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BACKGROUND: In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects. We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer, who were regarded as not potentially curable irrespective of response. METHODS: We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. 2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control group) was single-agent fluorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent irinotecan. Strategy B was fluorouracil until failure, then combination chemotherapy. Strategy C was combination chemotherapy from the outset. Within strategies B and C, patients were randomly assigned to receive, as the combination regimen, fluorouracil plus irinotecan (groups B-ir and C-ir) or fluorouracil plus oxaliplatin (groups B-ox and C-ox). The primary endpoint was overall survival, analysed by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 79877428. RESULTS: Median survival of patients allocated to control strategy A was 13.9 months. Median survival of each of the other groups was longer (B-ir 15.0, B-ox 15.2, C-ir 16.7, and C-ox 15.4 months). However, log-rank comparison of each group against control showed that only C-ir--the first-line combination strategy including irinotecan--satisfied the statistical test for superiority (p=0.01). Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less (HR=1.06, 90% CI 0.97-1.17). INTERPRETATION: Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.

Original publication




Journal article



Publication Date





143 - 152


Aged, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Colorectal Neoplasms, Drug Administration Schedule, Female, Fluorouracil, Humans, Irinotecan, Leucovorin, Male, Middle Aged, Organoplatinum Compounds, Oxaliplatin, Prognosis, Survival Analysis