Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial.
BACKGROUND
The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer.


METHODS
We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000.


RESULTS
17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16.3 (95% CI 14.3-18.1) months for sequential treatment and 17.4 (15.2-19.2) months for combination treatment (p=0.3281). The hazard ratio for combination versus sequential treatment was 0.92 (95% CI 0.79-1.08; p=0.3281). The frequency of grade 3-4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13%vs 7%; p=0.004).


CONCLUSIONS
Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cancer.
Koopman
Miriam
M
Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
Antonini
Ninja F
NF
Netherlands Cancer Institute (NKI), Biometrics Department, Amsterdam, Netherlands.
Douma
Joep
J
Rijnstate Hospital, Arnhem, Netherlands.
Wals
Jaap
J
Atrium Medical Centre, Heerlen, Netherlands.
Honkoop
Aafke H
AH
Isala Hospital, Zwolle, Netherlands.
Erdkamp
Frans Lg
FL
Maasland Hospital, Sittard, Netherlands.
de Jong
Robert S
RS
Martini Hospital, Groningen, Netherlands.
Rodenburg
Cees J
CJ
Meander Medical Centre, Amersfoort, Netherlands.
Vreugdenhil
Gerard
G
Maxima Medical Centre, Veldhoven, Netherlands.
Loosveld
Olaf Jl
OJ
Amphia Hospital, Breda, Netherlands.
van Bochove
Aart
A
Zaans Medical Centre, Zaandam, Netherlands.
Sinnige
Harm Am
HA
Jeroen Bosch Hospital, Den Bosch, Netherlands.
Creemers
Geert-Jan M
GM
Catharina Hospital, Eindhoven, Netherlands.
Tesselaar
Margot Et
ME
Leiden University Medical Centre, Leiden, Netherlands.
Slee
Peter H Th J
PHTJ
St Antonius Hospital, Nieuwegein, Netherlands.
Werter
Marjon Jbp
MJ
Viecuri Hospital, Venlo, Netherlands.
Mol
Linda
L
Comprehensive Cancer Centre East (IKO), Nijmegen.
Dalesio
Otilia
O
Netherlands Cancer Institute (NKI), Biometrics Department, Amsterdam, Netherlands.
Punt
Cornelis Ja
CJ
Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. Electronic address: c.punt@onco.umcn.nl.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D015996:Survival Rate
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin