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

BACKGROUND: A randomized phase II screening trial of gemcitabine, nab-paclitaxel, and cisplatin with a medically supervised ketogenic diet (MSKD) versus usual diet (non-MSKD) was conducted in patients with treatment-naive metastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients with untreated metastatic PDAC were randomized 1:1 to MSKD or non-MSKD while receiving gemcitabine, nab-paclitaxel, and cisplatin on days 1 and 8 of a 21-day cycle. The MSKD was guided by a remote health care team and daily ketone (beta-hydroxybutyrate) levels, with goal beta-hydroxybutyrate of 0.5 to 3.0 mM. The primary endpoint was progression-free survival (PFS) using a one-sided alpha level of 0.20. Secondary endpoints included overall survival (OS), safety, and quality of life (QOL). Changes in microbiome were an exploratory endpoint. FINDINGS: Overall, there were 32 evaluable patients. In the MSKD arm, 15 of 16 patients achieved nutritional ketosis; the median proportion of days in ketosis was 39.4%. The median PFS was 8.5 months in MSKD patients and 6.2 months in non-MSKD patients: hazard ratio, 0.53 (95% CI, 0.21-1.37); one-sided p = .096. The median OS was 13.7 months with MSKD and 10.2 months in the non-MSKD arm: hazard ratio, 0.58 (95% CI, 0.25-1.37); one-sided p = .107). All MSKD-related adverse events were grade 1-2. There were no significant differences in grade ≥3 chemotherapy-related adverse events between the arms. MSKD patients had no decline in QOL and had significant enrichment of beneficial taxa in the microbiome (p < .05, log-fold change ≥2). CONCLUSIONS: The MSKD is feasible in patients with PDAC and, although not powered for definitive outcomes, shows trends in improved PFS and OS when combined with gemcitabine, nab-paclitaxel, and cisplatin, without added toxicity or detriment to QOL. Larger studies are required to confirm these findings and establish the value of the MSKD in pancreatic cancer treatment.