Adjuvant chemoradiotherapy versus completion total mesorectal excision after local excision for early rectal cancer (TESAR): a multicentre, randomised, controlled, phase 3, non-inferiority trial.

This study aimed to assess the oncological outcomes of adjuvant chemoradiotherapy as an organ-preserving alternative in patients with high-risk pT1 and low-risk pT2 rectal cancer.

本研究旨在评估作为器官保留替代方案的辅助性放化疗在高危pT1和低危pT2直肠癌患者中的肿瘤学结果。

Methods

This multicentre, open-label, randomised, controlled, phase 3, non-inferiority trial was conducted at 25 hospitals across the Netherlands and France.

这项多中心、开放标签、随机对照、第三阶段、非劣效试验在荷兰和法国的25家医院进行。

Patients aged 18 years or older with locally excised high-risk pT1 and low-risk pT2 rectal cancer located below the sigmoid takeoff were randomly assigned (1:1), via an interactive web-response system, to adjuvant chemoradiotherapy (25 × 1·8 Gy limited to the mesorectum, with oral capecitabine 825 mg/m2 twice daily) or cTME through an interactive web-response system.

年龄在18岁或以上的患者，局部切除的高风险pT1和低风险pT2直肠癌位于乙状结肠起始部以下，通过交互式网络响应系统随机分配（1:1），接受辅助性化疗放疗（25 × 1·8 Gy仅限于直肠系膜，口服卡培他滨825 mg/m2每日两次）或通过交互式网络响应系统进行cTME。

Randomisation was done via minimisation with stratification for age (<75 years vs ≥75 years), American Society of Anaesthesiologists (ASA) classification (ASA 1 vs ASA ≥2), type of local excision (surgical vs endoscopic), pathological tumour stage (high-risk pT1 vs low-risk pT2), and resection margin status (<1 mm vs ≥1 mm).

随机化是通过最小化法进行的，根据年龄（<75岁与≥75岁）、美国麻醉医师协会（ASA）分类（ASA 1与ASA ≥2）、局部切除类型（手术与内镜）、病理肿瘤分期（高风险pT1与低风险pT2）以及切缘状态（<1毫米与≥1毫米）进行分层。

The primary endpoint was 3-year locoregional recurrence, with a prespecified non-inferiority margin of 7%.

主要终点是3年内的局部区域复发，预先设定的非劣效性边界为7%。

Secondary endpoints included unsalvageable locoregional recurrence, disease-free survival, overall survival, treatment-related morbidity within 30 days (assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events criteria for adjuvant chemoradiotherapy and the Clavien-Dindo classification and the Comprehensive Complication Index for cTME), stoma rate, and quality of life.

次要终点包括无法挽救的局部区域复发、无病生存、总生存、30天内治疗相关并发症（使用国家癌症研究所辅助化疗和放疗的不良事件通用术语标准进行评估，以及使用Clavien-Dindo分类和cTME的全面并发症指数进行评估）、造口率以及生活质量。

All comparative analyses were conducted according to the intention-to-treat(ITT) and per-protocol principles.

所有比较分析均按照意向治疗（ITT）和按方案原则进行。

The trial is registered on ClinicalTrials.gov, NCT02371304.

该试验已在ClinicalTrials.gov上注册，注册号为NCT02371304。

On Oct 1, 2024, the trial was converted to a patient-preference design due to loss of equipoise before reaching its target sample size of 302 patients.

截至2024年10月1日，在达到目标样本量302名患者之前，由于失去了平衡状态，该试验被转换为患者偏好设计。

The current analysis includes patients randomly assigned until this transition.

当前分析包括了在此过渡期间被随机分配的患者。

Enrolment is ongoing within the patient-preference design.

患者偏好设计中的招募工作正在进行中。

Results

Between Nov 1, 2015, and Sept 14, 2024, 202 patients were randomly assigned, of whom 197 were included in the ITT analysis (adjuvant chemoradiotherapy, n=101; cTME, n=96).

在2015年11月1日至2024年9月14日期间，共有202名患者被随机分配，其中197名患者被纳入意向治疗（ITT）分析（辅助化疗放疗，n=101；cTME，n=96）。

Of these patients, 118 (59·9%) were male and 79 (40·1%) female; mean age was 64·7 years (SD 7·4), and mean BMI was 26·5 kg/m2 (SD 4·0).

在这些患者中，118名（59.9%）为男性，79名（40.1%）为女性；平均年龄为64.7岁（标准差7.4），平均体重指数（BMI）为26.5 kg/m²（标准差4.0）。

After a median follow-up of 50·0 months (IQR 27·0-62·0), five locoregional recurrences were reported: four in the adjuvant chemoradiotherapy group and one in the cTME group.

