Introduction
Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the fifth in women.1 Adjuvant chemotherapy is an established standard therapy for colon cancer (CC) patients with radically resected stage III and ‘high-risk’ stage II disease. For patients with stage III CC, and the 5-year disease-free survival (DFS) was 63.6%, the recurrence rate was more than 20%.2 3 A higher T-stage and N-stage increase the risk of recurrence. For bulky nodal disease or clinical T4b disease, neoadjuvant treatment with FOLFOX or capecitabine plus oxaliplatin (CAPOX) may be considered before surgery. The recently published FOxTROT1 trial was a phase III randomised controlled trial to illustrate the clinical benefit of neoadjuvant chemotherapy (NAC) in patients with locally advanced CC (LACC).4 NAC was associated with a significant reduction in recurrence (16.8% vs 21.2%, p=0.042) and improvements in tumour downstaging, rate of complete (R0) resection and CC-specific survival. However, the pathological complete regression (pCR) rate was only 4%. Thus, developing novel and more effective treatment strategies for LACC is an area of clinical priority.
Radiotherapy (RT) is not widely used in CC, because of the uncertain position and small bowel toxicity, but may be considered in certain clinical scenarios. Patients with stage T4 disease had a high likelihood of locoregional recurrence,5 and perhaps locoregional RT could reduce the recurrence. A small sampled study had shown that patients with pT4b disease receiving adjuvant chemoradiotherapy enhanced locoregional control and DFS.6 A retrospective study analysed the National Cancer Database (NCDB) for patients with pT4 and/or positive margins; and showed that adjuvant radiation was associated with improved overall survival (OS) in patients with both pT4 and positive margins.7 A series of studies from Sun Yat-sen University Cancer Center, China have reported the effective and safety of neoadjuvant chemoradiotherapy (NACRT) with unresectable CC.8–10 Furthermore, pCR was 18%–38% and a clinical-downstaging rate was 81%–90% after received NACRT.
Recently, anti-PD-1/PD-L1 inhibitors have shown promising results for many kinds of malignant tumours. PD-1 antibody demonstrated excellent efficacy in advanced CRC patients with microsatellite instability-high (MSI-H).11 The anti-PD-1/PD-L1 alone did not show a good effect in patients with microsatellite stable (MSS). However, patients with MSI-H only account for about 5%, and the majority CRC population is MSS. Improving the immunotherapeutic sensitivity of patients with MSS remains a great challenge. Recent studies have shown promising synergistic effects of the combination of immunotherapy and RT, even in CRC patients with MSS. Preclinical studies have shown that radiation enhances the diversity of T-cell receptor repertoire of intratumoural T cells, and anti-CTLA4 inhibits T-regulatory cells (Treg cells), while the addition of PD-L1 blockade reverses T-cell exhaustion; thus the combination of radiation and immune checkpoint inhibitors results in better anticancer effects because they promote response and immunity through distinct mechanisms.12 13 Therefore, the combination of RT and immunotherapy is promising. We have tried the combination of anti PD-1 antibody, chemotherapy and RT in locally advanced rectal cancer (LARC) (TORCH trial, NCT04518280); the preliminary unpublished results showed a high CR rate and safety.14
From the dilemma of LACC and the inspiration of the studies of the combination of RT and immunotherapy in other cancers, especially the TORCH study, we attempted to perform TORCH-C trial to address the value of neoadjuvant RT and immunotherapy in LACC patients with MSS.
Methods and analysis
Patient and public involvement
Neither patients nor the public have been involved in the design, recruitment and conduct of this study. The results will be disseminated via scientific journals and academic conference.
Hypothesis
We hypothesise that combining serplulimab with short-course RT (SCRT) and chemotherapy before surgery can increase the pCR rate compared with NAC in LACC patients with MSS.
