Rationale, Feasibility and Acceptability of Ketogenic Diet for Cancer Treatment.

Ketogenic diet has been used for more than 80 years as a successful dietary regimen for epilepsy. Recently, dietary modulation by carbohydrate depletion via ketogenic diet has been suggested as an important therapeutic strategy to selectively kill cancer cells and as adjuvant therapy for cancer treatment. However, some researchers insist ketogenic diet to be highly undesirable as ketogenic diet may trigger and/or exacerbate cachexia development and usually result in significant weight loss. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possibility of the use of ketogenic diet for oncology patients. Article search was performed from 1985 through 2017 and finally 10 articles were analyzed. The review focused on the results of human trials for cancer patients and checked the feasibility of using ketogenic diet for cancer patients as adjuvant therapy. The main outcomes showed improvement of body weight changes, anthropometric changes, serum blood profiles, and reduction in novel marker for tumor progression, TKTL1, and increase of ketone body. Lactate concentration was reduced, and no significant changes were reported in the measurements of quality of life. Ketogenic diet may be efficacious in certain cancer subtypes whose outcomes appear to correlate with metabolic status, but the results are not yet supportive and inconsistent. Therefore, it warrants further studies.

INTRODUCTION

Diet and exercise interventions in cancer patients may be of benefit for ameliorating adverse events during cancer treatment and may increase overall survival.1–3 Metabolic processes in cancer are complex and highly regulated, and there is increasing evidence that dietary modulation can be efficacious in managing cancer, i.e., diet rich in fat and protein4 or calorie restriction.5,6 Calorie restriction has been shown to reduce the pro-growth signaling, partially achieved by temporarily reducing glucose and circulating insulin-like growth factor 1, which is highly associated with aging and cancer.7 Also, manipulation of the molecular pathways using calorie restriction has been shown to render cancer cells susceptible to standard cytotoxic treatment with radiation and chemotherapy especially strong for breast cancer. However, considering the high drop-out rate (25%), this indicates that adherence to this low-calorie diet requires high commitment to the study participants.

Ketogenic diet is designed specifically to result in ketosis and is emerging as a metabolic therapy for treating cancer. The mechanism can be explained by inducing shortage of glucose and/or lactate for tumor cells to survive. Vander Heiden et al.8 observed that tumors take up enormous amounts of glucose compared to the surrounding tissue and eventually produces lactate through aerobic glycolytic pathway. Therefore, limitation of glucose availability in cancer cell may reduce energy production of cancer cells, and thereby decreasing tumor proliferation.9

The aim of this review is to assess the clinical evidence of ketogenic diet intervention in cancer patients by analyzing human trials.

STUDY SEARCH AND SELECTION

1. Literature search

The eligible literatures were retrieved by searching through databases (PubMed, MEDLINE, and Springer link) from 1985 until July, 2017. Searching keywords included “ketogenic diet” or “ketone”, “cancer” or “tumor”, and “oncology” with no language restriction and was limited to human clinical trials.

2. Inclusion and exclusion criteria

Articles were included under the following criteria: (1) randomized clinical trials with/without control, (2) prospective cohort study, (3) adult population, and (4) ketone diet composition mentioned. The exclusion criteria were as follows: (1) articles with incomplete data, (2) case studies, and (3) reviews. Letters or comments were irrespective.

3. Data extraction

After the completion of article screening, two investigators independently extracted the data from the eligible studies according to the predesigned protocol. The extracted information was summarized by the first author’s name, journal name, publication year, geographical area of study population, mean age of the participants, sample size of the intervention and control groups, detailed dietary regimen and the length of the study, adherence rate, outcome measures, and results of each article, and finally reported side effects.

