Does diet or fasting impact cancer outcomes?

Questions from the Clinic:

What is a ketogenic diet? Does adoption of a ketogenic diet make cancer treatments more effective and easier to tolerate? Does fasting before treatments impact outcomes?

Figure 1: In a ketogenic diet, a person consumes fats for a majority of his calories and avoids carbohydrates, which forms the base of the standard food pyramid popularized by the United States Department of Agriculture in the 1990s.

I. Introduction

Accumulating scientific evidence is fortifying the long-suspected links between diet and the development of certain cancers.(1) As recognition of this relationship grows, so too will interest in nutritional regimens that can impact the progression of the disease. Already, nearly half of patients with cancer (48%) adopt some kind of diet with hopes of maximizing survival and preventing recurrence.(2) Among the most compelling, controversial options that patients with cancer consider is the ketogenic diet (Figure 1). First formulated as a treatment for childhood epilepsy in the 1920s, the ketogenic diet may have additional utility in making malignancies more susceptible to chemotherapy and radiation.(3,4) Clarifying the value and mechanisms underlying this natural, adjunctive intervention is imperative, as cancer remains a leading cause of mortality despite advances in pharmacotherapy.

II. The Science Underlying the Ketogenic Diet

In a ketogenic diet, individuals predominantly consume high-fat foods while limiting the consumption of carbohydrates. Traditionally, strict ketogenic dieters consume 4 grams of fat for every gram of carbohydrate and protein combined, such that fat provides upwards of 90% of caloric intake.(5) By restricting the consumption of carbohydrates, ketogenic dieters may selectively stress cancer cells that preferentially metabolize glucose to satisfy their energetic needs.(6) Notably, this cancer cell dependence on glycolysis occurs even in the presence of oxygen; this process is known as the Warburg effect.(7) Ordinary cells, in contrast, adapt to low glucose levels by entering ketosis and using fats to make ketones and then produce ATP efficiently with fewer metabolic byproducts (Figure 2). Because cancer cells cannot use ketones as substrates to generate adenosine triphosphate, they starve while the metabolically flexible and healthy cells survive. Low glucose levels additionally reduce concentrations of circulating insulin and insulin-like growth factor. These hormones bind receptors expressed by many cell types and activate downstream P13K/AKT signaling pathways that ultimately promote cell proliferation and survival.(8) Beyond metabolically stressing cancer cells, ketogenic diets lower triglyceride levels and blood pressure, thereby cutting the risk for cardiovascular disease and type 2 diabetes.(9) In practice, the most common delivery of this diet is a blend of modified fasting (drinking electrolytes and fluids) and reduced carbohydrate intake, and adequate fat and protein. The blend of fasting and low carbohydrates can also achieve the same goals and offer a more tailored approach to different eating habits and life schedules.

Figure 2: (a) Normal cells when deprived of glucose for glycolysis can satisfy energetic demands by burning ketone bodies. (b) Cancer cells, which are metabolically distinct from normal cells, lack such flexibility and cannot use ketone bodies as substrates for adenosine triphosphate (ATP) production. ATP is an energy-carrying molecule used in cells to drive biological processes. Figure courtesy of Talib et al.

III. Scientific Evidence – Case Reports & Ongoing Clinical Trials

To date, most clinical evidence supporting the adoption of ketogenic diets among patients with cancer comes from case reports and pilot/feasibility studies.(10) That said, researchers are increasingly conducting randomized, clinical trials to validate promising data collected over the last few decades. In one randomized clinical trial, investigators compared the effects of a ketogenic diet and an American Cancer Society (ACS) diet on central obesity and serum insulin in women with ovarian or endometrial cancer. After 12 weeks, the percentage decrease in visceral fat was significantly greater among those randomly assigned to the ketogenic diet group (-21.2%) than the ACS diet (-4.6%). Adjusted total lean mass, in contrast, did not differ between the groups. Additionally, the study authors noted that participants assigned a ketogenic diet had a lower adjusted fasting serum insulin (7.6 µU/mL) than their counterparts on an ACS diet (11.2 µU/mL). This reduction in insulin was accompanied by an increase in serum β-hydroxybutyrate and a decrease in insulin growth factor 1, the latter of which is commonly elevated in several common cancer types. Researchers believe that these changes are among those that create inhospitable conditions for cancer cells.(11)

