# Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations

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## Abstract

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## 1. Introduction

## 2. Ketosis and Spectrum of Ketogenic Diets (KD)

## 3. KD as a Therapeutic for Cancer: Hypothesized Mechanisms

## 4. Preclinical Studies of KD for Cancer

## 5. Clinical Studies of KD and Cancer

## 6. Limitations of Current Literature

## 7. Conclusions and Future Directions

## 8. Research Recommendations for Moving the Field Forward

- Conduct small, rigorous non-randomized trials with homogeneous patient groups and common cancer sites to assess whether KD produces a “signal” on selected outcomes (particularly those related to response to standard care (e.g., effectiveness, side effects)) that would justify the conduct of larger, randomized-controlled trials.
- In randomized-controlled trials, provide sufficient detail of the KD and control diets (ensuring that they are comparable on vitamins, mineral and other nutrients) so they could be replicated by other investigators.
- Develop a standardized method to monitor and quantify adherence and tolerance to the KD (e.g., [93]).
- Develop a set of standardized assessments and outcome measures that include the full array of relevant variables (e.g., imaging of tumor characteristics, body composition, quality of life, and survival).
- Distinguish trials based on whether they attempt to isolate the unique effects of KD versus those which seek to estimate its effects as an adjunctive therapy.
- Examine the effects of exogenous ketones, alone and in conjunction with a KD, to determine whether they have synergistic or additive effects.
- Because it is unlikely that KD will cure cancer, trials should focus on whether KD reduces cancer progression or recurrence in those who experience remission through standard care.

## Author Contributions

## Funding

## Conflicts of Interest

## References

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**Figure 1.**Sequential Research Recommendations for Investigating the Effects of the Ketogenic Diet (KD) on Human Cancers.

Cancer Type(s) | Sample Size | Dietary Intervention | Study Duration | Results/Outcomes | References |
---|---|---|---|---|---|

Prostate | N = 45 Arm A: N = 27 Arm B: N = 18 | Arm A: A low-carbohydrate diet, goal: (≤20 g per day), estimated actual carbohydrate intake: 37 g/day; Arm B: Control group (no dietary intervention) | 6 months | -Weight loss -BMI reduction -Waist circumference reduction | [51] |

Breast cancer | N = 60 Arm A: N = 30 Arm B: N = 30 | Arm A: Medium-chain triglycerides (MCT) based ketogenic diet (6% calories from Carbohydrates [CHO], 19% protein, 20% MCT, 55% fat); Patients received 500 mL of MCT oil from the Nutricia Company every 2 weeks Arm B: Standard Diet (55% CHO, 15% protein, and 30% fat) | 3 months | -Weight loss -BMI reduction -Reduction in body fat | [52] |

Ovarian/endometrial cancer | N = 45 Arm A: N = 25 Arm B: N = 20 | Arm A: Ketogenic diet (70% (≥125 g): 25% (≤100 g): 5% (<20 g) energy per day from fat, protein, and carbohydrates) Arm B: American Cancer Society diet (ACS: high in fiber, low in fat) Individual diet advice from certified dietitians. Weekly emails or phone calls. One face-to-face meeting after baseline assessment | 3 months | -Self-reported improvement in energy levels (intervention group) -Fewer cravings for starchy foods and fast-food fats -Reduction in total body | [53,54] |

Rectal cancer, head and neck cancer Breast cancer | N = 81 Arm A: N = 20 Arm B: N = 61 | Arm A: ketogenic diet with additional consumption of non-glucogenic amino acids Arm B: no dietary intervention | 30–40 days | -Decreased fat mass | [55] |

Pancreatic cancer Duodenal cancer Common bile duct cancer Ampulla of Vater cancer Cholangiocarcinoma Neuroendocrine tumor | N = 19 Arm A: N = 10 Arm B: N = 9 | Arm A: Ketogenic diet (3–6%, 14–27%; 70–80% energy per day from carbohydrates, protein, and fat) served as three meals and three snacks per day Arm B: usual Korean diet (55–65%, 7–20%, 15–30% energy per day from carbohydrates, protein and fat) served as three meals per day | 12 days | -Decreased body cell mass higher in General Diet arm | [56] |

