ompa

rato

r: O

ne

tum

our

(mT

HPC

-PD

T, 0.

3 m

g/kg

with

514

nm

)4t

h C

ompa

rato

r: 11

tu

mou

rs (

mT

HPC

-PD

T, 0.

15 m

g/kg

with

514

nm

)N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU a

t 10

d, 3

mth

, the

n 6-

mth

in

terv

als

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Ea

rly

SCC

of t

he

oeso

phag

usM

ain

elig

ibili

ty

crit

eria

Bio

psy

confi

rmed

ear

ly

SCC

. Pat

ient

s w

ith

porp

hyri

a w

ere

excl

uded

Pati

ent

char

acte

rist

ics

% M

ale:

92A

ge r

ange

: 42–

79 yr

Mea

n ag

e: 56

yrTw

enty

-tw

o pa

tient

s ha

d a

hist

ory

of

prim

ary

inva

sive

hea

d an

d ne

ck c

ance

r, tw

o ha

d no

suc

h hi

stor

y. Tw

o pa

tient

s ha

d sy

nchr

onou

s tu

mou

rs,

five

patie

nts

deve

lope

d m

etac

hron

ous

earl

y ca

ncer

sC

onco

mit

ant

trea

tmen

t N

one

Tria

l tre

atm

ents

HpD

PD

T v

s Ph

otof

rin

II PD

T

vs m

TH

PC 0

.15

mg/

kg (

652

nm)

PDT

vs

mT

HPC

0.

3 m

g/kg

(51

4 nm

) PD

T v

s m

TH

PC 0

.15

mg/

kg

(514

nm

) PD

TIn

terv

enti

on H

pD P

DT:

Intr

aven

ous

HpD

w

as in

ject

ed (

3 m

g/kg

), th

en P

DT

giv

en w

ith a

n ar

gon

ion

pum

ped-

dye

lase

r af

ter

72 h

r (6

30 n

m,

100

J/cm

2 , 80

mW

/cm

2 ) fo

r 21

min

. Sur

face

ir

radi

atio

n us

ing

180

or 2

40°

win

dow

ed c

ylin

dric

al

light

dis

trib

utor

s (1

5 m

m d

iam

eter

) w

as u

sed

Com

para

tor

Phot

ofri

n II

PDT:

intr

aven

ous

Phot

ofri

n II

was

inje

cted

(1

or 2

mg/

kg),

then

PD

T g

iven

with

an

argo

n io

n pu

mpe

d-dy

e la

ser

afte

r 72

hr

[630

nm

(m

ost

patie

nts)

or

514n

m,

mea

n lig

ht d

ose

100

J/cm

2 , 90

mW

/cm

2 ] fo

r 19

min

. Su

rfac

e ir

radi

atio

n us

ing

180°

or

240°

win

dow

ed

cylin

dric

al li

ght

dist

ribu

tors

(15

-mm

dia

met

er)

was

use

d2n

d co

mpa

rato

r m

TH

PC 0

.15

mg/

kg (

652

nm)

PDT:

Intr

aven

ous

mT

HPC

was

inje

cted

(0

.15

mg/

kg),

then

PD

T g

iven

with

an

argo

n io

n pu

mpe

d-dy

e la

ser

afte

r 20

hr

(652

nm

, 6 o

r 8

J/cm

2 , 40

mW

/cm

2 ) fo

r 3

min

. Sur

face

irra

diat

ion

usin

g 18

0 or

240°

win

dow

ed c

ylin

dric

al li

ght

dist

ribu

tors

(15

-mm

dia

met

er)

wer

e us

ed3r

d co

mpa

rato

r m

TH

PC 0

.3 m

g/kg

(51

4 nm

) PD

T: in

trav

enou

s m

TH

PC w

as in

ject

ed

(0.3

mg/

kg),

then

PD

T g

iven

with

a a

rgon

ion

pum

ped-

dye

lase

r af

ter

20 h

r (5

14 n

m, 3

0 J/c

m2 ,

50 m

W/c

m2 )

for

10 m

in. S

urfa

ce ir

radi

atio

n us

ing

180

or 2

40 w

indo

wed

cyl

indr

ical

ligh

t di

stri

buto

rs

(15-

mm

dia

met

er)

was

use

d4t

h co

mpa

rato

r m

TH

PC 0

.15

mg/

kg (

514

nm)

PDT:

intr

aven

ous

mT

HPC

was

inje

cted

(0

.15

mg/

kg),

then

PD

T g

iven

with

an

argo

n io

n pu

mpe

d-dy

e la

ser

afte

r 20

or

96 h

r (5

14 n

m,

75 J/

cm2 ,

90 m

W/c

m2 )

for

14 m

in. S

urfa

ce

irra

diat

ion

usin

g 18

0 or

240°

win

dow

ed c

ylin

dric

al

light

dis

trib

utor

s (1

5-m

m d

iam

eter

) w

as u

sed

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty N

o tr

uly

sele

ctiv

e ne

cros

is w

as s

een

with

HpD

, Ph

otof

rin

II or

mT

HPC

whe

n ir

radi

atio

n w

as a

t 20

hr. W

ith

mT

HPC

(ir

radi

atio

n at

96

h) s

ome

patie

nts

had

necr

oses

tha

t w

ere

sele

ctiv

e. C

R r

ates

: HpD

= 8

9%,

mT

HPC

= 8

6%, P

hoto

frin

II =

75%

. Fa

ilure

s of

tre

atm

ent

acco

rdin

g to

sen

sitis

er u

sed

wer

e 1/

9 (1

1%)

in t

he H

pD g

roup

; 2/8

(2

5%)

Phot

ofri

n II

grou

p; 2

/14

(14%

) m

TH

PC g

roup

. Fai

lure

s of

tre

atm

ent

acco

rdin

g to

w

avel

engt

h us

ed w

ere

2/15

(13

%)

for

630

or 6

52 n

m; 3

/16

(19%

) fo

r 51

4 nm

QoL

and

ret

urn

to n

orm

al

acti

vity

Not

ass

esse

dA

Es A

ll pa

tient

s re

port

ed

burn

ing

sens

atio

n du

ring

the

in

ject

ion

of m

TH

PC. M

ajor

co

mpl

icat

ions

wer

e: St

enos

es

(tw

o), o

esop

hago

trac

heal

fist

ulas

in

PD

T p

atie

nts

(630

or

652

nm)

(tw

o, o

ne o

f whi

ch c

ompl

icat

ed

by o

esop

hage

al s

teno

sis)

. Thr

ee

patie

nts

that

did

not

follo

w

pres

crib

ed p

reca

utio

ns (

not

in

met

hods

) de

velo

ped

2nd-

degr

ee

sunb

urn

on t

he fa

ce a

nd h

ands

(o

ne H

pD p

atie

nt a

t 2

mth

; 2

0.15

mg/

kg m

TH

PC p

atie

nts

at

6 d) Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

PD

T e

radi

cate

s ea

rly

SCC

s (T

1a a

nd T

1b)

of t

he

oeso

phag

us e

ffici

ently

. Tra

nsm

ural

ne

cros

es le

adin

g to

fist

ulas

can

be

avoi

ded

usin

g a

low

-pen

etra

ting

wav

elen

gth

of la

ser

light

(gr

een

light

at

514

.5 n

m in

stea

d of

red

ligh

t at

630

or

652

nm

). St

enos

es a

lway

s re

sult

from

circ

umfe

rent

ial i

rrad

iatio

n of

th

e oe

soph

agea

l wal

l, an

d th

is c

an

be a

void

ed b

y us

ing

a 18

0° o

r 24

0°

win

dow

ed c

ylin

dric

al li

ght

dist

ribu

tor

Bri

ef s

tudy

app

rais

al T

his

was

a

rela

tivel

y sm

all t

rial

with

mul

tiple

co

mpa

rato

r ar

ms,

the

met

hods

wer

e no

t cl

earl

y re

port

ed a

nd a

s th

e au

thor

s th

emse

lves

com

men

t –

the

smal

l sa

mpl

es p

recl

ude

any

firm

con

clus

ions

, so

the

res

ults

may

not

be

relia

ble

Appendix 17

262



263Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Sco

tinio

tis e

t al.

(200

0)11

0

Dat

a so

urce

Abs

trac

tC

ount

ry U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-R

CT

No.

of p

arti

cipa

nts

Tota

l: 37

Inte

rven

tion:

12

(PD

T)

Com

para

tor:

Six

EMR

2nd

Com

para

tor:

19

(oes

opha

gect

omy)

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od a

nd

freq

uenc

y M

ean

FU 1

5 m

th

(ran

ge 2

–28

mth

). PD

T a

nd

EMR

pat

ient

FU

4–6

wk

afte

r tr

eatm

ent,

then

eve

ry

3–6

mth

; oes

opha

gect

omy

patie

nt F

U d

icta

ted

by

sym

ptom

s

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y Su

perfi

cial

oes

opha

geal

ca

ncer

Mai

n el

igib

ility

cr

iter

ia S

uper

ficia

l oe

soph

agea

l can

cer

dete

rmin

ed b

y EU

S an

d C

T in

clud

ing

HG

D,

carc

inom

a in

situ

or

intr

amuc

osal

car

cino

ma

Pati

ent

char

acte

rist

ics

Mea

n ag

e: PD

T, 76

; EM

R, 7

3;

oeso

phag

ecto

my,

65T

hirt

y-si

x ad

enoc

arci

nom

as, o

ne

SCC

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

PD

T v

s EM

R v

s O

esop

hage

ctom

yIn

terv

enti

on P

DT:

No

deta

ils

repo

rted

Com

para

tor

EMR

: No

deta

ils

repo

rted

2nd

com

para

tor

Oes

opha

gect

omy:

No

deta

ils r

epor

ted

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty E

radi

catio

n of

lesi

ons

was

ac

hiev

ed in

9/1

2 (7

5%)

PDT,

5/6

(83%

) EM

R a

nd 1

8/19

(95

%)

oeso

phag

ecto

my

patie

nts

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

ass

esse

dA

Es

Stri

ctur

e oc

curr

ed in

6/1

2 (5

0%)

PDT,

0/6

EMR

and

10/

19

(53%

) oe

soph

agec

tom

y pa

tient

s. ≥

3 di

lata

tions

occ

urre

d in

4/1

2 (3

3%)

PDT,

0/6

EMR

and

7/1

9 (3

7%)

oeso

phag

ecto

my

patie

nts.

Oth

er

com

plic

atio

ns w

ere

repo

rted

for

smal

l nu

mbe

rs o

f pat

ient

sR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

In p

oor

surg

ical

can

dida

tes

with

sup

erfic

ial

oeso

phag

eal c

arci

nom

a PD

T

and

EMR

ach

ieve

d ou

tcom

es

com

para

ble

to o

esop

hage

ctom

y in

go

od s

urgi

cal c

andi

date

s. PD

T a

nd

EMR

are

rea

sona

ble

alte

rnat

ives

to

oeso

phag

ecto

my

for

sele

cted

pat

ient

sB

rief

stu

dy a

ppra

isal

Thi

s sm

all

stud

y w

as a

vaila

ble

only

as

an a

bstr

act

and

few

met

hodo

logi

cal d

etai

ls w

ere

repo

rted

. The

stu

dy p

opul

atio

ns fo

r th

e di

ffere

nt in

terv

entio

ns d

id n

ot a

ppea

r to

be

com

para

ble

at b

asel

ine

with

PD

T/

EMR

pat

ient

s ch

osen

if s

ubop

timal

for

surg

ery.

In a

dditi

on n

o st

atis

tical

tes

ts

wer

e ca

rrie

d ou

t to

ver

ify t

he fi

ndin

gs,

the

resu

lts o

f thi

s st

udy

may

the

refo

re

not

be r

elia

ble

The

auth

ors’

conc

lusio

ns d

o no

t fol

low

fro

m th

e re

sults

repo

rted

EMR

, end

osco

pic

muc

osal

res

ectio

n.

Appendix 17

262



263Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Zha

ng e

t al.

(200

3)11

9

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry C

hina

Lang

uage

Chi

nese

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

60In

terv

entio

n: 3

0C

ompa

rato

r: 30

No.

of r

ecru

itin

g ce

ntre

s O

ne h

ospi

tal

(out

patie

nts)

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU a

t 5

and

10 yr

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y A

dvan

ced

oeso

phag

eal c

ance

rM

ain

elig

ibili

ty c

rite

ria

Dia

gnos

ed w

ith a

dvan

ced

oeso

phag

eal c

ance

r, su

itabl

e fo

r tr

eatm

ent

Pati

ent

char

acte

rist

ics

Age

: und

er 7

0 yr

Can

cer

leng

th: 5

–10

cm. N

o m

etas

tase

sC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

PD

T w

ith

radi

othe

rapy

vs

radi

othe

rapy

alo

neIn

terv

enti

on P

DT

with

rad

ioth

erap

y: R

adio

ther

apy

for

4 w

k (4

0 G

y). T

hen

intr

aven

ous

haem

atop

orph

yrin

de

riva

tive

(5 m

g/kg

bw

) be

fore

ill

umin

atio

n w

ith 6

30-n

m r

ed li

ght

(400

–50

0 W/c

m2 a

t ea

ch p

art

of t

he t

umou

r fo

r 15

min

) at

48

and

72 h

rC

ompa

rato

r R

adio

ther

apy:

40 G

y fo

r 4

wk

Mor

talit

y T

he 5

-yr

surv

ival

rat

e w

as

29.9

% in

the

PD

T g

roup

com

pare

d w

ith

16.7

% (

p =

0.05

). The

10-

yr s

urvi

val r

ate

was

16.

7% in

the

PD

T g

roup

vs

10.0

%

(p <

0.0

5)M

orbi

dity

Not

ass

esse

dQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot a

sses

sed

AE

s All

PDT

pat

ient

s ex

peri

ence

d pi

gmen

tatio

n, a

nd s

wel

ling

and

itchi

ness

. A

ll PD

T p

atie

nts

also

exp

erie

nced

pa

in w

hen

swal

low

ing

for

3–5

d (s

ome

patie

nts

had

pain

for

> 10

d

and

disc

ontin

ued

trea

tmen

t). 2

3 di

ed

in t

he P

DT

gro

up: l

oss

to F

U t

wo;

un

cont

rolle

d lo

calis

atio

n 13

incl

udin

g on

e du

e to

blo

ckag

e of

oes

opha

gus;

met

asta

ses

eigh

t; ot

her

dise

ase

one;

un

know

n ca

use

one.

26

died

in t

he

radi

othe

rapy

gro

up: l

oss

to F

U o

ne;

unco

ntro

lled

loca

lisat

ion

18, i

nclu

ding

tw

o du

e to

blo

ckag

e of

oes

opha

gus;

met

asta

ses

four

; oth

er d

isea

se t

wo;

un

know

n ca

use

two

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

Rad

ioth

erap

y co

mbi

ned

with

PD

T c

ould

obv

ious

ly

enha

nce

the

long

-ter

m s

urvi

val r

ate

of

patie

nts

with

adv

ance

d oe

soph

agea

l ca

ncer

Bri

ef s

tudy

app

rais

al T

his

was

a

brie

f rep

ort

and

som

e m

etho

dolo

gica

l as

pect

s w

ere

not

clea

rly

repo

rted

. T

he p

-val

ues

wer

e no

t re

port

ed

cons

iste

ntly

bet

wee

n th

e ab

stra

ct a

nd

the

text

mak

ing

it di

fficu

lt to

cla

rify

the

si

gnifi

cant

diff

eren

ces

betw

een

grou

ps

Appendix 17

264



265Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Zha

ng e

t al.

(200

7)11

3

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry C

hina

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

140

Inte

rven

tion:

42

Com

para

tor:

98N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted;

ap

pear

s to

be

two

cent

res

in C

hina

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

at 1

mth

. Ove

r 70

%

patie

nts

wer

e fo

llow

ed

up fo

r 12

–36

mth

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y A

dvan

ced

oeso

phag

ocar

diac

ca

rcin

oma

Mai

n el

igib

ility

cr

iter

ia B

iops

y pr

oven

adv

ance

d oe

soph

agea

l ca

rcin

oma

Pati

ent

char

acte

rist

ics

% M

ale:

79A

ge r

ange

: 40–

81 yr

Med

ian

age:

PDT

58;

PD

T w

ith 5

-FU

62

Can

cer

stag

e: St

age

II 84

; sta

ge II

I 53;

st

age

IV 3

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

PD

T v

s PD

T w

ith 5

-FU

Inte

rven

tion

PD

T: A

fter

intr

aven

ous

inje

ctio

n of

the

pho

tose

nsiti

ser

PSD

-007

(p

hoto

carc

inor

in)

(3–5

mg/

kg b

w)

and

patie

nts

wer

e ke

pt in

the

dar

k. Ir

radi

atio

n w

as p

erfo

rmed

at

24 a

nd 4

8 hr

with

eith

er

630-

nm c

oppe

r va

pour

pum

ped-

dye

lase

r or

632

.8 n

m h

igh

pow

er H

e-N

e la

ser

(tot

al

dose

200

–400

J/cm

fibr

e le

ngth

, med

ian

300

J/cm

). Thi

s w

as d

eliv

ered

by

cylin

dric

al

diffu

sers

und

er e

ndos

cope

ass

ista

nce.

