Is ketosis and carbohydrate restriction a viable diet for brain cancer?

The idea that a ketogenic diet might have utility in the treatment of cancer is becoming increasing popular. A ketogenic diet, for those unfamiliar, is a diet which is low enough in insulin stimulating macronutrients (I.E. carbohydrates and protein) to lead to he production of “ketone bodies”, specifically 3-hydroxybutyrate, acetoacetate, and acetone.

The idea that a ketogenic diet will benefit cancer derives largely from the observation, first popularized by Otto Warburg (1), that cancer cells largely use glucose for energy perhaps due to their impaired mitochondria. This led some to speculate that avoiding glucose (carbohydrates) would reduce energy available to the cancerous tissue, limiting its growth.

Unfortunately, a common interpretation of this theory among layman is often along the lines of this:

“Cancer can only use glucose for energy so don’t eat carbs and you’ll starve those stupid cancer cells!”

This view ignores or discounts the fact that ketones can often be used for energy by cancer cells, albeit generally at a lower rate than glucose (3). Additionally, ketones can be used for lipid synthesis by these cells, meaning they can use them as building blocks for their replication (3). Additionally, the ketone acetone can be used to make glucose (4), so the idea of starving cancer cells is clearly less black and white then some assume. However, perhaps a ketogenic diet could still limit cancer growth to some extent, so it may yet be helpful.

Perhaps the type of cancer most commonly researched when examining the therapeutic value of a ketogenic diet is brain cancer. The evidence for this will be examined herein.

In 2007 Thomas Seyfred, perhaps the most prominent researcher of the role of a ketogenic diet on brain cancer, published a study which is often cited as evidence that a ketogenic diet retards brain cancer (5). However, in reality the evidence it provides to this end is highly limited.

While it was found that a calorie restricted ketogenic diet had beneficial effects on two different types of surgically transplanted brain tumors compared to a non-calorie restricted higher carbohydrate control diet, among mice on a non-calorically ketogenic diet had no such beneficial effects were observed.

The unrestricted ketogenic diet (KC-UR), compared to the unrestricted standard diet (SD-UR), produced no benefits in either tumor group on indices of tumor vascularity, survival, or tumor growth:

While the calorie restricted ketogenic diet benefited all these parameters, it can hardly be assumed to be a result of the ketogenic diet itself. Dr. Seyfred’s own research has previously that a restricting the calories from a typical, higher carbohydrate rodent diet benefits brain cancer as much as a calorie restricted ketogenic diet (6,7). Thus, without controlling for variables this study should not be used as evidence that a ketogenic diet benefits brain cancer.

In 2011 a similar study (8) was conducted and again concluded that a ketogenic diet showed no signs of benefiting brain cancer in mice:

In contrast to the previous experiments, one study reported a beneficial effect of a ketogenic diet on brain tumor growth in mice (9). Mice fed the ketogenic diet survived longer andwhen combined with radiation therapy, 9 of the 11 mice on the ketogenic diet seemed cured of their cancer:

Looking over the study, based on the weight gain of the animals, it does appear neither was calorically restricted relative to the other which suggests the effects of the ketogenic diet may have been due to the macronutrient content itself. However, this study used a diet known as Ketocure (registered trademark). Looking up the constituents of the diet suggest to me other elements of this diet could have been beneficial. The following is a list of nutrient information on Ketocure:

Although many elements of this diet are similar to the typical standard diets, this diet used whey as a protein source which some evidence suggests has greater cancer opposing properties than the types of protein sources (like casein and soybeans) commonly used in laboratory rodent diets (10,11). Additionally, this Ketocure diet included several nutrients not typically found in lab rat food, like carnitine and taurine. Preliminary evidence suggests these nutrients may be helpful in treating cancer (12-15). Given all this, one should be hesitant to conclude this diet was exceptional because it of its lack of carbohydrates as opposed to its other unique constituents.

In a better controlled study, researcher Adrienne Scheck and team conducted an experiment comparing the effects of a ketogenic diet with a higher carbohydrate rodent diet on brain cancer in mice (16). Both diets were fairly similar with respect to nutrients. This study reported a beneficial effect of the ketogenic diet on tumor growth and survival:

So while this study suggests a ketogenic diet is beneficial to brain cancer, the application of one study on mice with tumors surgically transplanted into their brain is perhaps limited with respect to humans.

As far as human studies go there have yet to be controlled trials. There have been a few case reports of people with brain cancer eating a ketogenic diet as a dietary adjunct to their treatment. In one of these studies (18) an older woman with glioblastoma multiforme saw an apparent, though temporary remission of her cancer while following a calorie restricted ketone if diet. However, due to the restriction of calories, which evidence suggests often helps limit cancer growth, the apparent positive findings of this study mean little in this context.

