Hyperthermiahyperthermia to treatment of primary or recurrent breast cancers. Hyperthermia when...
Transcript of Hyperthermiahyperthermia to treatment of primary or recurrent breast cancers. Hyperthermia when...
HYPERTHERMIA
Jackson Farrow 22 September 2010
the medical benefit of making someone hot under the collar
HYPERTHERMIA – History
► Spontaneous remission following febrile episodes?
Coley 1893 - erysipelas
Westmark 1898 - hot baths
► 1st International Congress on Hyperthermic Oncology held in Washington in 1975
Initial Results less than expected
►Failed to show evidence of beneficial effect from Hyperthermia
Subsequent review found that inadequate equipment was to blame
Preclinical findings unreliable in predicting in vivo results
► Interest resurgence due to improved technology producing promising results in new studies
HYPERTHERMIA – Mechanisms of Action
►Tumor Selective Effects? NO intrinsic difference between hyperthermia
sensitivity of normal and tumor cells
►Molecular Effects Cell membrane, Cytoskeleton Intracellular Proteins Nucleic Acids
►“Heat Shock Response” (aka Thermotolerance) Protein synthesis helps prevent against
inappropriate interaction by denatured proteins
►Cell Cycle dependent effectiveness Greatest thermosensitivity during S & M phases
HYPERTHERMIA – Mechanisms of Action
►Augmentation of Blood Flow Increased flow at moderate temperatures
► 40 - 42° C
Decreased flow above 42° C
►Solid Tumor Architecture difference in cellular organization results in a
selective advantage in targeting cancer cells chaotic growth that outstrips blood supply
► regional hypoxemia, acidosis►increased sensitivity to diminished blood flow
HYPERTHERMIA - Methods
► Local External Intraluminal/Endocavitary Interstitial
► Regional Deep Tissue Regional Perfusion Continuous Hyperthermic Peritoneal Perfusion
► Whole Body Temperature limitation of 41.8-42 C
►Thermal Conduction (surface heating) heated water suits, heated blankets, hot wax baths
►Extracorporeal Induction►Radiant/Electromagnetic Induction
von Ardenne's systemic Cancer Multistep Therapy
►WBH, hyperglycemia and hyperoxemia
HYPERTHERMIA - Thermal Radiosensitization► Radiotherapy limitations
decreased efficacy in hypoxemic environments► Oxygen presence increases free radical formation
ineffective against cells during S phase
► Adjunctive Benefit of Hyperthermia Protein denaturation complements DNA damage from Radiotherapy
► Diminished ability to repair radiation-induced damage
Increase in Radiotherapy’s capability of causing damage► Increase in blood flow allows for increase in Oxygen radical formation
S phase cell kill
► Cytotoxicity enhancement: Super Additive & Complementary Effect Enhancement influenced by proximity of administration
► Greatest benefit noted when modalities are applied synchronously
► “probably the most potent radiosensitiser known to date” van der Zee J, 2002
HYPERTHERMIA – Proven Benefits► Majority of information involves trials examining Hyperthermia’s
potential benefit in treating small, superficially located tumors Head/Neck
► Advanced nodal metastasis, Cervical Nodes Valdagni et al. showed increased complete response rates (82 vs 37%; p < .015) and an
improvement in 5-year survival rates (53 vs 0%; p = .02) in patients who received 2-6 Hyperthermia treatments in addition to full dose radiation.
Melanoma► Cutaneous, subcutaneous and peripheral lymph node metastasis
Randomized Phase III trial showed significantly higher 2 yr local-regional control rate among tumors having received adjuvant hyperthermia (46 vs 28%; p = .008) without any increase in acute or late reactions.
Breast► Local, regional recurrences
Collaborative phase III involving MRC/ESHO/PMH demonstrated examined the addition of hyperthermia to treatment of primary or recurrent breast cancers. Hyperthermia when combined with radiotherapy showed an improvement in complete response rate (59 vs 41%), lower relapse rate among complete responders at 2 yrs (17 vs 28%) and no increase in side effects.
► Chest wall metastasis, Superficial Lesions Randomized trial by RTOG involving lesions less than 3 cm showed an improvement in complete
response rates for radiation plus hyperthermia (55 vs 33%; p < .62). Upon further analysis of all superficial lesions smaller than 3 cm a statistically significant improvement in probability of local control at 12 months was demonstrated (80 vs 15%; p < .02).
