Background: Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. Methods: We 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 cyclo phosphamide, 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. Findings: In 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 regi mens 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. Interpretation: 10-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. Funding: Cancer Research UK; British Heart Foundation; UK Medical Research Council.
|Number of pages||13|
|Publication status||Published - 4 Feb 2012|
Bibliographical noteFunding Information:
MP holds patents on genome grade index and recurrence score (marketed by Ipsogen/Qiagen), KA has accepted infrequent honoraria for CME lectures and an ad hoc advisory board from Genomic Health Inc, and JB, ADL, KA, KP, and MP have each accepted honoraria or consultancy fees from 3–7 major pharmaceutical companies. SS and all internal writing committee members declare that they have no conflicts of interest. CTSU staff policy excludes honoraria or consultancy fees. EBCTCG is funded by Cancer Research UK, British Heart Foundation, and UK Medical Research Council grants. All writing committee members' institutions perform some trials sponsored by industry, government, or charity grants, which are undertaken and interpreted independently of the funders. Industrial support of trials contributing to EBCTCG meta-analyses is listed in the trial publications ( webappendix pp 64–68 ); although such sponsorship might delay data from recent studies, it does not otherwise affect the analyses.
This report is dedicated to Paul Meier (1924–2011), parent of Kaplan-Meier survival curves and effective advocate of widespread randomisation in US clinical research. 38,39 The main acknowledgment is to the many participants in the trials and the many staff who treated them, undertook trials, and shared the data. EBCTCG is funded by core support to the Oxford University CTSU from Cancer Research UK, the British Heart Foundation, and the UK Medical Research Council; DC is supported by the BHF Centre for Research Excellence (RE/08/04) .