Abstract: Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the seven trials that reported progression-free survival (time to first progression in the sequential arm), 637 women progressed out of the 846 women randomised. There was weak evidence of a higher risk of progression in the combination arm (HR 1.11; 95% CI 0.99 to 1.25; P = 0.08) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.16; 95% CI 1.06 to 1.28; P = 0.001) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome. There is weak evidence that sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

Plain-language summary: A literature search conducted in October 2013 resulted in 12 randomised controlled studies with 2317 patients that could be included in the analysis. The patients had metastatic breast cancer and either they had not been treated or had received one or two treatments after their diagnosis of metastatic breast cancer. The primary outcomes were overall survival and progression-free survival (time from randomisation to the time of disease progression). Secondarily, we compared the degree the tumour shrunk in response to chemotherapy (overall response rate), toxicity and quality of life. There was no difference in overall survival between the two groups but we found that when drugs were given one at a time there maybe more time before the tumours grew back again (longer progression-free survival). However, combination chemotherapy caused tumours to shrink more, although this did not result in longer survival than when using sequential chemotherapy. Rates of febrile neutropenia (infection) were higher in the combination arm but there was no difference in the rates of neutropenia (low white blood cells). There was no difference in quality of life between the two groups but there were only three trials that reported this information. Quality of life should be included as an outcome in future trials addressing this question. Overall, the studies did not consistently report the way patients were randomised and this may be a source of bias in the results. Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.