Total neoadjuvant treatment with short-course radiotherapy followed by sintilimab plus capecitabine-oxaliplatin versus short-course radiotherapy followed by capecitabine-oxaliplatin in patients with locally advanced rectal cancer (SPRING-01): a single-centre, open-label, phase 2, randomised controlled trial.

The potential synergistic effects of combining radiotherapy and immunotherapy might benefit patients with locally advanced rectal cancer.

结合放疗和免疫治疗的潜在协同效应可能对局部晚期直肠癌患者有益。

We aimed to compare the efficacy and safety of short-course radiotherapy followed by capecitabine-oxaliplatin chemotherapy with or without immunotherapy as total neoadjuvant therapy in patients with locally advanced rectal cancer.

我们旨在比较短程放疗后接受卡培他滨-奥沙利铂化疗，有或没有免疫治疗作为总新辅助治疗在局部晚期直肠癌患者中的疗效和安全性。

Methods

SPRING-01 was a single-centre, open-label, phase 2, randomised controlled trialdone at the Shandong Provincial Hospital, China.

SPRING-01是在中国山东省立医院进行的一项单中心、开放标签、2期、随机对照试验。

Patients were aged 18-85 years with an Eastern Cooperative Oncology Group performance status of 0-1 and had biopsy-confirmed, newly diagnosed, treatment-naive, primary, locally advanced rectal adenocarcinoma with at least one of the following features: clinical tumour stage T3-4 or greater, clinical nodal stage N1 or higher, extramural vascular invasion, mesorectal fascia involvement, or lateral lymph node metastasis.

患者年龄在18-85岁之间，东部肿瘤协作组表现状态为0-1，且通过活检确认为新诊断的、未经治疗的、原发性、局部晚期直肠腺癌，具有以下至少一个特征：临床肿瘤分期T3-4或更高级别，临床淋巴结分期N1或更高，脉管外血管侵犯，肠系膜筋膜受累，或侧方淋巴结转移。

Participants were randomly assigned (1:1) to receive either sintilimab plus capecitabine-oxaliplatin or capecitabine-oxaliplatin alone.

参与者被随机分配（1:1）接受 sintilimab 加卡培他滨-奥沙利铂治疗或仅接受卡培他滨-奥沙利铂治疗。

The randomisation sequence was generated using computer-generated random numbers with SAS software version 9.4, using a simple randomisation method without stratification or blocking, and allocation was concealed using opaque, sealed envelopes.

随机序列是使用 SAS 软件版本 9.4 生成的计算机随机数，采用简单的随机化方法，不进行分层或阻塞，并使用不透明的密封信封进行分配隐藏。

Neither patients nor clinical staff were masked to treatment allocation; however, pathological assessments and data analyses were conducted in a blinded manner.

患者和临床工作人员均未对治疗分配进行掩蔽；然而，病理评估和数据分析是以盲法进行的。

Patients received short-course radiotherapy (5 × 5 Gy over 5 days) followed by six cycles of intravenous capecitabine-oxaliplatin chemotherapy (intravenous oxaliplatin 130 mg/m2 over 2 h on day 1, and oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 3-week cycle) with or without intravenous sintilimab (200 mg/m2 on day 1 of each 3-week cycle), starting 1 week after completion of radiotherapy.

患者接受了短程放疗（5天内5次5 Gy）后，接受了六周期静脉注射卡培他滨-奥沙利铂化疗（静脉注射奥沙利铂130 mg/m2，持续2小时，第1天；口服卡培他滨1000 mg/m2，每天两次，每3周为一个周期的第1-14天），有或没有静脉注射信迪利单抗（每3周周期的第1天200 mg/m2），从放疗完成后的第1周开始。

Total mesorectal excision surgery, was done 2-3 weeks after the completion of total neoadjuvant therapy.

在完成全部新辅助治疗后的2-3周内进行了全直肠系膜切除术。

The primary endpoint was the pathological complete response rate in the intention-to-treatpopulation.

主要终点是在意向治疗人群中病理完全缓解率。

The trial was registered with the Chinese Clinical Trial Registry (ChiCTR2100052288).

该试验已在中国临床试验注册中心注册，注册号为ChiCTR2100052288。

Results

Between Oct 8, 2021, and Sept 26, 2023, 116 patients with locally advanced rectal cancer were screened, of whom 98 eligible patients were randomly assigned to the sintilimab plus capecitabine-oxaliplatin group (n=49) or the capecitabine-oxaliplatin group (n=49). 68 (69%) of 98 patients were male and 30 (31%) were female; all patients were Asian.

在2021年10月8日至2023年9月26日期间，共有116名局部晚期直肠癌患者接受了筛查，其中98名符合条件的患者被随机分配到 sintilimab 加卡培他滨-奥沙利铂组（n=49）或卡培他滨-奥沙利铂组（n=49）。98名患者中有68名（69%）为男性，30名（31%）为女性；所有患者均为亚洲人。

Median follow-up was 25 months (IQR 20-32).