Ir

radi

atio

n w

as c

arri

ed o

ut in

one

to

four

se

gmen

ts (

with

slig

ht o

verl

ap b

etw

een

each

seg

men

t) d

epen

ding

on

lesi

on le

ngth

an

d di

ffuse

r. Tre

atm

ent

coul

d be

rep

eate

d af

ter

1 m

th u

nles

s ev

alua

tion

show

ed

effe

ctiv

enes

s or

sym

ptom

s w

ere

rem

itted

. Pa

tient

s w

ere

advi

sed

to a

void

sun

light

ex

posu

re fo

r ov

er 1

mth

Com

para

tor

PDT

with

5-F

U: A

s fo

r PD

T b

ut in

add

ition

, bef

ore

irra

diat

ion,

20

0–50

0 m

g 5-

FU w

as lo

cally

inje

cted

into

tu

mou

r tis

sue

unde

r en

dosc

opic

gui

danc

e.

Befo

re in

ject

ion

the

exte

nt o

f the

lesi

ons

was

con

firm

ed. M

ost

patie

nts

rece

ived

four

to

eig

ht in

ject

ions

per

tum

our

Mor

talit

y M

ean

surv

ival

tim

e w

as 8

.9 m

th

with

PD

T a

lone

com

pare

d w

ith 1

5.1

mth

fo

r PD

T a

nd 5

-FU

(p <

0.0

1)M

orbi

dity

The

rat

e of

dys

phag

ia

rem

issi

on w

as 8

7% fo

r PD

T c

ompa

red

with

99%

with

PD

T a

nd 5

-FU

(p

< 0.

05).

Diff

eren

ces

in p

hary

ngea

l pai

n an

d w

eigh

t lo

ss w

ere

not

sign

ifica

nt. W

ith P

DT

alo

ne

one

patie

nt a

chie

ved

com

plet

e re

mis

sion

(v

s fiv

e w

ith c

ombi

ned

ther

apy,

p <

0.05

), ei

ght

sign

ifica

nt r

emis

sion

(vs

36)

and

five

no

rem

issi

on (

vs n

ine)

. With

com

bine

d th

erap

y 48

pat

ient

s al

so a

chie

ved

min

or

rem

issi

onQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot a

sses

sed

AE

s Su

bter

nal p

ain

due

to o

esop

hage

al

muc

osa

inju

ry a

nd g

astr

oeso

phag

eal r

eflux

1–

2 d

afte

r tr

eatm

ent

was

rep

orte

d by

se

ven

patie

nts

in P

DT

onl

y an

d ei

ght

patie

nts

in c

ombi

natio

n tr

eatm

ent

Eigh

t pa

tient

s in

tot

al a

ccid

enta

lly e

xpos

ed

them

selv

es t

o su

nlig

ht a

nd d

evel

oped

di

scol

orat

ion

of t

he s

kin

No

oeso

phag

eal s

teno

sis

or p

erfo

ratio

n re

port

ed in

eith

er g

roup

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ con

clus

ions

PD

T is

saf

e an

d ef

fect

ive

for

adva

nced

oes

opha

goca

rdia

c ca

ncer

. Its

the

rape

utic

effe

ct c

an b

e fu

rthe

r im

prov

ed w

hen

com

bine

d w

ith lo

cal

chem

othe

rapy

Bri

ef s

tudy

app

rais

al T

his

stud

y w

as p

oorl

y re

port

ed (

e.g.

met

hod

of

rand

omis

atio

n, w

heth

er IT

T a

naly

sis

was

us

ed)

but

mos

t im

port

antly

it a

ppea

rs t

hat

afte

r ov

er 4

0 pa

tient

s ha

d be

en t

reat

ed,

inte

rim

ana

lysi

s w

as c

arri

ed o

ut a

nd a

ll su

bseq

uent

pat

ient

s w

ere

trea

ted

with

co

mbi

ned

PDT

and

5-F

U. T

hese

ana

lyse

s w

ere

not

furt

her

repo

rted

. Giv

en t

his

shift

fr

om a

n R

CT

to

expe

rim

enta

l with

out

a co

mpa

rato

r it

is d

ifficu

lt to

det

erm

ine

the

relia

bilit

y of

the

stu

dy r

esul

ts o

vera

llTh

e au

thor

s’ co

nclu

sions

do

not f

ollo

w fr

om

the

resu

lts re

port

ed

Appendix 17

264



265

Appendix 18 Lung cancer data extraction

Appendix 18

266



267Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Baa

s et

al.

(199

4)12

1

Dat

a so

urce

Abs

trac

tC

ount

ry T

he

Net

herl

ands

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

s To

tal:

39In

terv

entio

n: 1

5C

ompa

rato

r: 12

2nd

Com

para

tor:

12N

o. o

f Rec

ruit

ing

Cen

tres

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

Not

sta

ted

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe o

f Lun

g C

ance

r an

d H

isto

logy

Non

-sm

all

cell;

no fu

rthe

r de

tails

gi

ven

Mai

n el

igib

ility

cri

teri

a H

isto

logi

cally

pro

ven

inop

erab

le lo

core

gion

al

NSC

LC, w

eigh

t lo

ss <

10%

an

d a

PS (

sic)

> 7

0%Pa

tien

t ch

arac

teri

stic

s%

Mal

e: 88

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

ERT

alo

ne v

s PD

T

prec

edin

g ER

T v

s H

DR

pre

cedi

ng E

RTIn

terv

enti

on P

hoto

frin

2 m

g/kg

, 20

0 J/c

m, 6

30 n

m g

iven

2 w

k be

fore

ERT

. O

ther

PD

T p

aram

eter

s no

t st

ated

Com

para

tor

ERT

alo

ne:

14 x

2.5

+ 8

x 2

.5 G

y to

the

tum

our

area

in

4 w

k2n

d co

mpa

rato

r H

DR

+ E

RT: A

s ab

ove

prec

eded

by

HD

R: 1

5 G

y at

1-c

m

dist

ance

alo

ng t

he t

umou

r 2

wk

befo

re

ERT

Mor

talit

y A

sses

sed

but

not

repo

rted

pe

r gr

oup

Mor

bidi

ty N

ot a

sses

sed

AE

s M

inor

hae

mop

tysi

s in

tw

o PD

T-ER

T p

atie

nts.

Skin

pho

tose

nsiti

vity

was

ac

cept

able

in p

atie

nts

trea

ted

with

PD

T

(no

data

pro

vide

d). O

ther

AEs

rep

orte

d bu

t no

t br

oken

dow

n by

gro

up

Aut

hors

’ con

clus

ions

No

conc

lusi

ons

spec

ific

to P

DT

Bri

ef s

tudy

app

rais

al T

his

smal

l st

udy

was

an

inte

rim

ana

lysi

s of

a R

CT

pr

esen

ted

in a

bstr

act

form

. Alth

ough

it

indi

cate

d th

at u

pdat

ed r

esul

ts w

ould

be

pre

sent

ed, n

o fu

rthe

r in

form

atio

n co

uld

be lo

cate

d. M

ost

of t

he s

tudy

’s m

etho

dolo

gica

l det

ails

wer

e no

t av

aila

ble

from

the

abs

trac

t an

d th

e m

ajor

ity o

f the

res

ults

wer

e no

t br

oken

do

wn

by t

reat

men

t gr

oup

Appendix 18

266



267Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Dia

z-Jim

enez

et a

l. (19

99)12

2

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry S

pain

Lang

uage

Eng

lish

Stud

y D

esig

nR

CT

No.

of p

arti

cipa

nts

Tota

l: 31

Inte

rven

tion:

14

Com

para

tor:

17N

o. o

f Rec

ruit

ing

Cen

tres

Not

sta

ted

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU a

t 1,

2, 3

, 6 a

nd

12 m

th (

and

18 m

th if

po

ssib

le)

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pes

of L

ung

Can

cer

and

His

tolo

gy N

on-s

mal

l cel

l 25

SCC

, thr

ee a

deno

carc

inom

a, th

ree

undi

ffere

ntia

ted

carc

inom

aM

ain

elig

ibili

ty c

rite

ria

Biop

sy-

prov

en in

oper

able

can

cer

with

tot

ally

or

par

tially

obs

truc

tive

endo

bron

chia

l le

sion

s w

ith o

r w

ithou

t ex

trab

ronc

hial

tu

mou

r. Pa

tient

s >

18 yr

, non

-pr

egna

nt, i

nfer

tile

or p

ostm

enop

ausa

l. K

arno

fsky

sta

tus ≥

40%

, ≥ 4

wk

from

la

st c

hem

othe

rapy

cyc

le a

nd ≥

3 w

k fr

om la

st r

adia

tion

dose

. Pat

ient

s w

ho

had

prev

ious

PD

T o

r N

d:YA

G w

ere

excl

uded

. Fur

ther

elig

ibili

ty c

rite

ria

wer

e re

port

edPa

tien

t ch

arac

teri

stic

s%

Mal

e: 10

0A

ge r

ange

: Not

sta

ted

Mea

n ag

e: 65

yrC

ance

r st

age:

Stag

e I,

four

pat

ient

s; st

age

II, o

ne; s

tage

IIIA

, six

; sta

ge II

IB,

10; s

tage

IV, s

even

No.

with

rec

urre

nt t

umou

r: th

ree

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

PD

T v

s N

d:YA

G la

ser

rese

ctio

nIn

terv

enti

on

Intr

aven

ous

DH

E at

dos

e of

2 m

g/kg

with

630

-nm

ar

gon

dye

lase

r, 40

–50

hr

afte

r in

ject

ion.

Max

imum

of

thr

ee d

oses

(si

x ph

otor

adia

tions

). O

ther

pa

ram

eter

s no

t re

port

edC

ompa

rato

r N

d:YA

G

rese

ctio

n us

ing

15-

to

80-W

pul

ses

of 0

.5–1

.5 s.

Pr

oced

ure

repe

ated

ev

ery

2–4

d as

nec

essa

ry

Mor

talit

y Su

rviv

al s

igni

fican

tly

long

er in

PD

T g

roup

(26

5 vs

95

d, p

= 0

.007

). 4/

14 (

PDT

) an

d 4/

17

(Nd:

YAG

) st

ill a

live

at e

nd o

f stu

dyM

orbi

dity

Sim

ilar

resp

onse

in

both

gro

ups:

38.5

% P

DT

vs

23.5

%

Nd:

YAG

at

1 m

th (

p =

ns).

PR

at 1

mth

in t

hree

PD

T a

nd fo

ur

Nd:

YAG

pat

ient

s. C

R a

t 1

mth

in

one

PDT

pat

ient

. Tim

e el

apse

d un

til

trea

tmen

t fa

ilure

: 50

d (P

DT

) vs

38

d (N

d:YA

G)

(p =

0.0

3)Q

oL a

nd r

etur

n to

nor

mal

ac

tivi

ty A

sses

sed

but

not

repo

rted

AE

s Br

onch

itis

was

the

mos

t co

mm

on (

four

cas

es in

PD

T g

roup

, on

e in

Nd:

YAG

gro

up)

Phot

osen

sitis

atio

n in

four

PD

T

patie

nts.

Five

pat

ient

s ha

d no

AEs

, al

l in

Nd:

YAG

gro

up. O

ne d

eath

pr

obab

ly r

elat

ed t

o PD

T

Aut

hors

’ con

clus

ions

PD

T is

a v

alid

met

hod

of

palli

atio

n in

par

tially

or

tota

lly o

bstr

uctin

g N

SCLC

Bri

ef s

tudy

app

rais

al D

ifficu

lt to

eva

luat

e re

sults

due

to

impo

rtan

t ba

selin

e di

ffere

nces

(p

rese

nce

of c

ough

, and

sta

ge o

f can

cer)

bet

wee

n gr

oups

. Kar

nofs

ky p

erfo

rman

ce a

nd F

U a

fter

1 m

th

asse

ssed

but

not

rep

orte

d. N

o de

tails

on

blin

ding

Appendix 18

268



269Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Lam

et a

l., (1

991)

123

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry C

anad

aLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 41

Inte

rven

tion:

20

Com

para

tor:

21N

o. o

f Rec

ruit

ing

Cen

tres

Not

sta

ted

Follo

w-u

p pe

riod

an

d fr

eque

ncy

FU

at 1

, 2, 3

, 6, 1

2, 1

8 an

d 24

mth

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pes

of L

ung

Can

cer

and

His

tolo

gy N

on-s

mal

l ce

ll 34

squ

amou

s ce

ll, th

ree

aden

ocar

cino

ma,

four

larg

e ce

llM

ain

elig

ibili

ty c

rite

ria

Biop

sy-p

rove

n st

age

III n

on-s

mal

l ce

ll br

onch

ogen

ic c

arci

nom

a w

ith o

bstr

uctin

g or

par

tially

ob

stru

ctin

g en

dobr

onch

ial l

esio

n.

Kar

nofs

ky r

atin

g ≥

40 a

nd a

bilit

y to

to

lera

te m

ultip

le b

ronc

hosc

opie

s. Pa

tient

s w

ho h

ad p

revi

ous

PDT

or

rad

ioth

erap

y, or

con

curr

ent

chem

othe

rapy

or

Nd:

YAG

lase

r th

erap

y w

ere

excl

uded

, as

wer

e pa

tient

s w

hose

tum

ours

wer

e in

vasi

ve t

o m

ajor

blo

od v

esse

ls o

n C

T s

can

Pati

ent

char

acte

rist

ics

% M

ale:

76M

ean

age:

Aro

und

67 yr

Tum

our

loca

tion:

78%

in m

ain

stem

br

onch

us, 2

2% in

loba

r br

onch

usC

onco

mit

ant

trea

tmen

t Se

e ‘E

ligib

ility

cri

teri

a’

Tria

l tre

atm

ents

PD

T +

radi

othe

rapy

vs

Rad

ioth

erap

y al

one

Inte

rven

tion

Intr

aven

ous

Phot

ofri

n at

2 m

g/kg

follo

wed

w

ith 4

0–50

hr

of r

ed (

630n

m)

light

from

arg

on-d

ye la

ser

deliv

ered

by

a si

ngle

-ste

p in

dex

quar

tz fi

bre

inse

rted

into

the

bi

opsy

cha

nnel

of a

flex

ible

fib

reop

tic b

ronc

hosc

ope

(a

cylin

dric

al d

iffus

er t

ip w

as

inse

rted

1–2

cm in

to t

umou

r).

Pow

er d

ensi

ty w

as 4

00 m

W/c

m,

tota

l lig

ht d

ose

was

200

J/cm

. R

esid

ual t

umou

r tr

eate

d by

a

repe

at li

ght

expo

sure

The

dur

atio

n of

ligh

t w

as n

ot

stat

ed. R

adio

ther

apy

– se

e be

low

Com

para

tor

Rad

iatio

n at

30

00 cG

y in

10

frac

tions

with

a

4-M

eV li

near

acc

eler

ator

ov

er 2

wk,

usin

g a

para

llel p

air

tech

niqu

e. F

ield

siz

e de

fined

by

the

50%

isod

ose

line

with

2-c

m

mar

gin

of n

orm

al t

issu

e

Mor

talit

y 16

pat

ient

s di

ed in

rad

ioth

erap

y-al

one

grou

p co

mpa

red

with

14

in P

DT

+ ra

diot

hera

py

grou

p, in

bot

h gr

oups

eig

ht d

eath

s w

ere

due

to

met

asta

ses.