Study design
The study is a phase II, multicentre, randonmised, prospective and superiority trial, comparing the adjuvant chemotherapy with SCRT combined with chemotherapy and immunotherapy in clinically cT4 or bulky nodes patients confirmed colon adenocarcinoma. Patients will be assigned into two arms: intervention arm and control arm. Stratification factors are the location of tumour and N stage. Patients will be randomly assigned using a central randomisation system without masking. Patients in the control arm will receive four cycles of CAPOX chemotherapy and then receive surgery. Patients in the intervention arm will receive SCRT (25 Gy/5 Fx), followed by four cycles of CAPOX chemotherapy and anti-PD-1 antibody (serplulimab, Shanghai Henlius Biopharmaceutical, China), and finally receive surgery. The trial has been registered in ClinicalTrials.gov on 16 February 2023 (Registration No. NCT05732493). The outline of the study workflow and design is depicted in figures 1 and 2. Patients or the public not involved in the design, or conduct, or reporting, or dissemination plans of our research.
Recruitment pathway. All patients considered for the TORCH-C trial will progress through these steps. Patients who are not eligible or do not consent to participation will be offered standard treatment. MDT, multidisplinary team; MSS, microsatellite stable;TORCH-C, TORCH-colon.
The TORCH-C platform. Patients who meet the eligibility criteria for the TORCH-C trial will be randomised to intervention arm or control. In the intervention arm, patients will receive SCRT followed by four cycles of CAPOX combined with serplulimab. In the control arm, patients with receive four cycles of CAPOX. CAPOX, capecitabine plus oxaliplatin; LACC, locally advanced colon cancer; MSS, microsatellite stable; pMMR, mismatch repair proficient; SCRT, short-course radiotherapy;TORCH-C, TORCH-colon.
Trial organisation, ethics approval, drug supply and insurance
The trial is principal investigators initiated by the Department of Radiation Oncology and the Department of Colorectal Surgery, Fudan University Shanghai Cancer Center. This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (approval number: 2211265-12). A total of six other medical centres in China are involved in the study, including the first people’s hospital of Changzhou, Yunnan Cancer Hospital, Anyang Cancer Hospital, Traditional Chinese Hospital of LuAn, the Second School of Medicine Wenzhou Medical University and the Second Affiliated Hospital of Soochow University. Serplulimab is free provided by Shanghai Henlius Biopharmaceutical Company, which has purchased liability insurance for clinical trial subjects. All participants will sign a written informed consent before randomisation.
Study population
Patients who present with LACC require a complete workup, including biopsy, pathological tissue review, total colonoscopy, complete blood count (CBC), chemistry profile, tumour markers determination and baseline CT scans of the chest, abdomen and pelvis. Testing for mismatch repair (MMR)/MSI should be done at diagnosis. CT should be with intravenous contrast. Participants are eligible to be included if they meet the inclusion criteria and exclusion criteria (table 1).
Inclusion and exclusion criteria
The withdrawal criteria include: (1) Distant metastasis is confirmed by postoperative pathology. (2) Patients receive other treatment, which is not related to this study. Patients receive subsequent therapy after relapse or metastasis is permitted. (3) Patients decide to withdraw from the study with any reasons. The trial was opened on 1 March 2023, and the first patient was recruited on 24 March 2023.
Statistical analysis
The primary endpoint of this study is pCR. In this study, the reference pCR rate of NAC was 5%. Our hypothesis is that the intervention increases a pCR rate to 30%. Patients will be randomly assigned to the two arms at a ratio of 1:1. If a probability value of at least 95% needs to be reached to select the superior group, the sample size should be 90 patients (45 patients/group). Taking into account the maximum drop-out rate of 20%, the final total sample size in this study will be 120 cases (60 cases per group). Randomisation will be performed using a computer-generated programme that incorporates a random element, which will ensure a balance of the following factors: location of primary tumour and lymph node status.
Study interventions: the clinical trial will include the following therapeutic interventions
Neoadjuvant chemotherapy
Patients in the control arm will receive four cycles of CAPOX. The regimen of CAPOX includes oxaliplatin 130 mg/m2 intravenously day 1 and capecitabine 1000 mg/m2 orally days 1–14 (3 weeks per cycle).
