Ketogenic diets: Part 5 – Cancer

Listen to the Influential Wellnesspreneur podcast interview with me on ketogenic diets:

Updated 14 November 2022

Previously in this series, I’ve discussed the origins of the ketogenic diet and the biological role of ketone bodies (Part 1), whether living in a state of ketosis is normal and natural (Part 2), and whether ketogenic diets are effective for weight loss (Part 3) and insulin resistance and diabetes (Part 4). In this instalment, I’m going to examine the claim – now spreading like wildfire over the Internet – that ketogenic diets can cure cancer by starving cancer cells of glucose.

This claim rests on a commonly-held belief that cancer cells are fuelled mostly, or entirely, by glucose, or in popular parlance, “sugar”. So…

Does sugar feed cancer?

Here’s a typical example of the claims made by ketogenic diet proponents:

Extraordinary claims require extraordinary evidence, as astronomer Carl Sagan famously said, and this is quite an extraordinary claim. So how does the evidence for it stack up? Not quite as well as keto-enthusiasts claim.

The evidence on ketogenic diets in cancer

A 2017 systematic review of the published evidence for ketogenic diets in cancer identified 15 studies (five case reports, eight prospective studies [six single-arm studies, one single-arm crossover study, and one three-arm study utilising total parenteral feeding], and two retrospective studies). They wrote that “no study with a methodological[ly] rigorous design was found” and concluded that

“Evidence supporting the effects of isocaloric ketogenic dietary regimes on tumor development and progression as well as reduction in side effects of cancer therapy is missing”.

Systematic review: isocaloric ketogenic dietary regimes for cancer patients

Worryingly, they also commented that researchers appeared to under-report side-effects and downplay the decreased quality of life in cancer patients following ketogenic diets.

Another review, published in April 2018 concluded:

“The limited number of studies and differences in study design and characteristics contribute to overall poor quality evidence, limiting the ability to draw evidence-based conclusions.”

A Nutritional Perspective of Ketogenic Diet in Cancer: A Narrative Review

In fact, the authors’ extensive literature search identified a total of just 14 studies on the effects of the ketogenic diet in cancer patients published between 1988 and 2016, that included only 206 individuals. Studies were characterised by small sample size (average of 15 participants), which increases the risk of false conclusions being drawn, and only one was a randomised controlled trial – that is, a study in which half of participants were put on a ketogenic diet during cancer treatment while the remaining patients were assigned to “usual care”.

Five of the studies were case reports, considered the lowest level of evidence in medical research. Patients were put on ketogenic diets for anywhere from five days to 12 months. Nine out of the 14 studies assessed the effects of the diet on tumour metabolism and/or disease progression, and of these, two found that patients on the ketogenic diet had worse results, two showed diverse results among participants, four did not report any difference between treatments, and one demonstrated an alteration in cancer cell metabolism.

A 2017 study conducted on pancreatic and lung cancer patients, which was not included in either of the systematic reviews, found high drop-out rates due to inability to tolerate the diet. However, there was

“No observed difference in PFS [progression-free survival] or OS [overall survival] between subjects who prematurely stopped the KD versus those who consumed the KD while receiving concurrent radiation and chemotherapy.”

Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung and Pancreatic Cancer: The University of Iowa Experience of Two Phase I Clinical Trials

A review article published in 2020 summarised the results of 30 papers on the use of ketogenic diets for human cancer patients. Only one of these was a randomised controlled trial. Most were case reports, presenting data from between one to a dozen or so individual patients, or pilot/feasibility studies. Drop-out rates were high and results were mixed, although some very positive outcomes were reported for several cancer types that are well-known to be highly and rapidly fatal, including advanced-stage malignant astrocytoma and recurrent glioblastoma.

A systematic review and meta-analysis of randomised controlled trials of a ketogenic diet used as an adjuvant (add-on) therapy in cancer patients undergoing surgery, chemotherapy, radiotherapy or immunotherapy was published in 2021. Just six papers, describing four studies, were identified. Only one of these studies measured cancer survival rate as an outcome, and two measured tumour markers (CEA, CA 19-9 and PSA). The majority of outcome measures related to how well patients could stick to their assigned diets, and the impact of the diet on their overall nutritional intake, weight, body composition and lipid profiles (cholesterol and triglycerides).

Out of all of these outcomes, the only measures that were significantly different between cancer patients assigned to eat a ketogenic diet, and those given standard dietary advice, was that levels of PSA (prostate specific antigen, which is used to track the progression of prostate cancer) were higher – meaning worse – in those eating a ketogenic diet, and the level of satisfaction with the diet was lower.

The authors sounded a note of caution on the lack of high-quality evidence on the use of ketogenic diets for cancer, and called for larger and more rigorous studies:

“The pooled results from the studies show inadequate evidence to support the beneficial effects of LCKDs on antitumor therapy. At present, there are not enough studies on the mechanism of the ketogenic diet. More studies are needed to clarify ketogenic diets’ efficacy and safety.”

