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
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
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
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
CAIRO study CKTO 2002-07
Arm A Arm B
Randomize
capecitabine
capecitabine +oxaliplatin
irinotecancapecitabine +
oxaliplatin
capecitabine +irinotecan1st line
2nd line
3rd line
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
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
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
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
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
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
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
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%
Median overall survival
Combination treatment 17.4 months (15.2-19.2)
----------- Sequential treatment 16.3 months (14.3-18.2)
p = 0.33
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
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
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
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
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
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
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