中位随访时间为25个月（四分位数间距20-32）。

The pathological complete response rate was significantly higher in the sintilimab plus capecitabine-oxaliplatin group than in the capecitabine-oxaliplatin group (29 [59·2%, 95% CI 45·4-72·9] vs 16 [32·7%, 19·5-45·8]; p=0·015).

sintilimab联合卡培他滨-奥沙利铂组的病理完全缓解率显著高于卡培他滨-奥沙利铂组（29 [59·2%，95% 置信区间 45·4-72·9] 对比 16 [32·7%，19·5-45·8]；p=0·015）。

Postoperative complications occurred in 11 (24% [95% CI 12-37]) of 45 patients in the sintilimab plus capecitabine-oxaliplatin group and in five (11% [2-21]) of 44 in the capecitabine-oxaliplatin group.

sintilimab联合卡培他滨-奥沙利铂组的45名患者中有11名（24% [95% 置信区间 12-37]）发生了术后并发症，而在卡培他滨-奥沙利铂组的44名患者中有5名（11% [2-21]）发生了术后并发症。

Treatment-related adverse events during neoadjuvant therapy occurred in 45 (92%) of 49 patients in the sintilimab plus capecitabine-oxaliplatin group and in 44 (90%) of 49 patients in the capecitabine-oxaliplatin group.

在新辅助治疗期间， sintilimab联合卡培他滨-奥沙利铂组的49名患者中有45名（92%）和卡培他滨-奥沙利铂组的49名患者中有44名（90%）出现了治疗相关的不良事件。

The most common treatment-related adverse events in the sintilimab plus capecitabine-oxaliplatin group and the capecitabine-oxaliplatin group were thrombocytopenia (18 [37%] vs 26 [53%]), leukopenia (19 [39%] vs 26 [53%]), anaemia (27 [55%] vs 33 [67%]), nausea or vomiting (25 [51%] vs 27 [55%]), and diarrhoea (21 [43%] vs 24 [49%]).

sintilimab联合卡培他滨-奥沙利铂组和卡培他滨-奥沙利铂组最常见的治疗相关不良事件是血小板减少症（18 [37%] 对比 26 [53%]）、白细胞减少症（19 [39%] 对比 26 [53%]）、贫血（27 [55%] 对比 33 [67%]）、恶心或呕吐（25 [51%] 对比 27 [55%]）和腹泻（21 [43%] 对比 24 [49%]）。

Grade 3-4 treatment-related adverse events were observed in 16 (33%) patients in the sintilimab plus capecitabine-oxaliplatin group and 17 (35%) patients in the capecitabine-oxaliplatin group.

在 sintilimab 加卡培他滨-奥沙利铂组中，观察到 16 (33%) 名患者出现 3-4 级治疗相关不良事件，在卡培他滨-奥沙利铂组中，有 17 (35%) 名患者出现 3-4 级治疗相关不良事件。

The most common grade 3-4 adverse eventwas thrombocytopenia, reported in six (12%) patients in the sintilimab plus capecitabine-oxaliplatin group and in 11 (22%) patients in the capecitabine-oxaliplatin group.

最常见的 3-4 级不良事件是血小板减少症，在 sintilimab 加卡培他滨-奥沙利铂组中报告了六 (12%) 名患者，在卡培他滨-奥沙利铂组中报告了 11 (22%) 名患者。

Serious adverse events occurred in 15 (31%) of 49 patients in the sintilimab plus capecitabine-oxaliplatin group and in nine (18%) of 49 patients in the capecitabine-oxaliplatin group.

在 sintilimab 加卡培他滨-奥沙利铂组的 49 名患者中，有 15 名（31%）发生了严重不良事件，在卡培他滨-奥沙利铂组的 49 名患者中，有 9 名（18%）发生了严重不良事件。

The most common serious adverse eventin both treatment groups was thrombocytopenia.

在两个治疗组中，最常见的严重不良事件是血小板减少症。

One (2%) patient in the capecitabine-oxaliplatin group died from septic shock due to acute ileus.

卡培他滨-奥沙利铂组中有一名（2%）患者因急性肠梗阻导致的败血性休克死亡。

No treatment-related deaths occurred in the sintilimab plus capecitabine-oxaliplatin group.

信迪利单抗联合卡培他滨-奥沙利铂组中未发生与治疗相关的死亡事件。

interpretation

In patients with locally advanced rectal cancer, short-course radiotherapy combined with sintilimab and capecitabine-oxaliplatin as a total neoadjuvant treatment significantly increased the pathological complete response rate while maintaining manageable safety profile.

在局部晚期直肠癌患者中，短程放疗联合 sintilimab 和卡培他滨-奥沙利铂作为总新辅助治疗显著提高了病理完全缓解率，同时保持了可控的安全性。

These findings suggest that this regimen might be a promising neoadjuvant treatment approach for locally advanced rectal cancer.

这些发现表明，这种方案可能是局部晚期直肠癌的一个有前途的新辅助治疗方法。

funding

The National Natural Science Foundation of China; The Special Foundation for Taishan Scholars Program of Shandong Province; The Key Research and Development Program of Shandong Province; The Natural Science Foundation of Shandong Province; The China Postdoctoral Science Foundation; and Innovent Biologics.

中国国家自然科学基金；山东省泰山学者特别基金；山东省重点研发计划；山东省自然科学基金；中国博士后科学基金；以及Innovent Biologics公司。

translation

For the Chinese translation of the abstract see Supplementary Materials section.

摘要的中文翻译请参见补充材料部分。