Cancer, Endocrine

A randomized phase II trial of gemcitabine, nab‐paclitaxel, cisplatin with or without a medically supervised ketogenic diet for patients with metastatic pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options, particularly in the metastatic setting. Interest has grown in metabolic therapies such as ketogenic diets, which restrict carbohydrates and elevate ketone bodies like beta-hydroxybutyrate (BHB). Preclinical studies suggest that ketogenic diets may exploit metabolic vulnerabilities in pancreatic tumors and potentially enhance chemotherapy efficacy.

This randomized phase II screening trial included 32 patients with treatment-naïve metastatic PDAC. Participants were randomized to receive gemcitabine, nab-paclitaxel, and cisplatin alongside either a medically supervised ketogenic diet (MSKD) or a usual diet. Patients assigned to the ketogenic intervention received remote dietary guidance and ketone monitoring to maintain BHB levels between 0.5 and 3.0 mmol/L. Progression-free survival was the primary endpoint, with overall survival, safety, metabolic markers, microbiome changes, and quality of life assessed as secondary outcomes.

Results:

Ketosis and Adherence

• 15 of 16 patients in the MSKD group achieved nutritional ketosis at some point during the study.
• The median proportion of days in ketosis was 39.4%, with average BHB levels of 0.49 mmol/L.

Progression-Free Survival (PFS) and Overall Survival (OS)

• Median PFS was 8.5 months in the MSKD group versus 6.2 months in the control group.
• Median OS was 13.7 months in the MSKD group compared with 10.2 months in the non-MSKD group.

Tumor Response

• Partial responses occurred in 68.8% of MSKD patients compared with 31.2% in the control group.

Metabolic Changes

• Patients on the ketogenic diet had lower glucose levels over time and greater reductions in HbA1c than the control group.
• Weight remained stable in the MSKD group during early treatment cycles.

Microbiome Effects

• The MSKD group showed enrichment of potentially beneficial gut bacteria such as Akkermansia muciniphila, Intestinimonas butyriciproducens, and Streptococcus thermophilus.

Safety and Quality of Life

• Diet-related adverse events were mild and included fatigue, constipation, and decreased appetite.
• Rates of severe chemotherapy-related adverse events were similar between groups.
• Quality-of-life scores remained stable in the ketogenic diet group, with no significant decline during treatment.
• Conclusion

In this randomized phase II screening trial, a medically supervised ketogenic diet was feasible and well tolerated in patients with metastatic pancreatic cancer undergoing chemotherapy. Although the study was not powered for definitive outcomes, patients following the ketogenic intervention showed trends toward improved progression-free and overall survival without increased toxicity or reduced quality of life. These findings support further investigation of ketogenic metabolic therapy as an adjunct to standard pancreatic cancer treatment in larger, adequately powered clinical trials.