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

MedStar author(s):
Citation: Lancet. 379(9814):432-44, 2012 Feb 4.PMID: 22152853Institution: Washington Cancer InstituteForm of publication: Journal ArticleMedline article type(s): Comparative Study | Journal Article | Meta-Analysis | Research Support, Non-U.S. Gov'tSubject headings: *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] | *Breast Neoplasms/dt [Drug Therapy] | Anthracyclines/ad [Administration & Dosage] | Breast Neoplasms/mo [Mortality] | Chemotherapy, Adjuvant | Female | Humans | Neoplasm Recurrence, Local | Randomized Controlled Trials as Topic | Survival Rate | Taxoids/ad [Administration & Dosage]Year: 2012Local holdings: Available online from MWHC library: 1995 - present, Available in print through MWHC library: 1983 - 2007ISSN:
  • 0140-6736
Name of journal: LancetAbstract: BACKGROUND: Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences.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 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.FUNDING: Cancer Research UK; British Heart Foundation; UK Medical Research Council. Copyright 2012 Elsevier Ltd. All rights reserved.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.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 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.All authors: Albain K, Bergh J, Clarke M, Cutter D, Darby S, Davies C, Di Leo A, Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Godwin J, Gray R, McGale P, Pan HC, Peto R, Piccart M, Pritchard K, Swain S, Taylor C, Wang YCFiscal year: FY2012Digital Object Identifier: Date added to catalog: 2013-09-17
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 22152853 Available 22152853

Available online from MWHC library: 1995 - present, Available in print through MWHC library: 1983 - 2007

BACKGROUND: Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences.

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 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.

FUNDING: Cancer Research UK; British Heart Foundation; UK Medical Research Council. Copyright 2012 Elsevier Ltd. All rights reserved.

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.

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 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.

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