Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.1,2
The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.3,4
We previously published a safety and feasibility study of the Modified Atkins Diet in metastatic cancer patients after failure of chemotherapy at the US Department of Veterans Affairs (VA) Pittsburgh Healthcare System.1 None of the patients were on chemotherapy at the time of enrollment. The Modified Atkins Diet consists of 60% fat, 30% protein, and 10% carbohydrates and is more tolerable than the ketogenic diet due to higher amounts of protein. Six of 11 patients (54%) had stable disease and partial response on positron emission tomography/computed tomography (PET/CT). Our study showed that patients who lost at least 10% of their body weight had improvement in quality of life (QOL) and cancer response.1 Here we present a case of a veteran with extensive metastatic colon cancer on concurrent ketogenic diet and chemotherapy subsequently followed by concurrent ketogenic diet and immunotherapy at Veterans Affairs Central California Health Care Systems (VACCHCS) in Fresno.
A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).
The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).
Due to disease progression, the patient’s treatment was changed to encorafenib and cetuximab for 4 months before progressing again with new liver mass and mediastinal lymphadenopathy. He then received pembrolizumab for 4 months until PET/CT showed progression and his carcinoembryonic antigen (CEA) increased from 95 to 1031 ng/mL by January 2021 (Figure 4).
The patient was started on trifluridine/tipiracil, and bevacizumab while concurrently initiating the ketogenic diet in January 2021. Laboratory tests drawn after 1 week of strict dietary ketogenic diet adherence showed low-level ketosis with a glucose ketone index (GKI) of 8.2 (Table 1).
A follow-up PET/CT showed disease progression along with a CEA of 94 ng/mL after 10 months of chemotherapy plus the ketogenic diet (Table 2).
The patient continued to experience excellent QOL based on the QOL Eastern Cooperative Oncology Group (ECOG) core quality of life questionnaire (QLC-C30) forms, which he completed every 3 months. Twenty-two months after starting the ketogenic diet, the patient’s CEA increased to 293 ng/mL although PET/CT continues to show stable disease (Figures 4, 5, and 6).