These positive findings align with recent observations made in case reports of patients who adopted a ketogenic diet while battling cancer. In the United Kingdom, clinicians noticed that a patient with IDH1-mutant glioblastoma multiforme managed to survive 80 months despite refusing medications forming the standard of care and concomitant steroids. Instead, the 32-year-old man adopted a ketogenic diet and took periodic supplements. Although median survival in glioblastoma multiforme tends to be longer among younger individuals and those harboring IDH1 mutations, researchers noted that the patient’s tumor grew much more slowly compared to untreated glioblastomas. The estimated volume doubling time for untreated glioblastomas is 49.6 days on average; the 32-year-old adopting a ketogenic diet had an estimated tumor doubling time of 432 days and has survived in excess of 1,400 days.(12) Despite these findings not being broadly generalizable to patients with glioblastoma multiforme, the case justifies future, adequately powered investigations of ketogenic diets in aggressive cancers like glioblastoma multiforme and triple-negative breast cancer. Currently, there are 12 clinical trials registered in the United States that are actively recruiting participants and assessing the efficacy and tolerability of ketogenic diets in various malignancies, namely breast cancer, brain cancer, and lymphatic cancers (Table 1). Another 5 trials are ongoing internationally; the full set of trials can be viewed at the following link: https://clinicaltrials.gov/ct2/results?term=ketogenic+diet&cond=Cancer&Search=Apply&recrs=a&age_v=&gndr=&type=&rslt= (13)

Table 1: Ongoing clinical trials in the United States assessing the utility of ketogenic diets in patients diagnosed with various cancers. Information was collected from Clinicaltrials.gov.

The fasting mimicking diet, much like ketogenic plans, largely consists of healthy fats and few sources of carbohydrates and proteins. As its name implies, this intermittent fasting regimen also restricts calories for a five-day period during which individuals eat foods in a pre-assembled meal kit, like soups, bars, drinks, olives, and crackers.(14) The first-day provisions are just short of 1,100 calories, whereas the remaining days only allow for the consumption of 725 calories. After this time, dieters return to their normal eating habits for 3 weeks and repeat the fasting phase until they achieve their desired goals.(15) By replicating starvation for a periodic, controlled period of time, dieters over 3 months can reduce body weight by an average of 6 pounds, their systolic blood pressure, and levels of IGF-1.(16) Valter Longo, the creator of the ProLon fasting mimicking diet, has conducted over 20 years of clinical research on the program and has since patented the strategy. That said, because the caloric restriction is strenuous and forces the body to burn fats, Longo and the L-Nutra website advise interested individuals to pursue the plan under the supervision of a licensed healthcare professional.14 Proponents of the plan also tout the diet’s ability to slow aging by enhancing cellular regeneration and autophagy – the body’s way of cleaning out damaged cells in order to regenerate newer, healthy cells.(17)

Clinical trial data on the fasting-mimicking diet are comparatively scant, although findings exist from at least one randomized controlled study conducted in 2020. In this investigation, researchers noted that this nutritional approach before the chemotherapy sessions “significantly reinforces the effects of neoadjuvant chemotherapy on the radiological and pathological tumor response” among patients with HER2-negative breast cancer. There was also a trend toward reduced side effects in the fasting arm. Taken together, these promising data support the examination of a fasting-mimicking diet and similar diets for other forms of cancer treated with different therapies.(18)

IV. Cost, Availability, and Accessibility

Because a ketogenic diet is an individual lifestyle choice, adopting one does not cost money. To facilitate adopting this nutritional plan, several companies offer meal preparation and delivery services that require little input and assembly from the consumer. These services, by Green Chef, Sunbasket, Factor 75, and Ketoned Bodies, cost on average between $11.00 and $15.00 per meal; shipping varies by location but ranges from $7 to $9 per box or order.(19) For individuals willing to prepare their meals independently, the cost of the diet falls considerably. According to one independent analysis, the daily cost of a standard ketogenic program consisting of 4 meals is approximately $15.00/day or $105.00/week in 2018 USD. With cost-efficient food substitutions, the daily cost can fall to as low as $10.00/day.(20) More economical foods include chicken thighs, ground beef and turkey, canned tuna and salmon, eggs, romaine lettuce, cauliflower, mixed frozen vegetables, and low-carb dairy products like cheese, butter, and heavy cream.(21)

