Miriam Koopman1, Ninja F Antonini2, Joep Douma3, Jaap Wals4, Aafke H Honkoop5, Frans Lg Erdkamp6, Robert S de Jong7, Cees J Rodenburg8, Gerard Vreugdenhil9, Olaf Jl Loosveld10, Aart van Bochove11, Harm Am Sinnige12, Geert-Jan M Creemers13, Margot Et Tesselaar14, Peter H Th J Slee15, Marjon Jbp Werter16, Linda Mol17, Otilia Dalesio2, Cornelis Ja Punt18. 1. Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. 2. Netherlands Cancer Institute (NKI), Biometrics Department, Amsterdam, Netherlands. 3. Rijnstate Hospital, Arnhem, Netherlands. 4. Atrium Medical Centre, Heerlen, Netherlands. 5. Isala Hospital, Zwolle, Netherlands. 6. Maasland Hospital, Sittard, Netherlands. 7. Martini Hospital, Groningen, Netherlands. 8. Meander Medical Centre, Amersfoort, Netherlands. 9. Maxima Medical Centre, Veldhoven, Netherlands. 10. Amphia Hospital, Breda, Netherlands. 11. Zaans Medical Centre, Zaandam, Netherlands. 12. Jeroen Bosch Hospital, Den Bosch, Netherlands. 13. Catharina Hospital, Eindhoven, Netherlands. 14. Leiden University Medical Centre, Leiden, Netherlands. 15. St Antonius Hospital, Nieuwegein, Netherlands. 16. Viecuri Hospital, Venlo, Netherlands. 17. Comprehensive Cancer Centre East (IKO), Nijmegen. 18. Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. Electronic address: c.punt@onco.umcn.nl.
Abstract
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 eitherfirst-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. FINDINGS: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). INTERPRETATION: 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.
RCT Entities:
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. FINDINGS: 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). INTERPRETATION: 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.
Authors: Karin Nielsen; Aukje A J M van Tilborg; Martijn R Meijerink; Matessa O Macintosh; Babs M Zonderhuis; Elly S M de Lange; Emile F I Comans; Sybren Meijer; M Petrousjka van den Tol Journal: World J Surg Date: 2013-06 Impact factor: 3.352