Glioblastoma multiforme | N = 53 Arm A: N = 6 Arm B: N = 47 | Arm A: self-administered KD Arm B: unspecified standard American diet | Duration: 3–12 months | - Two patients with grade 1 constipation, 4 patients with grade 1 fatigue, 1 patient with grade 2 fatigue, 1 patient with deep venous thrombosis during treatment, 1 patient with asymptomatic hypoglycemia, 1 patient with nephrolithiasis no grade 3 and higher toxicities or symptomatic hypoglycemia -Weight loss on non-calorie-restricted KD: 1 to 27 Ibs -Weight loss on calorie-restricted KD: 46 Ibs | [57] |

Fearon et al. [44] Ovarian, Lung, Gastric | N = 5 | Crossover study: Nasogastric tube feeding: normal, balanced regimen on days 1–6 KD containing same total calorie and protein on days 7–13 | 13 days | -Increase in body weight | [58] |

Diverse | Recruited patients N = 12 Analyzed patients N = 10 | KD with targeted CHO intake below 5% of total energy intake, written menus and samples of CHO-restriction products were provided | 28 days | -Five patients with grade 2 fatigue, 5 patients with grade 1 constipation, 1 patient with grade 1 leg cramps -Weight loss - Decreased caloric intake -Adherence: 5 of 12 patients completed all 28 days of the diet | [27] |

Diverse | Analyzed patients N = 78 Arm A: N = 7 Arm B: N = 6 Arm C: N = 65 | Arm A: full adoption of a non-specified KD, patients informed about a single company producing KD-related food Arm B: partial adoption of a non-specified KD, patients informed about a single company producing KD related food Arm C: patients who did not adopt a KD | Not specified | 1. Reduction in TKTL 1 was associated with adopting a KD; 2. Correlation between improvement in cancer status category and full adoption of a KD (χ2 = 33.26; df = 4; p = 0.00001 | [59] |

Diverse | Analyzed patients N = 6 | Self-administered KD (recommended CHO intake < 50 g/day) during the course of RT/RCT; patients received basic information on KD; counseling at least once per week | Patient-dependent from 32 to 73 days | -Decreased fat mass | [60] |

Glioblastoma | Assessed for eligibility: N = 57 Randomized: N = 12 Arm A: N = 6 Arm B: N = 6 Retention at 12 weeks. N = 4 Arm A: N = 3 Arm B: N = 1 | Arm A: MCTKD (75%; 15%; 10% of energy per day from fat, protein and carbohydrates, with 30% of fat from MCT nutritional products) Arm B: MKD (80%; 15%; 5% of energy per day from fat, protein and carbohydrates) | 12 weeks | 1. Arm A: Three patients retained for 3 months (drop-out = 50%) Arm B: One patient retained for 3 months (drop-out = 83%) 2. GHS at baseline: Arm A: patients who later withdrew: 72.2 ± 20.7; patients who retained: 75 ± 6.8 Arm B: patients who later withdrew: 70 ± 13.8; patients who retained: 80 ± 0 GHS: at week 6: Arm A: patients who withdrew at week 6: 41.7 ± 0; patients who retained: 66.7 ± 0 Arm B: patients who withdrew at week 6: 50 ± 0; patients who retained: 100 ± 0 3. Adverse events during the first 6 weeks: Arm A: diarrhea (n = 1, CTCAE grade 1), nausea (n = 1, CTCAE grade 1), vomiting (n = 1, CTCAE grade 2), dyspepsia (n = 1, CTCAE grade 1) Arm B: vomiting (n = 1, CTCAE grade 1), dry mouth (n = 1 MKD, CTCAE grade 1) | [61] |

Glioblastoma | Enrolled: N = 6 Completed intervention: N = 4 | MKD (70%: 3–5% (≤20 g) energy per day from fat and carbohydrates; protein consumption was not restricted | 12 weeks | -Constipation in two patients, resolved with dietary modification | [62] |

Glioblastoma | Included patients N = 20 Evaluable for efficiency N = 17 | KD with CO intake < 60 g/day, additionally highly fermented yoghurt drinks and two different plant oils were provided to be consumed at will. No calorie restriction, patients were instructed to always eat to satiety | Until progression of the disease | -Three out of 20 patients discontinued the diet after 2–3 weeks without progression, due to reduced QoL - Body weight reduction -Diarrhea, constipation, hunger and/or demand for glucose were present in some patients during the diet | [63] |

Diverse | Enrolled: N = 16 Completed intervention: N = 5 | KD with CHO limited to 70 g per day and 20 g per meal Two oil–protein shakes consumed in the morning and in the afternoon | 12 weeks | -11/16 Patients discontinued the diet - 3/11 were unable to adhere to the diet, -6/11 discontinued due to progressive disease -2/11 died from progressive disease - reported side effects included increase in appetite loss, constipation, diarrhea and fatigue during the diet - QoL was low at baseline and stayed relatively stable during the intervention; worsening of fatigue, pain, dyspnea and role function but emotional functioning and insomnia improved slightly | [64] |

Diverse | Enrolled: N = 17 Drop-out before first analysis: N = 6 Completed intervention: N = 4 | Modified Atkins Diet with 20 to 40 g of CHO and restricted consumption of high CHO foods no restrictions for calories, protein or fats | 16 weeks | -13/17 patients discontinued the diet before 16 weeks -weight loss -Reported adverse effects included: hyperuricemia (N = 7), hyperlipidemia (N = 2), pedal edema (N = 2), anemia (N = 2), halitosis (N = 2), pruritus (N = 2), hypoglycemia (N = 2), hyperkalemia (N = 2), hypokalemia (N = 2), hypomagnesemia (N = 2), flulike symptoms/fatigue (N = 2) | [65] |

Glioblastoma multiforme | Phase A: N = 9 Phase B: N = 8 Completed intervention N = 6 | Phase A: Fluid KD with a 4:1 ratio (4 g fat versus 1 g protein plus carbohydrates, 90% energy from fat) Patients were allowed a snack with the same 4:1 diet ratio once a day Phase B: Solid-food KD (diet ratio 1.5–2.0:1) with MCT; (70% energy from fat with the consistency of an emulsion) | 14 weeks | -6/9 patients included in phase A completed the 14 weeks KD - Reported adverse effects included: constipation (n = 7), nausea/vomiting (n = 2), hypercholesterolemia (n = 1), hypoglycemia (n = 1), low carnitine (n = 1) and diarrhea (n = 1). CTCAE grade 2: hallucinations (n = 1), allergic reaction (n = 1) and wound infection (n = 1) | [66] |

Glioma | N = 29 | MAD with a 0.8–1:1 ratio (0.8-1 g fat to 1 g carbohydrate plus protein Duration: 6 weeks | 6 weeks | -28/29 patients completed the 6-week diet - Reported adverse events: Grade 2 constipation (n = 1), grade 1 fatigue and nausea were present in the patients -Decreased BMI for all patients | [67] |

Lung | Enrolled patients: N = 7 Completed intervention: N = 2 | KD with 90%; 8%; 2% of energy per day from fat, protein and carbohydrates. All meals prepared for the patients | 42 days | -Weight loss - Reported adverse events included: constipation, diarrhea, nausea, vomiting and fatigue; hyperuricemia | [68] |

Pancreas | N = 2 | KD with 90%; 8%; 2% of energy per day from fat, protein and carbohydrates. All meals readily prepared for the patients | 34 days | -1/2 patients completed the intervention 2. Reported adverse events included: Constipation, diarrhea, nausea and vomiting, 1 patient experienced dehydration -Weight loss | [68] |

Desmoid tumor | N = 1 | TPN consisting of 28 kcal fat/kg body weight/day, 1.5 g protein/kg body weight/day; 40 g glucose/day | Desmoid tumor | -Body weight increased | [69] |

Glioma | N = 2 | ERKD: with a 3:1 ratio of ingested nutrients (3 g fat versus 1 g protein plus carbohydrates) 20% restriction of calories per day | 12 months | -Adherence: 1/2 patients completed the intervention -Reported headaches -Initial body weight decrease in both patients and remained stable afterward | [70] |

Glioblastoma multiforme | N = 1 | ERKD delivering 600 kcal per day, consisting of 42 g fat, 32 g protein and 10 g CHO per day | 56 days | -Bodyweight decreased in the first 14 days of the diet - Grade 4 hyperuricemia reported, resulted in diet change to calorie restricted non-ketogenic diet | [71] |

