Feasibility and Safety of a Ketogenic Diet During Systemic Therapy for Metastatic Renal Cell Carcinoma: Results From the Cetorein Pilot Study

Abstract Background: Metastatic renal cell carcinoma (mRCC) remains incurable despite advances with immune checkpoint inhibitors and tyrosine kinase inhibitors. Metabolic interventions, such as the ketogenic diet (KD), may modulate tumor biology and systemic inflammation, yet clinical evidence in mRCC is limited. Objective: To evaluate the feasibility, safety, and tolerability of KD combined with systemic therapy in mRCC patients. Design, Setting, and Participants: CETOREIN was a non-randomized, single-center pilot study enrolling 21 adult mRCC patients initiating systemic therapy. KD was initiated concurrently with treatment for up to 12 months, with follow-up at 1, 3, 6, and 12 months. Intervention: Participants followed a 2:1 KD (≈80% fat, 20% protein+carbohydrates) with dietitian-led counseling, medium-chain triglyceride supplementation, food diaries, and ketonuria monitoring. Outcome Measurements and Statistical Analysis: The primary endpoint was feasibility, defined by diet-related adverse events. Secondary endpoints included adherence, metabolic parameters, and clinical outcomes (response rate, progression-free survival [PFS], overall survival [OS]). Results: Eight patients (40%) completed 12 months on KD, with a mean duration of 7 months. Common diet-related toxicities were diarrhea (55%), weight loss (45%), hypercholesterolemia (40%), and dyspepsia (30%), with no severe events. Early weight loss was modest and transient. Ketonuria correlated with dietary records, confirming adherence. Median PFS was 9.5 months and median OS 39 months. Among four patients undergoing cytoreductive nephrectomy, PD-L1 expression decreased in three cases. Conclusions: KD is feasible and safe for selected mRCC patients, though long-term adherence is challenging. Future studies should evaluate shorter interventions and optimized dietary protocols in larger randomized trials.