a study of the Dutch Colorectal Cancer Group (DCCG)
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Transcript of a study of the Dutch Colorectal Cancer Group (DCCG)
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Randomized study of sequential versus combination chemotherapy with
capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer
a study of the Dutch Colorectal Cancer Group (DCCG)
CJA Punt, M Koopman, J Douma, J Wals, AH HonkoopFLG Erdkamp, RS de Jong, CJ Rodenburg,
L Mol, NF Antonini
ASCO 2007
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Effective cytotoxic drugs in advanced CRC
• Effective cytotoxic drugs in CRC: fluoropyrimidines, irinotecan, oxaliplatin
• Median overall survival is increased when these drugs are made available to patients with advanced CRC1
• No comparative data on sequential versus combined use of these drugs
1Grothey et al. J Clin Oncol 2004
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Background
• Salvage treatments have not been a prospective part of phase III studies in 1st line treatment of colorectal cancer
• Results on overall survival of these studies may be biased by imbalances in salvage treatments1
• UK FOCUS study2 only evaluates sequential versus combined use of either irinotecan or oxaliplatin with 5FU (amended during accrual period) 1 Punt Ann Oncol 2004
2 Seymour et al. ASCO 2005
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DCCG CAIRO study
• Primary objective: to determine whether 1st line combination treatment is superior in terms of overall survival compared to the sequential use of the same drugs
• This is the first phase III study in advanced colorectal cancer patients that prospectively evaluates sequential versus combination treatment when all three cytotoxic drugs with known efficacy are made available
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CAIRO study CKTO 2002-07
Arm A Arm B
Randomize
capecitabine
capecitabine +oxaliplatin
irinotecancapecitabine +
oxaliplatin
capecitabine +irinotecan1st line
2nd line
3rd line
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Dose/schedule of drugsall cycles given 3 weekly
• Capecitabine monotherapy: 1250 mg/m2 b.i.d. day 1-14
• Irinotecan monotherapy: 350 mg/m2 day 1
• CAPIRI1: capecitabine 1000 mg/m2 b.i.d. day 1-14 + irinotecan 250 mg/m2 day 1
• CAPOX2: capecitabine 1000 mg/m2 b.i.d. day 1-14 + oxaliplatin 130 mg/m2 day 1
1 Rea et al. Ann Oncol 20052 Borner et al. J Clin Oncol 2002
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Endpoints, statistics
Primary endpoint:
• overall survival
Secondary endpoints:
• progression-free survival
• response rate
• safety, quality of life
Statistics
• Designed to detect a difference in median overall survival of 3.5 months with 80% power, =0.05, 2- tailed test
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Inclusion criteria
• Histologically proven colorectal cancer
• Advanced disease not amenable to curative surgery
• Measurable or evaluable disease parameters (serum CEA as the only parameter for disease activity was not allowed)
• No previous systemic treatment for advanced disease
• Previous adjuvant chemotherapy was allowed provided that the last administration was given > 6 months prior to randomisation
• Age 18 years
• WHO performance score 0-2
• Adequate hepatic, bone marrow, and renal function
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Exclusion criteria
• Serious concomitant disease preventing the safe administration of chemotherapy or likely to interfere with the study assessments
• Other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix, and squamous or basal cell carcinoma of the skin
• Pregnancy or lactation; patients (M/F) with reproductive potential not implementing adequate contraceptives measures
• Central nervous system metastases
• Serious active infections
• Inflammatory bowel disease or other diseases associated with chronic diarrhoea
• Previous extensive irradiation of the pelvis or abdomen
• Concomitant (or within 4 weeks before randomization) administration of any other experimental drug
• Concurrent treatment with any other anti-cancer therapy
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Evaluation schedule
• Toxicity was evaluated at the start of each cycle (every 3 weeks)
• Tumor response was evaluated every 9 weeks (every 3 cycles)
• Central review of all patient files when death occurred < 30 days within the last administration of study drugs with death not directly related to disease progression
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Accrual
• 820 patients were randomized in 75 participating Dutch hospitals within 2 years (jan. ’03 - dec. ’04)
• Ineligible patients N=17
• Eligible patients N=803
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Trial profile
Arm A Arm B
Randomize
capecitabineN=397
capecitabine +oxaliplatin
N=143 (36%)
irinotecanN=251 (62%)
capecitabine +oxaliplatin
N=213 (53%)
capecitabine +irinotecan
N=398
1st line
2nd line