ELIGIBLE STUDIES

The process of search strategy is presented in Figure 1. The original search yielded a total of 468 citations (limited to clinical trials, human studies, and years from 1985–2017). First, there were 63 articles after removing the duplicates. Then, 47 articles were excluded because of obvious irrelevance after screening the title and abstract. Six among the remained 16 articles were removed after full-text review: 2 for case studies; 4 without available data. Finally, 10 articles were included in this review. The recommendation of the Cochrane Effective Practice and Organization of Care Review systematic review and meta-analyses, randomized controlled studies, and non-randomized controlled studies were included.10

Figure 1

Flowchart of study search and selection.

SUMMARY OF THE STUDY OUTCOMES OF ELIGIBLE ARTICLES

The detailed information of ketone diets from the selected articles are summarized in Table 1.11–20

Table 1

Clinical trials (including prospective cohort study) using KD in cancer patients

Author (journal and year)	No. of subjects and characteristics	Cancer type	KD intervention (duration and regimen)	Adherence	Outcome measures and results	Side effect
Fearon et al.11 (Am J Clin Nutr 1988)	Total n = 5Cachectic patients (mean age, 61 yr)Country: Italy	2 Gastric cancer2 Lung cancer1 Ovarian cancer	6 days balanced enteral formula (BD) → 7 days KD enteral formula (KD)BD: kcal: 44 kcal/kg/d prot: 1.5 g/kg/d (55% carbohydrate, 31% fat)KD: kcal: 44 kcal/kg/d prot: 1.5 g/kg/d (whey) 4.4 mmol argninine/kg/d  (70% of calorie as MCT)	100%	BD No change of body weight No change of nitrogen balance No change of prot turnoverKD Increased body weight No change of nitrogen balance No change of prot turnover	No GI upset
Rossi-Fanelli et al.12 (Clin Nutr 1991)	Total n = 27TNM stagedArm A: n = 9 (median age, 61 yr)Arm B: n = 9 (median age, 70 yr)Arm C: n = 9 (median age, 67 yr)Country: Italy	9 Oesophagus9 Stomach9 Colorectal	14 days interventionIso-kaloric regimenArm A: parenteral nutrition 100% dextrose 0.24 g/kg/d amino-acid Vitamin mineralsArm B: parenteral nutrition 80% as fat, 20% as dextrose 0.24 g/kg/d amino-acid Vitamin mineralsArm C: oral diet	100%	No group differences were found in S-phase fraction of cell cycle Total lymphocyte counts Blood glucose Triglycerides Body weight Mid-arm circumferences Serum albumin Pre-albumin Transferrin Retinol-binding prot	Not mentioned
Breitkreutz et al.13 (Wien Klin Wochenschr 2005)	Total n = 23Moderately malnourished cancer patientsGroup A: n = 11 (mean age, 60.6 yr)Group B: n = 12 (mean age, 58.8 yr)Country: Germany	12 Colorectal11 GastricAll metastases	Group A 8 weeks of 35 kcal/kg/d, 1.1 g prot/kg/d (normal meals) Nutritional counseling every 14 daysGroup B 8 weeks of 20 kcal/kg/d, 1.1 g prot/kg/d (fat-enriched liquid diet + normal meals) Nutritional counseling every 14 days	100%	Group A Average intake 1,556 ± 497 kcal Progressive weight loss Progressive loss of FFM Decrease in serum albumin No change TLC No change of QOLGroup B Average intake 1,865 ± 317 kcal Increased body weight Progressive increase of FFM No change in serum albumin Significant decrease of TLC No change of QOL	Not mentioned
Schmidt et al.14 (Nutr Metab (Lond) 2011)	Total n = 16Metastatic tumors (mean age, 50.4 yr)Country: Germany	3 Ovarian cancer1 Breast cancer1 Osteosarcoma5 Gastrointestinal cancer2 Thyroid cancer1 Endometrial1 Lung cancer1 Granulosa cell tumor1 Parotis carcinoma	3 months of low CHO diet (KD) - CHO limitation to 70 g/d, 20 g/meal - 2 liquid meals (21 g fat, 5 g CHO, 14 g prot)/meal	31% (2 died, 9 dropped out)	KD 3 patients reached ketosis No change: Global health status  Functional score  Blood glucose, TG  creatinine, Albumin Increase: appetite loss, constipation  Diarrhea (at 4 wk) Increase: fatigue, pain Decrease: insomnia	No diet related adverse events
