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时隔42天，《柳叶刀》终于发表了一篇新的乳腺癌研究报告，可惜却是结果阴性的旧闻。 2017年5月4日，英国《柳叶刀肿瘤学分册》在线发表剑桥大学、华威大学、利兹大学、伯明翰大学、伯恩茅斯大学、爱丁堡大学、伦敦帝国学院、爱尔兰都柏林大学圣文森特医院、爱尔兰肿瘤研究协作组、美国新基（赛尔基因）等机构的吉西他滨＋紫杉醇＋表柔比星＋环磷酰胺辅助化疗用于早期乳腺癌女性（tAnGo）非盲随机3期研究10年随访结果。 由于吉西他滨对转移性乳腺癌表现出显著的有效性，并且有证据表明与紫杉醇有良好的相互作用，故tAnGo研究探讨了吉西他滨加入蒽环类和紫杉类辅助化疗对早期乳腺癌的可能作用。 探戈（tAnGo）是一项国际、非盲、随机、3期优效研究，于2001年8月22日～2004年11月26日入组英国和爱尔兰127个临床中心和医院3152例≥18岁新诊断早期乳腺癌、化疗指征明确、任何淋巴结状态、任何激素受体状态、东部肿瘤协作组（ECOG）体力状态0～1、骨髓肝肾功能良好的女性，按1∶1随机分配接受两种治疗方案之一：表柔比星＋环磷酰胺＋紫杉醇（4个周期的表柔比星90mg/m²和环磷酰胺600mg/m²每3周第1天静脉给药，随后4个周期的紫杉醇175mg/m²每3周第1天静脉输注3小时）或表柔比星＋环磷酰胺＋紫杉醇＋吉西他滨（上述化疗方案紫杉醇给药期间加入吉西他滨1250mg/m²每3周第1天和第8天静脉输注0.5小时）。通过研究中心计算机化确定性最小化程序随机分配患者，按地区、年龄、放疗意向、淋巴结状态、雌激素受体、HER2状态进行分层。主要终点为无病生存，目标为检出治疗组之间的5年无病生存相差5%。2004年完成入组，本文为最终意向治疗分析。该研究已在欧盟、世界卫生组织、美国政府注册，编号：EudraCT（2004-002927-41）、ISRCTN（51146252）、ClinicalTrials.gov（NCT00039546）。 结果发现，吉西他滨组、对照组各1576例，其中分别有6例、5例由于入组前存在转移而不符合要求，故被排除于分析之外。根据该方案规定的最终分析，中位随访10年（四分位距：10～10），发生无病生存事件1087例和死亡914例。吉非他滨组、对照组的10年无病生存率分别为65%（63～68）、65%（62～67），无显著差异（校正风险比：0.97，95%置信区间：0.86～1.10，P=0.64）。 毒性、剂量强度、详细安全性亚组研究表明两种方案均安全、可行、可耐受。吉西他滨组、对照组均报告有3级和4级毒性，最常见为嗜中性白细胞减少症（34%比26%）、肌痛和关节痛（13%比12%），疲劳（13%比10%）、感染（13%比9%）、呕吐（9%比7%）、恶心（8%比7%）。 因此，在该剂量和疗程下，将吉西他滨加入蒽环类和紫杉类辅助化疗，对于早期乳腺癌的无病生存并无治疗优势，而且可以引起毒性增加。所以，对于任何亚组，吉西他滨尚未加入乳腺癌标准辅助化疗。 对此，希腊克里特大学伊拉克利翁医院的肿瘤内科专家发表同期评论：探戈（tAnGo）没有激起观众的兴趣。 虽然tAnGo研究结果为阴性，但是由于该3期随机研究按照国际指南进行，因此应该公开，并且明确报告详细结果。高质量研究的结果，例如tAnGo，即使为阴性，对于可使患者和社会避免过度的医疗毒性和经济负担的临床肿瘤医生而言也很重要，这些研究还有助于研究者通过分析以统一方案治疗患者获得的生物标本，以探索新的治疗方案。tAnGo研究结果的发表，也预示着大规模辅助研究时代的结束。当将来检验新疗法疗效的临床研究在设计时，如果能够考虑到乳腺癌的分子异质性，那么乳腺癌的辅助疗法就有可能出现进步。 此外，有趣的是，虽然当初礼来、百时美施贵宝、辉瑞赞助了tAnGo研究，但是参与最终结果发表的却是新基（赛尔基因）。 Lancet Oncol. 2017 May 4. [Epub ahead of print] Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Helena M Earl, Louise Hiller, Helen C Howard, Janet A Dunn, Jennie Young, Sarah J Bowden, Michelle McDermaid, Anna K Waterhouse, Gregory Wilson, Rajiv Agrawal, Susan O'Reilly, Angela Bowman, Diana M Ritchie, Andrew Goodman, Tamas Hickish, Karen McAdam, David Cameron, David Dodwell, Daniel W Rea, Carlos Caldas, Elena Provenzano, Jean E Abraham, Peter Canney, John P Crown, M John Kennedy, Robert Coleman, Robert C Leonard, James A Carmichael, Andrew M Wardley, Christopher J Poole; on behalf of the tAnGo trial collaborators. Addenbrooke's Hospital, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, Cambridge, UK; Cambridge Breast Cancer Research Unit, Cambridge, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Warwick Clinical Trials Unit, University of Warwick, Coventry, UK; Leeds Institute for Clinical Trials Research, University of Leeds, Leeds, UK; University of Birmingham, Birmingham, UK; Scottish Clinical Trials Research Unit, NHS National Services Scotland, Edinburgh, UK; The Christie NHS Foundation Trust, Manchester, UK; Shrewsbury & Telford Hospitals NHS Trust, Shrewsbury, UK; Clatterbridge Cancer Centre, Wirral, UK; Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK; Cancer Clinical Trials Unit (CaCTUS), Beatson West of Scotland Cancer Centre, Glasgow, UK; Royal Devon and Exeter NHS Foundation Trust, Exeter, UK; Poole Hospital, Poole Hospital NHS Foundation Trust/Bournemouth University, Poole, Dorset, UK; Edith Cavell Campus, Peterborough City Hospital, Peterborough and Stamford Hospitals NHS Foundation Trust, Peterborough, UK; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK; Institute of Oncology, St James's University Hospital, Leeds Teaching Hospital NHS Trust, Leeds, UK; St Vincent's University Hospital, Dublin, Ireland; Cancer Trials Ireland (formerly ICORG), Dublin, Ireland; Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK; Charing Cross Hospital, Imperial College London, London, UK; Celgene, Research and Development, San Diego, CA, USA; NIHR/CRUK Christie Clinical Research Facility, Manchester, UK; Arden Cancer Research Centre, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK. BACKGROUND: The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel. METHODS: tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0-1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m² intravenously administered epirubicin and 600 mg/m² intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m² paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m² gemcitabine to the paclitaxel cycles, administered intravenously as a 0.5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546). FINDINGS: Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10-10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63-68] in the gemcitabine group vs 65% [62-67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0.97 [95% CI 0.86-1.10], p=0.64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]). INTERPRETATION: The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup. FUNDING: Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer. DOI: 10.1016/S1470-2045(17)30319-4 Lancet Oncol. 2017 May 4. [Epub ahead of print] The tAnGo fell short of inspiring the audience. Dimitrios Mavroudis. Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece. DOI: 10.1016/S1470-2045(17)30311-X
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