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a study of the Dutch Colorectal Cancer Group (DCCG)

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 Honkoop FLG Erdkamp, RS de Jong, CJ Rodenburg,

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a study of the Dutch Colorectal Cancer Group (DCCG)

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  1. 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 Honkoop FLG Erdkamp, RS de Jong, CJ Rodenburg, L Mol, NF Antonini ASCO 2007

  2. 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

  3. 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

  4. 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

  5. Randomize Arm A Arm B capecitabine capecitabine + irinotecan 1st line irinotecan capecitabine + oxaliplatin 2nd line capecitabine + oxaliplatin 3rd line CAIRO studyCKTO 2002-07

  6. 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 1Rea et al. Ann Oncol 2005 2 Borner et al. J Clin Oncol 2002

  7. 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 with80% power, =0.05, 2- tailed test

  8. 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

  9. 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

  10. 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

  11. 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

  12. Randomize Arm B Arm A capecitabine N=397 capecitabine + irinotecan N=398 1st line irinotecan N=251 (62%) capecitabine + oxaliplatin N=213 (53%) 2nd line capecitabine + oxaliplatin N=143 (36%) 3rd line Trial profile

  13. Baseline characteristics

  14. Combination treatment 17.4 months (15.2-19.2) ----------- Sequential treatment 16.3 months (14.3-18.2) Median overall survival p = 0.33

  15. Efficacy results

  16. Grade 3-4 toxicity over all lines

  17. Grade 3-4 toxicities in first line

  18. 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

  19. 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

  20. 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 Nijmegen Independent Data Monitoring Committee: P.De Mulder, D.Sleijfer, G.Stoter

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