Thr

ee p

atie

nts

in t

he P

DT

+ ra

diot

hera

py

grou

p di

ed fr

om m

assi

ve h

aem

opty

sis

(67,

187

and

56

7 d,

res

pect

ivel

y, af

ter

trea

tmen

t), c

ompa

red

with

no

ne in

the

Rad

ioth

erap

y-al

one

grou

p. N

o di

ffere

nce

betw

een

grou

ps in

med

ian

surv

ival

tim

es (

444

d in

PD

T +

radi

othe

rapy

vs

445

d in

Rad

ioth

erap

y-al

one

grou

p)M

orbi

dity

Sig

nific

antly

gre

ater

red

uctio

n of

ha

emop

tysi

s an

d sh

ortn

ess

of b

reat

h, a

nd c

ough

at

1 an

d 3

mth

, in

the

PDT

+ ra

diot

hera

py g

roup

(p

< 0.

05)

14/2

0 PD

T +

radi

othe

rapy

and

2/2

1 ra

diot

hera

py

alon

e ac

hiev

ed c

ompl

ete

re-o

peni

ng o

f bro

nchi

al

lum

en. F

our

patie

nts

in R

adio

ther

apy-

alon

e gr

oup

faile

d to

res

pond

to

trea

tmen

t, no

ne fa

iled

in

PDT

+ ra

diot

hera

py g

roup

Med

ian

inte

rval

bet

wee

n tr

eatm

ent

and

loca

l rec

urre

nce

was

sig

nific

antly

long

er in

PD

T +

radi

othe

rapy

gro

up (

233

d vs

107

d, p

= 0

.005

)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y A

sses

sed

but

not

repo

rted

(K

arno

fsky

per

form

ance

)A

Es

Phot

osen

sitiv

ity w

ith m

ild e

ryth

ema,

whi

ch

reso

lved

with

out

trea

tmen

t, w

as s

een

in fo

ur o

f the

PD

T +

radi

othe

rapy

gro

up

Aut

hors

’ con

clus

ions

T

he a

dditi

on o

f PD

T p

rior

to

rad

ioth

erap

y pr

ovid

es

sign

ifica

ntly

bet

ter

and

long

er-la

stin

g lo

cal c

ontr

ol

than

rad

ioth

erap

y al

one

Bri

ef s

tudy

app

rais

al

No

deta

ils o

f met

hods

of

rand

omis

atio

n, a

lloca

tion

conc

ealm

ent

or b

lindi

ng

wer

e re

port

ed fo

r th

is s

mal

l st

udy

(rai

sing

rel

iabi

lity

issu

es).

Som

e ou

tcom

es

asse

ssed

but

not

rep

orte

d

Appendix 18

268



269

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Lam

et a

l. (1

987)

124

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry C

anad

aLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 11

Inte

rven

tion:

Fiv

eC

ompa

rato

r: Si

xN

o. o

f Rec

ruit

ing

Cen

tres

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU a

t 4

and

12 w

k, th

en q

uart

erly

th

erea

fter

(unl

ess

prog

ress

ion

of t

umou

r oc

curs

)

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pes

of L

ung

Can

cer

and

His

tolo

gy N

on-s

mal

l ce

ll: ni

ne s

quam

ous

cell,

two

larg

e ce

llM

ain

elig

ibili

ty c

rite

ria

Patie

nts

with

inop

erab

le

non-

smal

l cel

l bro

ncho

geni

c ca

rcin

oma,

part

ially

or

com

plet

ely

obst

ruct

ing

a ce

ntra

l air

way

, who

had

re

ceiv

ed n

o pr

ior

trea

tmen

t (e

.g. c

hem

othe

rapy

or

radi

othe

rapy

). Pa

tient

s w

ith e

vide

nce

of m

etas

tatic

di

seas

e w

ere

excl

uded

Pati

ent

char

acte

rist

ics

% M

ale:

82M

ean

age:

66 yr

All

patie

nts

had

tum

ours

at

mor

e th

an o

ne s

iteC

onco

mit

ant

trea

tmen

t N

ot s

tate

d

Tria

l tre

atm

ents

PD

T +

radi

othe

rapy

vs

Rad

ioth

erap

y al

one

Inte

rven

tion

Intr

aven

ous

Phot

ofri

n II

24–4

8 hr

pri

or t

o re

d lig

ht (

630

nm)

from

a c

ontin

uous

arg

on p

umpe

d-dy

e la

ser,

via

sing

le-s

tep

inde

x qu

artz

fibr

es

inse

rted

into

cha

nnel

of a

dou

ble

lum

en fl

exib

le fi

breo

ptic

bro

ncho

scop

e (o

r a

sing

le c

hann

el in

stru

men

t). A

cy

lindr

ical

diff

user

tip

(0.

5, 1

.0 o

r 1.

5 cm

) w

as in

sert

ed in

to t

he t

umou

r. Po

wer

den

sity

was

400

mW

/cm

and

to

tal l

ight

dos

e 30

0 J/c

m. C

lean

-up

bron

chos

copy

follo

wed

2 d

late

r, w

ith

furt

her

light

at

300

J/cm

(bu

t no

mor

e Ph

otof

rin

II) fo

r an

y re

sidu

al t

umou

rs.

PDT

was

giv

en 1

st, w

ith r

adio

ther

apy

star

ting

with

in 1

wk

of P

DT

Tum

ours

tha

t co

uld

not

be in

sert

ed

due

to s

mal

l siz

e, o

r ha

rdne

ss,

rece

ived

200

J/cm

2 at

pow

er d

ensi

ty o

f 20

0 m

W/c

m2 u

sing

mic

role

ns fi

bre

The

dos

e of

Pho

tofr

in a

nd d

urat

ion

of

light

wer

e no

t st

ated

. For

rad

ioth

erap

y, se

e be

low

Com

para

tor A

ll pa

tient

s ha

d 30

00 cG

y in

10

frac

tions

ove

r 2

wk

usin

g a

para

llel-p

air

tech

niqu

e fr

om

a 4

MeV

line

ar a

ccel

erat

or. F

ield

siz

e de

fined

by

the

50%

isod

ose

line

with

2-

cm m

argi

n of

nor

mal

tis

sue

Mor

talit

y O

ne p

atie

nt d

ied

in t

he

PDT

+ ra

diot

hera

py g

roup

vs

thre

e in

th

e R

adio

ther

apy-

alon

e gr

oup

Mor

bidi

ty B

oth

grou

ps h

ad

sign

ifica

ntly

impr

oved

res

pira

tory

sy

mpt

oms

at 4

wk

(with

mea

n sc

ores

falli

ng fr

om 7

to

1 in

the

PD

T +

radi

othe

rapy

gro

up, a

nd 7

to

4 in

the

Rad

ioth

erap

y-al

one

grou

p, p

< 0.

05). T

he m

ean

scor

e fo

r th

e R

adio

ther

apy-

alon

e gr

oup

was

bac

k up

to

7 at

12

wk,

but

the

PDT

+ ra

diot

hera

py g

roup

had

a m

ean

scor

e of

2, w

hich

was

sig

nific

antly

di

ffere

nt fr

om b

asel

ine

(p <

0.0

5)A

t 4

wk,

the

PDT

+ ra

diot

hera

py

grou

p ha

d a

sign

ifica

nt r

educ

tion

in%

ai

rway

obs

truc

tion

(99

vs 2

1) a

nd

impr

ovem

ent

in a

rter

ial o

xyge

n (6

3 vs

80,

bot

h p

< 0.

05)

whe

n co

mpa

red

to b

asel

ine,

with

per

cent

age

airw

ay

obst

ruct

ion

still

sig

nific

antly

impr

oved

at

12

wk

(99

vs 2

5, p

< 0

.05)

. The

re

wer

e no

sig

nific

ant

redu

ctio

ns in

the

R

adio

ther

apy-

alon

e gr

oup

QoL

and

ret

urn

to

norm

al a

ctiv

ity

At

4 w

k, th

e PD

T +

radi

othe

rapy

pat

ient

s ha

d si

gnifi

cant

impr

ovem

ents

(p

< 0.

05)

in

both

Kar

nofs

ky r

atin

g (7

8 vs

93)

and

Q

oL (

56 v

s 39

), co

mpa

red

to b

asel

ine

scor

es. T

here

wer

e no

sig

nific

ant

diffe

renc

es in

the

Rad

ioth

erap

y-al

one

grou

pA

Es

One

pat

ient

rec

eivi

ng P

DT

re

mai

ned

phot

osen

sitiv

e fo

r 8

wk

Aut

hors

’ con

clus

ions

The

add

ition

of

PD

T p

rior

to

radi

othe

rapy

pro

vide

s si

gnifi

cant

ly b

ette

r an

d lo

nger

-la

stin

g pa

lliat

ion,

tha

n ra

diot

hera

py

alon

e, fo

r pa

tient

s w

ith o

bstr

uctiv

e en

dobr

onch

ial t

umou

rs. T

he c

ombi

ned

trea

tmen

t m

ay a

lso

impr

ove

surv

ival

Bri

ef s

tudy

app

rais

al V

ery

smal

l sa

mpl

e si

ze c

oupl

ed w

ith p

oorl

y re

port

ed m

etho

ds m

ake

it di

fficu

lt to

dr

aw a

ny r

obus

t co

nclu

sion

s

Appendix 18

270 Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Ler

oy e

t al.

(199

8)12

5

Link

ed p

ublic

atio

ns21

2

Dat

a so

urce

Abs

trac

tC

ount

ry N

ot s

tate

dLa

ngua

ge E

nglis

hSt

udy

desi

gn R

CT

No.

of p

arti

cipa

nts

Tota

l: 14

1In

terv

entio

n: N

ot s

tate

dC

ompa

rato

r: N

ot s

tate

dN

o. o

f Rec

ruit

ing

Cen

tres

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU a

t 1

wk

and

1 m

th

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe o

f Lun

g C

ance

r an

d H

isto

logy

Non

-sm

all

cell

Mai

n el

igib

ility

cr

iter

ia N

ot s

tate

dPa

tien

t ch

arac

teri

stic

s N

ot

stat

edC

onco

mit

ant

trea

tmen

t N

ot

stat

ed

Tria

l tre

atm

ents

PD

T v

s N

d:YA

G

lase

rIn

terv

enti

on 2

mg/

kg o

f Pho

tofr

in

follo

wed

48

hr la

ter

by li

ght

activ

atio

nLi

ght

sour

ce a

nd d

urat

ion,

wav

elen

gth

of li

ght,

pow

er d

ensi

ty, t

otal

ligh

t do

se,

max

imum

no.

of s

essi

ons

allo

wed

, and

po

stop

erat

ive

advi

ce n

ot s

tate

dC

ompa

rato

r N

o de

tails

pro

vide

d

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty C

R +

PR

com

para

ble

betw

een

grou

ps a

t w

k 1

(PD

T 6

5% v

s N

d:YA

G 6

1%),

but

sign

ifica

ntly

diff

eren

t at

1 m

th (

PDT

61%

vs

Nd:

YAG

35%

, p

< 0.

05).

At

1 m

th P

DT

als

o im

prov

ed

sym

ptom

s of

dys

pnoe

a (2

8% v

s 13

%),

coug

h (3

3% v

s 11

%),

haem

opty

sis

(33%

vs

19%

), an

d sp

utum

pro

duct

ion

(22%

vs

14%

), p-

valu

es n

ot s

tate

dQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y N

ot a

sses

sed

AE

s M

ild-t

o-m

oder

ate

skin

ph

otos

ensi

tivity

in 2

1% o

f PD

T p

atie

nts.

No

furt

her

deta

ils

Aut

hors

’ con

clus

ions

Pho

tofr

in is

at

leas

t si

mila

r to

or

bett

er t

han

Nd:

YAG

th

erm

al a

blat

ion

in r

e-es

tabl

ishi

ng t

he

pate

ncy

of t

he o

bstr

ucte

d lu

men

and

pa

lliat

ing

sym

ptom

s at

wk

1 an

d m

th 1

fo

llow

ing

trea

tmen

tB

rief

stu

dy a

ppra

isal

The

ver

y lim

ited

info

rmat

ion

prov

ided

, pa

rtic

ular

ly o

n st

udy

met

hods

and

ba

sic

resu

lts (

e.g.

no n

umbe

rs o

n ra

ndom

isat

ion

by t

reat

men

t gr

oup)

m

akes

ass

essm

ent

of r

elia

bilit

y di

fficu

lt



271

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mai

er e

t al.

(200

2)12

7

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry A

ustr

iaLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-

RC

TN

o. o

f par

tici

pant

sTo

tal:

40In

terv

entio

n: 1

6C

ompa

rato

r: 24

No.

of R

ecru

itin

g C

entr

es O

neFo

llow

-up

peri

od

and

freq

uenc

y 1

wk

and

4 w

k

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe o

f Lun

g C

ance

r an

d H

isto

logy

Non

-sm

all c

ell

Mai

n el

igib

ility

cri

teri

a Pa

tient

s w

ith m

alig

nant

tra

cheo

bron

chia

l st

enos

is, n

ot e

ligib

le fo

r re

sect

ion

trea

tmen

t be

caus

e of

poo

r pe

rfor

man

ce s

tatu

s, fu

nctio

nal a

nd/

or a

nato

mic

al in

oper

abili

ty, a

nd/o

r re

fusi

ng s

urge

ryPa

tien

t ch

arac

teri

stic

s%

Mal

e: 75

Mea

n ag

e: A

LA, 6

4 yr

; Pho

tosa

n,

66 yr

Can

cer

stag

e: St

age

IIb, s

even

; Sta

ge

IIIa,

13; S

tage

IIIb

, six

; Sta

ge IV

, 14

Squa

mou

s ce

ll 27

, Ade

noca

rcin

oma

10, L

arge

cel

l car

cino

ma

thre

eSt

enos

is m

ean

(ran

ge):

ALA

, 79%

(5

0–90

%);

Phot

osan

, 50%

(20

–95%

)22

pat

ient

s w

ith r

adio

logi

cal

and

clin

ical

sig

ns o

f pos

tste

notic

pn

eum

onia

Kar

nofs

ky s

tatu

s m

ean

(ran

ge):

ALA

, 78

(60–

90);

Phot

osan

, 70

(60–

80)

Furt

her

patie

nt c

hara

cter

istic

s w

ere

repo

rted

Con

com

itan

t tr

eatm

ent

At

leas

t 4

wk

afte

r co

mbi

ned

PDT

/H

BO, a

ll pa

tient

s w

ere

cons

ider

ed

for

furt

her

trea

tmen

t, in

clud

ing

high

-dos

e ra

te b

rach

yrad

ioth

erap

y, ex

tern

al b

eam

irra

diat

ion

and/

or

chem

othe

rapy

Tria

l tre

atm

ents

PD

T w

ith 5

-ALA

an

d H

BO v

s PD

T w

ith P

hoto

san

and

HBO

Inte

rven

tion

ALA

was

ora

lly

adm

inis

tere

d at

a d

ose

of 6

0 m

g/kg

, 6–

8 hr

pri

or t

o PD

TIn

cas

es o

f sev

ere

tum

our

sten

osis

, PD

T w

as c

arri

ed o

ut b

y us

ing

a fib

re

with

a 2

-cm

tip

rad

ial l

ight

-diff

usin

g cy

linde

r, w

hich

was

inse

rted

thr

ough

th

e bi

opsy

cha

nnel

of t

he e

ndos

cope

. In

cas

es o

f mod

erat

e tu

mou

r st

enos

is

a 2-

cm b

allo

on a

pplic

ator

sys

tem

w

as u

sed

for

hom

ogen

eous

ligh

t di

stri

butio

n. D

urin

g tr

eatm

ent

the

radi

al li

ght

diffu

sing

cyl

inde

r an

d/or

ba

lloon

app

licat

or s

yste

m w

as c

lose

ly

appl

ied

to t

he s

urfa

ce o

f the

tum

our.

The

ligh

t do

se w

as 1

00 J/

cm2 .

Ligh

t at

630

nm

was

app

lied

by a

KT

P-N

d:

YAG

lase

r w

ith a

DY

E m

odul

e. In

bo

th g

roup

s ad

ditio

nal h

yper

bari

c ox

ygen

atio

n at

a le

vel o

f 2 A

TA in

a

wal

k-in

hyp

erba

ric

cham

ber

was

un

dert

aken

. Oxy

gen

was

app

lied

usin

g a

Scub

a va

lve

syst

em. E

ach

trea

tmen

t w

as p

erfo

rmed

und

er

shor

t-te

rm in

trav

enou

s an

aest

hesi

a w

ith e

ndot

rach

eal i

ntub

atio

n an

d sp

onta

neou

s br

eath

ing.

