Colorectal cancer (CRC) is a global health concern, ranking as the second leading cause of cancer-related deaths and the third most common cancer worldwide. In China, the burden is particularly high, with a significant portion of the global incidence attributed to this country. The majority of Chinese patients are diagnosed with advanced-stage CRC, often presenting with nonspecific symptoms that delay early detection.
The standard treatment for locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy (nCRT) followed by surgery, but its effectiveness in improving overall survival is limited. With a pathological complete response (pCR) rate of only 12-22% and a high incidence of distant metastasis, there is an urgent need for new treatment approaches to enhance survival and make organ preservation more feasible.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic colorectal cancer with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). However, these phenotypes are rare in rectal tumors, leaving the majority of patients without effective treatment options. This highlights the importance of exploring new combinations and strategies to improve outcomes.
Preclinical studies suggest that combining nCRT with ICIs may be a promising approach. Radiotherapy has been shown to induce immunogenic cell death, leading to the release of tumor antigens and the activation of cytotoxic T-cells. Recent Phase II trials have investigated different timing strategies for ICI administration in LARC, including induction, concurrent, and sequential approaches.
One notable study, VOLTAGE-A, demonstrated a significant increase in pCR rates when patients with microsatellite-stable (MSS) tumors received nivolumab consolidation after long-course chemoradiation. This was further supported by the NECTAR study, which reported an impressive 43.5% pCR rate when toripalimab was used concurrently with long-course chemoradiation.
Serplulimab, a fully humanized IgG4 monoclonal antibody targeting the PD-1 receptor, has shown promising results in metastatic colorectal cancer. In the ASTRUM-015 study, the addition of serplulimab to standard first-line treatment significantly improved progression-free survival and overall survival over a 2-year follow-up period.
However, the optimal sequencing and safety profile of PD-1 inhibitor-based combinations are still unknown. In this study, we aim to assess the safety and effectiveness of neoadjuvant long-course chemoradiation combined with serplulimab in patients with LARC.
Our retrospective cohort study included 29 patients who received neoadjuvant chemoradiotherapy (CRT) followed by serplulimab treatment and subsequent radical resection. The study population consisted of patients with high-risk LARC, characterized by advanced-stage tumors and the presence of multiple risk factors.
The treatment protocol involved intensity-modulated radiation therapy (IMRT) to the primary tumor and pelvic nodal basins, followed by concurrent chemotherapy with CapeOX or capecitabine. Serplulimab was administered every three weeks during the neoadjuvant phase.
The primary objective of the study was to determine the pCR rate, which was defined as the percentage of surgically treated patients achieving pCR. The secondary endpoint was to evaluate the adverse events that occurred during neoadjuvant treatment, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Our results showed a pCR rate of 31.0% and a major pathological response (MPR) rate of 65.5%. These outcomes are significantly higher than previous nCRT benchmarks and indicate the potential of this combination therapy. Additionally, 80% of patients with obstructive symptoms experienced early clinical relief, suggesting rapid tumor debulking.
Comparative analysis revealed that our cohort, despite having a higher baseline tumor burden, achieved comparable efficacy to other studies. The UNION trial, which used short-course radiotherapy with PD-1 inhibition, reported a pCR rate of 39.8%, highlighting the potential of this combination approach.
Grade ≥3 adverse events occurred in 48.3% of patients, primarily consisting of hematological toxicities such as neutropenia and lymphopenia. The safety profile was generally tolerable, mirroring the results of the TORCH study.
One notable finding was the high incidence of treatment-related lymphopenia (89.7%), which warrants further investigation. Preclinical models suggest that nodal irradiation may reduce circulating lymphocytes, essential for systemic antitumor immunity. Future protocols could explore reduced-field radiation techniques to preserve lymphatic function and maintain immunological competence.
While our study provides encouraging results, it is important to acknowledge its limitations, including the retrospective methodology, small sample size, and lack of long-term survival data. Prospective trials are needed to validate these findings and further explore the potential of serplulimab-enhanced nCRT in high-risk pMMR LARC.
In conclusion, our study demonstrates the feasibility and promising pathological response rates of serplulimab-enhanced nCRT in high-risk LARC. With tolerable toxicity levels, this combination therapy shows potential as a new treatment approach, offering hope for improved outcomes in this challenging disease.