Accessibility, rather than affordability, is arguably the greatest issue constraining the adoption and scientific examination of ketogenic diets. Low patient enrollment in clinical trials has historically thwarted researchers’ efforts to quantify the nutritional plan’s benefits in patients with cancer.(22,23,24) Tepid interest in these investigations may stem from the reality that complying with a ketogenic diet is difficult. Consequently, even when sufficient numbers of eager participants join a trial, dropout rates are high as many patients fail to follow the dietary restrictions necessary to induce ketosis. Over time, the perception has arisen that the ketogenic protocol is unsustainable over long periods of time, and data on long-term benefits are unfortunately scant.(5) Promoting adherence to a ketogenic diet requires strong personal commitment from the patient with cancer, along with support from family members, friends, and trained nutritionists who can ensure ketosis is maintained. Additional counseling may be required for patients who experience transient side effects when attempting a ketogenic diet; slow initiation and supplementation with vitamins and minerals can help mitigate nausea, headaches, and fatigue that can accompany a transition into ketosis.(10)

V. Conclusions

Although there are compelling data from multiple case reports and pilot studies, the efficacy of ketogenic diets in cancer is not yet definitively established. To resolve the existing controversy, several, randomized controlled trials are underway to assess the degree to which carbohydrate restriction can augment the standard of care used to combat various malignancies. In the interim, as researchers await data from these investigations, patients with cancer interested in pursuing a ketogenic diet should do so with the understanding that the change alone will not likely cure their underlying malignancy. That said, existing evidence suggests that adhering to a ketogenic lifestyle confers significant health benefits that can complement the effects of anticancer therapies administered to patients. Because adherence has historically proven difficult for many individuals, interested patients should consult closely with metabolic-trained dieticians and other members of their care team for guidance and continued support. With discipline, anyone can adopt this dietary regimen and create conditions that are unfavorable to the development and proliferation of cancer.

Stay strong and curious and be your own best doctor,

- Chuck

Charles J. Meakin MD, MHA, MS

Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.

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11 Cohen CW, Fontaine KR, Arend RC, et al. A ketogenic diet reduces central obesity and serum insulin in women with ovarian or endometrial cancer. J Nutr. 2018;148(8):1253-1260.

12 Seyfried TN, Shivane AG, Kalamian M, et al. Ketogenic metabolic therapy, without chemo or radiation, for the long-term management of IDH1-mutant glioblastoma: an 80-month follow-up case report. Front Nutr. 2021;8:682243.

13 Clinicaltrials.gov. Ketogenic diet | Recruiting Studies | Cancer. https://clinicaltrials.gov/ct2/results?term=ketogenic+diet&cond=Cancer&Search=Apply&recrs=a&age_v=&gndr=&type=&rslt=/. Accessed July 19, 2022.

14 Cording J. What is the fasting mimicking diet and is it healthy? Shape. https://www.shape.com/healthy-eating/diets/fasting-mimicking-diet/. Published October 28, 2020. Accessed July 19, 2022.

15 Howley EK. What is the fasting mimicking diet? U.S. News and World Report. https://health.usnews.com/wellness/food/articles/what-is-the-fasting-mimicking-diet/. Published December 7, 2020. Accessed July 19, 2022.

16 Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377):eaa18700.

17 Allison L. Five-day fast: a guide to the fasting mimicking diet for weight loss. Longevity.Technology. https://longevity.technology/lifestyle/five-day-fast-a-guide-to-the-fasting-mimicking-diet-for-weight-loss/. Updated December 30, 2021. Accessed July 19, 2022.

18 De Groot S, Lugtenberg R, Cohen D, et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicenter randomized phase 2 DIRECT trial. Nat Commun. 2020;11:3083.

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20 Reimers E. The cost of the keto diet vs. a “normal” diet. Bio Keto. https://bioketo.com/cost-of-the-keto-diet/. Published December 4, 2018. Accessed July 19, 2022.

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22 Ketogenic diet with chemoradiation for lung cancer (KETOLUNG). https://clinicaltrials.gov/ct2/show/NCT01419587/. Updated January 8, 2018. Accessed July 19, 2022.

23 Ketogenic diet with concurrent chemoradiation for pancreatic cancer (KETOPAN). https://clinicaltrials.gov/ct2/show/NCT01419483/. Updated January 8, 2018. Accessed July 19, 2022.

24 Reducing insulin, growth hormones, and tumors (RIGHT). https://clinicaltrials.gov/ct2/show/NCT03785808/. Updated August 12, 2019. Accessed July 19, 202.