在中位随访50.0个月（四分位数间距27.0-62.0）后，报告了五例局部区域复发：其中四例在辅助性同步放化疗组，一例在cTME组。

Estimated 3-year locoregional recurrence rates were 5·0% (95% CI 1·6-11·3) after adjuvant chemoradiotherapy and 1·1% (0·0-5·5) after cTME.

估计的3年局部区域复发率在辅助性同步放化疗后为5.0%（95%置信区间1.6-11.3），而在cTME后为1.1%（0.0-5.5）。

Adjuvant chemoradiotherapy did not meet the non-inferiority margin of 7% for 3-year locoregional recurrence (difference 3·9% [90% CI 0·0-9·4]; one-sided pnon-inferiority=0·16).

辅助性化疗放疗未达到3年局部区域复发的非劣效性边界值7%（差异3.9% [90% 置信区间 0.0-9.4]；单侧p非劣效性=0.16）。

However, four of the five locoregional recurrences (three in the adjuvant chemoradiotherapy group and one in the cTME group) were successfully salvaged, resulting in a 3-year unsalvageable locoregional recurrence rate of 1·3% (95% CI 0·1-6·1) after adjuvant chemoradiotherapy and 0·0% (0·0-5·6) after cTME. 3-year disease-free survival was 92·0% (95% CI 84·4-96·4) after adjuvant chemoradiotherapy compared with 96·3% (89·7-99·1) after cTME (hazard ratio[HR] 3·20 [95% CI 0·88-11·6]). 3-year overall survivalwas similar in both groups (98·9% [95% CI 94·1-99·9] for adjuvant chemoradiotherapy and 98·9% [93·7-99·9] for cTME; HR 1·64 [95% CI 0·22-18·0]).

然而，在五个局部区域复发中，有四个（辅助性化疗放疗组三个，cTME组一个）成功进行了挽救治疗，导致辅助性化疗放疗后3年无法挽救的局部区域复发率为1.3%（95% 置信区间 0.1-6.1），cTME后为0.0%（0.0-5.6）。辅助性化疗放疗后3年无病生存率为92.0%（95% 置信区间 84.4-96.4），而cTME后为96.3%（89.7-99.1）（风险比[HR] 3.20 [95% 置信区间 0.88-11.6]）。两组3年总生存率相似（辅助性化疗放疗为98.9% [95% 置信区间 94.1-99.9]，cTME为98.9% [93.7-99.9]；HR 1.64 [95% 置信区间 0.22-18.0]）。

Treatment-related toxicity occurred in 82 (78%) of 105 patients after adjuvant chemoradiotherapy (grade ≥3 in ten [9·5%] of 105 patients).

在接受辅助化疗放疗的105名患者中，有82名（78%）出现了治疗相关毒性（其中10名[9.5%]患者的毒性等级为3级或以上）。

Post-operative complications occurred in 32 (43·8%) of 73 patients after cTME (Clavien-Dindo grade ≥IIIa in 11 [15·1%] patients; median Comprehensive Complication Index 21·8 [IQR 8·7-39·7]). 3-year stoma rates were significantly lower after adjuvant chemoradiotherapy (2·6% [95% CI 0·5-8·3]) versus cTME (45·4% [35·0-55·3]; p<0·0001). 1-year quality-of-life outcomes were comparable or favoured adjuvant chemoradiotherapy across nearly all domains.

在接受cTME手术的73名患者中，有32名（43.8%）出现了术后并发症（其中11名[15.1%]患者的Clavien-Dindo分级为IIIa级或以上；综合并发症指数中位数为21.8[四分位数间距8.7-39.7]）。

interpretation

Non-inferiority of adjuvant chemoradiotherapy compared with cTME for 3-year locoregional recurrence could not formally be demonstrated.

辅助性化疗放疗与cTME相比，无法正式证明3年局部区域复发的非劣效性。

However, loss of equipoise hampered patient accrual, precluding the trial from reaching its prespecified sample size.

然而，平衡的丧失阻碍了患者的招募，使得试验无法达到其预定的样本量。

Although the 3-year locoregional recurrence rate numerically favoured cTME, adjuvant chemoradiotherapy resulted in low rates of unsalvageable locoregional recurrence, and substantially reduced treatment-related morbidity and stoma rates.

尽管3年局部区域复发率在cTME中数值上有所优势，但辅助性化疗放疗导致无法挽救的局部区域复发率低，并显著降低了治疗相关发病率和造口率。

These findings challenge cTME as the standard of care for patients with locally excised high-risk pT1 and low-risk pT2 rectal cancer.

这些发现对cTME作为局部切除高风险pT1和低风险pT2直肠癌患者的标准护理提出了挑战。

funding

Dutch Cancer Society.

荷兰癌症协会。