Duration of Chemotherapy for Metastatic Breast Cancer
Study Design: Systematic review of randomized controlled trials comparing shorter versus longer first-line chemotherapy duration in patients with metastatic breast cancer (MBC).
Study Eligibility: Eligible trials of first-line chemotherapy in MBC patients included: trials comparing a fixed number of cycles versus continuation of the same chemotherapy (CT) until disease progression; trials comparing a fixed number of cycles versus a larger fixed number of cycles of identical CT; and, trials comparing a fixed number of cycles of initial CT versus identical initial CT followed by additional cycles of an alternative CT. Additional trials included: all single and combination CT regimens found in the literature; trials with endocrine therapy in both treatment arms; trials of high-dose chemotherapy (HDCT) with peripheral bloodstream cell support. Exclusion criteria were trials comparing different CT regimens.
Enrollment: After identifying 153 relevant trials during a literature search, reviewers assessed the eligibility of each trial through screening and consensus. The final study consisted of 11 randomized trials with a total of 2,269 patients. All trials included patients with MBC and were published between 1987 and 2010. Ten trials were published in peer-reviewed journals, and one trial was a conference abstract.
Research Question: What is the impact of extending chemotherapy beyond a standard number of cycles on overall and progression-free survival in patients with MBC?
While the survival of metastatic breast cancer (MBC) patients has been modestly prolonged over time, there is inadequate evidence on optimal chemotherapy duration and cycle number, and treatment is typically based on patient responsiveness and physician preference. Though several individual studies have compared longer versus shorter duration chemotherapy, this meta-analysis seeks to determine the impact of first-line chemotherapy duration on overall and progression-free survival in MBC patients.
The systematic review resulted in a meta-analysis of 11 randomized controlled trials including 2,269 patients, with overall survival and progression-free survival as the endpoints of interest. All trials included patients with MBC, receiving first-line chemotherapy. The number of cycles of chemotherapy in the standard duration groups (control arms) ranged from three to eight while the number of maintenance chemotherapy cycles ranged from six to continue until disease progression or unacceptable toxicity. Hazard ratios and variances were taken from the published reports or calculated based on P values. Various statistical tests were performed in order to account for statistical heterogeneity of trial results. Lastly, subgroup analyses such as time of random assignment, type of chemotherapy, study design, and a number of cycles in the shorter arm were performed to investigate possible bias of these factors on efficacy of chemotherapy duration.
The researchers found that longer duration chemotherapy resulted in a 9% reduction in the hazard of death and a 36% reduction in the hazard of progression compared to shorter chemotherapy duration. These results suggest that longer first-line chemotherapy regimens are associated with statistically significant improvements in both overall survival and progression-free survival, but the improvements are only clinically meaningful for progression. Furthermore, this study suggests that benefits associated with extended duration first-line chemotherapy are independent of the type of chemotherapy, a number of cycles in the shorter arm, and co-administered endocrine therapy.
Will increasing the length of first-line chemotherapy improve the quality of life by delaying symptoms and disease in MBC patients? Future studies are warranted to investigate new treatment schedules/regimens for first-line MBC that combine chemotherapy and targeted agents; as well as the possibility of administering sequential, single chemotherapeutic agents for a set number of cycles to avoid toxicity build up and drug resistance. In terms of limitations, the authors cite differences in trial designs between the 11 studies, chemotherapy regimens, and a number of participants per trial. In addition, study regimens used in the late 1980s/early 1990s are most likely outdated compared to more recent regimens. An editorial posted in response to this study mentioned several critiques of the design, including failure to recognize the difference in dose reduction rules between clinical trials and clinical practice and the small patient sample size (2,269 is a small number for a meta-analysis). Lastly, because of the heterogeneity of the disease and the need for more individualized treatment, anyone trial or meta-analyses may not be appropriate for MBC.
Gennari A, Stockler M, Puntoni M, Sormani M, Nanni O, et al. Duration of Chemotherapy for Metastatic Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. JCO. 2011. 10.1200/JCO.2010.31.5374.