Node-Sparing Short-Course Radiation with CAPOX and Sintilimab for MSS Locally Advanced Colon Cancer: a Randomized, Prospective, Multicenter Study

Phase 2

Not yet recruiting

• Conditions: Microsatellite Stable (MSS) Colon Cancer; Locally Advanced Colon Cancer
• Interventions: Drug: Node-Sparing Short-Course Radiotherapy Combined with CAPOX and Sintilimab; Drug: CAPOX Chemotherapy

• Registration Number: NCT06594692
• Lead Sponsor: Sir Run Run Shaw Hospital

Brief Summary

This study aims to evaluate the use of node-sparing short-course radiotherapy combined with chemotherapy and Sintilimab, or chemotherapy alone, as neoadjuvant therapy for MSS-type locally advanced colon cancer. The goal is to explore the efficacy and safety of combining node-sparing short-course radiotherapy with chemotherapy and immunotherapy in the neoadjuvant setting for MSS-type locally advanced colon cancer, while also investigating the specific role of regional lymph nodes in tumor immunotherapy.

Detailed Description

Colorectal cancer is currently one of the most common malignant tumors in China. According to the latest data released by the National Cancer Center, it ranks second in incidence and fourth in mortality among all cancer types. Statistics indicate that approximately 50% of colon cancer patients in China are in stages II-III. Currently, adjuvant chemotherapy regimens containing oxaliplatin and 5-fluorouracil are the standard treatment for stage III and high-risk stage II colon cancer patients. However, under standard treatment protocols, the 5-year disease-free survival (DFS) rate for stage III colon cancer is less than 64%, with a recurrence rate exceeding 20%. Patients with higher T and N stages face a significantly increased risk of recurrence, severely impacting survival rates and imposing a substantial burden on both the healthcare system and society.

Neoadjuvant chemotherapy, which is administered before surgery, offers several theoretical advantages, including shrinking the primary tumor to improve surgical resection rates, reducing intraoperative tumor cell spread, and eliminating micrometastases and subclinical lesions to lower the risk of postoperative metastasis. However, data on neoadjuvant chemotherapy for locally advanced colon cancer remains limited. The FOxTROT study found that preoperative neoadjuvant chemotherapy significantly reduced the 2-year recurrence rate for locally advanced colon cancer, achieved tumor downstaging, and provided a 4% pathological complete response (pCR) rate. This study also demonstrated a strong correlation between pathological response to neoadjuvant therapy and recurrence risk, with patients achieving pCR or major pathological response (mPR) having significantly lower recurrence rates.

Recent studies have shown that combining immunotherapy with radiotherapy has a synergistic effect, even in MSS-type colorectal cancer patients. Radiotherapy can induce immunogenic cell death, releasing tumor-associated antigens and enhancing the function of dendritic cells, thereby increasing T-cell infiltration. Moreover, chemotherapy can alter the tumor microenvironment, promote angiogenesis, and improve oxygen distribution, further enhancing the efficacy of radiotherapy. One prospective phase II clinical trial involving locally advanced rectal cancer patients showed promising results, with a pCR rate of 46.2% in patients with proficient mismatch repair (pMMR), suggesting a favorable response to neoadjuvant therapy.

Lymph nodes, as secondary lymphoid organs, play a crucial role in tumor diagnosis and treatment. Recent preclinical studies have shown that tumor-draining lymph nodes (TDLNs) are essential in antigen activation and effector T-cell differentiation. On the other hand, tertiary lymphoid structures (TLS), which are organized immune cell aggregates formed in non-lymphoid tissues, have been associated with improved prognosis in cancer patients. However, the role of TDLNs in immunotherapy remains underexplored.

Based on these findings, the research team hypothesizes that tumor-draining lymph nodes play a positive role in immunotherapy response, and sparing these nodes during radiotherapy may enhance the efficacy of immunotherapy for MSS-type colorectal cancer. The team previously conducted a phase II clinical study (NCT04503694) investigating the safety and efficacy of node-sparing short-course radiotherapy combined with CAPOX chemotherapy and PD-1 inhibitors in MSS-type locally advanced rectal cancer. Results showed a 100% response rate to neoadjuvant therapy, with a pCR rate of 78.8% and a major pathological response (mPR) rate of 91%, while maintaining a high rate of organ preservation.

Given the high recurrence rates and treatment challenges associated with locally advanced colon cancer, and building on the promising results of previous studies, the research team intends to conduct the mRCAT-C study. This study aims to explore the clinical efficacy and safety of a node-sparing short-course radiotherapy combined with immunotherapy as a neoadjuvant treatment for MSS-type locally advanced colon cancer.

