Strategies of sequential therapies in unresectable metastatic colorectal cancer: a meta-analysis

Before the emergence of first-line combination chemotherapy, the standard of care for unresectable metastatic colorectal cancer (mcrc) was first-line monotherapy with modulated 5-fluorouracil. Several large phase iii randomized controlled trials, now completed, have assessed whether a planned sequential chemotherapy strategy-beginning with fluoropyrimidine monotherapy until treatment failure, followed by another regimen (either monotherapy or combination chemotherapy) until treatment failure-could result in the same survival benefit produced with an upfront combination chemotherapy strategy, but with less toxicity for patients.

The medline and embase databases, and abstracts from meetings of the American Society for Clinical Oncology and the European Society for Medical Oncology, were searched for reports comparing a sequential strategy of chemotherapy with an upfront combination chemotherapy in adult patients with mcrc. Publications that reported efficacy or toxicity data (or both) were included.

The five eligible trials that were identified included 4532 patients. A meta-analysis of those trials demonstrates a statistically significant survival advantage for combination chemotherapy (hazard ratio: 0.92; 95% confidence interval: 0.86 to 0.99). However, the median survival advantage (3-6 weeks in most trials) is small and of questionable clinical significance. Three trials reported first-line toxicities. Upfront combination chemotherapy results in significantly more neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, nausea, vomiting, and sensory neuropathy. Sequential chemotherapy results in significantly more hand-foot syndrome.

Given the small survival advantage associated with upfront combination chemotherapy, planned sequential chemotherapy and upfront combination chemotherapy can both be considered treatment strategies. Treatment should be chosen on an individual basis considering patient and tumour characteristics, toxicity of each strategy, and patient preference.