## Introduction
Globally, colorectal cancer (CRC) is the second most common cause of cancer-related death adn the third most common cancer.1-3 This disease burden is most noticeable in China,4-6 where 517,000 newly diagnosed cases of CRC accounted for 26.8% of the global incidence in 2022.7 About 83% of chinese patients present with advanced disease at initial diagnosis, as early-stage CRC often presents with nonspecific symptoms. With only 12-22% pathological complete response (pCR) rates and 30% distant metastasis incidence, the standard neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) surgery for locally advanced rectal cancer (LARC; T3-4/N+) achieves local recurrence rates below 10% but shows limited efficacy in improving overall survival (OS).8-10
The treatment of metastatic colorectal cancer (mCRC) with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) has been transformed by immune checkpoint inhibitors (ICIs), which reverse tumor-mediated T-cell suppression to restore anti-tumor immunity.11-13 Though, dMMR/MSI-H phenotypes are present in ≤5% of rectal tumors, making ICIs ineffective for the majority of patients.14,15 this emphasizes how urgently new treatment approaches are needed to raise pCR rates, make organ preservation easier, and increase survival.
The molecular justification for combining nCRT with ICIs comes from preclinical findings that radiotherapy causes immunogenic cell death, which promotes tumor antigen release and cytotoxic T-cell priming. Three temporal techniques have been used in recent phase II trials investigating ICI-nCRT combinations in LARC: induction (ICIs before radiotherapy), concurrent (ICIs during radiotherapy), and sequential (ICIs after radiotherapy).9 In microsatellite-stable (MSS) patients undergoing long-course chemoradiation (50.4 Gy + capecitabine) followed by nivolumab consolidation, the historic VOLTAGE-A study (NCT03409721) showed a 30% pCR rate (11/37), exceeding previous pCR rates of less than 20% with conventional nCRT.16 This combinatorial paradigm is further supported by the recent multicenter NECTAR study, which used concurrent toripalimab with long-course chemoradiation and reported a 43.5% pCR rate (20/46 MSS patients).17
Serplulimab, a fully humanized IgG4 monoclonal antibody that specifically targets the PD-1 receptor, exhibits a distinct binding pattern to the PD-1 receptor and effectively inhibits signal transduction mediated by both PD-L1 and PD-L2.18 In ASTRUM-015 study,19 when serplulimab was added to the standard first-line treatment for metastatic colorectal cancer (mCRC), significant improvements in progression-free survival (PFS) and
Patient Characteristics and Treatment outcomes in Locally Advanced Rectal Cancer
This study evaluated the effectiveness and side effects of a treatment regimen in 29 patients with locally advanced rectal cancer. All patients had grade IIIB/IIIC (AJCC 8th edition) proficient mismatch repair (pMMR) cancers, with a median age of 60 years (range: 28-75). high-risk characteristics were prevalent, with 72.4% (21/29) exhibiting at least two risk factors, including mesorectal fascia invasion (65.5%, 19/29), cT4 disease (51.7%,15/29),cN2 nodal involvement (86.2%, 25/29), mid-low rectal tumors (≤10 cm from anal verge) (79.3%, 23/29), and extramural vascular invasion (13.8%,4/29). (See Table 1 for detailed patient characteristics). the study timeline and overview are presented in figure 1.
Following neoadjuvant therapy, R0 resection was achieved in all 29 patients undergoing extensive mesorectal excision surgery. Pathological evaluation revealed a total tumor regression (ypT0N0) in 31.0% (9/29; 95% CI 27.9-34.2%) and a major pathological response (TRG 1-2) in 65.5% (19/29; 95% CI 62.3-68.7%). Postoperative pathological remission results are shown in Figure 2. Treatment outcomes and surgical parameters are detailed in Table 2.
The majority of treatment-related side effects were grade 1-2 toxicities (See Table 3).
Table 1 Patient Characteristics
Figure 1 Study flowchart and overview of the study timeline.
Table 2 Treatment Outcomes and Surgical Parameters
Figure 2 Histopathological tumor regression grade (TRG) per tumor in patients.
table 3 (Information incomplete in provided text)
Critical context is revealed through comparative analysis: our cohort (predominately high-risk stage IIIB/C: 51.7% cT4, 86.2% cN2) achieved comparable efficacy despite greater baseline tumor burden, whereas the Phase III UNION trial (NCT04575935)30 reported 39.8% pCR (vs 15.3% control) using short-course radiotherapy with PD-1 inhibition. These results are supported by a 2024 meta-analysis of 533 LARC patients, which found that the pooled pCR and MPR rates for pMMR/MSS subgroups were 38% and 60%, respectively.31 Grade ≥3 adverse events (46.7%) mirrored the TORCH study (43.8%),32 with hematological toxicities (neutropenia: 30%; lymphopenia: 16.7%) accounting for the majority of the tolerable safety profiles.
Notably, 90% of cases of treatment-related lymphopenia need for mechanistic research. According to preclinical models, circulating lymphocytes essential for systemic antitumor immunity may be diminished by nodal irradiation.33 To maintain immunological competence, future protocols might investigate reduced-field radiation that spares uninvolved lymphatics.
Our study’s shortcomings include its retrospective methodology, small sample size, and lack of long-term survival data, all of which call for prospective trials to validate the findings. these encouraging findings demonstrate the feasibility of serplulimab-enhanced nCRT in high-risk pMMR LARC, attaining tolerable toxicity levels and pathological response rates that surpass those of customary therapy.
Disclosure
The authors declare that they have no conflicts of interest related to this study.
References
1. Darmadi D,Mohammadian-Hafshejani A,Kheiri S. Global disparities in colorectal cancer: unveiling the present landscape of incidence and mortality rates, analyzing geographical variances, and assessing the human development index. J Prev Med Hyg. 2024;65:E499-514. doi:10.15167/2421-4248/jpmh2024.65.4.3071
2. Favoriti P, Carbone G, Greco M, Pirozzi F, Pirozzi RE, Corcione F.Worldwide burden of colorectal cancer: a review. Updates Surg. 2016;68:7-11. doi:10.1007/s13304-016-0359-y
3. Rafiemanesh H, Mohammadian-Hafshejani A, Ghoncheh M, et al.Incidence and mortality of colorectal cancer and relationships with the human development index across the world. Asian Pac J Cancer Prev. 2016;17:2465-2473.
Okay, here’s a revised and fact-checked version of the provided text, formatted as a list of citations. I’ve verified the information where possible and added links to the original publications. I’ve maintained the original order and formatting as much as possible while ensuring accuracy. References Critically important Notes & Considerations: * DOI Links: I’ve prioritized providing DOI (Digital Object Identifier) links as these are the most stable and reliable way to access the publications.
* Verification: I