Study Timeline

• Status Verified: 2024-09
• Study First Submitted: 2024-09-10
• Study First Submitted QC: 2024-09-10
• Last Update Submitted: 2024-09-10
• Study First Posted: 2024-09-13
• Last Update Posted: 2024-09-13
• Study Start: 2024-10
• Primary Completion: 2025-09-30
• Study Completion: 2026-09-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 140

Inclusion Criteria

• 1. Patients willing to undergo neoadjuvant treatment. 2. Age ≥ 18 years. 3. Tumor confirmed by colonoscopy and enhanced abdominal CT to be ≥ 12 cm from the anal verge.

  2. Histologically diagnosed adenocarcinoma; genetic testing indicates MSI-L or MSS, or immunohistochemistry from tumor biopsy shows pMMR (all four proteins-MSH1, MSH2, MSH6, and PMS2-are positive).

  3. Clinical staging by enhanced abdominal CT evaluates as cT3-4N0-2M0. 6. ECOG performance status score of 0-1. 7. No prior treatment with anti-tumor, immunotherapy, or abdominal radiation therapy before enrollment.

  4. Blood test results (without transfusion within 14 days and no use of granulocyte colony-stimulating factor or other hematopoietic stimulators within 7 days before the lab test):

  5. White blood cell count ≥ 3.5 × 10^9/L, absolute neutrophil count ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 10^9/L, hemoglobin concentration ≥ 9 g/dL;

  6. Liver function tests (bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 5 × ULN);

  7. Renal function (serum creatinine ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 50 mL/min);

  8. Coagulation (INR ≤ 1.5 × ULN, PT and APTT ≤ 1.5 × ULN);

  9. Thyroid function: TSH ≤ upper limit of normal (ULN); if abnormal, FT3 and FT4 levels must be evaluated, and if FT3 and FT4 are normal, the patient is eligible.

     9. Voluntary participation with a signed informed consent form.

Exclusion Criteria

• 1. History of other malignancies within the past 5 years. 2. Patients with metastases in other locations (stage IV). 3. Patients with MSI-H or dMMR. 4. Patients with conditions such as bowel obstruction, perforation, or bleeding requiring emergency surgery.

  2. Known allergy to the study drug or any of its excipients. 6. Patients with any unstable systemic diseases, including but not limited to severe infections, uncontrolled diabetes, uncontrolled hypertension, unstable angina, cerebrovascular accidents or transient ischemic attacks, myocardial infarction, congestive heart failure, or severe illnesses requiring medication (such as arrhythmias, liver, kidney, or metabolic diseases) that are life-threatening.

  3. History of active autoimmune diseases requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within the last 2 years. Replacement therapies (e.g., thyroid hormone, insulin, or physiological corticosteroid replacement for adrenal or pituitary insufficiency) are not considered systemic treatments.

  4. Known history of HIV infection or acquired immunodeficiency syndrome (AIDS). 9. Receipt of any investigational drug (including immunotherapy) or participation in another interventional clinical study within 30 days before screening.

  5. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study; men or women unwilling to use effective contraception during the study.

  6. Vulnerable populations, including those with mental illness, cognitive impairment, or critically ill patients.

  7. Any other conditions deemed inappropriate for participation by the investigator.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Node-Sparing Short-Course Radiotherapy Combined with CAPOX and Sintilimab	Node-Sparing Short-Course Radiotherapy Combined with CAPOX and Sintilimab	Intervention Procedure: 1. Radiotherapy: Short-course radiotherapy is administered, with a total dose of 25Gy (5Gy per session for 5 sessions) targeting the primary tumor. 2. Chemotherapy and Immunotherapy: On the 8th day after the start of radiotherapy, CAPOX chemotherapy combined with Sintilimab is initiated for 4 cycles. 3. Surgery: One week after the completion of chemotherapy and immunotherapy, patients will undergo radical total mesorectal excision surgery. 4. Postoperative Adjuvant Chemotherapy: Starting 3-4 weeks after surgery, patients will resume CAPOX chemotherapy for an additional 4 cycles as adjuvant treatment.
Preoperative CAPOX Regimen as Neoadjuvant Therapy	CAPOX Chemotherapy	Intervention Procedure: 1. Chemotherapy: Administer CAPOX chemotherapy for 4 cycles. 2. Surgery: One week after the completion of chemotherapy, patients will undergo radical total mesorectal excision surgery. 3. Postoperative Adjuvant Chemotherapy: Starting 3-4 weeks after surgery, patients will resume CAPOX chemotherapy for an additional 4 cycles as adjuvant treatment.

