Efficacy and Safety of Neoadjuvant Short-Course/Long-Course Radiotherapy Combined With Anti-PD-1/CTLA-4 Dual Immunotherapy for Locally Advanced Rectal Cancer: A Prospective, Randomized Controlled Trial (RADICAL Trial)

According to the latest statistics from the National Cancer Center of China, the incidence and mortality of colorectal cancer rank 2nd and 4th among all malignant tumors, respectively. Locally advanced rectal cancer (LARC) accounts for more than 60% of all colorectal cancer cases, predominantly presenting as mid-low and locally advanced stages[1]. The standard therapeutic paradigm for LARC centered on "neoadjuvant chemoradiotherapy (NCRT) + total mesorectal excision + adjuvant chemotherapy" has significantly improved local tumor control, reducing local recurrence rate to below 5% and achieving pathological complete response (pCR) in a subset of patients[2]. Total neoadjuvant therapy has also been widely applied in the treatment of high-risk rectal cancer, with notable short-term efficacy, yet its long-term benefit remains controversial. The distant metastasis rate of rectal cancer reaches 25%-30%, representing a critical determinant of prognosis.

To further improve therapeutic efficacy, reduce distant metastasis risk, and enhance long-term prognosis, the oncological efficacy of neoadjuvant immunotherapy combined with chemoradiotherapy has been validated by an increasing number of multicenter randomized controlled trials. The 2025 Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Colorectal Cancer has listed neoadjuvant immunotherapy combined with chemoradiotherapy as a Grade II recommended regimen for pMMR/MSS rectal cancer. Multiple randomized controlled trials have demonstrated that neoadjuvant immunotherapy combined with chemoradiotherapy can elevate the pCR rate from 15%-20% to 30%-50%, allowing patients with clinical complete response (cCR) to adopt the "wait-and-watch" strategy for organ and function preservation[2-4]. Despite remarkable therapeutic outcomes achieved by neoadjuvant immunotherapy combined with chemoradiotherapy, several clinical research priorities and challenges remain to be addressed through further investigation, including radiotherapy field selection, optimal timing of immunotherapy initiation, clinical efficacy of different radiotherapy fractionation regimens, prediction of neoadjuvant immunotherapy response, and precise screening of eligible candidates for the "wait-and-watch" strategy.

Distant metastasis remains the primary challenge affecting long-term prognosis of LARC patients after neoadjuvant therapy[2]. In recent years, the synergistic effect between immune checkpoint inhibitors and radiotherapy has provided a novel approach to overcome this dilemma[1-4]. Existing studies have shown that radiotherapy induces immunogenic cell death, releases tumor antigens, activates the STING/cGAS pathway, promotes type I interferon secretion, and upregulates MHC-I and PD-L1 expression, thereby enhancing CD8⁺ T cell infiltration, inhibiting immunosuppressive cell populations (e.g., Treg cells, M2 macrophages), and improving the immune microenvironment[5]. Other studies indicate that hypofractionated radiotherapy (e.g., short-course radiotherapy) exerts stronger DNA damage and danger signal release effects, which not only promotes dendritic cell maturation and antigen cross-presentation but also causes less damage to peripheral immune cells, facilitating the transformation of "cold tumors" to "hot tumors"[6].

1.1 Exploration and Limitations of Long-Course Chemoradiotherapy Combined with Immunotherapy Research on neoadjuvant long-course chemoradiotherapy combined with immunotherapy was initiated earlier, mainly comprising three modes: sequential, concurrent, and induction immunotherapy, yet its overall efficacy is inferior to short-course radiotherapy combined regimens. Regarding sequential immunotherapy: The Japanese VOLTAGE-A study first confirmed that sequential nivolumab after long-course radiotherapy increased the pCR rate to 30% in MSS LARC patients, with a grade 3 adverse event rate of 11.9%[7]. The Chinese NECTAR study adopted long-course radiotherapy followed by sequential tislelizumab for LARC, achieving a 40% pCR rate in 50 pMMR patients with a 4% grade 3 adverse event rate, demonstrating the potential of drug optimization[2]. Regarding concurrent immunotherapy: The Italian AVANA study investigated concurrent avelumab administration during long-course radiotherapy, reporting a 23% pCR rate in 96 patients, suggesting that direct killing of immune cells by radiotherapy may attenuate therapeutic efficacy[3]. Regarding induction immunotherapy: The US NRG-GI002 study employed a total neoadjuvant therapy modality, consisting of FOLFOX induction chemotherapy followed by sequential long-course radiotherapy plus pembrolizumab, which yielded a 30.9% pCR rate with no significant difference compared with the control group. It was hypothesized that the immunosuppressive effect of induction chemotherapy may offset the combined efficacy[4]. Overall, the pCR rate of long-course chemoradiotherapy combined with immunotherapy generally ranges from 23% to 40%, with limitations including long study duration, high time cost, potential attenuation of overall efficacy due to radiotherapy effects on lymphoid tissues, and possible suppression of peripheral blood lymphocytes by chemotherapy.

1.2 Breakthrough Progress of Short-Course Radiotherapy Combined with Immunotherapy The UNION study adopted the regimen of "short-course radiotherapy + CAPEOX chemotherapy + camrelizumab" for mid-low LARC, achieving a pCR rate of 39.8%, which was significantly superior to the 15.3% rate of traditional long-course chemoradiotherapy, establishing the standard therapeutic status of this regimen. The TORCH study employed the total neoadjuvant therapy modality of "short-course radiotherapy + CAPOX + toripalimab", reporting an overall CR rate of 55.4% in 121 LARC patients, with approximately 25% of patients achieving cCR and safely adopting the "wait-and-watch" strategy, while the pCR rate reached 50% in patients who underwent surgery[8]. The PRECAM study innovatively applied "sequential CAPEOX + envafolimab after short-course radiotherapy", achieving a pCR rate as high as 66.7% (12/18). Short-course radiotherapy enhances tumor immunogenicity through hypofractionated dose (5×5Gy), resulting in significant chemoradioimmunotherapy efficacy. However, acute toxicity within two weeks after short-course radiotherapy is more pronounced compared with long-course radiotherapy, and its biologically equivalent dose is lower than that of long-course radiotherapy[9]. The aforementioned studies have established the role of short-course radiotherapy combined with chemotherapy and immunotherapy in the perioperative treatment of LARC, and this modality demonstrates great potential for continuous optimization to further improve efficacy and reduce toxicity.