Skin

pr

otec

tion

was

man

aged

by

use

of a

ca

mou

flage

(C

over

mar

k, M

ilan,

Ital

y)

for

24 h

r af

ter

phot

osen

sitis

atio

nC

ompa

rato

r Ph

otos

an-3

was

ad

min

iste

red

intr

aven

ously

at

a do

sage

of 2

mg/

kg, 4

8 hr

pri

or t

o PD

T. Se

e in

terv

entio

n fo

r de

tails

of P

DT

de

liver

y. Sk

in p

rote

ctio

n w

as b

y us

ing

a co

mm

erci

ally

ava

ilabl

e su

n bl

ocke

r fo

r 12

wk

Mor

talit

y T

he m

ean

surv

ival

for

the

ALA

gro

up w

as 9

mth

and

the

Ph

otos

an g

roup

14

mth

(p

= 0.

020)

Mor

bidi

ty 4

wk

FUIn

the

ALA

gro

up, s

teno

sis

diam

eter

dr

oppe

d fr

om a

mea

n va

lue

of 7

9%

to 6

3%. I

n th

e Ph

otos

an g

roup

the

m

ean

valu

e dr

oppe

d fr

om 5

0% t

o 19

%,

p =

0.00

073,

in fa

vour

of P

hoto

san.

D

yspn

oea

was

impr

oved

in 1

0/16

ALA

pa

tient

s an

d 19

/24

Phot

osan

pat

ient

s. H

aem

opty

sis

subs

ided

in 1

3/16

ALA

pa

tient

s an

d 20

/24

Phot

osan

pat

ient

s. R

adio

logi

cal a

nd c

linic

al s

igns

of

post

sten

otic

pne

umon

ia s

ubsi

ded

in

5/9

ALA

pat

ient

s an

d 9/

13 P

hoto

san

patie

nts.

The

re w

as n

o st

atis

tical

ly

sign

ifica

nt d

iffer

ence

bet

wee

n gr

oups

on

pul

mon

ary

func

tion

para

met

ers

QoL

and

ret

urn

to n

orm

al

acti

vity

Mea

n K

arno

fsky

val

ue

chan

ged

from

78

to 7

9 in

the

ALA

gr

oup,

and

from

70

to 7

8 in

the

Ph

otos

an g

roup

, sho

win

g a

sign

ifica

nt

diffe

renc

e in

favo

ur o

f the

Pho

tosa

n gr

oup

(p =

0.0

0015

). O

ne p

atie

nt h

ad

an im

prov

emen

t of

10%

in t

he A

LA

grou

p, w

here

as 1

1 pa

tient

s in

the

Ph

otos

an g

roup

impr

oved

by

10%

an

d fiv

e im

prov

ed b

y 20

%. N

one

of

the

patie

nts

in t

he P

hoto

san

grou

p re

port

ed a

dec

reas

e in

QoL

due

to

long

-last

ing

need

for

skin

pro

tect

ion

AE

s N

o su

nbur

n oc

curr

ed in

eith

er

grou

p. N

o m

ajor

com

plic

atio

ns

rela

ting

to p

hoto

sens

itisa

tion,

PD

T

or H

BO w

ere

obse

rved

. Min

or

com

plic

atio

ns w

ere:

feve

r in

the

af

tern

oon

afte

r PD

T (

12 in

ALA

gro

up,

18 in

Pho

tosa

n gr

oup)

and

mild

che

st

pain

for

1 or

2 d

(6

in t

he A

LA g

roup

an

d 13

in t

he P

hoto

san

grou

p). N

one

of t

he A

Es r

equi

red

spec

ific

trea

tmen

t

Aut

hors

’ con

clus

ions

Pho

tosa

n se

ems

to b

e m

ore

effe

ctiv

e th

an A

LA

in P

DT

of m

alig

nant

tra

cheo

bron

chia

l st

enos

is. H

owev

er, t

hese

res

ults

wou

ld

need

con

firm

ing

in a

ran

dom

ised

, bl

inde

d tr

ial

Bri

ef s

tudy

app

rais

al T

his

smal

l pi

lot

stud

y w

as n

on-r

ando

mis

ed a

nd

the

grou

ps h

ad d

iffer

ence

s at

bas

elin

e w

hich

may

hav

e im

pact

ed o

n re

sults

. T

he s

urvi

val d

ata

do n

ot s

olel

y re

flect

the

effe

ctiv

enes

s of

the

PD

T

trea

tmen

t, as

4 w

k af

ter

PDT

pat

ient

s w

ere

elig

ible

to

rece

ive

a va

riet

y of

oth

er t

reat

men

ts. T

here

are

als

o do

ubts

as

to w

heth

er t

he A

LA d

osag

e w

as o

ptim

al

ATA

, atm

osph

ere

abso

lute

.

Appendix 18

272



273

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Mog

hiss

i et

al. (

1993

)126

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

K

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

26In

terv

entio

n: 1

5C

ompa

rato

r: 11

No.

of R

ecru

itin

g C

entr

es N

ot s

tate

dFo

llow

-up

peri

od

and

freq

uenc

y A

t 1,

2

and

3 m

th, t

hen

at

3-m

onth

ly in

terv

als

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe o

f Lun

g C

ance

r an

d H

isto

logy

Non

-sm

all c

ell

Mai

n el

igib

ility

cri

teri

a St

age

III in

oper

able

NSC

LC w

ith >

50%

in

tral

umin

al b

ronc

hial

obs

truc

tion

Pati

ent

char

acte

rist

ics

% M

ale:

81A

ge r

ange

: 43–

76 yr

Mea

n ag

e: In

terv

entio

n 60

, co

mpa

rato

r 66

(ns

)C

onco

mit

ant

trea

tmen

t So

me

patie

nts

had

addi

tiona

l mod

aliti

es o

f tr

eatm

ent

afte

r 1

mth

Tria

l tre

atm

ents

PD

T v

s N

d:YA

G

lase

rIn

terv

enti

on In

trav

enou

s Ph

otof

rin

or P

hoto

frin

II a

t do

se o

f 2 m

g/kg

fo

llow

ed 4

8–54

hr

late

r by

red

ligh

t (6

30 n

m)

from

a c

oppe

r va

pour

pu

mpe

d-dy

e la

ser

deliv

ered

thr

ough

a

600-

nm q

uart

z fib

re w

ith a

te

rmin

al c

ylin

dric

al d

iffus

er. D

ose

of

200

J/cm

at

400

mW

/cm

. Dur

atio

n of

lig

ht d

ose

was

500

s. F

urth

er s

essi

ons

prov

ided

if n

eede

d. T

horo

ugh

debr

idem

ent

and

phys

ioth

erap

y af

ter

trea

tmen

t. C

aref

ul c

ouns

ellin

g on

ph

otos

ensi

tivity

Com

para

tor

Nd:

YAG

lase

r (F

ibre

lase

100

, Pilk

ingt

on)

with

a

400-µ

m d

iam

eter

del

iver

y fib

re

usin

g 40

–50 W

pul

ses

of 3

–5 s.

Dos

e de

pend

ent

on e

xten

t of

tum

our.

Furt

her

sess

ions

pro

vide

d if

need

ed

Mor

talit

y N

o tr

eatm

ent-

rela

ted

mor

talit

y. Lo

nger

-ter

m m

orta

lity

not

asse

ssed

Mor

bidi

ty A

t 1-

mth

, lum

inal

di

amet

er, a

s pe

rcen

tage

of n

orm

al

diam

eter

, was

sig

nific

antly

gre

ater

in

PDT

gro

up (

83%

) th

an t

he N

d:YA

G

grou

p (6

1%),

p <

0.00

06. B

oth

FVC

an

d FE

V1 i

mpr

oved

sig

nific

antly

mor

e w

ith P

DT

1 m

th a

fter

trea

tmen

t w

hen

com

pare

d to

pre

-tre

atm

ent

mea

sure

men

ts: m

ean

diffe

renc

e in

FV

C, 0

.47

PDT

vs

–0.0

6 N

d:YA

G,

p <

0.05

, mea

n di

ffere

nce

in F

EV1,

0.35

PD

T v

s 0.

01 N

d:YA

G, p

< 0

.05

All

patie

nts

had

a PR

at

1 m

thA

Es

No

seri

ous

post

-tre

atm

ent

com

plic

atio

ns. M

ild fe

ver

in

two

Nd:

YAG

pat

ient

s. N

o ph

otos

ensi

tivity

in P

DT

pat

ient

s

Aut

hors

’ con

clus

ions

PD

T is

m

ore

effe

ctiv

e th

an N

d:YA

G in

pa

tient

s w

ith e

xten

sive

obs

truc

tive

lung

can

cer

Bri

ef s

tudy

app

rais

al A

sm

all

stud

y w

ith n

o de

tails

of m

etho

ds

of r

ando

mis

atio

n, a

lloca

tion

conc

ealm

ent

or b

lindi

ng (

rais

ing

relia

bilit

y is

sues

)

Appendix 18

272



273

Appendix 19 Biliary tract cancer data extraction

Appendix 19

274



275Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Dec

hene

et a

l. (2

007)

132

Dat

a so

urce

Abs

trac

tC

ount

ry N

ot s

tate

dLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-R

CT

No.

of p

arti

cipa

nts

Tota

l: 29

Inte

rven

tion:

16

Com

para

tor:

13N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

Not

sta

ted

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

Can

cer

and

His

tolo

gyN

on-r

esec

tabl

e bi

le d

uct

canc

erM

ain

Elig

ibili

ty C

rite

ria

Adv

ance

d bi

le d

uct

canc

er

(no

furt

her

deta

ils g

iven

)Pa

tien

t ch

arac

teri

stic

s%

Mal

e: 76

Med

ian

age:

67–7

0H

isto

logi

cal c

onfir

mat

ion

was

not

re

port

edC

onco

mit

ant

trea

tmen

t Pe

ri-in

terv

entio

nal a

ntib

iotic

pr

ophy

laxi

s

Tria

l tre

atm

ents

PD

T w

ith

Phot

osan

-3 v

s PD

T w

ith P

hoto

frin

IIIn

terv

enti

on 2

mg/

kg P

hoto

san-

3 ad

min

iste

red

48 h

r be

fore

rad

iatio

n.

A 4

-cm

qua

rtz

fibre

and

a d

iode

la

ser

syst

em (

635

nm; 1

, 1 W

, 22

0 J/c

m).

Ligh

t pr

otec

tion

was

ad

vise

d fo

r 4–

6 w

k. Fu

rthe

r PD

T

para

met

ers

wer

e no

t re

port

edC

ompa

rato

r 2

mg/

kg P

hoto

frin

II

adm

inis

tere

d 48

hr

befo

re

radi

atio

n. A

4-c

m q

uart

z fib

re a

nd

a di

ode

lase

r sy

stem

(63

5 nm

; 1,

1 W, 2

20 J/

cm).

Ligh

t pr

otec

tion

was

ad

vise

d fo

r 4–

6 w

k. Fu

rthe

r PD

T

para

met

ers

wer

e no

t re

port

ed

Mor

talit

y M

edia

n su

rviv

al in

the

PS

-3 g

roup

was

690

d (

95%

CI 4

48

to 9

31)

and

in t

he P

F2 g

roup

it w

as

494

d (9

5% C

I 84

to 9

03),

p =

NS

Mor

bidi

ty N

ot a

sses

sed

QoL

and

ret

urn

to n

orm

al

acti

vity

Not

ass

esse

dA

Es T

here

was

no

subs

tant

ial

skin

rea

ctio

n ob

serv

ed (

no d

ata

prov

ided

). 23

% o

f pat

ient

s in

the

PF2

gr

oup

and

26%

of p

atie

nts

in t

he

PS3

grou

p de

velo

ped

‘con

side

rabl

e’

chol

angi

tisR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

PD

T h

as t

he

pote

ntia

l to

cons

ider

ably

pro

long

su

rviv

al in

non

-res

ecta

ble

bile

duc

t ca

ncer

. The

effe

ct is

not

dep

ende

nt

on t

he t

ype

of h

aem

atop

orph

yrin

ph

otos

ensi

tiser

Bri

ef s

tudy

app

rais

al T

his

stud

y w

as r

epor

ted

in a

bstr

act

form

on

ly a

nd d

id n

ot p

rovi

de d

etai

ls o

f m

etho

dolo

gy s

uch

as r

ando

mis

atio

n,

blin

ding

and

allo

catio

n co

ncea

lmen

t. T

his

is a

sm

all t

rial

whi

ch m

ay b

e un

derp

ower

ed t

o de

tect

a d

iffer

ence

be

twee

n th

e ph

otos

ensi

tiser

s

Appendix 19

274



275Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Kah

aleh

et

al. (

2008

)133

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

SASt

udy

desi

gn

Non

-RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

48In

terv

entio

n: 1

9C

ompa

rato

r: 29

No.

of r

ecru

itin

g ce

ntre

s O

neFo

llow

-up

peri

od a

nd

freq

uenc

y FU

at

1 m

th a

nd e

very

3

mth

the

reaf

ter

(or

earl

ier

if th

ere

wer

e co

mpl

icat

ions

)

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y N

on-r

esec

tabl

e ch

olan

gioc

arci

nom

aM

ain

elig

ibili

ty c

rite

ria

Unc

lear

, PD

T o

ffere

d af

ter

Dec

embe

r 20

04 t

o al

l pa

tient

s w

ith n

on-r

esec

tabl

e ch

olan

gioc

arci

nom

a or

re

sect

able

lesi

ons

deem

ed

inop

erab

lePa

tien

t ch

arac

teri

stic

s%

Mal

e: 50

Age

ran

ge: 2

6–94

yrM

ean

age:

66.6

yrTu

mou

r ex

tens

ion:

Bis

mut

h I,

6%; B

ism

uth

II, 1

9%;

Bism

uth

III, 3

5%; B

ism

uth

IV, 4

0%Fu

rthe

r pa

tient

ch

arac

teri

stic

s w

ere

repo

rted

Path

olog

ical

dia

gnos

is w

as

confi

rmed

in 6

9% o

f cas

esC

onco

mit

ant

trea

tmen

t Tw

enty

-tw

o pa

tient

s ha

d ch

emot

hera

py a

nd 1

9 ha

d ra

diot

hera

py. A

ll pa

tient

s re

ceiv

ed p

erip

roce

dure

an

tibio

tic p

roph

ylax

is

Tria

l tre

atm

ents

ER

CP

with

PD

T a

nd s

tent

vs

ERC

P w

ith S

tent

alo

neIn

terv

enti

on S

elec

tive

deco

mpr

essi

on o

f all

opac

ified

, dila

ted

segm

ents

was

att

empt

ed w

ith

boug

ie a

nd b

allo

on d

ilata

tion

to a

ssis

t in

the

pl

acem

ent

of p

olye

thyl

ene

sten

tsIn

trav

enou

s Ph

otof

rin

at 2

mg/

kg 4

8 hr

pri

or t

o 63

3-nm

(±

3-nm

) lig

ht fr

om a

200

0-m

W d

iode

la

ser,

deliv

ered

thr

ough

a 3

-m le

ngth

fibr

e ha

ving

a

2.5-

cm-lo

ng c

ylin

dric

al d

iffus

er a

t di

stal

end

(d

iffus

er w

as in

sert

ed in

to a

10F

she

ath

of a

pl

astic

ste

nt)

Phot

oact

ivat

ion

perf

orm

ed a

t 63

3 nm

* w

ith a

lig

ht d

ose

of 1

80 J/

cm2 ,

fluen

ce o

f 0.2

5 W/c

m2 a

nd

dura

tion

of 7

50 s.

One

or

two

segm

ents

tre

ated

at

dis

cret

ion

of e

ndos

copi

st. P

DT

rep

eate

d at

3-

mth

inte

rval

s w

hen

all s

tent

s w

ere

repl

aced

(t

his

was

don

e ea

rlie

r if

prem

atur

e oc

clus

ion

or

mig

ratio

n oc

curr

ed)

*Alth

ough

rep

orte

d as

620

nm

in t

he p

aper

, bas

ed

on t

he t

ype

of la

ser

used

thi

s ap

pear

s to

hav

e be

en a

typ

ogra

phic

err

orC

ompa

rato

r Se

lect

ive

deco

mpr

essi

on o

f all

opac

ified

, dila

ted

segm

ents

was

att

empt

ed w

ith

boug

ie a

nd b

allo

on d

ilata

tion

to a

ssis

t in

the

pl

acem

ent

of p

olye

thyl

ene

sten

ts (

7F, 8

.5F

and

10F

in d

iam

eter

). R

epea

ted

if in

dica

ted

until

pa

tient

ref

usal

or

deat

h

Mor

talit

y A

t en

d of

stu

dy 1

0 pa

tient

s w

ere

still

al

ive,

eig

ht b

eing

from

the

PD

T g

roup

The

re w

as s

tatis

tical

ly s

igni

fican

t pr

olon

ged

surv

ival

in t

he P

DT

gro

up (

mea

n 16

.2 m

th, S

D

2.4)

com

pare

d w

ith t

he S

tent

-alo

ne g

roup

(m

ean

7.4

mth

, SD

1.6

), p

< 0.

