Addition of irinotecan to chemoradiotherapy as preoperative treatment for locally advanced rectal cancer (ARISTOTLE): a multicentre, open-label, phase 3, randomised controlled trial.

Concomitant systemic anticancer therapy with standard fluoropyrimidines has not generally improved outcomes.

与标准氟嘧啶类药物联合的全身性抗癌治疗通常并未改善治疗结果。

Small studies reported high pathological complete response rates and acceptable toxicity using irinotecan and fluoropyrimidine chemoradiation.

小规模研究表明，使用伊立替康和氟嘧啶类药物进行的放化疗可获得较高的病理完全缓解率，并且毒性反应可接受。

We aimed to explore the effect of the addition of concomitant irinotecan to standard-of-care chemoradiotherapy in patients with locally advanced rectal cancer.

我们旨在探讨在局部晚期直肠癌患者的标准治疗中加入伊立替康的联合放化疗的效果。

Methods

ARISTOTLE is a multicentre, open-label, parallel-design, phase 3, randomised controlled trialconducted at 75 UK hospital sites treating patients with rectal cancer.

ARISTOTLE是一项在英国75家医院进行的多中心、开放标签、平行设计、III期、随机对照试验，治疗直肠癌患者。

Patients were eligible if they were aged at least 18 years with MRI-defined, locally advanced rectal cancer threatening or involving resection margins without metastases.

患者年龄至少18岁，MRI定义的局部晚期直肠癌威胁或涉及切除边缘，但无转移，符合入选条件。

Patients were randomly assigned (1:1) to preoperative radiotherapy 45 Gy in 25 daily fractions, combined with either oral capecitabine 900 mg/m2 alone twice daily on weekdays (standard-of-care group) or oral capecitabine 650 mg/m2 twice daily on weekdays plus intravenous irinotecan 60 mg/m2 once weekly in weeks 1-4 (irinotecan group).

患者被随机分配（1:1）接受术前放疗，总剂量45 Gy，分25次每日一次，联合口服卡培他滨900 mg/m2，工作日每日两次（标准治疗组）或口服卡培他滨650 mg/m2，工作日每日两次，加上伊立替康60 mg/m2，每周一次，持续4周（伊立替康组）。

Randomisation was done centrally, with allocation concealed to investigators; masking of patients and treating clinicians was not feasible.

随机化由中心进行，分配情况对研究者保密；对患者和治疗医生进行盲法是不可行的。

Stratification was by radiotherapy centre, mesorectal fascia involvement, and presence or absence of equivocal metastatic disease.

分层是根据放射治疗中心、直肠系膜筋膜受累情况以及是否存在可疑转移性疾病。

The primary endpoint was disease-free survival, with analysis done on a modified intention-to-treatbasis (ie, all eligible patients who were randomly assigned to treatment).

主要终点是无病生存期，分析是基于修改后的意向治疗分析（即，所有被随机分配治疗的合格患者）。

Safety analyses were conducted in all patients who started protocol treatment (as-treated population).

安全性分析是在所有开始按方案治疗的患者中进行的（即治疗后人群）。

For time-to-event endpoints, patients without an event were censored at the date they were last known to be alive; missing radiological and pathological response assessments were classified as non-response.

对于时间到事件终点，没有事件发生的患者在他们最后已知存活的日期被截断；缺失的放射学和病理学反应评估被归类为无反应。

The study is registered with EudraCT, 2008-005782-59, and is complete.

该研究已在EudraCT上注册，编号为2008-005782-59，研究已完成。

Results

Between Oct 25, 2011, and July 5, 2018, 589 patients were randomly assigned to treatment; after exclusions, 564 were included in the modified intention-to-treatpopulation (284 in the standard-of-care group and 280 in the irinotecan group). 370 (66%) patients were male, 194 (34%) were female, and median age was 61 years (IQR 54-68); ethnicity data were not collected.