Primary Outcome Measures

Name	Time	Method
pathological complete response rate	2 weeks after surgery	The tumor specimen from node-sparing neoadjuvant chemoradiotherapy combined with immunotherapy, followed by sequential CME (complete mesocolic excision) surgery, showed no presence of cancer cells or lymph node metastasis under microscopic examination (ypT0N0M0).

Secondary Outcome Measures

Name	Time	Method
R0 resection rate	2 weeks after surgery	which is the percentage of patients who undergo a surgical procedure in which the tumor is completely removed with no cancer cells detected at the margins (edges) of the resected tissue. Achieving an R0 resection is a critical goal in cancer surgery, as it indicates that all visible and microscopic tumor cells have been removed, reducing the likelihood of recurrence.
Tumor downstaging rate	2 weeks after surgery	The tumor downstaging rate refers to the percentage of patients whose tumors decrease in size or extent (stage) following neoadjuvant treatment, compared to their initial stage at diagnosis. Downstaging means that the tumor has responded to treatment to the point where it moves from a more advanced stage (e.g., from stage III to stage II or I), which may improve the likelihood of successful surgical removal and lead to better prognosis.
The 3-year Event-Free Survival	3 years post-treatment	The 3-year Event-Free Survival (EFS) refers to the percentage of patients who remain free from certain negative events-such as cancer progression, recurrence, or death-within three years after treatment. In clinical trials, EFS is a critical measure of a treatment's long-term efficacy, indicating how long patients can live without the disease worsening or other significant events occurring during the follow-up period.
Objective Response Rate	2 weeks after surgery	Objective Response Rate (ORR) refers to the percentage of patients in a clinical study whose cancer shows a measurable reduction in tumor size in response to treatment.
The 3-year Local Recurrence Rate	3 years post-treatment	The 3-year Local Recurrence Rate (LRR) refers to the percentage of patients whose cancer returns at the original tumor site or nearby lymph nodes within three years after completing treatment. This measure is important for evaluating the long-term effectiveness of a treatment in preventing the return of cancer in the localized area where it was initially detected. A lower LRR suggests better local control of the disease.
3-year Disease-Free Survival	3 years post-treatment	3-year Disease-Free Survival (DFS) refers to the percentage of patients who remain free from any signs or symptoms of cancer for three years after completing treatment. It measures the length of time during which patients experience no recurrence of the disease and are considered to be in remission. DFS is commonly used to assess the effectiveness of a treatment in preventing cancer from returning within a specified time frame.
3-year Overall Survival	3 years post-treatment	3-year Overall Survival (OS) refers to the percentage of patients who are still alive three years after the completion of treatment, regardless of whether the cancer has recurred or progressed. It is a key indicator of the effectiveness of a treatment in prolonging life. Unlike Disease-Free Survival (DFS), OS does not take into account whether the disease has returned, focusing solely on survival.
The incidence of grade III/IV adverse events	2 weeks after surgery	The incidence of grade III/IV adverse events refers to the percentage of patients who experience severe or life-threatening side effects (classified as grade III or IV) during a clinical trial. Grade III adverse events are considered serious but not immediately life-threatening, often requiring medical intervention, while grade IV events are life-threatening and typically require urgent medical attention. This measure is crucial for assessing the safety and tolerability of a treatment.
EORTCQLQ-C30	3 years post-treatment	The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) is a standardized tool used to assess the quality of life of cancer patients. It contains 30 questions that cover a wide range of physical, emotional, and social aspects of well-being, including symptoms of cancer and treatment side effects, functioning (physical, role, emotional, cognitive, and social), and overall health. The questionnaire is widely used in clinical trials to evaluate how treatments impact the patient's quality of life during and after treatment.
EORTCQLQ-CR29	3 years post-treatment	The EORTC QLQ-CR29 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer Module) is a supplementary module to the QLQ-C30 designed specifically to assess quality of life in patients with colorectal cancer. It includes 29 questions that focus on colorectal cancer-specific symptoms and concerns, such as bowel function, body image, and sexual functioning, in addition to the general quality of life issues covered by the QLQ-C30. This questionnaire is used in clinical studies to evaluate the impact of colorectal cancer and its treatment on patients' quality of life.

Trial Locations

Locations (1)

Sir Run Run Shaw Hospital, Zhejiang University; 🇨🇳 Hangzhou, China