003.

Mor

talit

y ra

tes

wer

e si

gnifi

cant

ly lo

wer

in t

he P

DT

gro

up a

t 3

mth

(0%

vs

28%

, p =

0.0

1), a

nd 6

mth

(16

% v

s 52

%, p

= 0

.01)

, bu

t no

t at

12

mth

(56

% v

s 82

%, p

= 0

.08)

vs

Sten

t-al

one

grou

pM

orbi

dity

Bot

h gr

oups

had

sig

nific

antly

dec

reas

ed

leve

ls o

f ser

um b

iliru

bin

at 3

mth

whe

n co

mpa

red

to b

asel

ine

leve

ls (

p =

0.00

8 fo

r PD

T a

nd p

= 0

.000

1 fo

r st

ent

only

), al

thou

gh t

here

was

no

sign

ifica

nt

diffe

renc

e be

twee

n th

e tw

o gr

oups

in t

he d

egre

e of

dec

reas

e (p

= 0

.78)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

as

sess

edA

Es

Sten

t-al

one

grou

p: 1

0 pa

tient

s de

velo

ped

chol

angi

tis (

with

tw

o pa

tient

s dy

ing

as a

co

nseq

uenc

e). F

our

patie

nts

deve

lope

d pa

ncre

atiti

s an

d on

e ha

d du

oden

al p

erfo

ratio

n. F

urth

er r

esul

ts

repo

rted

. PD

T g

roup

: thr

ee p

atie

nts

expe

rien

ced

skin

pho

toto

xici

ty. S

even

pat

ient

s de

velo

ped

chol

angi

tis, t

wo

deve

lope

d ch

olec

ystit

is, a

nd t

wo

haem

obili

a. Fu

rthe

r re

sults

rep

orte

dR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

ER

CP

with

PD

T

seem

s to

incr

ease

su

rviv

al in

pat

ient

s w

ith u

nres

ecta

ble

chol

angi

ocar

cino

ma

whe

n co

mpa

red

with

ER

CP

alon

e, a

lthou

gh it

re

mai

ns t

o be

pro

ved

whe

ther

thi

s is

due

to

PDT

or

the

num

ber

or

ERC

P se

ssio

nsB

rief

stu

dy a

ppra

isal

T

he a

ims

of t

his

stud

y at

its

ince

ptio

n ar

e un

cert

ain

as t

he s

tudy

be

gan

in 2

001,

but

PD

T o

nly

beca

me

avai

labl

e fo

r us

e in

20

04. F

rom

thi

s po

int

on, P

DT

was

offe

red

to a

ll pa

tient

s, m

akin

g it

diffi

cult

to r

ecru

it gr

oups

with

sim

ilar

base

line

char

acte

rist

ics.

How

ever

, the

aut

hors

ac

know

ledg

ed t

hat

the

stud

y de

sign

pre

vent

ed

defin

itive

con

clus

ions

fr

om b

eing

dra

wn

F, T

he ‘F

renc

h si

ze’ o

f the

she

ath

used

to

intr

oduc

e a

sten

t.

Appendix 19

276 Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Ort

ner

et a

l. (20

03)13

4

Dat

a so

urce

Fu

ll pu

blis

hed

pape

rC

ount

ry

Ger

man

yLa

ngua

ge

Engl

ish

Stud

y de

sign

R

CT

No.

of

part

icip

ants

Tota

l: 39

Inte

rven

tion:

20

Com

para

tor:

19N

o. o

f re

crui

ting

ce

ntre

s Tw

oFo

llow

-up

peri

od a

nd

freq

uenc

y 14

d,

3 m

th, 6

mth

afte

r th

e in

terv

entio

n.

Surv

ivor

s th

en

follo

wed

up

at

6-m

th in

terv

als

Trea

tmen

t in

tent

ion

Palli

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y N

CC

Mai

n el

igib

ility

cri

teri

a In

clus

ion

crite

ria

wer

e pa

tient

s at

le

ast

18 yr

of a

ge w

ith a

pro

xim

al

mal

igna

nt t

umou

r of

the

bile

du

cts

(Bis

mut

h ty

pes

II–IV

, TN

M

stag

es II

I and

IV). T

hey

had

a la

rge

(> 3

cm in

dia

met

er),

imag

ing-

confi

rmed

, non

-res

ecta

ble

tum

our

(ass

esse

d by

tw

o in

depe

nden

t su

rgeo

ns),

posi

tive

hist

olog

y an

d no

evi

denc

e of

can

cer

of a

noth

er

orga

n. E

xclu

sion

cri

teri

a w

ere

porp

hyri

a, pr

evio

us c

hem

othe

rapy

or

rad

ioth

erap

y, pr

evio

us

tech

nica

lly s

ucce

ssfu

l ste

ntin

g (d

etai

ls in

pap

er),

inse

rtio

n of

a

met

al s

tent

, par

tial r

esec

tion

of

chol

angi

ocar

cino

ma,

diag

nost

ic

ERC

P m

ore

than

1 m

th p

revi

ously

an

d a

Kar

nofs

ky in

dex

of <

30%

. Fu

rthe

r de

tail

is p

rese

nted

in t

he

pape

rPa

tien

t ch

arac

teri

stic

s%

Mal

e: N

ot s

tate

dA

ge r

ange

: 53–

85M

edia

n ag

e: In

terv

entio

n 64

; co

ntro

l 68

(NS)

Can

cer

stag

e: St

age

III, s

even

; st

age

IVa,

19; s

tage

IVb

13Bi

smut

h ty

pe: I

I, tw

o; II

I, si

x; IV

, 31

100%

of a

ll ca

ses

wer

e hi

stol

ogic

ally

con

firm

edFu

rthe

r pa

tient

cha

ract

eris

tics

wer

e re

port

edC

onco

mit

ant

trea

tmen

t O

ral

cipr

oflox

acin

the

rapy

, 250

mg

twic

e da

ily, w

as s

tart

ed b

efor

e ER

CP

and

cont

inue

d fo

r 14

d

Tria

l tre

atm

ents

PD

T +

Dou

ble

sten

ting

vs St

entin

g al

one

Inte

rven

tion

See

com

para

tor

for

deta

ils o

f ste

ntin

g. PD

T p

atie

nts

rece

ived

Pho

tofr

in a

t a

dosa

ge o

f 2

mg/

kg b

ody

wt

intr

aven

ously

48

hr b

efor

e la

ser

activ

atio

n. E

ndop

rost

hese

s w

ere

rem

oved

and

an

end

osco

pic

Hui

breg

tse

Cot

ton

set

cath

eter

w

as in

trod

uced

pro

xim

ally

abo

ve t

he s

tric

ture

s. In

tral

umin

al p

hoto

activ

atio

n w

as p

erfo

rmed

with

a

lase

r qu

artz

fibr

e w

ith a

cyl

indr

ical

diff

user

tip

, len

gth

40 m

m, c

ore

diam

eter

400

µm

. Pho

toac

tivat

ion

was

pe

rfor

med

at

630

nm u

sing

a li

ght

dose

of 1

80 J/

cm2 ,

fluen

ce o

f 0.2

41 W

/cm

2 and

irra

diat

ion

time

of 7

50 s

unde

r a

cont

inuo

us s

alin

e pe

rfus

ion.

A n

ew s

et o

f en

dopr

osth

eses

was

inse

rted

afte

r co

mpl

etio

n of

PD

T. Fu

rthe

r te

chni

cal d

etai

ls o

f the

pro

cedu

re a

re

avai

labl

e in

the

pap

er. P

atie

nts

rem

aine

d in

a d

arke

ned

room

for

3–4

d af

ter

inje

ctio

n an

d th

erea

fter

patie

nts

wer

e gr

adua

lly a

dapt

ed t

o lig

ht. I

f any

FU

ex

amin

atio

n sh

owed

evi

denc

e of

tum

our

in t

he b

ile

duct

, PD

T w

as r

epea

ted.

Mea

n nu

mbe

r of

tre

atm

ents

w

as 2

.4 (

min

imum

1, m

axim

um 5

), th

e m

ean

no o

f ill

umin

atio

ns p

er p

atie

nt w

as 5

.3 a

nd t

he m

edia

n tr

eatm

ent

time

was

79

min

(m

inim

um 4

0; m

axim

um

180)

. All

patie

nts

rece

ived

oxyg

en v

ia a

nas

al c

athe

ter t

o op

timise

the

PDT

effe

ctC

ompa

rato

r En

dosc

opic

dou

ble-

sten

ting

follo

wed

dia

gnos

tic E

RC

P (a

ll pa

tient

s re

ceiv

ed

oral

cip

roflo

xaci

n th

erap

y 25

0 m

g tw

ice

daily

be

fore

ER

CP

and

cont

inue

d fo

r 14

d).

At

leas

t tw

o 10

F en

dopr

osth

eses

had

to

be p

lace

d ab

ove

the

mai

n st

rict

ures

in e

very

pat

ient

. End

osco

pic

plas

tic

endo

pros

thes

es o

r pe

rcut

aneo

us p

last

ic p

rost

hese

s w

ere

used

. Suc

cess

ful d

rain

age

afte

r te

chni

cally

su

cces

sful

ste

ntin

g (d

efini

tion

give

n in

pap

er)

was

de

fined

as

a de

crea

se in

bili

rubi

n le

vel >

50%

with

in

7 d

afte

r st

entin

g. W

hen

the

1st

proc

edur

e di

d no

t le

ad t

o te

chni

cally

suc

cess

ful s

tent

ing,

a 2n

d pr

oced

ure

was

per

form

ed. W

hen

the

2nd

proc

edur

e w

as n

ot s

atis

fact

ory,

perc

utan

eous

ste

ntin

g w

as

perf

orm

ed. P

atie

nts

wer

e ra

ndom

ised

onl

y af

ter

tech

nica

lly s

ucce

ssfu

l ste

ntin

g. St

ent

exch

ange

s w

ere

perf

orm

ed e

very

3 m

th. E

ight

pat

ient

s re

ceiv

ed

extr

a in

terv

entio

ns (

chem

othe

rapy

, fou

r; PD

T, th

ree;

im

mun

othe

rapy

, one

) as

a la

st r

esor

t tr

eatm

ent

Mor

talit

y M

edia

n su

rviv

al in

the

PD

T g

roup

was

493

d

(95%

CI 2

76 t

o 71

0) a

nd 9

8 d

in t

he S

tent

ing-

only

gro

up

(95%

CI 8

7 to

107

) p <

0.0

001.

RR

= 0

.21

(95%

CI 0

.12

to

0.35

). Tw

o pa

tient

s in

the

PD

T g

roup

wer

e st

ill a

live

at t

he

time

of e

valu

atio

n. t

he s

tudy

was

ter

min

ated

ear

ly d

ue t

o th

e su

peri

ority

of P

DT

Mor

bidi

ty S

ucce

ssfu

l dra

inag

e w

as a

chie

ved

in 2

1%

of p

atie

nts

in b

oth

grou

ps. A

fter

PDT

ser

um b

iliru

bin

reac

hed

low

er le

vels

rel

ativ

e to

bas

elin

e an

d st

entin

g (p

< 0

.01)

. Suc

cess

ful d

rain

age

was

obt

aine

d in

72%

Mea

n nu

mbe

r of

ste

nt e

xcha

nges

: PD

T g

roup

= 3

.8,

sten

ting

alon

e =

3.7

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

The

Kar

nofs

ky

inde

x im

prov

ed a

fter

PDT

with

a m

edia

n 80

% s

core

(m

inim

um 5

0%, m

axim

um 1

00%

); m

ean

chan

ge fr

om

base

line

3.00

but

did

not

impr

ove

in t

he S

tent

ing-

alon

e gr

oup.

The

diff

eren

ce in

cha

nge

from

bas

elin

e be

twee

n th

e PD

T +

Sten

ting

grou

p an

d th

e St

entin

g-al

one

grou

p w

as

11.4

3 (9

5% C

I 2.9

2 to

19.

95, p

< 0

.01)

. Afte

r PD

T p

hysi

cal

func

tioni

ng (

p <

0.01

) an

d gl

obal

QoL

(p

< 0.

001)

impr

oved

in

the

PD

T g

roup

but

not

in t

he S

tent

ing-

alon

e gr

oup.

The

re

sults

of i

ndiv

idua

l fac

tors

rel

atin

g to

QoL

mea

sure

s ar

e lis

ted

in t

he p

aper

AE

s Bu

rden

of t

reat

men

t w

as lo

wer

in P

DT

vs

Sten

ting

alon

e (p

< 0

.001

). Ph

otos

ensi

tivity

was

rep

orte

d by

tw

o (1

0%)

of P

DT

pat

ient

s; al

l rea

ctio

ns w

ere

mild

and

re

solv

ed c

ompl

etel

y. A

ny c

hola

ngiti

s oc

curr

ing

duri

ng F

U

was

con

side

red

an A

E. T

here

wer

e th

ree

case

s in

the

PD

T

grou

p an

d se

ven

in t

he S

tent

ing-

alon

e gr

oup.

Sten

osis

pr

obab

ly r

elat

ed t

o th

erap

y w

as r

epor

ted

by t

wo

in t

he

PDT

gro

up a

nd z

ero

in t

he S

tent

ing-

alon

e gr

oup.

Fata

l ch

olan

gitis

, sep

sis

poss

ibly

rel

ated

to

ther

apy:

PDT

gro

up

two

of 1

8, S

tent

ing-

alon

e gr

oup

six

of 1

9T

he fo

llow

ing

wer

e ca

uses

of d

eath

pro

babl

y no

t re

late

d to

the

rapy

:Pu

lmon

ary

embo

lism

: PD

T g

roup

one

of 1

8, S

tent

ing

alon

e th

ree

of 1

9C

ache

xia:

PDT

gro

up o

ne o

f 18,

Ste

ntin

g on

e of

19

Car

diac

failu

re: o

ne o

f 18,

one

of 1

9, r

espe

ctiv

ely

Met

asta

ses:

12 o

f 18,

eig

ht o

f 19,

res

pect

ivel

yC

hron

ic r

enal

failu

re: o

ne o

f 18,

zer

o of

19,

res

pect

ivel

yR

esou

rce

use

Not

ass

esse

d

Aut

hors

’ co

nclu

sion

s PD

T a

dded

to

best

sup

port

ive

care

impr

oves

su

rviv

al a

nd Q

oL

in p

atie

nts

with

N

CC

. Pro

long

ed

surv

ival

tim

e w

as

not

asso

ciat

ed

with

a h

igh

rate

of

AEs

Bri

ef s

tudy

ap

prai

sal T

his

was

a w

ell-

cond

ucte

d an

d re

port

ed t

rial

, w

hich

was

hal

ted

earl

y du

e to

the

su

peri

ority

of t

he

PDT

tre

atm

ent

NC

C, n

on-r

esec

tabl

e ch

olan

gioc

arci

nom

a.



277Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Witz

igm

ann

et a

l. (2

006)

135

Dat

a so

urce

Ful

l pub

lishe

d pa

per

Cou

ntry

Ger

man

yLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-R

CT

No.

of p

arti

cipa

nts

Tota

l: 18

4 (1

91 if

incl

udin

g se

ven

patie

nts

not

anal

ysed

du

e to

mis

sing

FU

dat

a)In

terv

entio

n: 6

8C

ompa

rato

r: 56

2nd

Com

para

tor:

60N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

Unc

lear

–

patie

nts

wer

e re

crui

ted

over

10

yr, w

hich

app

ears

to

be t

he F

U p

erio

d

Trea

tmen

t in

tent

ion

Cur

ativ

e pa

lliat

ive

Type

(s)

of c

ance

r an

d hi

stol

ogy

Hila

r ch

olan

gioc

arci

nom

aM

ain

elig

ibili

ty c

rite

ria

Not

sta

ted

Pati

ent

char

acte

rist

ics

% M

ale:

52A

ge r

ange

: 22–

91 yr

Tum

our

stag

e: Pa

tient

s fr

om

all s

tage

s, bu

t m

ostly

IB a

nd

IIA Tum

our

exte

nt: P

atie

nts

from

al

l Bis

mut

h ty

pes,

but

mos

tly

type

IV. A

ccor

ding

to

both

Bi

smut

h–C

orle

tte

and

UIC

C

clas

sific

atio

ns t

here

wer

e m

ore

adva

nced

tum

ours

in

the

pal

liativ

e tr

eatm

ent

grou

ps t

han

in t

he r

esec

tion

grou

p (p

< 0

.05)

. Fur

ther

pa

tient

cha

ract

eris

tics

wer

e re

port

edT

he n

umbe

r of

cas

es

confi

rmed

his

tolo

gica

lly w

as

not

clea

rly

repo

rted

Con

com

itan

t tr

eatm

ent

Che

mot

hera

py, r

adia

tion

ther

apy,

chem

orad

iatio

n an

d ir

idiu

m im

plan

ts w

ere

occa

sion

ally

use

d

Tria

l tre

atm

ents

PD

T +

sten

ting

vs S

tent

ing

alon

e vs

Res

ectio

nIn

terv

enti

on

PDT

+ st

entin

g: In

trav

enou

s Ph

otof

rin

at 2

mg/

kg w

ith

phot

oact

ivat

ion

afte

r 1–

4 d.

R

epea

ted

whe

n th

ere

was

evi

denc

e of

tum

our

prog

ress

ion.

Fur

ther

PD

T

para

met

ers

wer

e no

t re

port

ed. S

ee b

elow

for

sten

ting

Com

para

tor

Sten

ting:

At

leas

t tw

o 9F

or

11.5

F pl

astic

en

dopr

osth

eses

wer

e pl

aced

ab

ove

the

mai

n st

rict

ures

an

d ex

chan

ged

ever

y 3

mth

2nd

com

para

tor

Res

ectio

n: O

ne o

f rig

ht-

side

d he

mih

epat

ecto

my,

righ

t tr

iseg

men

tect

omy,

left

hem

ihep

atec

tom

y, hi

lar

rese

ctio

n al

one

or

liver

tra

nspl

anta

tion,

with

ad

ditio

nal t

ypes

of s

urge

ry

whe

n re

quire

d. N

eoad

juva

nt

PDT

and

bili

ary

drai

nage

als

o gi

ven

if re

quire

d

Mor

talit

y PD

T +

sten

ting

vs S

tent

ing

alon

e:1-

and

2-

yr s

urvi

val r

ates

wer

e 51

% a

nd 1

6% v

s 23

% a

nd 1

0%,

resp

ectiv

ely;

med

ian

surv

ival

tim

e 12

mth

vs

6.4

mth

(p

< 0

.01)

; 63(

93%

) vs

51(

91%

) pa

tient

s ha

d di

ed b

y th

e en

d of

the

stu

dy (

the

mai

n ca

uses

wer

e tu

mou

r pr

ogre

ssio

n an

d co

mpl

icat

ions

of c

hron

ic c

hola

ngiti

s).

Res

ectio

n: T

he 3

0- a

nd 6

0-da

y de

ath

rate

s w

ere

8.3%

and

11

.7%

, res

pect

ivel

y. M

ultip

le o

rgan

failu

re fr

om in

fect

ive

com

plic

atio

ns w

as t

he m

ost

com

mon

cau

se o

f dea

th.

Ove

rall

1-, 3

- an

d 5-

yr s

urvi

val r

ates

incl

udin

g po

st

op d

eath

s w

ere

73%

, 40%

and

27%

, res

pect

ivel

y, w

ith

a m

edia

n su

rviv

al o

f 23

mth

. Neo

adju

vant

PD

T b

efor

e re

sect

ion

resu

lted

in 1

-, 3-

and

5-y

r su

rviv

al r

ates

of 8

8%,

42%

and

42%

com

pare

d w

ith 6

6%, 2

8% a

nd 1

9% a

fter

surg

ery

alon

e (n

s). T

here

was

no

sign

ifica

nt d

iffer

ence

in

med

ian

surv

ival

tim

e be

twee

n th

e (R

1 an

d R

2) r

esec

tion

grou

p an

d th

e PD

T +

Sten

ting

grou

pM

orbi

dity

PD

T +

sten

ting

and

Sten

ting

alon

e: A

t 3

mth

, in

the

PD

T +

sten

ting

grou

p, th

ere

was

a s

igni

fican

t di

ffere

nce

in m

ean

bilir

ubin

leve

ls r

elat

ive

to b

asel

ine

(p <

0.0

01).

PDT

+ st

entin

g gr

oup

had

sign

ifica

ntly

low

er

leve

ls o

f bili

rubi

n th

an t

he S

tent

ing-

alon

e gr

oup

(4.1

mg/

dl

vs 7

.3 m

g/dl

, p <

0.0

5). S

ucce

ssfu

l dra

inag

e ac

hiev

ed in

75

% o

f pat

ient

s re

ceiv

ing

PDT

+ st

entin

g co

mpa

red

with

39

% r

ecei

ving

ste

ntin

g al

one.

Res

ectio

n: R

ecur

renc

e in

27

patie

nts

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

At

3 m

th, m

edia

n pr

e-tr

eatm

ent

Kar

nofs

ky p

erfo

rman

ce s

tatu

s in

crea

sed

by 2

% fo

r PD

T +

Sten

ting

and

decr

ease

d by

8%

in

Sten

ting-

alon

e gr

oup

(p <

0.0

1)A

Es

PDT

+ st

entin

g/St

entin

g al

one:

The

re w

ere

no

proc

edur

e-re

late

d de

aths

. Eig

ht P

DT

pat

ient

s ha

d sk

in

toxi

city

(gr

ades

I an

d II)

. Bac

teri

al c

hola

ngiti

s se

en in

38

PDT

+ St

entin

g pa

tient

s an

d 32

Ste

ntin

g-al

one

patie

nts

(ns)

. Res

ectio

n: m

ajor

com

plic

atio

ns r

epor

ted

in 5

2% o

f pa

tient

s (3

7% r

equi

red

rela

paro

tom

y). T

he m

ost

com

mon

co

mpl

icat

ion

was

bile

leak

age

(eig

ht p

atie

nts)

Res

ourc

e us

e M

edia

n ho

spita

l sta

ys w

ere

65 d

for

PDT

+ st

entin

g, 44

d fo

r st

entin

g al

one,

and

48

d fo

r re

sect

ion

Aut

hors

’ con

clus

ions

O

nly

com

plet

e tu

mou

r re

sect

ion,

incl

udin

g he

patic

re

sect

ion,

ena

bles

long

-ter

m

surv

ival

for

patie

nts

with

hi

lar

chol

angi

ocar

cino

ma.

Palli

ativ

e PD

T +

Sten

ting

resu

lted

in lo

nger

sur

viva

l th

an s

tent

ing

alon

e an

d ha

s a

sim

ilar

surv

ival

tim

e co

mpa

red

with

inco

mpl

ete

R1

and

R2

rese

ctio

nB

rief

stu

dy a

ppra

isal

N

o fir

m c

oncl

usio

ns

can

be d

raw

n fr

om t

he

resu

lts o

f thi

s st

udy

for

seve

ral r

easo

ns. T

here

was

he

tero

gene

ity o

f tre

atm

ents

w

ithin

the

thr

ee g

roup

s (e

.g. s

ome

patie

nts

in

the

rese

ctio

n gr

oup

also

re

ceiv

ed n

eoad

juva

nt P

DT

). T

he g

roup

s w

ere

also

cl

inic

ally

het

erog

eneo

us

(sig

nific

antly

diff

eren

t at

bas

elin

e fo

r se

vera

l pa

ram

eter

s), a

nd t

here

was

w

ide

vari

atio

n in

leng

th o

f FU

bet

wee

n gr

oups

and

pa

tient

s

UIC

C, I

nter

natio

nal U

nion

Aga

inst

Can

cer.

Appendix 19

278



279

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Zoe

pf e

t al.

(200

5)13

6

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry G

erm

any

Lang

uage

Eng

lish

Stud

y de

sign

RC

TN

o. o

f par

tici

pant

sTo

tal:

32In

terv

entio

n: 1

6C

ompa

rato

r: 16

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od a

nd

freq

uenc

y 1,

3, 6

, 9, 1

2 an

d ev

ery

3 m

th. E

arlie

r en

dosc

opic

inte

rven

tions

w

ere

perf

orm

ed w

hen

need

ed in

cas

e of

clo

ttin

g or

dis

loca

tion

Trea

tmen

t in

tent

ion

Palli

ativ

eM

ain

elig

ibili

ty c

rite

ria

Adv

ance

d, n

on-r

esec

tabl

e BD

CPa

tien

t ch

arac

teri

stic

s%

Mal

e: 63

Med

ian

age:

68 yr

(ra

nge

52–8

0 yr

)C

ance

r st

age:

Stag

e II

+ ly

mph

no

des,

one;

sta

ge IV

, 31

Initi

al m

edia

n K

arno

fsky

pe

rfor

man

ce s

tatu

s: 90

%

(70–

100)

Ove

rall

63%

of c

ases

wer

e co

nfirm

ed h

isto

logi

cally

Con

com

itan

t tr

eatm

ent

All

patie

nts

rece

ived

pro

phyl

actic

an

tibio

tic t

reat

men

t be

fore

th

e pr

oced

ure

with

1 g

of

Cef

tria

xon,

giv

en in

trav

enou

sly

30 m

in b

efor

e in

terv

entio

n.

Ong

oing

ant

ibio

tic o

ral

trea

tmen

t w

ith c

hino

lone

was

gi

ven

for

a to

tal o

f 14

d. T

he

1st

eigh

t PD

T p

atie

nts

had

intr

aven

ous

Cef

riax

on o

ver

3 d

but

did

not

rece

ive

cont

inui

ng

oral

ant

ibio

tic t

reat

men

t

Tria

l tre

atm

ents

PD

T +

end

osco

pic

drai

nage

vs

Endo

scop

ic d

rain

age

alon

eIn

terv

enti

on P

hoto

san-

3 w

as g

iven

in

trav

enou

sly a

t a

dose

of 2

mg/

kg b

w

48 h

r be

fore

lase

r ir

radi

atio

n. A

flex

ible

cy

lindr

ical

diff

user

pro

be w

as u

sed.

The

pr

obe

was

mou

nted

on

a 40

0-µ

m q

uart

z fib

re w

ith a

n ac

tive

leng

th o

f 4cm

and

a

radi

opaq

ue m

arke

r at

the

dis

tal fi

bre

tip.

A d

iode

lase

r sy

stem

with

a m

axim

um

pow

er o

utpu

t of

2 W

and

a w

avel

engt

h of

633

± 3

nm

was

use

d as

ligh

t so

urce

. Ir

radi

atio

n tim

e w

as c

alcu

late

d fo

r a

light

en

ergy

den

sity

of 2

00 J/

cm2 .

In m

ost

case

s th

is w

as a

roun

d 55

0 s.

the

pow

er d

ensi

ty

was

450

–500

mW

/cm

and

ene

rgy

dose

w

as 2

50–2

75 J/

cm o

f diff

user

leng

th. F

or

tran

spap

illar

y PD

T t

he li

ght

appl

icat

or w

as

inse

rted

thr

ough

the

wor

king

cha

nnel

of

a du

oden

osco

pe. F

or p

ercu

tane

ous

PDT

th

e qu

artz

fibr

e w

as g

uide

d in

four

pat

ient

s th

roug

h th

e pa

rtia

lly r

emov

ed p

ercu

tane

ous

cath

eter

and

in o

ne p

atie

nt t

hrou

gh t

he

wor

king

cha

nnel

of a

cho

lang

iosc

ope.

T

he 1

st P

DT

ses

sion

was

per

form

ed a

t a

med

ian

of 4

.5 m

th (

1–9)

afte

r di

agno

sis

of

BDC

. Nin

e pa

tient

s re

ceiv

ed a

2nd

PD

T

sess

ion

afte

r 3–

9 m

th a

nd o

ne p

atie

nt a

3rd

se

ssio

n 6

mth

afte

r th

e 2n

d se

ssio

n. F

urth

er

PDT

par

amet

ers

wer

e no

t re

port

ed.

All

patie

nts

wer

e pr

ovid

ed w

ith p

last

ic

endo

pros

thes

es im

med

iate

ly a

fter

the

PDT

tr

eatm

ent

Com

para

tor T

he a

im o

f the

en

dopr

osth

etic

tre

atm

ent

was

bila

tera

l hila

r dr

aina

ge. E

ndop

rost

hese

s w

ere

regu

larl

y ch

ange

d ev

ery

3 m

th o

r ea

rlie

r in

cas

e of

cl

ottin

g or

dis

loca

tion

Mor

talit

y T

he P

DT

gro

up h

ad a

long

er

surv

ival

tim

e co

mpa

red

to t

he e

ndop

rost

hesi

s gr

oup

(21

mth

vs

7 m

th, p

= 0

.01)

. In

the

PDT

gr

oup,

30-d

mor

talit

y w

as 0

% a

nd 6

% in

the

en

dopr

osth

esis

gro

up. A

t th

e tim

e of

eva

luat

ion,

th

ree

patie

nts

in t

he P

DT

gro

up a

nd o

ne in

th

e en

dopr

osth

esis

gro

up w

ere

still

aliv

e. T

he

PDT

pat

ient

s w

ere

deem

ed t

o be

in g

ood

clin

ical

con

ditio

n w

ithou

t si

gnifi

cant

cho

lest

asis

. N

o de

tails

wer

e pr

ovid

ed o

n th

e su

rviv

or in

th

e en

dopr

osth

esis

gro

up. I

n th

e PD

T g

roup

12

pat

ient

s di

ed o

f tum

our-

rela

ted

caus

es,

and

one

patie

nt o

f a p

erfo

rate

d ga

stri

c ul

cer.

Cau

ses

of d

eath

wer

e no

t re

port

ed fo

r th

e en

dopr

osth

esis

gro

upM

orbi

dity

4 w

k af

ter

initi

al P

DT,

mos

t PD

T p

atie

nts

show

ed a

n al

mos

t co

mpl

ete

elim

inat

ion

of b

ile d

uct

sten

osis

in t

he t

reat

ed

area

as

show

n w

ith c

hola

ngio

grap

hy (

data

no

t pr

ovid

ed).

Med

ian

bilir

ubin

leve

l afte

r 1s

t in

terv

entio

n w

as n

ot s

igni

fican

tly d

iffer

ent

betw

een

the

grou

psQ

oL a

nd r

etur

n to

nor

mal

act

ivit

y Q

oL

as a

sses

sed

by t

he K

arno

fsky

sca

le d

id n

ot

sign

ifica

ntly

impr

ove

afte

r PD

TA

Es T

hree

pat

ient

s de

velo

ped

an in

fect

ed

bilio

ma

with

pro

long

ed c

hola

ngiti

s af

ter

PDT

tre

atm

ent,

whi

ch c

ould

be

man

aged

by

ant

ibio

tic t

reat

men

t. A

noth

er p

atie

nt

deve

lope

d ch

olec

ystit

is 2

mth

afte

r a

2nd

trea

tmen

t se

ssio

n, w

hich

led

to s

urgi

cal

lapa

rosc

opic

cho

lecy

stec

tom

y. T

here

was

no

skin

pho

toto

xici

ty o

bser

ved

in a

ny o

f the

th

ree

patie

nts.

One

pat

ient

dev

elop

ed s

ever

e ba

cter

ial c

hola

ngiti

s du

ring

end

opro

sthe

tic

ther

apy,

whi

ch w

as s

ucce

ssfu

lly t

reat

ed b

y st

anda

rd a

ntib

iotic

the

rapy

Res

ourc

e us

e N

ot a

sses

sed

Aut

hors

’ co

nclu

sion

s PD

T is

min

imal

ly

inva

sive

but

the

re

is a

con

side

rabl

e ri

sk o

f cho

lang

itis

afte

r th

e pr

oced

ure.

