Many challenges exist in the management of metastatic breast cancer (MBC). As opposed to early disease, for which level 1 evidence exists for the majority of treatment alternatives, there are few recognized therapeutic standards for MBC, particularly following initial chemotherapy (1
). Randomized controlled trials in MBC are usually conducted in the first-line setting and address specific questions regarding the efficacy, safety, and tolerability of individual drugs. The design of these trials is sometimes at odds with the questions clinical oncologists face in daily practice. Several international guidelines for adjuvant therapy are widely used (2
), but consensus statements regarding the management of MBC are lacking (5
). Acknowledging the urgent need for these initiatives, the European School of Oncology (ESO) joined with the European Breast Cancer Conference (EBCC) to create an MBC Task Force in 2005. The task force held its first open meeting at the EBCC-5 in Nice in March 2006. This interactive session addressed many of the main issues in MBC, and 12 consensus statements regarding MBC management were subsequently published (1
At the EBCC-6 in Berlin in April 2008, the second public session on MBC Guidelines was held. During this session, three of the most controversial issues outlined in the 12 statements were selected for further discussion. Here, we summarize the discussion and the related recommendations regarding the optimal use of chemotherapy in MBC, focusing on the still unresolved issue of whether it is better to treat MBC patients sequentially with single cytoxic agents or to treat them simultaneously with a combination of drugs.
The initial consensus statement regarding this subject (consensus statement 9) from the ESO-MBC Task Force guidelines reads: “The choice between sequential use of single cytotoxic drugs and combination chemotherapy should be taken after consideration of the factors mentioned in , with greatest emphasis on the need for a rapid and significant response and on quality of life (QoL). For the majority of patients, overall survival (OS) outcomes from sequential use of single cytotoxic drugs are equivalent to combination chemotherapy. Duration of each regimen and number of regimens should be tailored to each individual patient” (1
Factors to consider when choosing between sequential and combination chemotherapy
Although the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview established the survival benefit of adjuvant polychemotherapy (6
), the role of polychemotherapy in MBC remains largely unsettled. Unlike the adjuvant setting, in which the goal of therapy is cure, the aim of therapy in the setting of MBC is essentially palliation. Stepwise advances in chemotherapy have produced statistically significant improvements in survival (7
). Nevertheless, tolerability and QoL are important factors in therapeutic decision making that must be balanced with any potential gains in disease response or survival.
Objective improvements in OS are difficult to demonstrate in individual trials (8
), leading some authors to question whether OS is an appropriate endpoint for clinical trials testing novel therapeutic approaches for metastatic disease (9
). Accordingly, many recent registration trials were designed to detect improvements in progression-free interval and were not adequately powered to evaluate the impact of new treatments on OS (10
). Crossover to the novel agent following progression in the monotherapy arm was not mandated, limiting the application of these studies to the clinically important question of the relative benefits of combination vs sequential monotherapy. Recent data from single-institution series and population-based registries demonstrate that the survival of patients with MBC has improved over time, coincident with the widespread availability of newer and more effective systemic therapies (13
). Although these data suggest a possible change in the natural history or staging procedures of MBC, they do not provide insight regarding the optimal timing, sequence, or combination of systemic agents in the treatment of MBC.
In particular, few appropriately powered randomized clinical trials have addressed the question of the sequential use of single cytotoxic agents vs upfront combination chemotherapy for MBC, with evaluation of the comparative impact of these palliative strategies on patients’ QoL. In contrast to adjuvant therapy, for which trials are designed to include thousands of patients to identify small absolute differences in disease-free survival, most studies that address MBC involve smaller numbers of participants and are underpowered to detect potentially meaningful differences in progression-free interval and/or OS between combination and sequential approaches.
A Cochrane Review (15
) of 28 trials with 5707 MBC patients who were randomly assigned to either single-agent or combination chemotherapy found that combination chemotherapy was associated with a higher response rate (RR) (odds ratio for tumor response
1.28, 95% confidence interval [CI]
1.15 to 1.42, P
< .001), longer time to progression (hazard ratio [HR] for disease progression
0.78, 95% CI
0.73 to 0.83, P
< .001), and longer OS (HR for death
0.88, 95% CI
0.83 to 0.94, P
< .001) when compared with single-agent therapy. More toxicity (nausea and vomiting, leucopenia, and alopecia) was also observed with combination therapy. Few studies included in the Cochrane analysis formally assessed differences in QoL between combination and single-agent therapy.
In addition, most trials included in the Cochrane meta-analysis did not systematically investigate the combination vs the sequential approach. Very few trials included in the overview reported the rate of “crossover” to an additional agent following progression in the monotherapy arm. Such studies test the value of two agents vs a single agent but do not address whether a combination or sequential monotherapy strategy should be pursued.
It is also important to remember that the terms sequential
chemotherapy are often used to encompass a variety of different therapeutic approaches. For example, sequential therapy may refer to the consecutive administration of several chemotherapies, with each successive regimen introduced following either radiographic and/or symptomatic disease progression. Alternatively, it may refer to a planned multicourse sequence of chemotherapies without interruption between treatment regimens (16
). Combination therapy may also involve the pairing of a cytotoxic drug with a novel biological therapy, such as a taxane and trastuzumab in women with HER2-positive MBC. This ESO-MBC Task Force publication, however, will focus exclusively on the combination of cytotoxic chemotherapies vs sequential single-agent therapies and will not address the optimal addition of biological therapies to chemotherapy.