Neoadjuvant RT
Patients in the intervention arm will first receive SCRT. The target volume is the colon primary lesion and enlarged lymph nodes, not including the lymphatic drainage area. The prescription dose is 25 Gy in 5 fractions over 5 days. Intensity-modulated radiation therapy will be conducted. The titanium clip will be markered at the proximal and distant side of the tumour through coloscopy for image guiding during every fraction of radiation.
Neoadjuvant immunotherapy
In the intervention arm, 2 weeks after the completion of RT, four cycles of CAPOX and anti-PD-1 antibody (serplulimab) treatment will be performed. Serplulimab will be administrated intravenously at a fixed dose of 300 mg on the first day and repeated every 3 weeks. The regimen of CAPOX is the same as in the control arm.
Surgery
All patients will undergo restaging 2 or 4 weeks after the completion of neoadjuvant treatment. Radical resection will be undertaken after evaluation. The specific surgical approach will be determined by the surgeons. The preferred surgical procedure is colectomy with en bloc removal of the regional lymph nodes. The extent of colectomy should be based on the tumour location.
Adjuvant chemotherapy
All patients in both control and intervention arms will receive adjuvant chemotherapy of four cycles of CAPOX. The regimen of CAPOX is as the standard regimen.
Criteria for discontinuing or modifying allocated interventions
In the case of grades 3–4 adverse effect (AE), the treatment should be adjusted. The dose of oxaliplatin and capecitabine should be reduced 20% in case of serious thrombocytopenia or leucopenia. Serplulimab should be discontinued if immune-related adverse events do not recover to grade 2 or lower before the next cycle. Oxaliplatin and serplulimab are administered in hospital, and capecitabine will be taken home and take orally for 2 weeks. We will record the days and doses of capecitabine for all the patients. Medicines such as antihypertension and antidiabetes can continue to be used. Liver protection medicine, granulocyte colony-stimulating factor and thrombopoietin can be used if hepatic injury or myelosuppression. Painkiller and other symptomatic treatment are promitted. Traditional Chinses medicines and other anticancer treatment are prohibited.
Study endpoints and assessment
The primary endpoint of this study is the pCR. The second endpoint includes tumour downstaging rate, the R0 resection, 3-year DFS rate, 3-year OS rate, 3-year local recurrence-free survival, toxicity, postoperative complications and quality of life (QoL). The pCR status is defined as no viable tumour cells by a complete histological assessment. Pathological tumour regression grade and pCR will be evaluated by two independent pathologists.
Patients will receive evaluation at the following time points: baseline and before surgery and during regular follow-up. The examinations include imaging examinations (pelvic CT/MRI, abdominal CT/MRI and chest CT), tumour markers (CAE, CA199, etc), CBC, blood biochemical examination (aspartate aminotransferase, alanine aminotransferase, Cr, etc) and toxicity-associated examinations, including thyroid hormone, adrenal hormone and myocardial enzymogram, etc. The response evaluation criteria in solid tumours (RECIST V.1.1) and immune RECIST will be used to assess the response.
Acute AEs will be documented at every cycle of treatment and classified according to the Common Terminology Criteria for Adverse Events V.5.0. The QoL will be evaluated at the end of neoadjuvant therapy and at every 6 months during the follow-up using the EORTC QLQ-C30 (Europe Organization for Research and Treat- ment of Cancer,Quality of Life Questionnaire-C30).
Protocol version
Version 2.0.
Discussion
Presently, some prospective NAC clinical studies on LACC have been carried out. The FOxTROT trial was the first prospective randomised controlled clinical study showed that NAC combining two chemotherapeutic agents (oxaliplatin and 5-fluorouracil) had a significant effect on tumour downstaging, but only 2-4% pCR rate.15 A pilot phase II study has shown that patients received neoadjuvant triple chemotherapy (oxaliplatin and irinotecan combined with folinic acid and 5-fluorouracil), 91.5% had reduction in tumour volume and 56.5% had grades 3–4 toxicity, only 4% (1/23) had gained pathological pCR rate.16
LACC has traditionally been managed with surgical resection followed by adjuvant chemotherapy. To achieve R0 resection, about 30% T4 stage CC patients must receive multivisceral resection.17 However, locoregional recurrence and distant metastases rates were still high. Lymph node metastasis is a major predictor of survival outcome; furthermore, it is difficult to acquire R0 resection for bulky nodes. Hence, local and systemic therapy should be strengthened for patients with T4 and bulky node disease.
