Surgery is the primary treatment for rectal cancer. However, in patients with locally advanced disease, direct surgery often fails to achieve complete tumor resection. In such cases, neoadjuvant therapy is required to downstage the tumor before surgery. The current standard neoadjuvant approach consists of preoperative radiotherapy and then surgery. Although effective, standard radiotherapy uses large target volumes, which results in significant toxicities, increased surgical complications, and reduced patient compliance and quality of life. In addition, excessive radiation fields can compromise the intensity and timing of systemic therapy, potentially increasing the risk of distant metastasis. This may be one of the key reasons why current neoadjuvant radiotherapy mainly improves local control but has not translated into prolonged overall survival.
Emerging evidence suggests that combining immunotherapy with radiotherapy may further enhance treatment efficacy. However, large radiation fields may impair the effectiveness of immunotherapy. Therefore, reducing the radiotherapy target volume may not only decrease treatment-related toxicity but also augment the immunotherapy response.
This clinical study is designed to evaluate whether reducing the radiotherapy target volume, when combined with chemotherapy and immunotherapy prior to surgery, can decrease radiotherapy-related toxicities and reduce the risk of distant metastasis, without increasing the local recurrence rate, compared with the current standard radiotherapy fields. The ultimate goal is to improve the efficacy of neoadjuvant therapy in locally advanced rectal cancer while minimizing treatment toxicity, thereby providing new strategies and evidence for preoperative management.
Voluntarily agrees to participate and provides written informed consent
Age 18 to 75 years, male or female
Histologically confirmed rectal adenocarcinoma
MRI confirms that the upper margin of the tumor is ≤12 cm from the anal verge
Presence of distant metastasis
Prior pelvic radiotherapy
Chemotherapy or immunotherapy within the past 3 months
Refusal to undergo radical surgery for rectal cancer
Parallel
Reduced-field short-course radiotherapy
RadiationA dose of 25 Gy in 5 fractions was delivered as short-course radiotherapy, with one fraction per day, completing treatment within one week. The target volume was delineated using both CT and MRI. Compared to conventional radiotherapy fields, the irradiated volume was significantly reduced to include only the primary tumor and any metastatic lymph nodes as identified on MRI and CT.
Immunotherapy combined with chemotherapy
DrugAfter completion of radiotherapy, chemotherapy with the XELOX regimen (oxaliplatin 130 mg/m² on day 1 plus capecitabine 1500 mg/m² on days 1-14, every 3 weeks) was initiated in combination with sintilimab immunotherapy (200 mg every 3 weeks) for 4 cycles.
Standard short-course radiotherapy
Radiation"Patients in the standard short-course radiotherapy group will receive 25 Gy in 5 fractions, once daily. Target volumes will be delineated according to the 2023 Guidelines for Target Volume Delineation and Planning of Rectal Cancer (National Cancer Center/National Cancer Quality Control Center), including the primary tumor, mesorectal region, and internal iliac and obturator lymph node drainage areas."
Standard long-course radiotherapy
RadiationPatients in the standard long-course radiotherapy group will receive 50 Gy in 25 fractions, once daily, five days per week, with concurrent oral capecitabine chemotherapy. Target volumes will be delineated according to the 2023 Guidelines for Target Volume Delineation and Planning of Rectal Cancer (National Cancer Center/National Cancer Quality Control Center), including the primary tumor, mesorectal region, and internal iliac and obturator lymph node drainage areas.
Chemotherapy
DrugTwo weeks after the completion of radiotherapy, patients will receive four cycles of CAPOX chemotherapy.
Two-year local control rate after rectal cancer surgery
Incidence of pelvic recurrence or distant metastasis within 2 years after surgery among the enrolled cohort
Pathological Complete Response (pCR) Rate
Proportion of patients achieving pathological complete response (pCR) after neoadjuvant treatment.
Resection Rate
Proportion of patients who undergo surgical resection after neoadjuvant therapy
Incidence of Grade ≥3 Radiation-induced Proctitis
Number and proportion of patients experiencing grade 3 or higher radiation-induced proctitis, assessed according to CTCAE criteria.
Overall Survival (OS)
Time from surgery to death from any cause.
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Longhao Li
Lead sponsor
First Affiliated Hospital of Chongqing Medical University
Sponsor institution
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