Gayle Jameson, Denise J. Roe, Erkut Borazanci, Diana L. Hanna, Caroline G. P. Roberts, Meredith S. Pelster, Richard C. Frank, Angela Alistar, Alan M. Miller, J. Erin Wiedmeier‐Nutor, Sandra D. Algaze, Alison R. Zoller, Sarah J. Hallberg, Betsy C. Wertheim, Keehoon Lee, Derek Cridebring, Joshua D. Rabinowitz, Stephen Gately, Jennifer Keppler, Sunil Sharma, Daniel D. Von Hoff, Drew Rasco
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.