Investigating the Ketogenic Diet As Treatment for Primary Aggressive Brain Cancer: Challenges and Lessons Learned

Abstract

Survival of glioblastoma multiforme (GBM) with the current recommended treatment is poor. Reported median survivals are approximately 8–15 months. Based on recent publications from animal models, combining cancer drugs, radiation, and diet-metabolic treatments may be a new route to better survivals. To investigate this possibility, we have begun a clinical trial that has enrolled 15 subjects using a ketogenic diet (KD) as an addition to current standard treatments that include surgery, radiation therapy, and chemotherapy. Of the 15 enrolled, 10 completed the protocol. This perspective describes the challenges and lessons learned during this clinical trial and discusses the critical elements that are essential for investigating treatment with a KD. We also reviewed and compared various types of KDs. We believe that the diet selected should be standardized within individual clinical trials, and more importantly, the patients’ blood should be monitored for glucose and ketones twice daily so that the supervising dietitian can work with the patient and their caregivers to make appropriate changes in the diet. Compliance with the diet is best in highly motivated patients who have excellent home support from a family member or a friend who can help to overcome administrative, physical, and cognition deficiencies associated with the disease. Treatment of GBM using a KD represents a reasonable investigative approach. This perspective summarizes the challenges and lessons learned implementing and continuing KD therapy while the patients are concurrently being treated with radiation and chemotherapy.

Treatment Of Glioblastoma Multiforme With “classic” 4:1 Ketogenic Diet Total Meal Replacement

“…While preclinical data suggests great promise for KD treatment of GBM, few clinical studies have been done [24][25][26][27][28][29][30][31]. Part of the reason is the difficulty of doing KD.…”

“…KD poses three main challenges: lack of palatability, the complicated nature of meal preparation, and lack of standardization. Of the four published KD GBM studies with > 2 patients, three concluded that KD cannot be tolerated for more than 6-12 weeks [26][27][28], and that the maximally tolerated diet is 3:1 with 20 g CH. In a German study of restrictive calorie ketogenic diet in end-stage malignant tumors only 5/16 subjects completed the 3-month treatment period [32].…”

“…In patients with GBM, hyperglycemia is associated with shorter survival [23]. There have been seven reports of KD treatment of patients with GBM: 3 of 1-2 patients and 4 with 9-20 patients [24][25][26][27][28][29][30].…”

“…These studies have varied widely. They have ranged in treatment duration from 6-14 weeks, in disease stage from adjunctive treatment with standard initial care to recurrent GBM, in diet design CH content from 60 g CH/day or 25% of calories derived from CH to 4:1 KD [26][27][28]30], in fat content, and in presence, absence and degree of caloric restriction.…”

Diet in Brain Health and Neurological Disorders: Risk Factors and Treatments

“…Diet adherence and compliance remain significant barriers to successful implementation and an adequate assessment of KD efficacy. Common methodologies to assess and document KD adherence in adults beyond patient self-report include frequent measurements of serum β-hydroxybutyrate or urine acetoacetate concentrations during the first few weeks on the diet and/or collection of dietary food records [57,121,128]. As examples, daily urine ketone assessments are traditionally used in adults with epilepsy during MAD initiation until moderate to large levels of ketosis are reached and serum ketone assessments using drops of blood from a finger stick have been used to guide short-term KD therapy in patients with GBM [53,128].…”