PD

T w

as fo

und

to

resu

lt in

a s

ubst

antia

l pr

olon

gatio

n of

su

rviv

al t

ime

but

this

wou

ld n

eed

confi

rmat

ion

in

furt

her

patie

nt

seri

es. P

DT

has

the

po

tent

ial t

o re

sult

in a

ch

ange

over

of c

urre

nt

palli

ativ

e tr

eatm

ent

of B

DC

Bri

ef s

tudy

ap

prai

sal A

sm

all t

rial

with

cl

ear

repo

rtin

g of

pr

oced

ures

. The

re

sults

app

ear

to b

e re

liabl

e bu

t w

ould

ne

ed c

onfir

mat

ion

in

a la

rger

tri

al

Appendix 19

278



279

Appendix 20 Brain cancer data extraction

Appendix 20

280 Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Elja

mel

et

al. (

2008

)139

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

KLa

ngua

ge E

nglis

hSt

udy

desi

gn

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

27 a

naly

sed

(42

rand

omis

ed?)

Inte

rven

tion:

13

Com

para

tor:

14N

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

3-m

onth

ly, u

ntil

deat

h

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y G

BMM

ain

Elig

ibili

ty

Cri

teri

aPa

tient

s ov

er 1

7 yr

, w

ith a

new

MR

I di

agno

sis

of G

BM a

nd

a K

arno

fsky

sco

re

≥ 60

Pati

ent

char

acte

rist

ics

% M

ale:

67M

ean

age:

59.8

yrM

ean

Kar

nofs

ky

perf

orm

ance

sco

re:

70 Con

com

itan

t tr

eatm

ent

Som

e st

udy

patie

nts

rece

ived

add

ition

al

trea

tmen

ts s

uch

as c

hem

othe

rapy

an

d fu

rthe

r su

rger

y. H

owev

er, t

here

w

ere

no s

tatis

tical

ly

sign

ifica

nt d

iffer

ence

s be

twee

n th

e gr

oups

in

pat

ient

s re

ceiv

ing

addi

tiona

l tre

atm

ents

Tria

l tre

atm

ents

Flu

ores

cenc

e-gu

ided

re

sect

ion

and

repe

titiv

e PD

T a

nd

radi

othe

rapy

vs

stan

dard

res

ectio

n an

d ra

diot

hera

pyIn

terv

enti

on P

DT:

Pat

ient

s w

ere

give

n 2

mg/

kg P

hoto

frin

intr

aven

ously

48

h be

fore

sur

gery

, and

20

mg/

kg A

LA o

rally

3

h be

fore

sur

gery

. Afte

r re

mov

al o

f bul

k of

tum

our

viol

et-b

lue

light

(37

5–44

0 nm

) w

ith a

440

-nm

obs

erva

tion

filte

r w

as u

sed

to il

lum

inat

e th

e ca

vity

with

fluo

resc

ence

de

tect

ed b

y a

high

-qua

lity

phot

odia

gnos

is

cam

era,

and

dete

cted

tum

our

was

rem

oved

un

til n

o fu

rthe

r flu

ores

cenc

e w

as d

etec

ted.

A

lase

r-ba

sed

(405

nm

) pr

otop

orph

yrin

-IX

spec

tros

copy

det

ectio

n sy

stem

was

use

d to

det

ect

any

rem

aini

ng t

umou

r ce

lls a

t th

e m

argi

ns, w

hich

wer

e re

mov

ed. A

siz

e-10

bal

loon

cat

hete

r w

as in

flate

d to

fit

the

cavi

ty w

ith 0

.8%

intr

alip

id s

olut

ion.

Afte

r th

e pa

tient

aw

oke

from

sur

gery

the

1st

PD

T t

reat

men

t, us

ing

630-

nm d

iode

lase

r (6

00 m

W),

was

giv

en in

the

atre

rec

over

y at

100

J/cm

2 ; m

ore

PDT

was

giv

en a

t 72

, 96

, 120

and

144

hr.

Patie

nts

also

rec

eive

d st

anda

rd r

adio

ther

apy.

Adv

ice

was

giv

en o

n su

n pr

otec

tion

mea

sure

sC

ompa

rato

r Tum

our

rem

oval

usi

ng

the

sam

e ne

uron

avig

atio

n an

d su

rgic

al

mic

rosc

ope

as t

he P

DT

gro

up. P

atie

nts

also

re

ceiv

ed s

tand

ard

radi

othe

rapy

Mor

talit

y M

ean

surv

ival

in t

he P

DT

gro

up

was

52.

8 w

k vs

24.

2 w

k in

the

sur

gery

gr

oup

(p <

0.0

01)

Mor

bidi

ty T

here

was

no

resi

dual

tum

our

on d

isch

arge

sca

n in

10/

13 P

DT

pat

ient

s vs

4/

14 s

urge

ry p

atie

nts.

Mea

n tim

e to

tum

our

prog

ress

ion

was

8.6

mth

in t

he P

DT

gro

up

vs 4

.8 m

th in

the

sur

gery

gro

up (

p <

0.01

)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y T

he

Kar

nofs

ky s

core

at

6 m

th h

ad im

prov

ed

from

70

(at

base

line)

to

80 in

the

PD

T

grou

p, al

thou

gh t

he a

utho

rs r

epor

ted

an

impr

ovem

ent

of 2

0 po

ints

. The

sco

res

rem

aine

d th

e sa

me

for

the

surg

ery

grou

p (a

t 70

)A

Es T

hree

pat

ient

s ha

d de

ep v

ein

thro

mbo

sis,

two

of w

hich

wer

e in

the

PD

T

grou

p. N

o in

fect

ions

or

seiz

ures

occ

urre

dR

esou

rce

use

The

re w

as n

o di

ffere

nce

betw

een

the

grou

ps in

leng

th o

f hos

pita

l st

ay (

both

had

a m

ean

stay

of 7

d)

Aut

hors

’ con

clus

ions

ALA

and

Pho

tofr

in

fluor

esce

nce-

guid

ed r

esec

tion

with

re

petit

ive

PDT

offe

r a

wor

thw

hile

sur

viva

l ad

vant

age,

with

out

adde

d ri

sk, t

o pa

tient

s w

ith G

BMB

rief

stu

dy a

ppra

isal

The

Kar

nofs

ky

resu

lts w

ere

repo

rted

inco

nsis

tent

ly w

ithin

th

e pa

per,

mak

ing

inte

rpre

tatio

n di

fficu

lt.

It w

as u

ncle

ar h

ow m

any

patie

nts

had

actu

ally

bee

n ra

ndom

ised

and

tre

ated

, as

14

patie

nts

with

neg

ativ

e bi

opsy

res

ults

wer

e su

bseq

uent

ly e

xclu

ded

from

ana

lyse

s. T

he

anal

ysed

pop

ulat

ion

does

not

the

refo

re

appe

ar t

o re

flect

the

pop

ulat

ion

pres

entin

g cl

inic

ally

(pa

tient

s w

ith a

n M

RI d

iagn

osis

). A

lthou

gh t

he s

tudy

mad

e us

e of

blin

ding

to

ass

ess

outc

omes

, it

was

nev

erth

eles

s un

clea

r w

heth

er s

uita

ble

met

hods

had

bee

n us

ed t

o ra

ndom

ise

and

allo

cate

par

ticip

ants

to

tre

atm

ents

. No

resu

lts w

ere

repo

rted

on

pos

sibl

e ph

otos

ensi

tisat

ion

effe

cts.

The

au

thor

s di

d th

ough

ack

now

ledg

e th

e ne

ed

for

a m

uch

larg

er s

tudy

GBM

, glio

blas

tom

a m

ultif

orm

e; M

RI,

mag

netic

res

onan

ce im

agin

g.



281Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

K

rish

nam

urth

y et

al.

(200

0)13

8

Dat

a so

urce

Ful

l pu

blis

hed

pape

rC

ount

ry U

SALa

ngua

ge E

nglis

hSt

udy

desi

gn

Non

-RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

18In

terv

entio

n: S

ixC

ompa

rato

r: Si

x2n

d C

ompa

rato

r: Si

xN

o. o

f rec

ruit

ing

cent

res

One

Follo

w-u

p pe

riod

an

d fr

eque

ncy

Day

s 1

and

2, a

t di

scha

rge

from

ho

spita

l, at

1, 4

and

6

wk,

then

at

3-m

th

inte

rval

s

Trea

tmen

t in

tent

ion

Cur

ativ

e Pa

lliat

ive

Type

(s)

of c

ance

r an

d hi

stol

ogy

12 g

liobl

asto

ma,

five

anap

last

ic

astr

ocyt

oma,

one

mal

igna

nt

epen

dym

oma

Mai

n el

igib

ility

cri

teri

a Pa

tient

s ag

ed 1

8–75

yr, w

ith s

upra

tent

oria

l pr

imar

y m

alig

nant

bra

in t

umou

rs

≤ 5

cm in

dia

met

er, a

Kar

nofs

ky

ratin

g ≥

60, a

nd w

ho h

ad r

ecur

rent

or

res

idua

l tum

ours

wer

e el

igib

le.

Patie

nts

had

to h

ave

rece

ived

ra

diat

ion

ther

apy

> 3

mth

pri

or t

o PD

T t

reat

men

t. Fu

rthe

r el

igib

ility

cr

iteri

a w

ere

repo

rted

Pati

ent

char

acte

rist

ics

Age

ran

ge: 3

2–70

yrM

edia

n K

arno

fsky

sco

re: 9

0Tu

mou

r lo

catio

ns a

lso

repo

rted

. All

patie

nts

had

initi

al s

urge

ry, r

adia

tion

ther

apy

and

chem

othe

rapy

bef

ore

recu

rren

ceC

onco

mit

ant

trea

tmen

t St

eroi

d th

erap

y if

requ

ired

Tria

l tre

atm

ents

PD

T 1

500–

3700

J vs

PD

T 3

700–

4400

J vs

PD

T 4

400–

5900

JIn

terv

enti

on P

DT

150

0–37

00 J

(gro

up 1

): In

trav

enou

s Ph

otof

rin

at 2

mg/

kg, f

ollo

wed

24

hr la

ter

by a

naes

thet

ic a

nd C

T o

r M

RI

scan

whi

ch lo

cate

s tu

mou

r us

ing

ster

eota

ctic

arc

sys

tem

. Six

opt

ical

di

ffusi

on t

ip fi

bres

(1.

6 m

m)

and

cent

ral fi

bre

inse

rted

thr

ough

dri

ll ho

les

into

sku

ll. R

ed li

ght

(630

nm

) fr

om a

n ar

gon

pum

ped-

dye

lase

r w

as

deliv

ered

thr

ough

opt

ical

fibr

es a

nd

beam

spl

itter

s to

indi

vidu

al d

iffus

ion

tip fi

bres

. Tum

ours

wer

e bi

opsi

ed

(and

if n

o m

alig

nanc

y w

as fo

und

the

patie

nt w

as e

xclu

ded

from

the

stu

dy).

Patie

nts

wer

e ad

vise

d ab

out

sunl

ight

pr

otec

tion,

and

abo

ut a

void

ing

dire

ct

sunl

ight

and

bri

ght

artifi

cial

ligh

t fo

r 6

wk

Com

para

tor

PDT

370

0–44

00 J

(gro

up 2

): Se

e ab

ove

2nd

com

para

tor

PDT

440

0–59

00 J

(gro

up 3

): Se

e ab

ove

Mor

talit

y M

ean

surv

ival

tim

e w

as

314

d (s

d =

106)

in g

roup

2 v

s 23

8 d

in

grou

p 3

(sd

= 61

). G

roup

1 n

ot s

tate

dM

orbi

dity

16

patie

nts

had

recu

rren

ce a

fter

PDT

(fo

ur in

gro

up

1, s

ix in

gro

up 2

and

six

in g

roup

3),

and

two

did

not.

Tim

e to

tum

our

recu

rren

ce w

as a

mea

n of

150

d in

gr

oup

2 vs

131

d in

gro

up 3

. Gro

up 1

no

t st

ated

QoL

and

ret

urn

to n

orm

al

acti

vity

Med

ian

Kar

nofs

ky r

atin

g ch

ange

d fr

om 9

0 (p

re-P

DT

) to

85

(pos

t PD

T)

AE

s Fi

ve p

atie

nts

had

post

oper

ativ

e pe

rman

ent

neur

olog

ical

def

ects

(ze

ro

in g

roup

1, t

wo

in g

roup

2, a

nd t

hree

in

gro

up 3

)R

esou

rce

use

Not

ass

esse

d

Aut

hors

’ con

clus

ions

Incr

easi

ng

the

light

dos

e in

crea

ses

the

odds

of

havi

ng p

erm

anen

t ne

urol

ogic

al d

efici

t, bu

t do

es n

ot in

crea

se s

urvi

val t

ime,

or

tim

e to

tum

our

prog

ress

ion.

The

re

was

no

diffe

renc

e in

rec

urre

nce

with

in

crea

sing

ligh

t do

seB

rief

stu

dy a

ppra

isal

Thi

s no

n-ra

ndom

ised

stu

dy a

ppea

red

to h

ave

far

too

smal

l a s

ampl

e si

ze t

o pr

ovid

e cl

inic

ally

mea

ning

ful r

esul

ts. R

esul

ts

wer

e no

t al

way

s pr

ovid

ed fo

r al

l thr

ee

grou

ps



283



283

Appendix 21 Head and neck cancer data extraction

Appendix 21

284



285Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Li e

t al

. (20

06)14

1

Dat

a so

urce

Fu

ll pu

blis

hed

pape

rC

ount

ry C

hina

Lang

uage

En

glis

hSt

udy

desi

gn

RC

TN

o. o

f pa

rtic

ipan

tsTo

tal:

30In

terv

entio

n: 1

5C

ompa

rato

r: 15

No.

of

recr

uiti

ng

cent

res

Not

st

ated

Follo

w-u

p pe

riod

and

fr

eque

ncy

FU

at 1

, 3 a

nd 6

m

th

Trea

tmen

t in

tent

ion

Not

sta

ted,

ap

pear

s pa

lliat

ive

Type

(s)

of c

ance

r an

d hi

stol

ogy

Nas

opha

ryng

eal

carc

inom

aM

ain

elig

ibili

ty

crit

eria

Pat

ient

s w

ho h

ad r

elap

sed

and

who

had

faile

d ra

diot

hera

pyPa

tien

t ch

arac

teri

stic

s%

Mal

e: 80

Age

ran

ge: 2

8–72

Mea

n ag

e: 54

yrC

ance

r st

age:

All

stag

e IV

and

had

loca

l re

laps

e. A

ll ha

d pr

ior

(faile

d) r

adio

ther

apy;

som

e al

so h

ad p

rior

ch

emot

hera

py,

6–12

mth

bef

ore

tria

l tr

eatm

ent

Con

com

itan

t tr

eatm

ent

Ant

i-vo

miti

ng t

reat

men

t fo

r ch

emot

hera

py

grou

p. C

hine

se h

erbs

(u

nspe

cifie

d)

Tria

l tre

atm

ents

PD

T v

s C

hem

othe

rapy

(c

ispl

atin

and

5-F

U)

Inte

rven

tion

Intr

aven

ous

Phot

ofri

n of

2

mg/

kg. L

ocal

ana

esth

etic

(lid

ocai

ne)

befo

re

light

(63

0 nm

) at

200

–300

J/cm

from

a d

iode

la

ser

thro

ugh

a cy

lindr

ical

diff

user

(1–

5 cm

) 48

hr

afte

r in

ject

ion.

Lig

ht w

as a

pplie

d to

on

e to

thr

ee o

verl

appi

ng s

egm

ents

for

12 m

in p

er s

egm

ent.

Segm

ents

had

at

leas

t a

0.5-

cm m

argi

n be

yond

the

lesi

on. A

fter

48-h

r ne

crot

ic t

issu

e re

mov

ed b

y bi

opsy

forc

eps

and

new

ly e

xpos

ed le

sion

s w

ere

re-t

reat

ed

afte

r cl

eani

ng. C

lean

ing

was

rep

eate

d w

hen

nece

ssar

y. Pa

tient

s as

ked

to a

void

sun

light

fo

r 4–

6 w

k af

ter

trea

tmen

t. M

axim

um

num

ber

of s

essi

ons

was

not

sta

ted

Com

para

tor

Cis

plat

in 8

0 m

g/m

2 and

5-F

U

500

mg/

m2 ,

both

div

ided

into

five

. Eac

h cy

cle

last

ed 4

wk.

Two

cycl

es w

ere

give

n

Mor

talit

y N

ot a

sses

sed

Mor

bidi

ty O

vera

ll cl

inic

al r

espo

nse

was

st

atis

tical

ly s

igni

fican

tly b

ette

r w

ith P

DT

th

an c

hem

othe

rapy

(p

= 0.

