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International Guidelines for Management of Metastatic Breast Cancer: Combination vs Sequential Single-Agent Chemotherapy
Fatima Cardoso
Philippe L. Bedard
Eric P. Winer
Olivia Pagani
Elzbieta Senkus-Konefka
Lesley J. Fallowfield
Stella Kyriakides
Alberto Costa
Tanja Cufer
Kathy S. Albain
on behalf of the ESO-MBC Task Force
Compared with treatment options for early-stage breast cancer, few data exist regarding the optimal use of chemotherapy for metastatic breast cancer (MBC). The choice of using a combination of cytotoxic chemotherapies vs sequential single agents is controversial. At the 6th European Breast Cancer Conference, the European School of Oncology Metastatic Breast Cancer Task Force convened an open debate on the relative benefits of combination vs sequential therapy. Based on the available data, the Task Force recommends sequential monotherapy as the preferred choice in advanced disease, in the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control. Patient- and diseaserelated factors should be used to choose between combination and sequential single-agent chemotherapy for MBC. Additional research is needed to determine the impact of therapy on patient-rated quality of life and to identify predictive factors that can be used to guide therapy.
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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 (24),
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 [Table 1], 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).
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
Patient related
Menopausal status
Biological age and comorbidities (including organ dysfunction)
Performance status and adverse effects of prior therapy
Socioeconomic and psychological factors
Patient preference
Available therapies in the patients country
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 (1012). Crossover
to the novel agent following progression in the monotherapy arm
was not mandated, limiting the application of these studies (...truncated)