There has recently been significant discussion in clinical circles about the appropriateness of the ketogenic diet for the treatment of ovarian cancer. There is, as with most cancer forms and their most appropriate dietary treatment, vociferous debate between advocates of low-carbohydrate and ketogenic diets, and those more inclined towards higher-carbohydrate approaches. There is also a lot of complexity due to the very diverse nature of cancers and cancer cells, even within an individual. In this article, I summarise the available research on ketogenic diets and ovarian cancer to shed some light on whether it is or isn’t appropriate…

Tumours of the abdomen, including ovarian cancer, are characterised by widespread and rapid metastases in the peritoneal cavity.¹ In particular, they have a clear predilection to metastasis to the omentum (a large ‘apron-like’ fold of peritoneum that hangs down from the stomach). It has been demonstrated that adipocytes (fat cells) of the omentum promote migration and invasion by ovarian cancer cells and that these processes are mediated by inflammatory adipokines including interleukin-8 (IL-8). In addition, in vitro and in vivo analysis has shown that ovarian cancer cells induce lipolysis in adipose tissue and increased β-oxidation in the cancer cells, suggesting that adipocytes are used as a source of fatty-acid-derived energy to fuel cancer growth. It is thought that this occurs due to upregulation of adipocyte Protein 2 (a fatty-acid carrier protein) in omental metastases compared to primary ovarian tumours.² Ovarian cancer cells co-cultured with primary human omental adipocytes also express high levels of the fatty-acid receptor, CD36, which imports fatty acids into the cell for use.¹

These findings taken together, suggest that ovarian cancer cells, when migrated to areas with a relative abundance of adipocytes (like the omentum) can induce adipose tissue to release fatty-acids and that this can be used efficiently as a fuel.

Some observational studies have suggested an association between NNS consumption and development of metabolic diseases or obesity;² however, while sweeteners are associated with higher body weight and metabolic disease in observational studies, randomised controlled trials demonstrate that non-nutritive sweeteners may support weight loss, particularly when used alongside behavioural support.^{3, 4} This suggests that the observed association between sweeteners and obesity is one of correlation, not causation.

Is a low-carb or ketogenic diet inappropriate for Ovarian Cancer?

In Ovarian Cancer patients, no difference in blood lipids was seen between a ketogenic diet and low-fat diet after 12 weeks.³ Furthermore, in another randomised, controlled trial, after 12 weeks, those following a ketogenic diet, compared to the American Cancer Society diet had lower total fat mass (35.3 compared with 38.0 kg, p < 0.05) and a greater change in visceral fat mass (–21.2% compared with –4.6%, p < 0.05), with no difference in lean mass. In addition, the ketogenic diet group had lower fasting insulin (7.6 compared with 11.2 µU/mL, p < 0.01), and β-hydroxybutyrate had a significant inverse association with IGF-I concentration (r = –0.57; P < 0.0001), i.e. greater βOHB (the main ‘fuel’ ketone) levels were associated with lower levels of IGF-1, a known driver of cancer growth. The authors concluded “elevated serum β-hydroxybutyrate may reflect a metabolic environment inhospitable to cancer proliferation”.⁴

In another trial comparing the American Cancer Society diet to a ketogenic diet, ketogenic diet participants reported a significant reduction in fatigue (p < 0.05). There were no significant between-group differences in mental function, hunger, or appetite. However, the ketogenic diet group exhibited significantly fewer cravings for starchy foods and fast food fats at 12 weeks (p < 0.05). The authors concluded; “in women with ovarian or endometrial cancer, a ketogenic diet does not negatively affect quality of life and in fact may improve physical function, increase energy, and diminish specific food cravings.”⁵

Conclusions

Serum fatty acids and triglyceride levels are often tightly linked. It has been demonstrated on countless occasions that low-carbohydrate and ketogenic diets reduce triglycerides more than other diets. In fact, in the only study to date which has compared different lower-carbohydrate diets, differing in the magnitude of carbohydrate restriction, we demonstrated that the greatest change in triglyceride levels occurred in the very-low-carbohydrate, ketogenic diet,⁶ with no change seen in the moderate carbohydrate group  (25% of TE from carbohydrate). This suggests that despite there being a potential (but not necessarily excessive) increase in fat intake on a low-carbohydrate or ketogenic diet, this does not necessarily lead to greater levels of fatty acid availability to cancer cells.

It must also be considered that ovarian cancer cells do not simply take up fatty acids alone or in isolation and are flexible cancer cells that can utilise a variety of substrate, including (and probably most prominently) glucose. In addition, ovarian cancer metastasis through the abdominal cavity and elsewhere and can induce the liberation of fatty acids from adipocytes (and also become more efficient at using that fuel source). But, perhaps most importantly, this process does not relate to the fatty acid quotient of the diet per se but instead to the presence of ovarian cancer cells, adjacent adipocytes AND to the fatty acid balance of the adipocytes and the metabolic status of the individual.

Dietary interventions should focus on reducing total fuel availability to cancer cells and also on reducing known drivers of cancer growth and proliferation.  

So, it is known that low-carbohydrate diets reduce known cancer drivers like IGF-1, reduce average glucose and insulin levels, and do not predispose to greater triglyceride/fatty acid availability. Furthermore, ketone levels (βOHB) do not need to be excessively high, and for the purposes of ovarian cancer treatment, a modified ketogenic diet approach, rich in phytonutrients, sufficient in protein (to reduce muscle-wasting), and not excessively high in fat (so as to allow for sufficient fuelling without excessive βOHB levels) is likely to be both safe and, based on the extant literature, may also improve cancer outcomes versus standard care.

References

1.            Ladanyi A, Mukherjee A, Kenny HA, Johnson A, Mitra AK, Sundaresan S, et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene. 2018;37(17):2285-301.

2.            Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498-503.

3.            Cohen CW, Fontaine KR, Arend RC, Gower BA. A Ketogenic Diet Is Acceptable in Women with Ovarian and Endometrial Cancer and Has No Adverse Effects on Blood Lipids: a Randomized, Controlled Trial. Nutrition and Cancer. 2019:1-11.

4.            Cohen CW, Fontaine KR, Arend RC, Alvarez RD, Leath III CA, Huh WK, et al. A Ketogenic Diet Reduces Central Obesity and Serum Insulin in Women with Ovarian or Endometrial Cancer. The Journal of Nutrition. 2018;148(8):1253-60.

5.            Cohen CW, Fontaine KR, Arend RC, Soleymani T, Gower BA. Favorable Effects of a Ketogenic Diet on Physical Function, Perceived Energy, and Food Cravings in Women with Ovarian or Endometrial Cancer: A Randomized, Controlled Trial. Nutrients. 2018;10(9):1187.

6.            Harvey CJdC, Schofield GM, Zinn C, Thornley SJ, Crofts C, Merien FLR. Low-carbohydrate diets differing in carbohydrate restriction improve cardiometabolic and anthropometric markers in healthy adults: A randomised clinical trial. PeerJ. 2019;7:e6273.