University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Hills Road, Cambridge, UK; National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
Lancet Oncol. 2014 Feb;15(2):201-12. doi: 10.1016/S1470-2045(13)70554-0. Epub 2013 Dec 19.
Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine).
In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278).
Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection.
Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer.
Cancer Research UK, Eli Lilly, Bristol-Myers Squibb.
在过去的十年中，蒽环类药物和紫杉烷类药物一直是乳腺癌新辅助化疗的标准药物。我们旨在评估吉西他滨联合表柔比星、环磷酰胺和加速紫杉醇的安全性和有效性，以及蒽环类药物和环磷酰胺与紫杉醇（联合或不联合吉西他滨）两种方案的顺序对疗效的影响。
在我们的随机、开放标签、2×2 析因 3 期试验（Neo-tAnGo）中，我们在英国的 57 个中心招募了新诊断为乳腺癌（肿瘤大小>20mm）的女性（年龄>18 岁）。患者通过中央随机分配程序被随机分配到表柔比星和环磷酰胺然后紫杉醇（联合或不联合吉西他滨）或紫杉醇（联合或不联合吉西他滨）然后表柔比星和环磷酰胺。每个药物均给予 4 个周期。主要终点是病理完全缓解（pCR），定义为乳房和腋窝淋巴结中无浸润性癌。本研究在 EudraCT（2004-002356-34）、ISRCTN（78234870）和 ClinicalTrials.gov（NCT00070278）注册。
在 2005 年 1 月 18 日至 2007 年 9 月 28 日期间，我们随机分配了 831 名患者；207 名患者接受表柔比星和环磷酰胺然后紫杉醇治疗；208 名患者接受紫杉醇然后表柔比星和环磷酰胺治疗；208 名患者接受表柔比星和环磷酰胺联合吉西他滨治疗；208 名患者接受紫杉醇和吉西他滨联合表柔比星和环磷酰胺治疗。828 名患者符合分析条件。中位随访时间为 47 个月（IQR 37-51）。207（25%）名患者有炎症或局部晚期疾病，169（20%）名患者肿瘤大于 50mm，413（50%）名患者腋窝淋巴结有临床受累，276（33%）名患者雌激素受体（ER）阴性疾病，191（27%）名患者 HER2 阳性疾病。添加吉西他滨并未增加 pCR：在接受表柔比星和环磷酰胺然后紫杉醇治疗的 404 名患者中，有 70 名（17%，95%CI 14-21）达到 pCR，而接受额外吉西他滨治疗的 408 名患者中有 71 名（17%，14-21）（p=0.98）。蒽环类药物前接受紫杉烷治疗与 pCR 改善相关：在接受紫杉醇联合或不联合吉西他滨治疗后接受表柔比星和环磷酰胺治疗的 406 名患者中，有 82 名（20%，95%CI 16-24）达到 pCR，而接受表柔比星和环磷酰胺治疗的 406 名患者中，有 59 名（15%，11-18）达到 pCR（p=0.03）。报告了预期水平的 3 级毒性：接受治疗并具有完整治疗细节的 812 名患者中有 173 名（21%）出现 3 级中性粒细胞减少症，66 名（8%）发生感染，41 名（5%）出现疲劳，41 名（5%）出现肌肉和关节疼痛，37 名（5%）出现恶心，36 名（4%）出现呕吐，34 名（4%）出现神经病变，23 名（3%）出现转氨酸升高，16 名（2%）出现急性过敏反应，20 名（2%）出现皮疹。86 名（11%）名患者出现 4 级中性粒细胞减少症，3 名（<1%）名患者出现 4 级感染。
尽管吉西他滨联合表柔比星、环磷酰胺和紫杉醇化疗并不能提高 pCR，但在乳腺癌标准新辅助化疗中，使紫杉烷类药物先于蒽环类药物序贯治疗可能会提高 pCR。
英国癌症研究中心、礼来公司、百时美施贵宝公司。