Efficacy of Low-Carbohydrate Ketogenic Diet as an Adjuvant Cancer Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

All in all, these inconsistent and patchy results are not quite what I would call “extraordinary evidence” that ketogenic diets are beneficial in the treatment of cancer.

Are all cancer cells hungry for glucose? The Warburg effect and the reverse Warburg effect

The notion that a ketogenic diet is an effective therapy for cancer rests largely on the observation that the mitochondria (internal power plants) of cancer cells have reduced efficiency, resulting in a decreased energy yield from glucose. Known as the “Warburg effect” after Otto Warburg, who won the 1931 Nobel Prize for Physiology or Medicine for discovering it, this metabolic inefficiency results in cancer cells taking up more glucose from the bloodstream.

Bloggers and authors of popular books have distorted this observation into the oft-repeated claim that “sugar feeds cancer”, which then forms the basis of advice to eliminate all forms of carbohydrate from the diet, including fruit, whole grains and legumes (foods which have been shown to reduce the risk of developing cancer – see for example this study on fruit and vegetable consumption and cancer, this one on whole grains and this one on legumes).

It’s important to realise that the phenomenon we call “cancer” is not a single disease. The defining characteristic of cancer cells is that they acquire multiple mutations in genes that govern their metabolic pathways both during and after the process of turning cancerous. Consequently, not all cancer cells are avid consumers of glucose, as ketogenic diet advocates claim.

In fact, in a study of 33 human cancer cell lines, all were found to express key ketolytic enzymes, which enable them to take up ketone bodies and use them as a fuel. The level of expression varied significantly between different cell lines, meaning that some cancer cell types have a stronger preference than others for using ketone bodies.

Interestingly, the researchers found “no correlation between glycometabolism and ketone body metabolism”, meaning that cancer cells with high glycometabolism (use of glucose as a fuel) didn’t necessarily have a lower level of key ketolytic enzymes. Some cancer cells, it seems, are able to use glucose and ketone bodies quite interchangeably, depending on what is available to them.

Some cancer cells show a strong preference for using ketone bodies, and they cause the body to make more ketones in order to fuel their growth. An oncogenic (cancer-causing) mutation in the BRAF V600E gene activates MEK1, which stimulates the growth of cancer. The ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Which types of cancer does this mutation occur in?

  • Over 50% of melanomas;
  • 10% of colorectal cancers;
  • 100% of hairy cell leukemias; and
  • 5% of multiple myelomas.

For people whose cancers express this BRAF V600E mutation, adopting a ketogenic diet would pour fuel on the fire; in mice who were implanted with human melanomas expressing the BRAF V600E mutation, a high fat diet “increased growth rates, masses and sizes of tumors”.

Researchers have also identified a “reverse Warburg effect” in which fibroblasts (connective tissue cells that produce the extracellular matrix, or stroma, in which all cells, including cancer cells, live) “feed” ketone bodies to adjacent cancer cells, stimulating tumour growth and metastasis. The human MDA-MB-231 breast cancer cell line is one that has been found to overexpress key enzymes involved in ketone metabolism.

Here is how the researchers described the two-way relationship between cancer cells and surrounding fibroblasts that increases the amount of ketones available to fuel tumour growth:

“Ketogenic fibroblasts promote the growth of adjacent breast cancer cells, by driving increased mitochondrial biogenesis. Thus, the tumor stroma may serve as a reservoir for ketone body production, while cancer cells upregulate the enzymes required for ketone body re-utilization, driving oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells.”

Ketone body utilization drives tumor growth and metastasis

They concluded that

“Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis… In summary, ketone bodies behave as onco-metabolites, and we directly show that the [ketolytic] enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes [genes with the potential to cause cancer]”.

Ketone body utilization drives tumor growth and metastasis

An enzyme involved in the generation of ketone bodies was found to be upregulated in high grade prostate cancer, and the concentration of the ketone body β-hydroxybutyrate was higher in these cells, indicating that aggressive prostate cancer cells use ketone bodies to “gain a survival advantage allowing them to become increasingly aggressive and gain androgen-independent properties.”

This is a critical point, because conventional prostate cancer therapy includes androgen blockade, but androgen deprivation decreases the ability of prostate cancer cells to take up glucose from the bloodstream and use it as a fuel. This “decrease in the activity of the glycolytic pathway places prostate cancer cells under stress to generate energy in a quick manner in order to carry out necessary cellular functions. One avenue through which such an effect can be achieved is to increase energy production through the breakdown of fatty acids via the β-oxidation pathway” – that is, through utilising ketone bodies.

Ketone bodies were also found to increase the growth rate of HeLa cells, a cervical cancer cell line that is extensively used in cancer research.

Brain cancer and ketogenic diets

On the other hand, certain tumours may indeed respond well to ketogenic diet therapy. Some patients with a type of brain tumour known as glioma have been shown to have reduced tumour growth when put on an energy-restricted ketogenic diet, however, results are highly inconsistent, and even proponents of the diet acknowledge that its effects are fairly marginal (even when tumour shrinkage occurs, patients don’t live appreciably longer) and it “probably has no significant clinical activity when used as single agent in recurrent glioma”.

