1998年至2019年，总部位于英国伦敦的早期乳腺癌试验者协作组EBCTCG在国际四大医学期刊之一英国《柳叶刀》正刊先后发表的4篇荟萃分析结果表明，蒽环类＋紫杉类化疗与不化疗相比，可将早期乳腺癌患者前10年死亡率降低最多可达40%。不过，由于对蒽环类心脏骨髓毒性等短期和长期副作用的担忧，导致越来越多临床医师改用不含蒽环类的紫杉类化疗，这是否影响疗效？既往各个随机对照试验方案设计和患者入组标准各不相同，结果互相矛盾，故有必要对近年来全部随机对照试验进行患者个体水平数据荟萃分析，也就是通常所说的“一锅炖”。 2023年4月14日，创刊200周年的《柳叶刀》正刊再次发表EBCTCG研究报告，对全球女性早期可手术乳腺癌蒽环类和紫杉类化疗随机对照试验进行患者个体水平数据荟萃分析，比较不同蒽环类化疗方案的获益和风险，以及不同蒽环类＋紫杉类化疗方案的获益。其中，3项中国随机对照试验入选，包括复旦大学附属肿瘤医院牵头的2项全国多中心大样本随机对照试验PATTERN和MASTER。该协作组编写委员会和指导委员会目前仅3位专家来自中国，其中包括复旦大学附属肿瘤医院的邵志敏教授和余科达教授。该荟萃分析由英国癌症研究中心和英国医学研究委员会提供资助。 作者首先对美国国家医学图书馆文献数据库、荷兰医学文摘数据库、英国循证医学数据库以及国际会议摘要数据库进行系统检索，筛选出开始于2012年1月1日之前、比较紫杉类与无蒽环类化疗方案的早期乳腺癌术前新辅助或术后辅助治疗随机对照试验患者个体水平数据，更新既往比较蒽环类与无紫杉类化疗方案的荟萃分析，并分析6项相关比较中的44项试验。主要结局为乳腺癌复发率和特定原因所致死亡率。对首次事件发生率比值比和置信区间进行对数秩分析。 结果，共确定28项紫杉类±蒽环类的随机对照试验，其中23项符合条件，15项可提供1万8103例女性数据，其中MASTER和PATTERN分别为1047例和647例。 根据提供患者个体数据的全部15项试验，紫杉类±蒽环类化疗方案相比：- 乳腺癌复发率平均低14%（比值比：0.86，95%置信区间：0.79～0.93，P=0.0004）
- 非乳腺癌所致死亡人数未增加，但是每700例接受治疗女性增加1例急性髓细胞白血病
相同剂量的多西他赛＋环磷酰胺±蒽环类相比，乳腺癌复发率降低最显著：10年复发率为12.3%比21.0%，绝对值低8.7%（95%置信区间：4.5～12.9）相对降低42%（比值比：0.58，95%置信区间：0.47～0.73，P<0.0001）。该组10年乳腺癌所致死亡率降低4.2%（95%置信区间：0.4～8.1，P=0.0034）。 序贯方案紫杉类＋蒽环类与多西他赛＋环磷酰胺相比，乳腺癌复发率未显著降低（比值比：0.94，95%置信区间：0.83～1.06，P=0.30）。 对35项随机对照试验共计5万2976例患者个体数据荟萃分析表明，蒽环类±紫杉类化疗方案相比：- 当蒽环类累积剂量相同（1万1167例）乳腺癌复发率降低13%（比值比：0.87，95%置信区间：0.82～0.93，P<0.0001）
- 当蒽环类累积剂量翻倍（1万4620例）乳腺癌复发率仅降低4%（比值比：0.96，95%置信区间：0.90～1.03，P=0.27）
蒽环类与紫杉类化疗方案的直接比较表明，累积剂量较高和剂量强度较高的方案更有效。 对于雌激素受体阳性或雌激素受体阴性乳腺癌，紫杉类＋蒽环类的乳腺癌复发比例降低相似，无论年龄、淋巴结状态、肿瘤大小或分级。 因此，该全球随机对照试验患者个体数据荟萃分析结果表明，蒽环类＋紫杉类化疗方案对减少乳腺癌复发和死亡最有效。蒽环类＋紫杉类累积剂量较高的方案获益最大，挑战了目前临床实践和指南非蒽环类化疗的趋势，尤其较短方案，例如4个周期的多西他赛＋环磷酰胺。通过汇总几乎全部相关试验的数据，该荟萃分析提供了可靠的循证依据，为个体治疗决策、临床指南和未来临床试验设计提供信息。 不过，值得注意的是，复旦大学附属肿瘤医院牵头的2项全国多中心大样本随机对照试验MASTER和PATTERN分别以1047例和647例患者个体数据，与西德研究协作组B计划一起，扭转了蒽环一边倒的优势，为早期乳腺癌中低风险患者免蒽环化疗方案提供了有力证据。 对此，中国医学科学院北京协和医学院北京协和医院沈松杰、中国科学院动物研究所和中国科学院大学存济医学院刘长梅发表同期评论：早期乳腺癌化疗越多越好？Lancet. 2023 Apr 15;401(10384):1277-1292. IF: 202.731Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100000 women from 86 randomised trials.Early Breast Cancer Trialists' Collaborative Group (EBCTCG).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 18103 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=52976) 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=11167) 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=14620). 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.DOI: 10.1016/S0140-6736(23)00285-4Lancet. 2023 Apr 15;401(10384):1243-1245. IF: 202.731Chemotherapy for early-stage breast cancer: the more the better?Song-Jie Shen, Chang-Mei Liu.Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; Institute of Zoology Chinese Academy of Sciences, Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.DOI: 10.1016/S0140-6736(23)00094-6
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