Background It is commonly thought that combining chemotherapy agents for treating women with metastatic breast cancer will result in regimens that are more active, offer superior tumour response rates with more time before progression and improve overall survival. However, it is not known whether giving patients more intensive chemotherapy regimens (judged according to some measure eg dose, dose intensity, response rate, or toxicity) results in better health outcomes. One way to investigate the effect of more versus less-intensive chemotherapy is to compare regimens containing a single drug (and hence possibly less active treatment) with regimens containing a greater number of drugs (and hence possibly more active but more toxic), even when adjustments are made to dosages or schedules to account for toxicity. Objectives To compare use of single chemotherapy agents with regimens containing a combination of agents for the treatment of metastatic breast cancer. Search strategy The Specialised Register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the group to create the register, and the procedure used to code references, are described in the group's module on The Cochrane Library. Selection strategy Randomised trials comparing single agent chemotherapy with combination therapy in women with metastatic breast cancer. Data collection and analysis Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present. Main results Thirty seven eligible trials were identified of which 28 had published time-to-event data. The quality of randomisation was generally not described. Data, based on an estimated 4220 deaths in 5707 women, show a modest advantage for combination chemotherapy regimens compared with single agents with a hazard ratio (HR) for overall survival of 0.88 (95% CI= 0.83-0.94, P < 0.0001) and no evident heterogeneity. Results are similar if the analysis is limited to trials in women receiving first-line chemotherapy. Combination regimens are favourably associated with time to progression (overall HR of 0.78 (95% CI= 0.73-0.83, P < 0.00001) and tumour response rates (OR 1.28, CI= 1.15-1.42, P < 0.00001) although significant heterogeneity was observed (P=0.002 and P < 0.00001 respectively). This probably reflects the varying efficacy of the comparator regimens used in the trials. Women receiving combination regimens experienced a higher toxicity level for leukopenia, hair loss and nausea and vomiting compared with those receiving a single agent, which was statistically significant. Authors' conclusions Compared with single-chemotherapy agents, combination regimens show a statistically significant advantage for tumor response and time to progression in women with metastatic breast cancer, a modest improvement in overall survival and significantly worse toxicities.