► Good local control rates have been documented for superficial metastases of multiple tumors including Hodgkin’s, Merkel cell tumors, adenoid cystic carcinomas and penile metastases from prostatic cancer
HYPERTHERMIA – Head/Neck Adjunct
Study Type Complete Response Rate p value
Radiotherapy Radiotherapy
+Hyperthermia
Arcangeli et al.(1985)
Nonrandomized 42 79 < .05
Valdagni et al.(1986)
Historical Controls
35 68 .034
Valdagni et al.(1988)
Prospectively Randomized
37 82 .015
HYPERTHERMIA – Head/Neck Adjunct
Study Fields Local Control Rate (%) Time Scale
Radiotherapy Radiotherapy+
Hyperthermia
Arcangeli et al.(1984)
81 14 58 24 month
Valdagni(1994)
36 24 69 60 month
HYPERTHERMIA – Melanoma Adjunct
Study Type Complete Response Rate p value
Radiotherapy Radiotherapy+
Hyperthermia
Kim et al.(1982)
Nonrandomized, Matched Pair and Paired Lesions
42 79 < .05
Overgaard Matched Pair 20 73 < .05
Overgaard et al. Nonrandomized and Matched Pair
59 91 < .05
Gonzalez et al.(1986)
Nonrandomized Controls
50 83 –
Emani et al. (1988)
Nonrandomized Controls
24 59 .0003
HYPERTHERMIA – Melanoma Adjunct
Study Type Local Control Rate (%) Time Scale
Radiotherapy Radiotherapy+
Hyperthermia
Gonzalez et al.(1986)
24 17 83 < 36 mo
Overgaard(1987)
67 56 86 18 months
HYPERTHERMIA - Breast Adjunct
Study Type Complete Response Rate p value
Radiotherapy Radiotherapy+
Hyperthermia
Steves et al.(1986)
Matched Pair 31 45 < .05
Perez et al.(1989)
Randomized 33 55 .062
Van ser zee et al. (1988)
Nonrandomized Controls
27 82 –
RTOG Randomized 33% 55% < .62
HYPERTHERMIA - Breast AdjunctStudy Fields Local Control Rate (%) Time
ScaleRadiotherapy Radiotherapy
+Hyperthermia
RTOG 15 80 12 months
Perez et al.(1986)
70 31 61 6 months
Lindholm et al.(1987)
34 30 53 12 months
cont’d 34 30 45 24 months
TUMOR TREATMENT PATIENTS END POINT EFFECT w/ HT EFFECT w/o
Lymph nodes of Head/Neck Tumors
RT 41
CR rate 83% 41%
5-year local control 69% 24%
5-year survival 53% 0%
Melanoma RT 70
CR rate 62% 35%
2-year local control 46% 28%
Breast RT 306 CR rate 59% 41%
Glioblastoma multiforme Surgery, RT 68Median survival 85 weeks 76 weeks
2-year survival 31% 15%
Bladder, Cervix, Rectum RT 298CR rate 55% 39%
3-year survival 30% 24%
BladderRT, surgery 102 3-year survival 94% 67%
CT 52 pCR 66% 22%
CervixRT 40 CR 85% 50%
RT 64 CR 55% 31%
Various RT 92 Response 82% 63%
Lung CT 44 Response 68% 36%
Vulva/vagina CT 65 Response 59% 19%
Esophagus
RT, CT 66 CR 25% 6%
RT, CT, surgery 53 Palliation 70% 8%
RT 125 3-year survival 42% 24%
RectumRT, surgery 115 5-year survival 36% 7%
RT, surgery 122 pCR 23% 5%
van der Zee J. Heating the Patient: a promising approach?
Summary of randomized trials showing significantly better results following addition of Hyperthermia
HYPERTHERMIA - Thermal
Chemosensitization
► Adjunctive Benefit of Hyperthermia Increased blood flow allows for increased Drug concentrations Drug activity enhancement with increased temperature
►Nitrosureas, Cisplatin, Bleomycin, Doxorubicin► Resistance – Overcome or Induce?
Platinum-based compounds demonstrate increased efficacy when given in temperatures > 42° C
MDR induction► heat dependant inactivation of Topoisomerase II
► Molecular Effects Changes in fluid and electrolyte balance in addition to pH
changes alter the solubility and volume distribution of the chemotherapeutic agents
► LIMITED INFORMATION Increased Preclinical Data is needed to help direct Clinical Study
HYPERTHERMIA – Limitations ►Dosing
Difficult to produce reliable uniformity
►Different tissues absorb heat at different rates, have different levels of sensitivity
Nervous tissue (central > peripheral)
►Side effects electrolyte abnormalities decreased platelet count coagulation prolongation LFTs elevation (mild liver necrosis) CPK elevation (mild muscle necrosis) Increased CO (increased pulse rate)
►risk for arrhythmia, pulmonary edema, seizures
HYPERTHERMIA - References
►Further Research Needed
Randomized, Phase III trials
► WBH vs Local/Regional
► Proven Adjunct Benefit
Hyperthermic vs Normothermic
►Improvement in Temperature Distributions
Absolute Value
Homogeneity
HYPERTHERMIA - References
1) Luk KH, Hulse RM, Phillips TL. Hyperthermia in Cancer Therapy. West J Med 132: 179-185, Mar 1980
2) van der Zee J. Heating the patient: a promising approach? Annals Onc 13: 1173-1184, 2002
3) Hildebrandt B, Wust P, Ahlers O et al. The Cellular and Molecular Basis of Hyperthermia. Critical Reviews in Oncology/Hematology 43: 33-56, 2002.
4) Kapp DS, Hahn GM, Carlson RW. Principles of Hyperthermia. Cancer Medicine 6, 2000.