Objective: Total
neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced
rectal cancer. This study aims to investigate the safety and feasibility of
programmed cell death protein 1 (PD-1) antibody combined with total
neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low
rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low
rectal cancer with high-risk factors receiving PD-1 antibody combined with
neoadjuvant chemoradiotherapy in
Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal
adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of
tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant
metastases; (6) no prior pelvic
radiation therapy, no prior
chemotherapy or surgery for
rectal cancer; (7) no systemic
infection requiring
antibiotic treatment and no
immune system disease. Exclusion criteria: (1) anticipated unresectable
tumor after
neoadjuvant treatment; (2) patients with a history of a prior
malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or
experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received
immunotherapy (PD-1 antibody). The
neoadjuvant therapy consisted of three stages: PD-1 antibody (
sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated
radiation therapy (IMRT) with gross
tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after
radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the
tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the
tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the
neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic
bleeding and 1 of
pseudomembranous enteritis), 3 cases of grade I anastomotic
stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated
adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their
tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the
tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with
signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total
neoadjuvant chemoradiotherapy in the treatment of locally advanced
rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.