Lancet Oncol：丝裂霉素/氟尿嘧啶放化疗方案可有效治疗肛门鳞状细胞癌

在ACT I研究之后，放化疗已成为了肛门肿瘤的标准治疗方案。然而，通过治疗仅有2/3的患者达到了局部控制，其5年生存率为50%，因此我们需要更好的治疗方案来改善这类患者的预后。来自英国Kent肿瘤中心的Roger D James等设计了相关研究以回答下述问题：一是在放化疗方案中将丝裂霉素替换成顺铂对改善患者治疗反应的影响，二是在放化疗后继续进行维持化疗是否会改善患者的生存情况，他们的研究结果发表在Lancet Oncol 4月的最新在线期刊上。

本研究为2×2析因研究，在本研究中纳入的受试者为来自于英国的59个中心，她们组织学确诊为肛门鳞状细胞癌、并且不存在转移性病变。符合入组标准的患者被随机分为4组，研究方案如下，丝裂霉素（12mg/m2，第一天）或顺铂（60mg/m2，第一天），同时应用氟尿嘧啶（1000mg/m2/天，第1-4天和第29-32天）和放疗（28天的总放射剂量为50.4Gy）；随后继续接受/不接受2个疗程的维持化疗（方案：在第11周和第14周应用氟尿嘧啶和顺铂）。研究者采用由电脑生成的随机序列对患者进行随机化分组，并根据肿瘤的部位、T和N分期、性别、年龄和肾功能对患者进行分层。在本研究中，患者和研究者都知道患者所接受的治疗方案。本研究的主要终点是在第26周时患者对治疗的反应、急性毒性反应（放化疗阶段）和无进展生存期（维持化疗阶段）。研究者主要采用意向治疗分析法对研究结果进行分析。本研究在controlled-trials.com注册，注册号为26715889。

研究者共纳入了940名患者，其中472人接受丝裂霉素治疗，在这472人中有246人不接受维持化疗，而226人接受维持化疗。接受顺铂治疗的患者有468人，其中246人不接受维持化疗，而有222人接受维持化疗。对这些患者的中位随访时间为5.1年。在丝裂霉素组的432名患者中有391人（90.5%）在第26周时达到了完全应答，而在顺铂组的431人中有386人（89.6%）达到了完全应答，两组差异不具有显著统计学意义。总体来看，丝裂霉素组和顺铂组的毒性反应相似，在丝裂霉素组的472人中有334人（71%）出现毒性反应，而在顺铂组的468人中有337人（72%）出现毒性反应。最常见的3-4级毒性反应为皮肤反应（丝裂霉素：228/472 [48%]；顺铂组222/468 [47%]）、疼痛（丝裂霉素：122/472 [26%]；顺铂组135/468 [29%]）、血液学反应（丝裂霉素：124/472 [26%]；顺铂组73/468 [16%]）和胃肠道反应（丝裂霉素：75/472 [16%]；顺铂组85/468 [18%]）。在维持化疗组和不维持化疗组的患者的3年无进展生存率分别为74%和73%，差异不具有显著统计学意义。

本研究是至今为止针对肛门癌治疗研究的最大规模的临床研究，来自本研究的结果指出氟尿嘧啶和丝裂霉素联合50.4Gy（28天放疗剂量）的放疗是英国的标准治疗方案。
与细胞癌相关的拓展阅读：

• JAMA：手术后抗病毒治疗可能降低HBV相关的肝细胞癌的复发风险
• CID：HCV相关肝硬化患者实现SVR后仍长期处于肝细胞癌风险中
• Ann Surg：淋巴结呈阳性的肝细胞癌患者预后与局部晚期患者类似
• Lancet Oncol：阿西替尼可作为转移性肾细胞癌患者的二线治疗方案
• PLoS One：吴一龙等确认喉鳞状细胞癌预后的影响因素
• Ann Surg：肝细胞癌TNM分期似应考虑肿瘤破裂因素
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Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial
Background
Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival.
Methods
In this 2×2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m2 on day 1) or cisplatin (60 mg/m2 on days 1 and 29), with fluorouracil (1000 mg/m2 per day on days 1—4 and 29—32) and radiotherapy (50·4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889.
Findings
We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5·1 years (IQR 3·9—6·9). 391 of 432 (90·5%) patients in the mitomycin group versus 386 of 431 (89·6%) in the cisplatin group had a complete response at 26 weeks (difference −0·9%, 95% CI −4·9 to 3·1; p=0·64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3—4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69—77; maintenance) versus 73% (95% CI 68—77; no maintenance; hazard ratio 0·95, 95% CI 0·75—1·21; p=0·70).
Interpretation
The results of our trial—the largest in anal cancer to date—show that fluorouracil and mitomycin with 50·4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK.
Funding
Cancer Research UK.