Fine et al.15 (Nutrition 2012)	Total n = 109Incurable, advanced cancer (mean age, 62.9 yr)Country: USA	2 Breast cancer3 Colorectal1 Ovary1 Fallopian tube2 Lung1 Esophagus	26–28 days KD intervention - < 5% of kcal as CHO - Increase fat and prot encouraged	100%	KD Increased weight loss (−3.0 kg) Energy deficit (−35%) No change of serum glucose Increased dietary ketosis Inverse relationship of insulin vs. β-hydroxybutyrate	No unsafe adverse effectsExcept constipation, leg cramps, reversible fatigue
Schroeder et al.16 (Nutr Cancer 2013)	Total n = 12Head and neck cancer (mean age, 64 yr)Country: Germany	2 Larynx3 Oral cavity2 Hypopharynx3 OropharynxUnknown primary	5 days KD interventionMicrodialysis	100%	KD Increase of urea in tumor tissues No change in plasma glucose Decrease in lactate concentration in tumor tissues Decrease in lactate/pyruvate ratio	Not mentioned
Rieger et al.17 (Int J Oncol 2014)	Total n = 20Patient from ERGO trial (mean age, 57 yr)Country: Germany	Recurrent malignant glioma	36 days interventionKD diet: ketogenic ratio, 3.41 : 1 - CHO limitation to less than 60 g/d - No calorie restriction - 500 mL yoghurt + plant oil	85%	KD Increased weight loss No change in blood glucose, HbA1c, lipid profiles Leukcytopenia in 2 patients Overall survival 32 weeks	Few reports on diarrhea, constipation but no major concern or toxicity
Jansen and Walach18 (Oncol Lett 2016)	Total n = 78Prospective cohort study (mean age, 68 yr)Country: Germany	18 Breast16 Prostate9 Colon5 Lung5 Otoharyngeal25 Other	10 mo–2 yr65 not ketogenic6 partially ketogenic7 fully ketogenic	Not mentioned	KD Reduction of TKTL1 (novel marker associated with tumor progression) 3 out of 7 patients had improvement 1 had full remission	Not mentioned
Klement and Sweeney19 (BMC Res Notes 2016)	Total n = 6 (mean age, 60.3 yr)Country: Germany	1 Breast1 Prostate3 Rectum1 Lung during RT	32–73 dKD with weekly counseling - CHO limitation to 50 g/d - Encourage to consume olive oil, coconut oil, butter, fatty fish, cheese, meat	Not mentioned	KD - Decreased BW in 2 patients - Decreased fat mass in 2 patients - No change in hydration status - Decreased phase angle - Increased ketone body	Not mentioned
Tan-Shalaby et al.20 (Nutr Metab (Lond) 2016)	Total n = 17Advanced cancer pts not on hemotherapy (mean age, 65 yr)Country: USA	6 Gastrointestinal2 Lung3 Skin cancer1 Prostate1 Thyroid2 Brain cancer1 Head/neck1 Renal	16 weeks (checked every 4 wk)KD - CHO limitation to 20–40 g/d (no restriction of cal, prot, fat)	64.7% (6 for 8 wk, 4 for 16 wk, 3 beyond 16 wk)	KD - 13% wt loss at week 16 No changes in glucose, creatinine, SBP/DBP, lipid profile, WBC count, uric acid, albumin, ALT Slight improvement of EORTC QLQ-30	8 Weight loss7 Hyperuicemia2 Hyperlipidemia2 Pedal edema2 Anemia2 Halitosis2 Pruritus2 Hypoglycemia2 Hyperkalemia2 Hypokalemia2 Hypomagnesemia2 Flu-like symptom

KD, ketogenic diet; BD, balanced diet; MCT, medium chain triglyceride; prot, protein; GI, gastrointestinal; FFM, fat free mass; TLC, total lymphocyte count; QOL, quality of life; CHO, carbohydrate; TG, total cholesterol; RT, radiation therapy; BW, body weight; wt, weight; SBP, systolic blood pressure; DBP, diastolic blood pressure; WBC, white blood cell; ALT, alanine aminotransferase; EORTC QLQ-30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.

