Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials

Abstract

SummaryBackgroundModerate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences.MethodsWe undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44 000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18 000); and polychemotherapy versus no chemotherapy (n=32 000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported.FindingsIn trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities.Interpretation10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both.FundingCancer Research UK; British Heart Foundation; UK Medical Research Council.

Chemotherapy in Early Breast Cancer: When, How and Which One?

“…It is evident that the magnitude of chemotherapy benefit depends on the level of risk of the individual patient [1]. In order to avoid both over- and undertreatment, it is advisable to select the appropriate treatment strategy on the basis of a careful risk assessment for each individual patient.…”

“…The advantage of anthracycline-containing 3-drug combinations over CMF was unequivocally confirmed in an individual-patient data meta-analysis of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) [1]. Altogether, 100,000 patients in 123 randomized trials were included.…”

“…The aforementioned meta-analysis also included for the first time taxane-based versus non-taxane chemotherapy (n = 44,000) [1]. Subgroup analyses of breast cancer mortality showed that taxane-containing therapy slightly but significantly improved the outcome in comparison with an anthracycline-based control regimen (HR 0.872; p < 0.00001).…”

Endocrine Therapy in Older Women with Early-Stage Hormone Sensitive Breast Cancer

“…Many older women receive adjuvant endocrine therapy due to the high proportion of hormone receptor positivity (80% to 85%) [4], more favourable toxicity profile, and limited evidence supporting chemotherapy use in women age 70 and over due to their underrepresentation in clinical studies [13]. With the increasing prevalence of breast cancer combined with 5-year survival rates of close to 90% [2], primary care physicians and geriatricians are increasingly relied upon to see and manage patients receiving these therapies [14].…”

A Phase I Study of Capecitabine Combined with CPT-11 in Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes

“…The increased number of breast cancer patients in Japan has forced a rapid adoption of treatment guidelines and consensus approaches, such as the National Comprehensive Cancer Network (NCCN) guidelines and the St. Gallen consensus. The Early Breast Cancer Trialists' Collaborative Group meta-analysis also revealed that anthracyclines reduce the incidences of recurrence and death in modern adjuvant chemotherapy, as do taxanes, particularly for node-positive patients [4]. Recent patients with recurrent breast cancer tend to have already been treated with anthracyclines and taxanes in an adjuvant setting, and will be treated with capecitabine as one of the first-line agents in a metastatic treatment.…”