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

Abstract

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 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.

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.

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Time to recurrence, breast cancer mortality, and overall mortality for taxane-plus-anthracycline-based regimens (Tax+anth) versus control with (left) the same or (right) more non-taxane chemotherapy Trials versus the same non-taxane chemotherapy (usually 4AC) just added four extra taxane-only cycles. RR (and its 95% CI)=event rate ratio, from summed log-rank statistics for all time periods combined. Gain (and its SE)=absolute difference between ends of graphs. Event rates, %/year, are followed by (first events/woman-years). Error bars show ±1 SE.

Figure 2

Subgroup analyses of breast cancer mortality (mortality with recurrence, by log-rank subtraction) for taxane-plus-anthracycline-based regimens versus the same, or more (less than doubled or roughly doubled), non-taxane cytotoxic chemotherapy D=docetaxel. P=paclitaxel. 4(D100) q3w=four doses of docetaxel 100 mg/m2 at intervals of 3 weeks. 4(P175) q3w=four doses of paclitaxel 175 mg/m2 at intervals of 3 weeks. ER=oestrogen receptor. NS=not significant. *First four subgroups are as in the forest plots (webappendix pp 21-26) that give details of each trial's cytotoxic regimens. † Taxane courses do not overlap other chemotherapy courses. ‡Taxane given concurrently with anthracycline.

Figure 3

Time to recurrence, breast cancer mortality, and overall mortality for selected anthracycline-based regimens versus standard or near-standard CMF Left: regimens with cumulative dosage greater than 240 mg/m2 doxorubicin or 360 mg/m2 epirubicin (eg, CAF or CEF). Right: standard 4AC (cumulative dosage 240 mg/m2 doxorubicin). All graphs exclude regimens with less than 60 mg/m2 doxorubicin or 90 mg/m2 epirubicin per cycle. RR (and its 95% CI)=event rate ratio, from summed log-rank statistics for all time periods combined. Gain (and its SE)=absolute difference between ends of graphs. Anth=anthracycline. Event rates, %/year, are followed by (first events/woman-years). Error bars show ±1 SE.

Figure 4

Subgroup analyses of breast cancer mortality (mortality with recurrence, by log-rank subtraction) for any anthracycline-based regimen versus standard CMF (or near-standard CMF) A=doxorubicin (Adriamycin). E=epirubicin. Dose/cycle (and cumulative dosage) is given after the drug name in mg/m2; A60/E90 means 60 mg/m2 of doxorubicin or 90 mg/m2 of epirubicin. iv=intravenous. NS=not significant. ER=oestrogen receptor. IHC=immunohistochemistry. *First four subgroups are as in the forest plots (webappendix pp 27-32) that give details of each trial's cytotoxic regimens.

Figure 5

Time to recurrence, breast cancer mortality, and overall mortality for chemotherapy versus no adjuvant chemotherapy Left: four or more cycles of any anthracycline (Anth)-based regimen—eg, standard 4AC. Right: standard or near-standard CMF. RR (and its 95% CI)=event rate ratio, from summed log-rank statistics for all time periods combined. Gain (and its SE)=absolute difference between ends of graphs. CTX=chemotherapy. Event rates, %/year, are followed by (first events/woman-years). Error bars show ±1 SE.

Figure 6

Subgroup analyses of breast cancer mortality (mortality with recurrence, by log-rank subtraction) for any anthracycline-based regimen versus no chemotherapy A=doxorubicin (Adriamycin). E=epirubicin. Dose/cycle (and cumulative dosage) is given after the drug name in mg/m2; A60/E90 means 60 mg/m2 of doxorubicin or 90 mg/m2 of epirubicin. NS=not significant. ER=oestrogen receptor. *First four subgroups are as in the forest plots (webappendix pp 33-38) that give details of each trial's cytotoxic regimens. † In the SWOG 8814 trial of CAF in postmenopausal ER+ disease, tamoxifen started randomly with or after the chemotherapy.

Figure 7

At least four cycles of any anthracycline-based regimen (with mean effect roughly as for standard 4AC) versus no adjuvant chemotherapy: analyses of 10-year breast cancer mortality by age and ER status RR (and its 95% CI)=event rate ratio, from summed log-rank statistics for all time periods combined. Gain (and its SE)=absolute difference between ends of graphs. ER=oestrogen receptor. Anth=anthracycline. Event rates, %/year, are followed by (first events/woman-years). Error bars show ±1 SE

Uncited reference