A total of 214 subjects were included in the review. Most of the studies were intervention trials except for one prospective cohort study. The mean age of the studies was mostly from late fifties to early seventies. Eight out of ten articles were submitted from European countries (Germany and Italy) and only two were from USA. The duration of experimental intervention ranged from 5 days to 2 years and the outcome measures were mainly focused on the body weight and composition and blood profile. One article measured quality of life (QOL). The adherence rate in 5 studies were 100%, and the rest were from 31% to 85%. Reported side effects in the studies were relatively minor and included only few reported constipation, leg cramps, diarrhea, etc. Subjects maintained on ketogenic diet for a relatively short period (2 weeks in the study by Rossi-Fanelli et al.,12; 1 week in the study by Fearon et al.,11; 5 days in the study by Schroeder et al.16) did not show any significant changes of the markers, such as body weight or blood profile except for decrease in lactate concentration in the tumor tissues. Meanwhile, when subjects were maintained for a longer period, such as 8 weeks, ketogenic diet (normal meal + fat-enriched liquid diet) successfully showed increased energy intake and body weight of the subjects.13 Ketogenic diet in this study was used for only malnourished gastro-intestinal cancer patient with metastases, suggesting the possibility of application in specific cancer patients. Evaluation on anticancer biomarkers was not measured in most of the articles except for study by Jansen and Walach18 who found that TKTL1, a novel marker associated with tumor progression, was reduced by a 2-year ketogenic diet.

Notably, the results from Fine et al.,15 Rieger et al.,17 and Klement and Sweeney19 showed that ketone diet increased significant weight loss. These results showed that unlike the consistent ketogenic effects on epilepsy patients, ketogenic effects on cancer patients were not consistent in this review.

KETOGENIC DIET AS A CANCER THERAPEUTIC STRATEGY

Recently, ketogenic diet has been newly emerged as a cancer therapy in both animal models and humans. Some of the preclinical studies have shown the effect of ketogenic diet to reduce tumor growth and improve survival in animal models of malignant glioma,21–23 prostate cancer,24–26 colon cancer,27 and gastrointestinal cancer.28 Low calorie diet, such as fasting inducing a state of ketosis, has been shown to enhance the responsiveness of cancer cells to chemotherapy in pre-clinical cancer therapy models and to ameliorate some of chemotherapy-induced side effects in normal tissues.29

More recently, numerous case reports were reported. First report was derived from confirmed glioblastoma multiforme treated with standard therapy together with a restricted ketogenic diet, and the response observed in the case suggested the possibility of calorie-restricted ketogenic diet.30

Ketogenic diet has been studied intensively in the European country including Germany. In these studies, the physical condition was successfully improved and tumor shrinkage was observed by ketogenic diet.14 The studies here reviewed lack greatly in the homogeneity of type of cancer, location of cancer, the stages of cancer, and the treatment course of the cancer, and thus the results cannot be generalized. Because ketogenic diet normally results in an increased weight loss, there are continuous concerns to apply this diet for cancer patients. In this review, however, we found that ketogenic diet showed no significant adverse effects. It may be possibly because the subjects were adults, while in children long-term ketogenic diet induces renal damage such as kidney stones.31 Any adverse effects reported in this review were constipation, diarrhea, fatigue, etc. In healthy obese adults with low-carbohydrate ketogenic diet for 6 months, the only adverse effects reported were an increase in the level of low-density lipoprotein cholesterol and some shakiness and uneasiness.32

Studies described in this review assessed the effects of a ketogenic diet in cancer patients. Only ten studies were analyzed and the characteristics and study design, the ketogenic diet regimen, the length of study, cancer type and stage, and site were heterogeneous, thereby contributing to a poor conclusion.

As for ongoing clinical trials, there are currently 62 trials assessing low carbohydrate diets as a potential therapy for a variety of diseases of which 13 trials are assessing ketogenic diet as an adjuvant cancer therapy. Three of the studies are not initiated, but, one study with pancreatic cancer patients was terminated because of the low participation and adherence (Table 2).

Table 2

Ongoing clinical trials from clinicalTrials.gov (https://clinicaltrials.gov) (accessed on 08/04/2017)

	Title	Recruitment	Study Results	Conditions	Interventions
1	Ketogenic Diet for Recurrent Glioblastoma	Completed	Has results	Recurrent glioblastoma	Dietary supplement: TAVARLIN
2	Ketogenic Diet as Adjunctive Treatment in Refractory/End-stage Glioblastoma Multiforme: A Pilot Study	Recruiting	No results available	Glioblastoma multiforme	Other: ketogenic diet
3	Ketogenic Diet and Prostate Cancer Surveillance Pilot	Enrolling by invitation	No results available	Prostate cancer	Other: surveillance
4	Ketogenic Diet Adjunctive to Salvage Chemotherapy for Recurrent Glioblastoma: A Pilot Study	Recruiting	No results available	Glioblastoma multiforme	Dietary supplement: ketogenic dietDietary supplement: standard diet
6	Impact of a Ketogenic Diet Intervention During Radiotherapy on Body Composition	Recruiting	No results available	Neoplasms	Dietary supplement: ketogenic breakfastDietary supplement: ketogenic dietRadiation: radio(chemo)therapy
7	Ketogenic Diet Phase 1 for Head & Neck Cancer	Terminated	No results available	Head and neck neoplasms	Dietary supplement: Ketogenic diet
8	Ketogenic Diet With Concurrent Chemoradiation for Pancreatic Cancer	Terminated	No results available	Pancreatic neoplasms	Dietary supplement: ketogenic diet
9	Ketogenic Diet Treatment Adjunctive to Radiation and Chemotherapy in Glioblastoma Multiforme: A Pilot Study	Recruiting	No results available	Glioblastoma multiforme of brain	Other: ketogenic dietOther: standardized diet
10	Calorie-restricted, Ketogenic Diet and Transient Fasting During Radiation for Patients With Recurrent Glioblastoma	Recruiting	No results available	Recurrent glioblastoma	Dietary supplement: calorie-restricted ketogenic diet and transient fastingDietary supplement: standard nutrition
11	Ketogenic Diets as an Adjuvant Therapy in Glioblastoma	Recruiting	No results available	GlioblastomaGlioblastoma multiforme	Other: MKDOther: MCT
12	Restricted Calorie Ketogenic Diet as a Treatment in Glioblastoma Multiforme	Recruiting	No results available	Glioblastoma multiforme	Other: ketogenic diet
13	Ketogenic Diet in Advanced Cancer	Completed	Has results	Cancer	Other: ketogenic diet

MKD, modified ketogenic diet; MCT, medium chain triglyceride ketogenic diet.

CONCLUSION

Our main aim in this review was to assess the feasibility and acceptability of ketogenic diet and to assess the changes of outcome variables, such as body composition, biochemical blood profiles, and QOL. From this review, we found further evidence that ketogenic diet in cancer patients is safe and feasible as an adjuvant therapy. As described above, we could conclude that in order to see any significant progression or improvement by ketogenic diet, at least 3 to 4 weeks of ketogenic diet is required. Additionally, we suggest that not only body composition but also biomarker or measures for tumor size or tumor metabolism assessment is essential. We also conclude that the acceptability for ketone diet may be better in some cancer type (better in glioblastoma than gastric cancer).

In conclusion, ketogenic diet can be safely used to cancer patients if carefully monitored. Most importantly, we have to establish standardized treatment protocol which include the length and regimen for ketogenic diet.