Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study
Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study
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DOI：
10.1016/s1470-2045(13)70599-0
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发表时间：
2014-02-01
期刊：
影响因子：
51.1
通讯作者：
Collette, Laurence
中科院分区：
文献类型：
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作者：
Bosset, Jean-Francois;Calais, Gilles;Collette, Laurence
EORTC试验22921研究了直肠癌患者术前放疗基础上增加术前或术后化疗。在中位随访5年后，化疗-无论时间-显著改善了局部控制。辅助化疗并没有改善生存率，但Kaplan-Meier曲线发散，提示可能的延迟获益。在这里，我们报告更新的长期result.Methods我们随机分配临床分期T3或T4可切除的直肠癌患者接受术前放疗或不伴随化疗手术前，无论是辅助化疗或监测。使用机构、性别、T分期和肿瘤到肛门边缘的距离等因素的最小化进行随机化。研究协调员、临床医生和患者均知晓分配情况。放射治疗包括45戈伊的后骨盆，在5周内，25个部分的1.8戈伊。每疗程化疗包括氟尿嘧啶（350 mg/m2/d，静脉推注）和亚叶酸（亚叶酸; 20 mg/m2/d，静脉推注）。对于术前化疗，给予两个疗程（在放疗的第1周和第5周）。辅助化疗共4个周期，每3周1次。主要终点是总生存期。该试验在ClinicalTrials.gov注册，编号NCT 00002523。结果1011例患者在1993年4月至2003年3月期间被随机分配到治疗组（术前放疗组252例，其他三组各253例）。中位随访10.4年（IQR 7.8-13.1）后，术前放疗组的10年总生存率为49.4%（95% CI 44.6-54.1），术前放疗和化疗组为50.7%（45.9-55.2）（HR 0.99，95% CI 0.83-1.18; p=0.91）。10-辅助化疗组的1年总生存率为51.8%（95%CI 47.0-56.4），监测组为48.4%（43.6-53.0）（HR 0.91，95%CI 0.77-1.09，p=0.32）。10-术前放疗组的年无病生存率为44.2%（95% CI 39.5-48.8），术前放疗和化疗组为46.4%（41.7-50.9）（HR 0.93，95% CI 0.79-1.10; p=0.38）。10-辅助化疗组的年无病生存率为47.0%（95%CI 42.2-51.6），监测组为43.7%（39.1-48.2）（HR 0.91，95%CI 0.77-1.08，p=0.29）。10年时，局部复发的累积发生率为22.4%（95% CI 17.1-27.6）单独放疗，11.8%（7.8-15.8）新辅助放疗和化疗，放疗和辅助化疗组为14.5%（10.1-18.9），辅助和新辅助化疗组为11.7%（7.7-15.6）（p=0.0017）。远处转移的累积发生率无差异（p=0.52）。长期副作用的频率在四组之间没有差异（p=0.22）。解释术前放疗后辅助氟尿嘧啶化疗（有或无化疗）不影响无病生存或总生存。我们的试验不支持目前的做法，辅助化疗后，术前放疗与化疗或不。新的治疗策略，包括新辅助化疗是必要的。
Background EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy-irrespective of timing-significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results.Methods We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1.8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m(2) per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m(2) per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523.Findings 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10.4 years (IQR 7.8-13.1), 10-year overall survival was 49.4% (95% CI 44.6-54.1) for the preoperative radiotherapy group and 50.7% (45.9-55.2) for the preoperative radiotherapy and chemotherapy group (HR 0.99, 95% CI 0.83-1.18; p=0.91). 10-year overall survival was 51.8% (95% CI 47.0-56.4) for the adjuvant chemotherapy group and 48.4% (43.6-53.0) for the surveillance group (HR 0.91, 95% CI 0.77-1.09, p=0.32). 10-year disease-free survival was 44.2% (95% CI 39.5-48.8) for the preoperative radiotherapy group and 46.4% (41.7-50.9) for the preoperative radiotherapy and chemotherapy group (HR 0.93, 95% CI 0.79-1.10; p=0.38). 10-year disease-free survival was 47.0% (95% CI 42.2-51.6) for the adjuvant chemotherapy group and 43.7% (39.1-48.2) for the surveillance group (HR 0.91, 95% CI 0.77-1.08, p=0.29). At 10 years, cumulative incidence of local relapse was 22.4% (95% CI 17.1-27.6) with radiotherapy alone, 11.8% (7.8-15.8) with neoadjuvant radiotherapy and chemotherapy, 14.5% (10.1-18.9) with radiotherapy and adjuvant chemotherapy and 11.7% (7.7-15.6) with both adjuvant and neoadjuvant chemotherapy (p=0.0017). There was no difference in cumulative incidence of distant metastases (p=0.52). The frequency of long-term side-effects did not differ between the four groups (p=0.22).Interpretation Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required.