3rd line
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Baseline characteristics
Number of eligible pts Sequential (N=401) Combination (N=402)
Median age 64.0 63.0
Gender
Male
Female
63%
37%
63%
37%
Performance status
PS0/1
PS2
95%
5%
96%
4%
Predominant localisation of metastases
Liver
Extrahepatic
Unknown
69%
29%
2%
71%
29%
<1%
LDH at randomization
Normal
Abnormal
64%
36%
64%
36%
Prior adjuvant therapy
Yes
No
14%
86%
14%
86%
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Median overall survival
Combination treatment 17.4 months (15.2-19.2)
----------- Sequential treatment 16.3 months (14.3-18.2)
p = 0.33
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Efficacy results
Sequential
N=401
Combination
N=402
p value
Median overall survival (months) 16.3 17.4 0.33
Hazard ratio for death 1.08
One-year survival rate (%) 64 67
Median PFS (months) 1st line 5.8 7.8 0.0002
Overall response rate (CR + PR)*
1st line
2nd line
3rd line
77 (20%)
23 (10%)
5 (4%)
139 (41%)
24 (12%)
-
Disease control rate (CR + PR + SD)*
1st line
2nd line
3rd line
280 (74%)
162 (71%)
72 (57%)
297 (87%)
121 (63%)
* Percentages are based on patients evaluable for response
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Grade 3-4 toxicity over all lines
Toxicity
SequentialN = 397
Combination N = 398 p value
Hand-foot syndrome 13% 7% 0.004
Diarrhea 23% 27% 0.23
Nausea 8% 9% 0.45
Vomiting 7% 10% 0.16
Stomatitis 3% 2% 0.15
Thrombosis/embolism 9% 10% 0.48
Febrile neutropenia 5% 7% 0.18
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Mortality
SequentialN = 401
CombinationN = 402
60-day mortality 3.0% 4.5%
Death probably related to treatment *
sepsis **
diarrhea
neutropenic fever
8
6
1
1
3
2
1
0
Sudden death *** 1 5
* In 9/11 patients major protocol violations were detected
** In 7/8 patients neutropenia was present
*** In 4/6 patients cardiopulmonary risk factors were present
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Grade 3-4 toxicities in first line
Toxicity
Arm Acapecitabine
N = 397
Arm B capiri
N = 398p value
Hand-foot syndrome 12% 6% 0.002
Diarrhea 11% 26% <0.001
Nausea 4% 10% 0.004
Vomiting 3% 9% 0.0002
Stomatitis <1% 2% 0.16
Thrombosis/embolism * 7% 10% 0.20
Febrile neutropenia <1% 7% <0.001
* All grades
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Quality of life
• Participation to this part of the study was proposed to the first 620 patients entered in the study (QLQ-C30 questionnaire of the EORTC)
• 403 patients were evaluable for quality of life
• Quality of life scores were comparable between the two arms, except for diarrhoea which was reported more frequently in combination treatment
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Conclusions
• Combination treatment is not superior in terms of efficacy to sequential treatment in patients with advanced colorectal cancer
• Our results on median overall survival for sequential treatment are the highest reported when a fluoropyrimidine is administered as monotherapy in 1st line
• Sequential treatment is a useful alternative for combination treatment
• Our results may be useful for strategies in which chemotherapy is combined with targeted agents
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DCCG CAIRO study acknowledgements
Investigators:C.Rodenburg, Amersfoort; J.van der Hoeven, Amstelveen; D.Richel, M.Schweitzer, B.de Valk, M.Soesan, Amsterdam; J.Douma, Arnhem; P.Nieboer,Assen; F.Valster, Bergen op Zoom; R.Rietbroek, Beverwijk; G.Ras, O.Loosveld, Breda; D.Kehrer, Capelle a/d IJssel; M.Bos, Delft; Z.Erjavec, Delfzijl; H.Sinnige, C.Knibbeler, Den Bosch; W.Van Deijk, F.Jeurissen, H.Sleeboom, Den Haag; H.de Jong, Den Helder; A.Imholz, Deventer; E.Muller, Doetinchem; H.van Kamp, Drachten; E.Balk, Ede; G.Creemers, M.Dercksen, Eindhoven; M.Legdeur, Enschede; H.van Halteren, Goes; A.van der Torren, Gouda; G.Hospers, R.de Jong, Groningen; P.Zoon, Harderwijk; J.Wals, Heerlen; V.Derleyn, Helmond; C.Gerrits, Hengelo; C. de Swart, Hoofddorp; J.Haasjes, Hoogeveen; W.Meijer, Hoorn; C.de Swart, Haarlem; M.Polee, Leeuwarden; M.Tesselaar, Leiden; G.Jonkers, Leiderdorp; R.Brouwer, Leidschendam; R.Jansen, Maastricht; P.de Jong, Nieuwegein; C.Punt, H.Oosten, Nijmegen; J.van Wissen, Oosterhout; M.Kuper, Oss; M.den Boer, Roermond; A.Planting, A.vander Gaast, J.Stouthard, F.de Jongh, T.Kok, Rotterdam; J.Braun, Schiedam; F.Erdkamp, Sittard; G.Veldhuis, Sneek; C.Geers, Spijkenisse; P.van der Werf, Stadskanaal; A.van Reisen, Terneuzen; H.Roerdink, Tilburg; D.ten Bokkel Huinink, R.Oltmans, S.van der Vegt, E.Voest, Utrecht; L.van Hulsteijn, Veghel; G.Vreugdenhil, Veldhoven; M.Werter, Venlo; J.Ruit, Vlaardingen; L.Kerkhofs, Vlissingen; W.Jaspers, Winschoten; P.Schiphorst, Winterswijk; J.Holleman, Woerden; A.van Bochove, Zaandam; O.van Dobbenburgh, Zutphen; J.de Graaf, A.Honkoop, Zwolle. Statistician: O.Dalesio, Amsterdam Central Datamanagement: J.Akkermans, F.van Leeuwen, IKO NijmegenIndependent Data Monitoring Committee: P.De Mulder, D.Sleijfer, G.Stoter