A novel neoadjuvant treatment approach combining short-course radiotherapy with immunotherapy has demonstrated encouraging long-term survival outcomes in patients with locally advanced rectal cancer (LARC), according to 3-year follow-up data from a phase 2 trial published in BMC Medicine.
The study evaluated neoadjuvant short-course radiotherapy (SCRT) followed by the PD-1 inhibitor camrelizumab and CAPOX chemotherapy in 30 patients with previously untreated T3-4N0M0 or T1-4N+ M0 rectal adenocarcinoma. With a median follow-up of 40.8 months, the treatment achieved a 3-year disease-free survival (DFS) rate of 80.2% (95% CI 58.6-91.3%) and overall survival rate of 93.3% (95% CI 75.9-98.3%).
Treatment Protocol and Patient Population
The trial enrolled patients aged 18 to 75 years with tumors located within 10 cm of the anal verge and ECOG performance status of 0 or 1. The treatment regimen consisted of five daily doses of 5 Gy radiotherapy over five consecutive days, followed one week later by two cycles of camrelizumab (200 mg intravenously) plus CAPOX chemotherapy administered every three weeks. Total mesorectal excision was scheduled one week after completion of neoadjuvant treatment.
The patient population included challenging cases, with 86.7% having positive lymph nodes and 33.3% presenting with N2 disease. Notably, 70% had positive circumferential resection margins and 40% had extramural venous invasion at baseline. The majority of patients (93.3%) had microsatellite-stable (MSS) tumors, a population that typically shows limited response to immunotherapy.
Superior Outcomes in High-Risk Patients
The survival outcomes appeared numerically superior to standard total neoadjuvant therapy strategies, which typically achieve 3-year DFS rates of 64.5-76% and overall survival rates of 86.1-91%. This improvement is particularly noteworthy given the high-risk features present in the study population.
"Our data support the potential efficacy of neoadjuvant SCRT followed by camrelizumab and CAPOX regimen in LARC, as indicated by 3-year survival outcomes, suggesting that this may be an alternative therapeutic strategy, especially with the potential to address an unmet need for MSS patients," the researchers wrote.
Predictive Factors for Enhanced Outcomes
Subgroup analyses revealed several factors associated with improved 3-year DFS outcomes. Patients achieving pathological complete response (pCR) demonstrated 100% 3-year DFS compared to 63.5% in non-responders (p=0.018). Similarly, patients with postoperative pathological node-negative status achieved 94.4% 3-year DFS versus 50% in those with positive nodes (p=0.003).
Additional favorable prognostic factors included negative baseline circumferential resection margin (100% vs 69.5% 3-year DFS, p=0.036), negative extramural venous invasion (100% vs 54.5%, p=0.036), and PD-L1 combined positive score ≥1 (100% vs 74.3%).
Safety Profile and Treatment Completion
Of the 27 patients who underwent surgery, 21 (77.8%) received subsequent adjuvant CAPOX chemotherapy with a median of four cycles. The treatment maintained a favorable safety profile, with no grade 5 adverse events or emergent toxicities observed during the extended follow-up period. Two patients required dose reductions due to weight loss and hand-foot syndrome, while three discontinued oxaliplatin due to grade 2 toxicities.
Clinical Implications for MSS Patients
The results are particularly significant for patients with MSS tumors, who represent the vast majority of rectal cancer cases but have historically shown limited benefit from immunotherapy. The combination of SCRT with sequential immunotherapy and chemotherapy may offer a promising alternative to standard approaches.
"SCRT upregulates programmed cell death-ligand 1 (PD-L1) expression and maintains it at a high level prior to surgery, which may synergize with immunotherapy at an early stage to mitigate the immunosuppressive effects and improve efficacy," the researchers explained.
The findings have been further validated in the phase 3 UNION trial, supporting the potential for this approach to become a new treatment standard for locally advanced rectal cancer patients, particularly those with high-risk features and MSS tumors.
