顺铂联合吉西他滨与紫杉醇联合吉西他滨一线治疗转移性三阴性乳腺癌（CBCSG006）：一项随机、开放标签、多中心、III 期临床试验。
Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial.
机构信息
Department of Medical Oncology, Fudan University Shanghai Cancer Centre, Collaborative Innovation Centre for Cancer Medicine, Shanghai, China; Department of Oncology, Shanghai Medical College, Shanghai, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Centre, Collaborative Innovation Centre for Cancer Medicine, Shanghai, China; Department of Oncology, Shanghai Medical College, Shanghai, China.
出版信息
Lancet Oncol. 2015 Apr;16(4):436-46. doi: 10.1016/S1470-2045(15)70064-1. Epub 2015 Mar 18.
BACKGROUND
Platinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non-inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.
METHODS
For this open-label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18-70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0-1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1·2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624.
FINDINGS
From Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16·3 months (IQR 14·4-26·8) in the cisplatin plus gemcitabine group and 15·9 months (10·7-25·4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0·692 (95% CI 0·523-0·915; pnon-inferiority<0·0001, psuperiority=0·009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7·73 months (95% CI 6·16-9·30) in the cisplatin plus gemcitabine group and 6·47 months (5·76-7·18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [<1%]), vomiting (13 [11%] vs one [<1%]), musculoskeletal pain (none vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1-4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1-4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths.
INTERPRETATION
Cisplatin plus gemcitabine could be an alternative or even the preferred first-line chemotherapy strategy for patients with metastatic triple-negative breast cancer.
FUNDING
Shanghai Natural Science Foundation.
背景
铂类化疗在转移性三阴性乳腺癌的治疗中具有一定作用，但可能尚未充分发挥其潜力。我们评估了顺铂联合吉西他滨方案是否不劣于或优于紫杉醇联合吉西他滨方案，作为转移性三阴性乳腺癌患者的一线治疗。
方法
这是一项在中国 12 家机构或医院进行的、开放性、随机、3 期、混合设计试验，纳入了此前未经治疗、组织学证实的转移性三阴性乳腺癌且 ECOG 体能状态为 0-1 的年龄在 18-70 岁的中国患者。这些患者按 1:1 比例随机分配（1:1）接受顺铂联合吉西他滨（顺铂 75mg/m2 于第 1 天，吉西他滨 1250mg/m2 于第 1 天和第 8 天）或紫杉醇联合吉西他滨（紫杉醇 175mg/m2 于第 1 天，吉西他滨 1250mg/m2 于第 1 天和第 8 天）治疗，每 3 周静脉给药 1 次，最多 8 个周期。通过使用大小为 8 的交互网络响应系统进行中心随机分组，无分层因素。患者和研究者均了解分组情况。主要终点是无进展生存期，所有至少接受 1 次指定治疗的患者均纳入分析。用于确定非劣效性的边界为 1.2。如果顺铂联合吉西他滨与紫杉醇联合吉西他滨相比非劣效，则进一步测试其优越性。试验在 ClinicalTrials.gov 上注册，编号为 NCT01287624。
结果
从 2011 年 1 月 14 日至 2013 年 11 月 14 日，有 240 名患者接受了入组评估并随机分配至治疗组（顺铂联合吉西他滨组 120 例，紫杉醇联合吉西他滨组 120 例）。120 名患者接受了至少 1 个周期的指定化疗，并纳入改良意向治疗分析（每组 118 例）。在中位随访 16.3 个月（IQR 14.4-26.8）后，顺铂联合吉西他滨组和紫杉醇联合吉西他滨组的无进展生存期的风险比为 0.692（95%CI 0.523-0.915；p<0.0001），非劣效性检验成立，p>0.05，因此顺铂联合吉西他滨与紫杉醇联合吉西他滨相比既非劣效又更优。顺铂联合吉西他滨组和紫杉醇联合吉西他滨组的中位无进展生存期分别为 7.73 个月（95%CI 6.16-9.30）和 6.47 个月（5.76-7.18）。两组间差异有统计学意义的 3-4 级不良事件包括恶心（8 例[7%] vs 1 例[<1%]）、呕吐（13 例[11%] vs 1 例[<1%]）、肌肉骨骼疼痛（无 vs 10 例[8%]）、贫血（39 例[33%] vs 6 例[5%]）和血小板减少（38 例[32%] vs 3 例[3%]）。此外，顺铂联合吉西他滨组患者的 1-4 级脱发事件发生率明显低于紫杉醇联合吉西他滨组（12 例[10%] vs 42 例[36%]）和周围神经病变（27 例[23%] vs 60 例[51%]），但顺铂联合吉西他滨组患者的 1-4 级厌食症（33 例[28%] vs 10 例[8%]）、便秘（29 例[25%] vs 11 例[9%]）、低镁血症（27 例[23%] vs 5 例[4%]）和低钾血症（10 例[8%] vs 2 例[2%]）发生率明显更高。紫杉醇联合吉西他滨组有 3 例患者发生严重药物相关不良事件（间质性肺炎、过敏反应和严重中性粒细胞减少症），顺铂联合吉西他滨组有 4 例患者发生严重药物相关不良事件（病理性骨折、血小板减少伴皮下出血、严重贫血和心源性晕厥）。无治疗相关死亡病例。
结论
顺铂联合吉西他滨可能是转移性三阴性乳腺癌患者的另一种选择，甚至可能是首选的一线化疗方案。
资助
上海市自然科学基金。
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