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.

中文翻译：

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含蒽环类药物和紫杉烷类药物治疗早期可手术乳腺癌的化疗：对来自 86 项随机试验的 10 万名女性进行的患者水平荟萃分析

 背景

与不进行化疗相比，针对早期乳腺癌的蒽环类-紫杉烷类化疗可显着提高生存率。然而，对蒽环类药物短期和长期副作用的担忧导致越来越多地使用不含蒽环类药物的紫杉烷化疗，这可能会损害疗效。我们的目的是更好地描述包含蒽环类药物的益处和风险，以及不同蒽环类药物-紫杉烷疗法的相对益处。

 方法

我们对比较紫杉类药物治疗方案与不含蒽环类药物的随机试验进行了个体患者水平的荟萃分析，并更新了之前对含紫杉类药物与不含紫杉类药物的蒽环类药物治疗方案的荟萃分析，并分析了 6 项相关比较中的 44 项试验。我们检索了数据库，包括 MEDLINE、Embase、Cochrane 图书馆和会议摘要，以确定评估蒽环类药物和紫杉烷类化疗的试验。如果辅助或新辅助试验在 2012 年 1 月 1 日之前开始，则符合资格。主要结局是乳腺癌复发和特定原因死亡率。对数秩分析得出首次事件发生率 (RR) 和 CI。

 发现

确定了 28 项含或不含蒽环类药物的紫杉烷治疗方案试验，其中 23 项被认为符合条件，15 项提供了 18 103 名女性的数据。在提供个体数据的所有 15 项试验中，使用包含蒽环类药物的紫杉烷方案比不使用包含蒽环类药物的方案的复发率平均降低 14%（RR 0·86，95% CI 0·79–0·93；p=0·0004）。非乳腺癌死亡人数没有增加，但每 700 名接受治疗的女性中，就会增加 1 例急性髓性白血病病例。与多西紫杉醇加环磷酰胺同时添加蒽环类药物与相同剂量的多西紫杉醇加环磷酰胺相比，复发率明显降低（10 年复发风险 12·3% vs 21·0%；风险差异 8·7%，95% CI） 4·5–12·9；RR 0·58、0·47–0·73；p<0·0001）。该组的 10 年乳腺癌死亡率降低了 4·2% (0·4–8·1；p=0·0034)。与多西他赛加环磷酰胺相比，紫杉烷加蒽环类药物序贯治疗方案并未发现复发风险显着降低（RR 0·94、0·83–1·06；p=0·30）。为了分析含紫杉烷类药物与不含紫杉烷类药物的蒽环类药物治疗方案，35 项试验 (n=52 976) 提供了个体患者数据。当每组蒽环类药物累积剂量相同时，在蒽环类药物治疗方案中添加紫杉烷可显着降低复发率（RR 0·87、0·82–0·93；p<0·0001；n=11 167）。对照组非紫杉烷（主要是蒽环类药物）累积剂量比紫杉烷组高两倍的试验（RR 0·96、0·90–1·03；p=0·27；n=14 620） 。蒽环类药物和紫杉烷类药物治疗方案之间的直接比较表明，较高的累积剂量和较高的剂量强度方案更有效。 在雌激素受体阳性和雌激素受体阴性疾病中，紫杉烷加蒽环类药物的复发率降低比例相似，并且在年龄、淋巴结状态或肿瘤大小或级别方面没有差异。

 解释

蒽环类药物加紫杉烷疗法对于减少乳腺癌复发和死亡最有效。具有较高累积剂量的蒽环类药物加紫杉烷的治疗方案可提供最大的益处，挑战当前临床实践的趋势和非蒽环类化疗的指南，特别是较短的治疗方案，例如四个周期的多西紫杉醇-环磷酰胺。通过汇集几乎所有相关试验的数据，这项荟萃分析提供了可靠的证据基础，为个体治疗决策、临床指南和未来临床试验的设计提供信息。

 资金

英国癌症研究中心，英国医学研究委员会。