001)

. No

patie

nts

achi

eved

CR

. The

PD

T g

roup

had

mor

e pa

tient

s w

ith a

sig

nific

ant

resp

onse

(i.e

. 50

% r

educ

tion

for

1 m

th, 1

2 vs

2).

In t

hose

pa

tient

s w

ith n

asal

obs

truc

tions

PD

T

prod

uced

mor

e ef

fect

ive

debu

lkin

g (p

= 0

.04)

(s

ubgr

oup

of 1

6 pa

tient

s, 7/

8 im

prov

ed v

s 2/

8)Q

oL a

nd r

etur

n to

nor

mal

act

ivit

y PD

T

grou

p ha

d a

stat

istic

ally

sig

nific

ant

grea

ter

impr

ovem

ent

in K

arno

fsky

sco

re (

p =

0.02

). PD

T g

roup

incr

ease

d fr

om 4

5 to

70

vs

chem

othe

rapy

gro

up in

crea

sed

from

40

to

50 AE

s All

PDT

rel

ated

adv

erse

effe

cts

and

reac

tions

wer

e to

lera

ble.

Tre

atm

ent

to

the

lary

ngop

hary

nx a

rea

resu

lted

in s

light

pa

in a

nd in

crea

sed

nasa

l cav

ity s

ecre

tion

– re

solv

ed in

3–5

dO

ne c

ase

of s

ever

e la

ryng

opha

rynx

sw

ellin

g an

d pa

in. R

esol

ved

with

tre

atm

ent

1 w

k la

ter,

may

be

rela

ted

to li

ght

expo

sure

One

cas

e of

pho

tose

nsiti

vity

der

mat

itis

afte

r ac

cide

ntal

exp

osur

e to

day

light

. Res

olve

d af

ter

trea

tmen

t, 1

wk

late

rO

ne c

ase

of s

kin

pigm

enta

tion,

no

trea

tmen

t re

quire

d

Aut

hors

’ con

clus

ions

PD

T is

effe

ctiv

e an

d sa

fe fo

r th

e tr

eatm

ent

of a

dvan

ced

nasa

l ph

aryn

geal

can

cer

and

the

man

agem

ent

of

nasa

l obs

truc

tion

Bri

ef s

tudy

app

rais

al T

his

smal

l pilo

t st

udy

prov

ided

no

deta

ils o

n ra

ndom

isat

ion,

bl

indi

ng a

nd o

ther

stu

dy q

ualit

y pa

ram

eter

s ra

isin

g qu

estio

ns a

bout

the

val

idity

of

the

resu

lts. T

reat

men

t de

tails

wer

e w

ell

desc

ribe

d. It

doe

s no

t ap

pear

to

have

led

on

to a

larg

er s

tudy

, tho

ugh

the

auth

ors

righ

tly

stat

ed t

hat

furt

her

inve

stig

atio

n w

as n

eede

d

Appendix 21

284



285

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Lou

katc

h et

al.

(199

5)14

2

Dat

a so

urce

Abs

trac

tC

ount

ry U

krai

neLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-R

CT

No.

of p

arti

cipa

nts

Tota

l: 14

5In

terv

entio

n: 4

2C

ompa

rato

r: 51

2nd

Com

para

tor:

52N

o. o

f rec

ruit

ing

cent

res

Not

sta

ted

Follo

w-u

p pe

riod

and

fr

eque

ncy

3 yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

Can

cer

and

His

tolo

gyPl

anoc

ellu

lar

canc

er o

f lar

ynx

Mai

n el

igib

ility

cri

teri

a N

ot

stat

edPa

tien

t ch

arac

teri

stic

s C

ance

r st

age:

Stag

e Ib

, 79;

sta

ge II

a, 66

. All

canc

ers

wer

e of

mid

dle

loca

lisat

ion.

N

o fu

rthe

r ch

arac

teri

stic

s w

ere

repo

rted

Con

com

itan

t tr

eatm

ent

Not

st

ated

Tria

l tre

atm

ents

Sur

gery

/in

trao

pera

tive

PDT

vs

Surg

ery/

intr

aope

rativ

e PD

T w

ithou

t la

ser

vs S

urge

ry a

lone

Inte

rven

tion

Cor

dect

omy

with

lo

cal a

naes

thet

ic, f

ollo

wed

by

adm

inis

trat

ion

of 0

.4%

sol

utio

n of

m

ethy

lene

blu

e ph

otos

ensi

tiser

. A

He-

Ne

lase

r of

wav

elen

gth

633

nm e

mitt

ing

at 2

5–30

mW

/cm

2 fo

r 5

min

was

use

d. F

urth

er P

DT

pa

ram

eter

s w

ere

not

repo

rted

Com

para

tor

Cor

dect

omy

with

lo

cal a

naes

thet

ic fo

llow

ed b

y la

ser

only

(sa

me

para

met

ers

as P

DT

gr

oup)

2nd

com

para

tor

Cor

dect

omy

with

loca

l ana

esth

etic

onl

y

Mor

bidi

ty A

fter

3 yr

the

re w

as

recu

rren

ce in

one

pat

ient

(2%

) an

d no

cas

es o

f met

asta

sis

in t

he P

DT

gr

oup,

four

cas

es o

f rec

urre

nce

(8%

) in

the

lase

r gr

oup

and

one

case

of m

etas

tasi

s, an

d fiv

e ca

ses

of r

ecur

renc

e (1

0%)

and

two

case

s of

met

asta

sis

in t

he S

urge

ry-a

lone

gr

oup

QoL

and

ret

urn

to n

orm

al

acti

vity

Not

ass

esse

dA

Es

PDT

gro

up: S

ome

patie

nts

had

oede

ma

of la

ryng

eal m

ucou

s m

embr

ane

and

one

patie

nt h

ad a

sm

all h

aem

orrh

age.

Sur

gery

-alo

ne

grou

p: O

ne p

atie

nt h

ad a

sm

all

haem

orrh

age.

Bot

h ha

emor

rhag

es

wer

e m

anag

ed b

y co

nser

vativ

e tr

eatm

ent

Aut

hors

’ con

clus

ions

In

trao

pera

tive

PDT

in p

atie

nts

with

sta

ges

I and

II la

ryng

eal c

ance

r co

uld

be e

ffect

ive

for

prev

entin

g re

curr

ence

and

met

asta

sis

of

tum

ours

Bri

ef s

tudy

app

rais

al T

his

stud

y us

ed c

ompa

rato

r tr

eatm

ents

suc

h th

at t

he r

esul

ts o

ffer

little

insi

ght

to h

ow P

DT

com

pare

s to

oth

er

trea

tmen

ts a

djun

ctiv

e to

sur

gery

. T

he s

tudy

als

o ex

amin

ed fe

w

outc

omes

and

the

re w

as s

pars

e re

port

ing

of m

etho

ds, p

atie

nt

char

acte

rist

ics

and

resu

lts

Appendix 21

286 Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Lo

ukat

ch e

t al.

(199

6)14

3

Dat

a so

urce

A

bstr

act

Cou

ntry

U

krai

neLa

ngua

ge

Engl

ish

Stud

y de

sign

N

on-R

CT

No.

of

part

icip

ants

Tota

l: 49

Inte

rven

tion:

19

Com

para

tor:

152n

d C

ompa

rato

r: 15

No.

of

recr

uiti

ng

cent

res

Not

st

ated

Follo

w-u

p pe

riod

and

fr

eque

ncy

3 yr

Trea

tmen

t in

tent

ion

Cur

ativ

eTy

pe(s

) of

can

cer

and

hist

olog

y SC

C in

la

ryng

eal p

art

of p

hary

nxM

ain

elig

ibili

ty c

rite

ria

Not

sta

ted

Pati

ent

char

acte

rist

ics

Can

cer

stag

e: St

age

II, 2

5;

stag

es II

I and

IV, 2

4N

o fu

rthe

r ch

arac

teri

stic

s w

ere

repo

rted

Con

com

itan

t tr

eatm

ent P

hary

ngot

omy

for

stag

e II

patie

nts

and

hem

ilary

ngop

hary

ngot

omy

for

stag

e III

–IV

pat

ient

s w

ith g

ener

al a

naes

thet

ic.

Post

oper

ativ

e co

balt

ther

apy

(45-

Gy

dose

). N

eck

diss

ectio

n op

erat

ion

for

patie

nts

deve

lopi

ng

met

asta

ses

Tria

l tre

atm

ents

PD

T v

s PD

T w

ith L

aser

onl

y vs

PD

T

with

Pho

tose

nsiti

ser

only

Inte

rven

tion

PD

T w

ith

met

hyle

ne b

lue

(inje

cted

lo

cally

) as

pho

tose

nsiti

ser,

follo

wed

by

633-

nm li

ght

for

5 m

in fr

om a

He-

Ne

lase

r at

25–

30 m

W/c

m2 .

Furt

her

PDT

par

amet

ers

wer

e no

t re

port

edC

ompa

rato

r As

for

PDT

gro

up b

ut w

ithou

t ph

otos

ensi

tiser

2nd

com

para

tor

As

for

PDT

gro

up b

ut w

ithou

t la

ser

Mor

talit

y2-

yr s

urviv

alPD

T g

roup

, 100

% (

stag

e II)

, 89%

(st

ages

III a

nd IV

); La

ser-

only

gro

up: 8

8% (

stag

e II)

, 86%

(st

ages

III a

nd

IV);

Phot

osen

sitis

er-o

nly

grou

p: 7

1% (

stag

e II)

, 75%

(s

tage

s III

and

IV)

3-yr

sur

vival

PDT

gro

up, 1

00%

(st

age

II), 6

7% (

stag

es II

I and

IV

); La

ser-

only

gro

up: 4

3% (

stag

es II

I and

IV);

Phot

osen

sitis

er-o

nly

grou

p: 3

8% (

stag

es II

I and

IV).

Stag

e II

resu

lts n

ot a

vaila

ble

for

last

tw

o gr

oups

Mor

bidi

ty A

fter

1 ye

ar, n

one

of t

he s

tage

II p

atie

nts

had

recu

rren

ce o

r m

etas

tasi

s. Fo

r st

age

III a

nd s

tage

IV

pat

ient

s, th

ere

was

rec

urre

nce

in o

ne p

atie

nt

(11%

) in

the

PD

T g

roup

, tw

o pa

tient

s (2

9%)

in t

he

Lase

r-on

ly g

roup

and

tw

o pa

tient

s (2

5%)

in t

he

Phot

osen

sitis

er-o

nly

grou

pA

fter

2 yr

, in

the

PDT

gro

up: r

ecur

renc

e in

10%

(st

age

II) a

nd 1

1% (

stag

es II

I and

IV);

in t

he L

aser

-onl

y gr

oup:

re

curr

ence

in 2

5% (

stag

e II)

, and

43%

(st

ages

III a

nd

IV);

in t

he P

hoto

sens

itise

r-on

ly g

roup

: rec

urre

nce

in

43%

(st

age

II), a

nd 5

0% (

stag

es II

I and

IV)

Dur

ing

the

3-yr

per

iod

ther

e w

ere

regi

onal

m

etas

tase

s in

0%

of P

DT

gro

up (

stag

e II)

, 11%

in

PDT

(st

ages

III a

nd IV

), 13

% o

f Las

er-o

nly

grou

p (s

tage

II),

14%

Las

er-o

nly

(sta

ges

III a

nd IV

), 14

%

Phot

osen

sitis

er-o

nly

(sta

ge II

), 25

% P

hoto

sens

itise

r-on

ly (

stag

es II

I and

IV)

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

ass

esse

dA

Es

No

com

plic

atio

ns p

osto

pera

tivel

y, ex

cept

som

e pa

tient

s ha

d m

inor

oed

ema

of t

he p

hary

ngea

l muc

ous

mem

bran

e (r

esol

ved

with

in 5

d)

Aut

hors

’ con

clus

ions

PD

T a

ppea

rs

effe

ctiv

e in

tre

atin

g tu

mou

rs o

f the

pha

rynx

, bu

t la

rger

stu

dies

with

long

er F

U a

re n

eede

dB

rief

stu

dy a

ppra

isal

Thi

s st

udy

used

co

mpa

rato

r tr

eatm

ents

suc

h th

at t

he r

esul

ts

offe

r lit

tle in

sigh

t to

how

PD

T c

ompa

res

with

ot

her

trea

tmen

ts a

djun

ctiv

e to

sur

gery

. The

re

was

spa

rse

repo

rtin

g of

met

hods

and

pat

ient

ch

arac

teri

stic

s, an

d re

sults

wer

e so

met

imes

in

com

plet

e



287

Stud

y de

tails

Popu

lati

on d

etai

lsTr

eatm

ent

deta

ilsR

esul

tsIn

terp

reta

tion

Aut

hors

Vak

ulov

skay

a (2

007)

144

Link

ed p

ublic

atio

ns21

3

Dat

a so

urce

Abs

trac

tC

ount

ry R

ussi

aLa

ngua

ge E

nglis

hSt

udy

desi

gn N

on-R

CT

No.

of p

arti

cipa

nts

Tota

l: 52

Inte

rven

tion:

Not

sta

ted

Com

para

tor:

Not

sta

ted

No.

of r

ecru

itin

g ce

ntre

s N

ot s

tate

dFo

llow

-up

peri

od a

nd

freq

uenc

y N

ot s

tate

d (a

lthou

gh s

urvi

val m

onito

red

up t

o 3

yr)

Trea

tmen

t in

tent

ion

Not

sta

ted

Type

(s)

of c

ance

r an

d hi

stol

ogy

Ora

l can

cer

(SC

C)

Mai

n el

igib

ility

cr

iter

ia N

ot s

tate

dPa

tien

t ch

arac

teri

stic

s Pa

tient

s ha

d tu

mou

rs in

the

ora

l ca

vity

, oro

phar

ynx

or

low

er li

p. Fu

rthe

r pa

tient

ch

arac

teri

stic

s w

ere

not

repo

rted

Con

com

itan

t tr

eatm

ent

Not

sta

ted

Tria

l tre

atm

ents

PD

T w

ith

Phot

osen

se v

s PD

T w

ith R

adac

hlor

inIn

terv

enti

on In

trav

enou

s Ph

otos

ense

(0

.4–0

.8 m

g/kg

) w

ith s

emic

ondu

ctiv

e la

sers

(M

ilon

660,

Bio

spec

672

) at

a

tota

l lig

ht d

ose

of 4

00–6

00 J/

cm2 .

Furt

her

PDT

par

amet

ers

wer

e no

t re

port

edC

ompa

rato

r In

trav

enou

s R

adac

hlor

in

(1.2

–2.4

mg/

kg)

with

sem

icon

duct

ive

lase

rs (

Milo

n 66

0, B

iosp

ec 6

72)

at

a to

tal l

ight

dos

e of

200

–300

J/cm

2 . Fu

rthe

r PD

T p

aram

eter

s w

ere

not

repo

rted

Mor

talit

y N

ot b

roke

n do

wn

by

trea

tmen

t gr

oup

Mor

bidi

ty F

or P

hoto

sens

e a

CR

was

se

en in

57%

of p

atie

nts

and

a PR

in

38%

. For

Rad

achl

orin

a C

R w

as s

een

in

20%

and

a P

R in

50%

QoL

and

ret

urn

to n

orm

al a

ctiv

ity

Not

ass

esse

dA

Es

Mai

n si

de e

ffect

with

Pho

tose

nse

was

incr

ease

d sk

in s

ensi

tivity

to

dire

ct s

unlig

ht, w

ith R

adac

hlor

in s

kin

sens

itivi

ty is

sho

rt t

erm

. No

furt

her

deta

ils w

ere

give

n

Aut

hors

’ con

clus

ions

Our

ex

peri

ence

sho

wed

pro

noun

ced

effic

acy

of P

DT

with

hig

h fu

nctio

nal

and

cosm

etic

effe

cts

for

oral

can

cer

of

diffe

rent

loca

lisat

ions

Bri

ef s

tudy

app

rais

al M

inim

al

repo

rtin

g of

bot

h m

etho

ds a

nd r

esul

ts

mea

ns li

ttle

can

be

dedu

ced

from

thi

s co

nfer

ence

abs

trac

t

NETSCC, Health Technology Assessment Alpha HouseUniversity of Southampton Science ParkSouthampton SO16 7NS, UKEmail: [email protected] ISSN 1366-5278

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Appendix 5 Appendices Appendix 6

Documents

Transcript of Appendix 5 Appendices Appendix 6