A Phase 1 Trial of Ketogenic Diet With Concurrent Chemoradiation (CRT) in Head and Neck Squamous Cell Carcinoma (HNSCC)

Abstract

Purpose/Objective(s): Ketogenic diet (KD) combined with CRT reduced tumor growth and improved survival in preclinical models. We hypothesized stage III-IVb HNSCC patients would be able to remain compliant with KD because of percutaneous endoscopic gastrostomy (PEG) tube requirement during CRT. Materials/Methods: This institutional review board-approved phase 1 clinical trial enrolled stage III-IVb definitive and postoperative HNSCC patients receiving concurrent platinum-based CRT. PEG placement was required up front, but subjects were encouraged to continue KD by mouth due to benefits in continued swallowing activity on ultimate function. KD recipe ideas and shakes were provided to subjects for daily consumption for 5 weeks concurrent with CRT. Shakes could also be delivered by way of PEG tube for caloric requirements. Fingerstick ketones (FK) were checked Monday through Friday, and serum beta-hydroxybutyrate (BHB), glucose, and uric acid were checked weekly. Lipid panel was checked at week 3. In addition, serum oxidative stress parameters were assessed prior to, during, and after completing KD. Results: Median follow-up for all enrolled subjects (n=9) from completion of RT was 7.1 months (range: 0-12.9 months). Three of 9 subjects successfully completed 5 weeks of KD as prescribed. Successful subjects used scheduled antiemetics, consumed shakes by way of PEG tube as opposed to orally, and had strong social support. Median days on KD for those who discontinued was 6 (range: 0-8). Reasons for discontinuation included additional stress of diet compliance (1 of 6 patients), Common Terminology Criteria for Adverse Events version 4.0 grade 2 nausea (2 of 6 patients), grade 3 nausea (1 of 6 patients), grade 3 fatigue (1 of 6 patients), and grade 4 hyperuricemia (1 of 6 patients). SAEs (n=6) included parotiditis, nausea, vomiting, neutropenic fever, hyperuricemia, and pancreatitis, of which hyperuricemia and pancreatitis were possibly attributed to KD and considered DLTs. The trial was temporarily suspended after the grade 4 hyperuricemia (12.7 nd/dL; nl ref 2.4-7.0); the protocol was amended to initiate allopurinol and address treatment of diet-related hyperuricemia. In those who completed KD, the median days FK were elevated and weeks the BHB levels were above baseline were 24 days (range: 19-25) and 5 weeks (range: 4-5), respectively. FK levels were impacted by dexamethasone given for chemotherapy and by carbohydrates in liquid medications. Median uric acid levels were 5.3 nd/dL (range: 4.4-5.4). Lipids remained normal. Serum oxidative stress markers, as assessed by protein carbonyls, increased linearly with increasing days on KD. Conclusion: While challenging despite PEG availability, KD compliance is possible when combined with concurrent CRT for HNSCC. Enrollment continues and updated results will be presented.