Rectal | N = 1 | Paleolithic KD, nutrients consumed in a fat:protein ratio of 2:1 animal fat, red meats and organ meats were encouraged, root vegetables were allowed, all other foods were prohibited | 24 months | -Decreased bodyweight -Initial decrease in volume after concomitant radiotherapy -Tumor volume remained stable but four hepatic metastases were detected at the end of the diet | [72] |

Diverse | N = 12 | Single 3 h infusion of glucose-based (GTPN) or a lipid-based TPN (LTPN) containing 4 mg glucose/kg/min or 2 mg lipid/kg/min, respectively | 3 h | -No statistically significant stimulation or suppression of FDG uptake | [73] |

Recurrent Breast | N = 1 | Self-administered high doses of oral vitamin D3 (10,000 IU/day), and KD rich in oleic acid. Duration: 3 weeks | 3 weeks | -Progesterone receptor status positivity increased -HER2 positivity decreased | [74] |

Astrocytoma | N = 2 | KD with 60%; 20%; 10%, 10% of energy per day from MCT oil, protein, carbohydrates and dietary fat plus additional supplements | 8 weeks | -Dose uptake ratio tumor: decreased normal cortex decreased -Adherence: 100% patients were able to complete the dietary intervention | [75] |

Esophagus Stomach Colon-rectum | N = 27 Arm A: N = 9 Arm B: N = 9 Arm C: N = 9 | Arm A: glucose-based TPN (100% of the calorie from dextrose); Arm B: lipid-based TPN (80% of the calorie from fat, 20% from dextrose); Arm C: oral diet All diets were iso-caloric and isonitrogenous. Duration: 2 weeks | 2 weeks | No statistically significant changes | [76] |

Head and neck | N = 12 | Unspecified Western diet followed by unspecified KD | Variable, up to 4 days | Decline of mean lactate concentration in the tumor tissue during the KD | [77] |

Brain | Included: N = 9 intervention: N = 5 retrospectively added control N = 4 | KD based on ready-made formula, with a 4:1 ratio of ingested nutrients (4 g fat versus 1 g protein plus carbohydrates) | variable from 2 to 31 months | -Diet tolerated by 4/5 patients,(strict adherence only in 2 patients) -Four out of 50 MRI spectroscopy scans detected ketone bodies in the brains of the patients following the KD | [78] |

Lung | N = 44 | Mild KD (patients were encouraged to avoid high CHO food) in combination with HBO, hyperthermia and polychemotherapy administered during induced hypoglycemia | 24 weeks | -Adverse events reported—during treatment period: grade 5 neutropenia (N = 1), grade 3 neutropenia (N = 3), grade 3 anemia (N = 10), grade 4 thrombocytopenia (N = 3), grade 3 fatigue (N = 5), grade 3 diarrhea (N = 8), grade 3 neuropathy (N = 1), all of which were attributed to chemotherapy | [79] |

Pancreas | N = 25 | Mild KD (patients were encouraged to avoid high CHO food) in combination with HBO, hyperthermia and polychemotherapy administered during induced hypoglycemia | Duration: mean follow-up: 25 months | -Adverse events reported: during treatment period: grade 3/4 neutropenia (N = 9), febrile neutropenia (N = 1), grade 3 anemia (N = 7), grade 4 thrombocytopenia (N = 4), grade 3 diarrhea (N = 2), all of which were attributed to chemotherapy | [80] |

Brain | N = 8 | MAD with20g CHO/day restriction | 2-24 months: mean- 13 months | -7/8 completed intervention -Decreased body weight -Reduction in seizure frequency per week | [81] |

Glioblastoma multiforme | N = 1 | Energy-restricted KD with a 4:1 ratio of calorie intake (fat versus protein plus carbohydrates) Total calories calculated 25% below BMR | 4 months | -No metabolically active tumor detected | [82] |

Glioblastoma multiforme | N = 1 | KD with a 4:1 ratio of calorie intake (fat versus protein plus carbohydrates), delivered as calorie-restricted diet, combined with intermittent fasting, HBOT, other novel therapies and SOC treatment | 20 months | -Good surgical outcome and regressive changes in histopathology -Decreased body weight | [83] |

