Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial
Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial
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DOI：
10.1016/s1470-2045(13)70554-0
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发表时间：
2014-02-01
期刊：
影响因子：
51.1
通讯作者：
Caldas, Carlos
中科院分区：
文献类型：
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作者：
Earl, Helena M.;Vallier, Anne-Laure;Caldas, Carlos
研究背景：蒽环类和紫杉烷类药物是近十年来乳腺癌新辅助化疗的标准药物。我们的目的是评估吉西他滨加至加速紫杉醇与表阿霉素和环磷酰胺的安全性和有效性，以及表阿霉素和环磷酰胺和紫杉醇阻断序列的影响。方法在我们的随机、开放标签、2 × 2析因3期试验中，（Neo-tAnGo），我们在英国的57个中心招募了患有新诊断的乳腺癌（肿瘤大小>20 mm）的女性（年龄>18岁）。患者通过中心随机化程序随机分配至表柔比星和环磷酰胺，然后是紫杉醇（联合或不联合吉西他滨）或紫杉醇（联合或不联合吉西他滨），然后是表柔比星和环磷酰胺。每种组分均进行了四次循环。主要终点是病理学完全缓解（pCR），定义为乳腺和腋窝淋巴结中没有浸润性癌症。本研究已在EudraCT（2004-002356-34）、ISRCTN（78234870）和www.example.com注册ClinicalTrials.gov在2005年1月18日至2007年9月28日期间，我们随机分配了831名参与者; 207名接受了表阿霉素和环磷酰胺，然后是紫杉醇; 208名接受了紫杉醇，然后是表阿霉素和环磷酰胺; 208名接受了表阿霉素和环磷酰胺，然后是紫杉醇和吉西他滨; 208例接受紫杉醇和吉西他滨，然后接受表阿霉素和环磷酰胺。828例患者符合分析条件。中位随访时间为47个月（IQR 37-51）。207例（25%）患者患有炎症或局部晚期疾病，169例（20%）患者患有大于50 mm的肿瘤，413例（50%）患者临床累及腋窝淋巴结，276例（33%）患者患有雌激素受体（ER）阴性疾病，191例（27%）患者患有HER 2阳性疾病。添加吉西他滨未增加pCR：表阿霉素+环磷酰胺+紫杉醇组404例患者中有70例（17%，95% CI 14-21）达到pCR，而接受额外吉西他滨的408例患者中有71例（17%，14-21）达到pCR（p=0.98）。在蒽环类药物治疗前接受紫杉烷治疗与pCR改善相关：406例接受紫杉醇联合或不联合吉西他滨治疗，随后接受表阿霉素和环磷酰胺治疗的患者中有82例（20%，95% CI 16-24）达到pCR，而406例先接受表阿霉素和环磷酰胺治疗的患者中有59例（15%，11-18）达到pCR（p=0.03）。3级毒性报告为预期水平：812例接受治疗并有完整治疗详情的患者中，173例（21%）发生3级中性粒细胞减少，66例（8%）发生感染，41例（5%）发生疲乏，41例（5%）发生肌肉和关节疼痛，37例（5%）发生恶心，36例（4%）发生呕吐，34例（4%）发生神经病变，23例（3%）有转氨酶升高，16例（2%）有急性超敏反应，20例（2%）有皮疹。86例（11%）患者发生4级中性粒细胞减少，3例（
Background 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).Methods In our randomised, open-label, 2x2 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).Findings 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 (