Targeting the Warburg effect: Mitochondrial metabolic modulation with intermittent fasting during neoadjuvant chemoradiation in rectal cancer compared with standard neoadjuvant chemoradiation and total neoadjuvant therapy.

3612 Background: Cancer cells demonstrate metabolic inflexibility characterized by glycolytic dependence and dysfunctional mitochondrial oxidative phosphorylation [Warburg Effect]. Fasting and glucose restriction induce a metabolic shift toward mitochondrial fatty acid oxidation and ketone utilization in normal cells, while cancer cells are unable to adapt, resulting in increased oxidative stress and radio-sensitization. We evaluated whether inducing a fasting-mimicking metabolic state during neoadjuvant chemoradiation improves pathological complete response (pCR) rates in rectal cancer compared with total neoadjuvant therapy (TNT) and standard neoadjuvant chemoradiation (nCRT). Methods: 90 patients with locally advanced rectal adenocarcinoma were analyzed (30 per group). All patients had cT3N+ disease. Radiotherapy was delivered using IMRT/IGRT or adaptive techniques, receiving long-course radiotherapy (50.4 Gy in 28 fractions) with concurrent capecitabine. Group 1 received nCRT under a fasting-mimicking metabolic state using a structured low-carbohydrate diet [Non-Calorie Restricted] with ≥14 hours of daily fasting, titrated using continuous glucose monitoring [CGM] to achieve 16–17 hours per day with blood glucose levels <90 mg/dL. Group 2 received TNT consisting of nCRT followed by CAPEOX. Group 3 received standard nCRT without dietary intervention. The primary endpoint was pCR (ypT0N0) at surgery. pCR rates were compared between groups using the chi-square test or Fisher’s exact test, as appropriate, with a two-sided p value <0.05 considered statistically significant. Results: Baseline characteristics were balanced across groups; all patients had cT3N+ disease. Median age was 55 years, with all adenocarcinoma histology. pCR rates were 93.3% (28/30) in the fasting-state nCRT group, 73.3% (22/30) in the TNT group, and 33.3% (10/30) in the standard nCRT group. Fasting-state nCRT was associated with significantly higher pCR rates compared with standard nCRT (χ²=25.2, df=2; p<0.001). TNT was also superior to standard nCRT (p=0.004). The difference between fasting-state nCRT and TNT showed a strong numerical trend but did not reach statistical significance (p=0.08). Conclusions: Fasting-state metabolic modulation during neoadjuvant chemoradiation was associated with a striking increase in pCR rates. Mitochondrial stress induced by glucose restriction may enhance tumor radio-sensitivity through increased reactive oxygen species and impaired metabolic compensation. Precision-guided fasting represents a promising, low-cost therapeutic strategy warranting prospective larger cohort validation. Clinical trial information: CTRI/2024/10/075843. Comparison pCR p-value Fasting-state nCRT 93.3% (28/30) < 0.001 TNT 73.3% (22/30) 0.004 Standard nCRT 33.3% (10/30) 0.08