A systematic review found 6 peer-reviewed articles (3 case reports, 2 prospective cohort/pilot studies and 1 retrospective cohort study), involving 42 patients – 40 adults and 2 children – on the use of ketogenic diets or caloric restriction for malignant glioma. The authors of the review “found reports on treatment efficacy to be mostly ‘inconclusive’… however, results from 2 studies indicated at least a ‘possible benefit’.”

In all, “a possible benefit following stand-alone or concurrent KMT [ketogenic metabolic therapy] treatment was observed in almost one third of all reviewed patients (13 out of 42 patients).” Hardly a ringing endorsement of the ketogenic diet, but gliomas have such a poor prognosis, that it may be worth considering.

However, not all glioma patients will respond positively to a ketogenic diet, because some glioma cells express ketolytic enzymes and hence can use ketone bodies as a fuel. As the researchers concluded, “Our results showing that malignant gliomas have differential expression of ketolytic and glycolytic enzymes are consistent with previous studies that have shown that these are genetically heterogeneous tumors”.

Since cancer cells continuously mutate due to their genomic instability, some cells within a single tumour will develop mutations that cause them to show a preference for ketone bodies, and others for glucose. Only tumours in which a majority of cells have low expression of ketolytic enzymes are likely to be controlled by ketogenic diets.

Do ketone bodies have specific anti-cancer effects?

The cancer-controlling effects of ketogenic diets are typically attributed to the ketone bodies themselves. For example, improved mitochondrial function has been found to inhibit cancer cell growth and reverse the resistance of cancer cells to chemotherapy drugs. Ketogenic diet advocates credit the ketone body β-hydroxybutyrate (BHB) with being responsible for improving mitochondrial respiration.

However, research by Dr Valter Longo and his co-workers on fasting and fasting-mimicking diets indicates that ketosis is not required to improve mitochondrial function and induce “differential stress sensitisation” (also called differential stress resistance) – a condition in which cancer cells are weakened and made susceptible to chemotherapy, while normal, healthy cells are strengthened and made resistant to it. Instead, reduced levels of insulin-like growth factor 1 (IGF-1) and mechanistic target of rapamycin (mTOR) induce differential stress sensitisation. Both IGF-1 and mTOR are reduced by fasting, and low protein diets.

Fasting, protein restriction and cancer

Fasting has been found to decrease side-effects and increase the tumour cell-killing effects of both conventional cytotoxic chemotherapy and tyrosine kinase inhibitors. Cycles of fasting followed by refeeding stimulate rejuvenation of stem cells, including those in bone marrow, allowing blood counts to “bounce back” faster after cytotoxic chemotherapy.

While evidence for the benefits of a ketogenic diet in cancer treatment are sparse and inconsistent, a randomised controlled trial of a low fat, high carbohydrate plant-based diet (the direct opposite of a ketogenic diet) was shown to significantly decrease PSA and dramatically reduce the risk of progression in men with early stage prostate cancer, and favourably affect a wide range of genes involved in cancer.

Water-only fasting followed by a wholefood plant-based diet with no added sugar, salt or oil – again, high in carbohydrates, low in fat and relatively low in protein was shown to shrink lymphoma and maintain remission.

Final thoughts: research consistently clearly indicates that diets rich in minimally-processed plant foods (and therefore, by definition, rich in unrefined carbohydrates), and relatively low in protein, promote healthy longevity. In an email exchange with me about ketogenic diets (shared with his permission), Valter Longo’s colleague and co-author of many of his research papers, Dr Sebastian Brandhorst, made two critical points:

“1. The relatively high protein content of most ketogenic diets does generally not align with diets that are most beneficial with regards to human health and lifespan

2. Fasting and FMDs [fasting mimicking diets] induce cellular atrophy that is followed by a stem-cell based regeneration/rejuvenation upon normal caloric intake; to the best of my knowledge this has not been demonstrated for ketogenic diets. We believe that this can only be achieved by periodic starvation [fasting]/refeeding intervals.”

Sebastian Brandhorst, email to author

In other words, the ketogenic diet is not conducive to human longevity, and does not offer the benefits that fasting (and fasting-mimicking diets) provide for cancer patients, in terms of reducing the side-effects of medical treatment and enhancing its effectiveness.

The extraordinary claim that ketogenic diets cure cancer is not supported by extraordinary evidence, but by a patchwork of conjectures and hypotheses about the metabolism of cancer cells that have, in many if not most cases, failed to stand up to scrutiny. While further research is justified in the case of highly fatal cancer types that have shown some response, including certain types of brain tumour, when it comes to cancer treatment, ketogenic diets are not ready for prime time.

Are you currently dealing with cancer? Do you have a family history of cancer, or are you a cancer survivor who wants to do everything you can to prevent it from coming back? Looking for guidance in applying cancer research to your situation? Apply for a Roadmap to Optimal Health consultation today!

Read Part 1, Part 2, Part 3, Part 4 and Part 6 of this series.

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