从2011年10月25日到2018年7月5日，共有589名患者被随机分配接受治疗；排除后，有564名患者被纳入修改后的意向治疗人群（标准治疗组284人，伊立替康组280人）。370（66%）名患者为男性，194（34%）名患者为女性，中位年龄为61岁（四分位数间距54-68岁）；未收集种族数据。

Staging in both groups was similar: 223 (79%) patients in the standard-of-care group and 212 (76%) in the irinotecan group had mrT3 tumours; 44 (15%) and 45 (16%) had mrT4 tumours, respectively.

两组的分期相似：标准治疗组有223（79%）名患者和伊立替康组有212（76%）名患者为mrT3肿瘤；分别有44（15%）名和45（16%）名患者为mrT4肿瘤。

Patients in the irinotecan group were less likely to receive 45 Gy radiotherapy than in the standard-of-care group (208 [75%] of 276 vs 251 [89%] of 283) or at least 90% of the planned capecitabine dose (187 [68%] of 276 vs 253 [89%] of 283).

伊立替康组的患者比标准治疗组更不可能接受45 Gy放射治疗（276名患者中的208名[75%] vs 283名患者中的251名[89%]）或至少90%的计划卡培他滨剂量（276名患者中的187名[68%] vs 283名患者中的253名[89%]）。

With a median follow-up was 78 months (95% CI 75-86), 36-month disease-free survival was 68% (95% CI 63-73) in the irinotecan group versus 67% (61-72) in the standard-of-care group (hazard ratio0·91 [95% CI 0·68-1·23]; p=0·54).

中位随访时间为78个月（95%置信区间75-86），伊立替康组的36个月无病生存率为68%（95%置信区间63-73），而标准治疗组为67%（61-72）（风险比0·91 [95%置信区间0·68-1·23]；p=0.54）。

Deaths occurred in 88 (31%) patients in the irinotecan group and 92 (32%) in the standard-of-care group; rectal cancer was the leading cause, occurring in 59 (67%) patients in the irinotecan group and 67 (73%) in the standard-of-care group.

伊立替康组有88名（31%）患者死亡，标准治疗组有92名（32%）患者死亡；直肠癌是主要死因，伊立替康组有59名（67%）患者，标准治疗组有67名（73%）患者。

There were five deaths related to protocol treatment: three in the irinotecan group (two had a thromboembolic event and one had multiorgan failure plus sepsis) and two in the standard-of-care group (one cardiac arrest and one febrile neutropenia).

与方案治疗相关的死亡有五例：伊立替康组三例（两例发生血栓栓塞事件，一例发生多器官衰竭伴败血症），标准治疗组两例（一例心脏骤停，一例发热性中性粒细胞减少症）。

Grade 3 or worse were more frequent in patients receiving irinotecan than those receiving standard of care (215 [78%] vs 148 [52%]), including haematological investigations (235 [85%] vs 109 [39%]) and gastrointestinal events (57 [21%] vs 35 [12%]), notably diarrhoea (38 [14%] vs ten [4%]), lymphocyte count decreased (181 [66%] vs 100 [35%]), and neutrophil count decreased (27 [10%] vs three [1%]).

接受伊立替康治疗的患者中，3级或更严重的不良事件比接受标准治疗的患者更频繁（215 [78%] vs 148 [52%]），包括血液学检查（235 [85%] vs 109 [39%]）和胃肠道事件（57 [21%] vs 35 [12%]），特别是腹泻（38 [14%] vs 十 [4%]），淋巴细胞计数减少（181 [66%] vs 100 [35%]），和中性粒细胞计数减少（27 [10%] vs 三 [1%]）。

interpretation

For MRI-defined, high-risk, locally advanced rectal cancer, the addition of irinotecan to standard of care did not improve outcomes and should not be used in combination with radiotherapy plus capecitabine.

对于MRI定义的高风险局部晚期直肠癌，将伊立替康加入标准治疗并未改善结果，不应与放疗加卡培他滨联合使用。

funding

Cancer Research UK.

癌症研究英国。