Diverse | N = 6 | Very low CHO diet (not further specified) with a multitude of supplements, including amino acids and Vitamin D3 combined with SOC therapy | Varied | -Shrinkage of tumor or stable disease was reported during the intervention -Subjective improvement reported in some cases | [84] |

Head and neck | N = 14 | KD with as little CHO as possible (estimated < 50 g per day), combined with insulin administration 3 × per day | Not specified | Visible remission after 2–3 weeks, but rebound effect after 2–3 months on the diet | [85] |

Extra-cranial | N = 30 | KD with as little CHO as possible (estimated < 50 g per day), combined with insulin administration 3 × per day | Not specified | Tumor shrinkage in some cases Improvement in general condition and positive effects on clinical symptoms | [86] |

Exra-cranial | N = 23 | KD with as little CHO as possible (estimated < 50 g per day), combined with insulin administration 3 × per day | Not specified | -Reduced pain severity, fatigue but deteriorated orientation | [87] |

Pancreatic cancer Duodenal cancer Common bile duct cancer Ampulla of Vater cancer Neuroendocrine tumor | N = 18 | LCKD: Energy content: 1500 kcal/d, provided 4% from carbohydrate, 16% from protein and 80% from fat. Ketogenic ratio of 1.75:1 (F: C + P w/w) | 4 weeks | -Patients were in a poorer nutrition state after surgery, but this was alleviated at week 4; - LCKD induced ketone body production -Week 4, there were no significant differences in ketone levels | [88] |

Glioma | N = 13 newly diagnosed= 6 recurrent=7 | KD + MCT + Metformin 850 | 6 weeks (recurrent) 2 weeks (newly diagnosed) | Increase in survival rate. Synergistic interaction between radiation therapy and KD. | [89] |

Invasive Rectal | N = 359 | KD ≥ 40% kcal fat and <100 g/day glycemic load (48) | Not specified | Reduced risk of cancer-specific deaths | [90] |

Glioblastoma | N = 32 | KD 50% kcal fat, 25% kcal CHO, 1.5 g/kg protein (17), CD (15) | 3 months | No change in glucose increased ketosis No change in body weight | [91] |


**Table 2.**Overview of Strength of Evidence for Beneficial Effects of the Ketogenic Diet for Cancer and Related Outcomes in Pre-Clinical and Clinical Studies.

Strength of Evidence | ||||
---|---|---|---|---|

Strong | Moderate | Weak | Unknown | |

Pre-Clinical Studies | ||||

Tumor weight | X | |||

Antitumor effect/Tumor growth | X | |||

Progression-free survival | X | |||

Tumor volume | X | |||

Overall survival time | X | |||

Cells’ responsiveness to therapy | X | |||

Body composition | X | |||

Clinical Studies as an Adjunctive Therapy | ||||

Tumor weight | X | |||

Antitumor effect/Tumor growth | X | |||

Progression-free survival | X | |||

Tumor volume | X | |||

Overall survival time | X | |||

Cells’ responsiveness to therapy | X | |||

Quality of life | X | |||

Body composition | X |


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**MDPI and ACS Style**

Lane, J.; Brown, N.I.; Williams, S.; Plaisance, E.P.; Fontaine, K.R.
Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations. *Nutrients* **2021**, *13*, 3562.
https://doi.org/10.3390/nu13103562

**AMA Style**

Lane J, Brown NI, Williams S, Plaisance EP, Fontaine KR.
Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations. *Nutrients*. 2021; 13(10):3562.
https://doi.org/10.3390/nu13103562

**Chicago/Turabian Style**

Lane, Jordin, Nashira I. Brown, Shanquela Williams, Eric P. Plaisance, and Kevin R. Fontaine.
2021. "Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations" *Nutrients* 13, no. 10: 3562.
https://doi.org/10.3390/nu13103562

**APA Style**

Lane, J., Brown, N. I., Williams, S., Plaisance, E. P., & Fontaine, K. R.
(2021). Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations. *Nutrients*, *13*(10), 3562.
https://doi.org/10.3390/nu13103562