The other case report was on two young children being treated for advanced stage astrocytoma brain tumors (17). Both responded with no apparent negative effects, one of these children even seeming to have gone into complete remission. According to the lead researcher this child remains alive more than 15 years later. While this observational is impressive, it’s not unheard of for children with high grade astrocytomes (18). This remission could have been the result of the child’s ketogenic diet or a freak coincidence. That’s the problem with case studies; we can make inferences based on what is expected, but can hardly show strong evidence of cause and effect.

Ketosis, or limiting carbohydrates, is increasingly thought to be a viable way of improving one’s chances of winning the fight against brain cancer. However, with the available evidence I think it’s clear the benefit of ketosis to brain is far from proven. Some interesting data exists which I hope inspire a randomized, controlled clinical trial on this subject, but until such time it seems those using a ketogenic diet to treat brain cancer are entering mostly uncharted waters.

Citations:

1) Warburg O. On the origin of cancer cells. Science 1956;123:309–314.

2) Hasselbalch SG, Knudsen GM, Jakobsen J, Hageman LP, Holm S, Paulson OB. Brain metabolism during short-term starvation in humans. J Cereb Blood Flow Metab. 1994 Jan;14(1):125-31.

3) Roeder LM, Poduslo SE, Tildon JT. Utilization of ketone bodies and glucose by established neural cell lines. J Neurosci Res. 1982;8(4):671-82.

4) Has acetone a role in the conversion of fat to carbohydrate in mammals? Josep M. Argilés Trends in Biochemical Sciences – 1 February 1986 Vol. 11, Issue 2, pp. 61-63

5) Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond). 2007 Feb 21;4:5.

6) Mukherjee P, Abate LE, Seyfried TN. Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res. 2004 Aug 15;10(16):5622-9.

7) Seyfried T, Sanderson T, El-Abbadi M, McGowan R, Mukherjee P (2003) Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. British journal of cancer 89: 1375–1457.

8) Maurer GD, Brucker DP, Bähr O, Harter PN, Hattingen E, Walenta S, Mueller-Klieser W, Steinbach JP, Rieger J. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer. 2011 Jul 26;11:315.

9) Abdelwahab M, Fenton K, Preul M, Rho J, Lynch A, et al. (2012) The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PloS one 7.

10) Bounous G, Batist G, Gold P. Whey proteins in cancer prevention. Cancer Lett. 1991 May 1;57(2):91-4. Review.

11) Kennedy RS, Konok GP, Bounous G, Baruchel S, Lee TD. The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study. Anticancer Res. 1995 Nov-Dec;15(6B):2643-9.

12) Lubec B, Hoeger H, Kremser K, Amann G, Koller DY, Gialamas J. Decreased tumor
incidence and increased survival by one year oral low dose arginine supplementation in the mouse. Life Sci. 1996;58(25):2317-25.

13) Xue MeiLan; Zhang HuaRong; Jiang ChangQing; Zhang XiuZhen, 2008: Study on the anticancer action of taurine on 7, 12-dimethylbenz a anthracene DMBA induced breast-cancer in rats. Acta Nutrimenta Sinica 30(1): 57-60

14) Sadzuka Y, Matsuura M, Sonobe T. The effect of taurine, a novel biochemical modulator, on the antitumor activity of doxorubicin. Biol Pharm Bull. 2009 Sep;32(9):1584-7.

15) Kraft M, Kraft K, Gärtner S, Mayerle J, Simon P, Weber E, Schütte K, Stieler J, Koula-Jenik H, Holzhauer P, Gröber U, Engel G, Müller C, Feng YS, Aghdassi A, Nitsche C, Malfertheiner P, Patrzyk M, Kohlmann T, Lerch MM. L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN)–a randomized multicentre trial. Nutr J. 2012 Jul 23;11:52.

16) Stafford P, Abdelwahab MG, Kim do Y, Preul MC, Rho JM, Scheck AC. The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab (Lond). 2010 Sep 10;7:74.

17) Nebeling LC, Miraldi F, Shurin SB, Lerner E: Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr 1995, 14:202–208. PubMed Abstract

18) Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, Seyfried TN: Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutr Metab (Lond) 2010, 7:33.

19) Safdie FM, Dorff T, Quinn D, et al. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY). 2009;1(12):988–1007.

20) Sposto R, Ertel IJ, Jenkin RD, Boesel CP, Venes JL, Ortega JA, Evans AE, Wara
W, Hammond D. The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. J Neuro oncol. 1989 Jul;7(2):165-77.

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