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.
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BACKGROUND: Neoadjuvant short-course radiotherapy combined with chemotherapy as total neoadjuvant therapy increases the pathological complete response rate for patients with locally advanced rectal cancer. The potential synergistic effects of combining radiotherapy and immunotherapy might benefit patients with locally advanced rectal cancer. 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. METHODS: SPRING-01 was a single-centre, open-label, phase 2, randomised controlled trial done at the Shandong Provincial Hospital, China. 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. Participants were randomly assigned (1:1) to receive either sintilimab plus capecitabine-oxaliplatin or capecitabine-oxaliplatin alone. 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. Neither patients nor clinical staff were masked to treatment allocation; however, pathological assessments and data analyses were conducted in a blinded manner. 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. Total mesorectal excision surgery, was done 2-3 weeks after the completion of total neoadjuvant therapy. The primary endpoint was the pathological complete response rate in the intention-to-treat population. The trial was registered with the Chinese Clinical Trial Registry (ChiCTR2100052288). FINDINGS: 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. Median follow-up was 25 months (IQR 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). 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. 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. 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%]). 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. The most common grade 3-4 adverse event was thrombocytopenia, reported in six (12%) patients in the sintilimab plus capecitabine-oxaliplatin group and in 11 (22%) patients in the capecitabine-oxaliplatin group. 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. The most common serious adverse event in both treatment groups was thrombocytopenia. One (2%) patient in the capecitabine-oxaliplatin group died from septic shock due to acute ileus. No treatment-related deaths occurred in the sintilimab plus capecitabine-oxaliplatin group. 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. These findings suggest that this regimen might be a promising neoadjuvant treatment approach for locally advanced rectal cancer. 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. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.