Adjuvant RT presented better OS and cancer-specific survival than patients who did not receive RT for pT4N2M0 CC patients from the data of the SEER (Surveillance, Epidemiology, and End Results) database.18 From several small sampled studies, neoadjuvant RT improved the R0 resection rate and decreased local recurrence in LACC. A retrospective study with NCDB has shown that the use of neoadjuvant RT for T4 disease had higher R0 resection rates and increased 5-year OS rates.19 Cukier et al performed a retrospective study found that neoadjuvant CRT in LACC patients with T4b disease could lead to high R0 resection and excellent local control.20 These studies showed that T4 CC patients benefitted from neoadjuvant RT. A phase III study intergroup 0130 compared adjuvant chemoradiotherapy with adjuvant chemotherapy alone in patients with CC,21 no significant difference in severe non-haematological toxicity was observed. Long-course RT was used in all of the published studies in CC. The radiation dose was 1.8–2.0 Gy per fraction and was given five times per week. The total irradiation dose was 45–50.4 Gy.
The immunotherapy with PD-1/PD-L1 immunocheckpoint blockade (ICB) turned out a breakthrough in cancer treatment among different tumour types, including CRC. The effect of ICBs has so far been demonstrated in small phase I/II studies and predominantly in treatment-refractory stage IV disease and disease with dMMR. The Keynote-177 trial has shown that single-agent immunotherapy pembrolizumab improved PFS versus chemotherapy (16.5 m vs 8.2 m) in patients with newly diagnosed MSI-H or dMMR metastatic CRC (mCRC).11 Immunotherapy has recently emerged as a neoadjuvant therapy that could change the treatment strategy in CRC. In the NICHE trial,22 the effect of neoadjuvant immunotherapy by doublet ICB nivolumab and ipilimumab were investigated both in MSI-H/dMMR and MSS/pMMR patients, among the pMMR tumours, 4 (3 major and 1 partial response) of 15 had pathological responses.
Preoperative RT combined with chemotherapy and immunotherapy showed a satisfied effect in LARC. A phase II Chinese study used 5×5 Gy SCRT followed by two cycles of CAPOX and camrelizumab before surgery in LARC. Among the 26 patients with MSS disease, the pCR rate was as high as 48.1%,23 and no grade 3–4 immune-related AEs were observed. The Averectal trial performed SCRT followed by six cycles of FOLFOX and avelumab in LARC, and found that 37.5% of the patients achieved pCR24. No grades 3–4 immune-related AEs were found. Furthermore, there are many ongoing studies on neoadjuvant immunotherapy combined with chemoradiotherapy in rectal cancer. However, very few similar studies on CC. We have tried the combination of anti PD-1 antibody, CAPOX and SCRT in LARC in the TORCH trial at our centre; the preliminary unpublished results showed a high CR rate and safety in patients with MSS.14 CC and rectal cancer have similar biological behaviour, we believe that the TORCH mode will also play good in LACC.
In summary, TORCH-C is a randomised, prospective, multicentre, double-arm, phase II trial of SCRT combined with CAPOX and Serplulimab in LACC patients to investigate whether NACRT combined with immunotherapy can bring good tumour response, good tolerance and better prognosis. We look forward to obtaining exciting results and bring a better treatment strategy for LACC.
Ethics and dissemination
This study was conducted in compliance with Declaration of Helsinki principles. All procedures involving human subjects were approved by the Ethics Committee of Fudan University Shanghai Cancer Center. FUSCC is in charge of study design, data collection, analysis, interpretation and reporting, playing a role in ensuring ethicalconsiderations, patient safety and adherence to regulatory guidelines throughout the entire research process. All patients signed informed consent forms before recruitment. The corresponding results will be disseminated via peer-reviewed journals and academic conference presentations. The participants and their personal data in the study will be kept confidential in all study-related documents and publications.
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