Two groundbreaking multi-institutional studies have demonstrated that combining immune checkpoint inhibitors (ICIs) with total neoadjuvant therapy (TNT) significantly improves treatment outcomes for patients with microsatellite stable (MSS) or proficient mismatch repair (pMMR) locally advanced rectal cancer (LARC), a population that traditionally shows limited response to immunotherapy alone.
Enhanced Response Rates with Immunotherapy Integration
The first study, conducted across four medical centers in China, compared 211 patients receiving either ICIs combined with TNT (ICIs + TNT) or ICIs combined with standard neoadjuvant chemoradiotherapy (ICIs + nCRT). The ICIs + TNT group demonstrated a significantly higher pathological complete response (pCR) rate of 49.4% compared to 35.3% in the ICIs + nCRT group (P=0.039), representing a relative risk of 1.796.
"The ICIs + TNT regimen demonstrated superior pCR and tumor downstaging rates," the researchers reported, with 80.9% of patients achieving favorable tumor regression grades (TRG 0-1) compared to 68.0% in the standard group (P=0.037).
A complementary study from Henan Cancer Hospital evaluated 141 patients treated with immunotherapy-based TNT (iTNT), achieving remarkable complete response rates of 55.6% in the short-course radiotherapy followed by immunochemotherapy group (SCRT-IC) and 53.6% in the induction immunochemotherapy followed by SCRT group (IC-SCRT).
Treatment Protocols and Safety Profiles
The TNT approach utilized a consolidation strategy combining long-course chemoradiotherapy (50.4 Gy in 28 fractions with concurrent capecitabine) alongside PD-1 inhibitors, followed by two cycles of capecitabine and oxaliplatin (CAPOX) with continued immunotherapy. Various PD-1 inhibitors were employed, including camrelizumab, sintilimab, pembrolizumab, tislelizumab, nivolumab, and durvalumab.
Safety analysis revealed that treatment-related adverse events occurred in 63.9% of ICIs + TNT patients and 76.4% of ICIs + nCRT patients. Grade 3-4 adverse events were observed in 16.9% and 9.0% of patients, respectively. The most common severe toxicities included decreased lymphocyte count and thrombocytopenia.
In the iTNT study, grade 3-4 adverse reactions occurred in 44.4% of SCRT-IC patients and 42.0% of IC-SCRT patients, with thrombocytopenia being the most prevalent severe toxicity (23.6% vs. 33.3%).
Surgical Outcomes and Organ Preservation
Both studies demonstrated excellent surgical outcomes with R0 resection rates exceeding 97%. Sphincter-preserving surgery was achieved in 88.8% of ICIs + TNT patients and 83.6% of ICIs + nCRT patients. The iTNT study showed even higher sphincter preservation rates, with 71.7% in the SCRT-IC group and 82.5% in the IC-SCRT group undergoing sphincter-preserving procedures.
Notably, the iTNT study implemented a watch-and-wait approach for patients achieving clinical complete response, with 34 patients (17 in each group) maintaining sustained complete response during follow-up, including 19 patients with responses lasting over 12 months.
Long-term Survival Outcomes
Despite the improved pathological response rates, both studies found comparable long-term survival outcomes between treatment groups. The multi-institutional study reported 3-year disease-free survival rates of 84.3% for ICIs + TNT and 81.9% for ICIs + nCRT (P=0.620), with overall survival rates of 94.0% and 91.1%, respectively (P=0.634).
Multivariate analysis identified age as an independent predictor of both pathological complete response and survival outcomes. Patients aged >50 years demonstrated superior treatment responses and survival compared to younger patients.
Clinical Implications and Future Directions
These findings represent a significant advancement in treating MSS/pMMR LARC, a population comprising 90-95% of rectal cancer cases that traditionally shows resistance to immune checkpoint blockade. The combination of radiotherapy with immunotherapy appears to overcome this resistance through mechanisms including immunogenic cell death induction and tumor microenvironment modulation.
"Our findings suggest that ICIs + TNT and ICIs + nCRT are comparable in terms of toxicity and perioperative complications," the researchers concluded, while noting that "ICIs + TNT demonstrated numerically higher rates of pCR and tumor downgrading."
The studies provide preliminary evidence supporting the integration of immunotherapy into standard neoadjuvant protocols for LARC, potentially offering more patients opportunities for organ preservation and improved quality of life. However, the researchers emphasize that larger prospective randomized trials with extended follow-up are necessary to validate these findings and establish optimal treatment protocols.
Both studies acknowledge limitations including their retrospective design, relatively small sample sizes, and short follow-up periods. Future research will focus on biomarker-driven patient selection, optimal sequencing of treatments, and long-term oncologic outcomes to further refine this promising therapeutic approach.
