A randomized phase II trial reports feasibility of and trends towards improved progression-free survival (PFS) and overall survival (OS) with medically supervised ketogenic diet (MSKD) in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (PDAC) receiving gemcitabine, nab‐paclitaxel and cisplatin chemotherapy.
Study rationale
The ketogenic diet (KD) is a higher‐fat, lower‐carbohydrate, moderate‐protein regimen, which exploits the metabolic vulnerabilities of cancer cells by reducing glucose and insulin levels and increasing levels of the ketone bodies, β‐hydroxybutyrate (BHB), acetoacetate, and acetone. [Cancer Cell 2020;37:767‐785; Annu Rev Nutr 2017;37:51‐76] In murine pancreatic cancer models, adding KD to gemcitabine, nab‐paclitaxel and cisplatin synergistically suppressed tumour growth, tripling the survival benefit of chemotherapy alone. [Medicine 2022;3:119‐136]
In the present study, patients in the MSKD arm (n=16; median age, 66.1 years; male, 50 percent) received dietary recommendations to restrict total carbohydrate intake to ≤30 g/day (typically ≤10 percent of total energy intake), consume 1.5 g of protein per 1 kg of reference body weight, and incorporate dietary fats to satiety. They were required to monitor BHB levels twice daily via a home blood ketone monitor during the first month, then daily thereafter. [Cancer 2026;132:e70343]
“Accumulating evidence supports BHB as an antitumour effector alongside cytotoxic therapy and immunotherapy in PDAC,” wrote the researchers. “Mechanistically, BHB has far‐reaching effects on cancer cell metabolism, epigenetic and transcriptional regulation, the gut microbiome, and histone deacetylation inhibition.” [Nutrients 2021;13:3202]
In addition, setting a BHB level goal was intended to objectively reflect compliance while making any diet heterogeneity between study participants irrelevant, and to avoid reliance on patients’ recollection and the assumption of accurate recording of intake into food diaries, which makes capturing compliance cumbersome and less reliable.
Patients in the non‐MSKD arm (n=16; median age, 65.9 years; male, 56.2 percent) did not have any nutritional intervention and served as controls. They were instructed to follow their regular diet and not a ketogenic diet.
All patients in the study were treatment-naïve, had metastatic PDAC, and received intravenous (IV) nab‐paclitaxel 125 mg/m2, gemcitabine 1,000 mg/m2, and cisplatin 25 mg/m2 on days 1 and 8 every 21 days until development of unacceptable toxicity, disease progression, or clinical deterioration.
“The purpose of such a screening trial design was to decide whether the MSKD warrants a larger, definitive phase III trial,” explained the researchers. “To our knowledge, this is the first randomized study to evaluate an MSKD by continuous care intervention in patients with PDAC receiving first‐line chemotherapy.”
Feasibility of ketogenic diet
Based on daily ketone tracking, 15 of 16 patients in the MSKD arm achieved nutritional ketosis (defined as 0.5–3.0 mmol/L blood BHB) at any point during the study, with a mean BHB level of 0.49 mmol/L and median proportion of days in ketosis of 39.4 percent.
All MSKD‐related adverse events (AEs) were of grade 1–2 and included fatigue (n=3), constipation (n=3), weight loss (n=3), decreased appetite (n=1), dehydration (n=1), dizziness (n=1), nausea (n=1) and body ache (n=1). “The incidence of these grade 1–2 MSKD‐related AEs was not different from … the incidence in non‐MSKD participants. None of the patients stopped the MSKD due to AEs,” reported the researchers.
There were no unexpected chemotherapy‐related AEs and no treatment‐related deaths on study. When examining grade ≥3 chemotherapy‐related AEs, there were no significant differences in anaemia, diarrhoea, or platelet count decrease between the two arms.
Efficacy and survival outcomes
The primary endpoint of median PFS based on RECIST criteria was 8.5 vs 6.2 months in the MSKD vs non-MSKD arm (hazard ratio [HR], 0.53; 95 percent confidence interval [CI], 0.21–1.37; one‐sided p=0.096). The median OS in the MSKD vs non-MSKD arm was 13.7 vs 10.2 months (HR, 0.58; 95 percent CI, 0.25–1.37; one-sided p=0.107). The researchers stressed that the small sample size was not powered for definitive outcomes, yet noted the trends towards improved PFS and OS with MSKD.
The disease control rate at 9 weeks did not significantly differ between the MSKD and non‐MSKD arms (93.8 vs 87.5 percent; p=1.000). More patients in the MSKD arm achieved a best overall response of partial response compared with the non‐MSKD arm, but this did not reach statistical significance (68.8 vs 31.2 percent; p=0.110).
Changes in metabolic parameters, microbiome and QoL measures
Over the course of the study, patients in the non‐MSKD arm gained more weight than in the MSKD arm (linear mixed effects model, pinteraction<0.001). At the same time, weight remained stable in the MSKD arm.
During study treatment, glucose levels were higher in the non‐MSKD arm than in the MSKD arm (area under the curve, p=0.019), while glycated hemoglobin levels decreased more over time in the MSKD vs non-MSKD arm (linear mixed effects model, pinteraction=0.076). No significant differences between arms were seen in insulin levels throughout the study duration.
Microbiome profiles between the two groups remained distinct through the intervention period. Differential abundance analysis revealed a significant enrichment of beneficial taxa in the MSKD vs non-MSKD group (p<0.05; log‐fold change ≥2), including Akkermansia muciniphila (species linked to improved response to immune checkpoint inhibitors; p=0.018), Intestinimonas butyriciproducens (a short‐chain fatty acid and butyrate producer; p<0.0001), and Streptococcus thermophilus (a supporter of gut mucosal health; p<0.0001).
During the study, only MSKD patients showed sustained increases in Roseburia hominis (short‐chain fatty acid/butyrate producer; p<0.0001) and Lacticaseibacillus rhamnosus (which has anti‐inflammatory and immune‐modulating properties; p<0.0001), along with a marked reduction in potentially pro‐inflammatory Actinomyces spp (p<0.0001). “Findings from microbiome analysis in our study demonstrated enrichment of anti‐inflammatory and immune‐mediating bacteria in the MSKD group, which may have partly contributed to the improved outcomes and warrant further exploration,” remarked the researchers.
With respect to quality of life (QoL) measures, over the course of therapy, summary scores increased more in the non‐MSKD vs MSKD arm (linear mixed effects model, pinteraction=0.005). “Patients in the non‐MSKD arm experienced improved Quality of Life Questionnaire [QLQ‐C30] Global Health Status scores during the first three cycles of chemotherapy, which is consistent with previous studies of the triplet regimen, whereas those on MSKD did not demonstrate improvement. Importantly, there was no decline in QoL in the MSKD group,” noted the researchers. [Cancer Med 2024;13:e7412]
Larger study warranted
The present study found that MSKD is feasible and safe in patients with treatment‐naïve metastatic PDAC receiving gemcitabine, nab‐paclitaxel, and cisplatin, while also showing trends towards improved PFS and OS.
“This was a phase II screening trial that used a relaxed alpha level of 0.20 for the outcomes of PFS and OS. As such, the results of our study are ultimately hypothesis‐generating and intended to guide the decision whether to proceed with a phase III trial. Although it did not meet its primary endpoint by conventional statistical standards, the observed trends warrant further investigation in a larger, adequately powered trial,” concluded the researchers.