Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial
Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial
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DOI：
10.1016/s1470-2045(17)30086-4
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发表时间：
2017-03-01
期刊：
影响因子：
51.1
通讯作者：
Martling, Anna
中科院分区：
文献类型：
--
作者：
Erlandsson, Johan;Holm, Torbjorn;Martling, Anna
背景放射治疗可降低直肠癌局部复发的风险。然而，最佳的放射治疗分割和放射治疗与手术之间的间隔仍然存在争议。我们的目的是研究在三种不同放疗方案之间随机分配的患者的复发情况，这些放疗方案与分割和手术时间有关。（斯德哥尔摩III），所有经活检证实的直肠腺癌患者，无不可切除或远处转移的体征，无严重的心血管合并症，并计划从18家瑞典医院进行腹部切除术。受试者随机分配排列区组，按参与中心分层，接受5 x 5戈伊放射剂量，1周内手术（短程放疗）或4-8周后手术（短程放疗延迟）或25 x 2戈伊放射剂量，4-8周后手术（长程放疗延迟）。在方案修订后，根据医院偏好，随机化可包括所有三种治疗或仅两种短程放疗治疗。主要终点是从随机化日期至局部复发日期计算的至局部复发时间。如果风险比（HR）的双侧90% CI上限不超过1.7，则认为治疗组之间的比较具有非劣效性。根据所有终点的意向治疗对患者进行分析。该研究在www.example.com注册ClinicalTrials.gov，编号NCT 00904813。结果在1998年10月5日至2013年1月31日期间，招募并随机分配了840名患者;三组随机化中的385例患者，其中129例患者被随机分配接受短程放疗，128例患者被随机分配接受短程放疗延迟，128例患者被随机分配接受长程放疗延迟，455例患者在两组随机分组中，其中228例随机分配接受短程放疗，227例随机分配接受短程延迟放疗。在任何局部复发患者中，汇总短程放疗比较中，短程放疗组从随机化日期至局部复发的中位时间为33.4个月（范围18.2-62.2），短程放疗延迟组为19.3个月（8.5-39.5）。长期放疗延迟组的中位局部复发时间为33.3个月（范围17.8-114.3）。在整个试验中，局部复发的累积发生率为接受短程放疗的357例患者中有8例，接受短程放疗延迟的355例患者中有10例，接受长程放疗的128例患者中有7例（HR vs短程放疗：短程放疗延迟1.44 [95% CI 0.41-5.11];长程放疗延迟2.24 [0.71-7.10]; p=0.48;两者均被视为非劣效）。急性辐射引起的毒性记录在一个病人（
Background Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery.Methods In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 x 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 x 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1.7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813.Findings Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33.4 months (range 18.2-62.2) in the short-course radiotherapy group and 19.3 months (8.5-39.5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33.3 months (range 17.8-114.3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1.44 [95% CI 0.41-5.11]; long-course radiotherapy with delay 2.24 [0.71-7.10]; p=0.48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (