Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials

Abstract

Background: Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens.

Methods: We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs.

Findings: 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0·86, 95% CI 0·79-0·93; p=0·0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12·3% vs 21·0%; risk difference 8·7%, 95% CI 4·5-12·9; RR 0·58, 0·47-0·73; p<0·0001). 10-year breast cancer mortality in this group was reduced by 4·2% (0·4-8·1; p=0·0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0·94, 0·83-1·06; p=0·30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82-0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90-1·03; p=0·27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade.

Interpretation: Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials.

Funding: Cancer Research UK, UK Medical Research Council.

Figure 1:. Recurrence of breast cancer (first invasive local, distant, or new contralateral primary) in the 15 trials with patient-level data comparing taxane plus anthracycline versus taxane without anthracycline

24 trials in total. One trial (N-SAS-BC 02) is shown on two lines as it was a 2 X 2 trial. Eight trials did not provide data. Taxanes were D and P. Anthracyclines were A and E. Other agents were C, F, M, Trz, Vrb, Cap, Cpt, and Ptz. 99% CIs are provided for individual trial data; 95% CIs are provided for subtotal and total data. A=doxorubicin. AUC=area under the curve. C=cyclophosphamide. Cap=capecitabine. Cpt=carboplatin. D=docetaxel. d=day of cycle. E=epirubicin. F=fluorouracil. M=methotrexate. O–E=observed minus expected. P=paclitaxel. Ptz=pertuzumab. q1=weekly. q2=every 2 weeks. q3=every 3 weeks. q4=every 4 weeks. Trz=trastuzumab. Vrb=vinorelbine. v.v=vice versa. yr=year. 2p=two-sided p value. *Any unstated doses are the same as for the non-anthracycline comparator. The regimens being compared in each study are described by the number of cycles, the drug abbreviation and dose in mg/m², and the frequency of the doses; a solidus (/) indicates or; a semicolon indicates then (sequential treatment). †For balance, control patients in three-way trials or trial strata count half or twice in subtotal(s) and in the final total of events and patients. ‡Pre-operative chemotherapy.

Figure 2:. 10-year cumulative risk of outcomes with taxane plus anthracycline versus taxane without anthracycline

All analyses included 18 103 participants (9076 in taxane plus anthracycline group, 9027 in taxane only group). 10-year cumulative risk of any invasive recurrence (A), breast cancer mortality (B), death without recurrence (C)*, and any death (D)*. Error bars show 95% CI. O–E=observed minus expected. RR=rate ratio. V=variance. 2p=two-sided p value. *Smoothed after 5 years (denoted by dotted line).

Figure 3:. 10-year cumulative risk of any recurrence and breast cancer mortality in patients on taxane-based regimens with anthracycline versus without anthracycline

Risk of recurrence (A) or breast cancer mortality (B) in 2469 patients on concurrent anthracycline plus docetaxel plus cyclophosphamide (n=1236) versus same cumulative dose docetaxel plus cyclophosphamide (n=1233), and risk of recurrence (C) or breast cancer mortality (D) in 11 386 patients on sequential anthracycline and taxane (n=5722) versus higher cumulative dose docetaxel plus cyclophosphamide (n=5664), smoothed after 5 years (denoted by dotted line). Error bars show 95% CI. O–E=observed minus expected. RR=rate ratio. V=variance. 2p=two-sided p value.

Figure 4:. Subgroup analyses of recurrence with concurrent anthracycline plus docetaxel plus cyclophosphamide versus same dose docetaxel plus cyclophosphamide

Subgroup analyses of first invasive recurrence of breast cancer. O–E=observed minus expected. ER=oestrogen receptor. NS=not significant. N0=node-negative. N+=node-positive. PR=progesterone receptor. 2p=two-sided p value.*99% CIs are provided for individual subgroup data; 95% CI is provided for the total data.

Figure 5:. 10-year cumulative risk of recurrence with concurrent anthracycline plus docetaxel plus cyclophosphamide versus same dose docetaxel plus cyclophosphamide, by oestrogen receptor and nodal status

10-year risk of any recurrence in 836 patients on concurrent anthracycline plus docetaxel plus cyclophosphamide (n=417) versus same dose docetaxel plus cyclophosphamide (n=419) who were ER-negative (A) and 1633 patients (819 vs 814) who were ER-positive (B), both smoothed after 5 years (dotted line), and in 885 patients (432 vs 453) with node-negative cancer (C) and 1584 patients (804 vs 780) with node-positive cancer (D), both smoothed after 4 years (dotted line). Error bars show 95% CI. ER=oestrogen receptor. O–E=observed minus expected. RR=rate ratio. V=variance. 2p=two-sided p value.

Figure 6:. 10-year cumulative risk of any recurrence and breast cancer mortality with anthracycline-based regimens with taxane versus without taxane

Risk of recurrence (A) or breast cancer mortality (B) in 11 167 patients with anthracycline plus taxane (n=5590) versus the same chemotherapy without taxane (n=5577), risk of recurrence (C) or breast cancer mortality (D) in 27 089 patients with anthracycline plus taxane (n=13 528) versus a higher (but less than double) dose of non-taxane chemotherapy (n=13 561), and risk of recurrence (E) or breast cancer mortality (F) in 14 620 patients with taxane plus anthracycline (n=7322) versus double the dose of non-taxane chemotherapy (n=7298) . Error bars show 95% CI. O–E=observed minus expected. RR=rate ratio. V=variance. 2p=two-sided p value.