To explore the efficacy and safety of adding a ketogenic diet and/or high-dose intravenous vitamin C to neoadjuvant short-course radiotherapy followed by mFOLFOX6 chemotherapy combined with serplulimab in patients with locally advanced pMMR/MSS rectal adenocarcinoma through a prospective, randomized, controlled phase II clinical study, providing preliminary evidence for optimizing neoadjuvant treatment strategies for this population.
Patients with locally advanced rectal adenocarcinoma characterized by proficient mismatch repair or microsatellite stability (pMMR/MSS) generally derive limited benefit from immune checkpoint inhibitor monotherapy. Metabolic interventions may enhance the efficacy of chemotherapy and immunotherapy by modulating tumor metabolism and the tumor immune microenvironment. High-dose vitamin C has multitarget antitumor effects. Preclinical evidence suggests that it may activate the AMPK pathway, downregulate PD-L1 expression in colorectal cancer cells, and promote T-cell infiltration into the tumor microenvironment, thereby providing a mechanistic rationale for its combination with PD-1 blockade. In the phase III VITALITY trial, high-dose intravenous vitamin C combined with chemotherapy did not significantly improve progression-free survival in the overall population with metastatic colorectal cancer; however, a prespecified subgroup analysis demonstrated prolonged progression-free survival among patients with RAS-mutant tumors. A ketogenic diet may also exert antitumor effects by altering glucose availability, cellular energy metabolism, and the immune microenvironment. Emerging evidence suggests that dietary patterns, including high-fiber diets in patients receiving immunotherapy and ketogenic diets in those receiving chemotherapy, may be associated with improved treatment responses, although these findings require prospective validation. Therefore, this study aims to investigate whether adding a ketogenic diet and/or high-dose intravenous vitamin C to short-course radiotherapy followed by mFOLFOX6 chemotherapy combined with the PD-1 monoclonal antibody serplulimab can improve the pathological complete response and organ preservation rates in patients with locally advanced pMMR/MSS rectal adenocarcinoma. The efficacy and safety of four treatment strategies-no metabolic intervention, a ketogenic diet alone, high-dose intravenous vitamin C alone, and their combination-will be evaluated.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Patients undergo SCRT at a dose of 5Gy × 5 fractions
Patients receive six cycles of immunotherapy with serplulimab injection, a PD-1 monoclonal antibody, at a fixed dose of 200 mg per cycle.
Patients receive six cycles of the mFOLFOX6 regimen, consisting of oxaliplatin (85 mg/m²) and leucovorin (200 mg/m²) administered intravenously over 2 hours, followed by a bolus of fluorouracil (400 mg/m²) and a continuous infusion of fluorouracil (2,400 mg/m²) over 46 hours.
Sixth Affiliated Hospital, Sun Yat-sen University
Guangzhou, Guangdong, China
pCR rate
Pathological complete response rate, ypT0N0 for TME surgery and ypT0rN0 for local excision
Time frame: 1 year
Adverse Events Associated with Neoadjuvant Therapy
Incidence of adverse events related to neoadjuvant therapy as assessed by CTCAE v5.0
Time frame: 1 year
MPR
Major pathological response rate
Time frame: 1 year
Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate
Completion rate of neoadjuvant therapy
Time frame: 1 year
R0 resection rate
R0 resection rate in participants
Time frame: 1 year
TRG
Tumor regression grade
Time frame: 1 year
3 years DFS Rate
3 years Disease Free Survival Rate
Time frame: 3 years
3 years OS rate
3 years Overall Survival Rate
Time frame: 3 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Purpose
TREATMENT
Masking
NONE
Enrollment
100
A modified Atkins diet (MAD) is used, with the goal of maintaining nutritional ketosis, defined as a blood β-hydroxybutyrate (BHB) level of 1.5-3.0 mmol/L. The ketogenic dietary intervention begins after completion of SCRT and continues throughout six cycles of mFOLFOX6 chemotherapy and immunotherapy until the completion of neoadjuvant treatment.
Surgery either local excition or total mesorectal excision is performed 2 weeks after the completion of neoadjuvant therapy.
Vitamin C is administered intravenously at a dose of 1.5 g/kg/day, diluted in 250-500 mL of normal saline, over 2 hours for 3 consecutive days (Days 1-3). Each treatment cycle is repeated every 2 weeks and synchronized with the neoadjuvant treatment cycle.