A. Summary.
A ketogenic diet is a very low carbohydrate diet. It is not a high protein diet, so is necessarily a high fat diet.
The metabolic syndrome [Mets] increases the risk for cardiovascular disease [CVD], diabetes, non-alcoholic fatty liver disease [NAFLD] & prostate cancer (PCa). A lower carbohydrate:fat ratio can reduce MetS symptoms & the risk of disease.
The Mediterranean diet is often touted as being ideal in terms of CVD risk & is probably ideal for reducing PCa risk too. PCa rates are very low in most Mediterranean countries.
The Med diet is 40% fat & one should not mess too much with that percentage. Olive oil is traditional & one should avoid pro-inflammatory oils such as corn.
With the ketogenic diet, which has much more fat than the Med diet, there is not enough carbohydrate to meet glucose needs for energy, so cells switch to fatty acids & ketones. For cancers other than that of the prostate, where the need for glucose is greatly increased, the ketogenic is quite attractive. But can it help in PCa, which prefers fatty acids?
The ketogenic diet can lower two growth factors associated with PCa: IGF-I (Insulin-like Growth Factor-I) & insulin. Tumor growth is slowed.
Dr Steve Freedland's research - albeit on mice - points to a 20% carb diet as being perhaps optimal, since at lower levels compliance would be poor.
How might this be achieved? The Mediterranean diet is probably the best starting point. Cut out all starchy carb: bread, pasta, grains, etc. Find ways to add more fat to dishes (not cheese, though). Eat as much as you want of non-starchy (low calorie) vegetables. Enjoy salads drenched in an olive oil dressing, etc. I have never been a fan of eggplant, but boy can it soak up olive oil.
Triglycerides moving closer to the HDL-cholesterol number indicate increased insulin sensitivity - i.e. reduced insulin resistance & levels. An increase in the PSA doubling time implies a slowing of PCa growth.
Who should consider the diet? Those with a poor triglycerides:HDL ratio (>2, IMO). Those with a very short PSADT - it's worth a try.
B. Introduction.
The ketogenic diet is an extreme low-carbohydrate diet.
I thought it best to start with the rationale for low-carbohydrate diets. I expect that many are skeptical, since low-carbohydrate = high-fat. At diagnosis I was not following a rigid diet. I decided that all decisions related to foods, vitamins & minerals would be driven by PCa study results.
The figures given below are pretty damning. And there is a biological basis to the hypothesis that the U.S. food pyramid exacerbates metabolic symptoms that are associated with a poorer PCa prognosis.
The U.S. food pyramid [Ba] places starchy carbohydrates (the "bread, cereal, rice & pasta group, 6-11 servings") at the base & fats ("use sparingly") at the apex.
The American supermarket contains countless 'No-Fat' & 'Lo-Fat' products. This is not because the food industry is sadistically forcing those products on a docile public - companies are merely catering to demand. Do you think it's easy to produce a no-fat salad dressing? i.e. 100% carbohydrate, but mimicking the mouth-feel of clasic oil-based dressings.
It is clear that most Americans have taken the pyramid to heart & view dietary fat as the cause of their own excess body fat.
The American Diabetes Association [Bb] estimated in 2014 that while diabetics numbered 21 million, with a further 8 million undiagnosed, prediabetics numbered 86 million. In total, that is more than a third of the population with a glucose problem. The percentage is far higher in older adults, of course (& very low in the young).
The CDC use the same numbers [Bc]. The advice from the CDC: "Eat Healthy". Very helpful!
A UCLA study [Bd] of Californian adults found 16% diabetes & 60% prediabetes in the 55-69 age group.
A type 2 diabetic is likely to encounter the same attitudes as those with lung cancer. These diseases are considered to be self-inflicted. I disagree. When three-quarters of older American adults are diabetic or prediabetic, there is something wrong with the general understanding of what comprises a 'healthy' diet. Something wrong with the advice people are exposed to - &, of course, the pyramid.
A serious, but largely ignored problem is Non-Alcoholic Fatty Liver Disease. Here is what the American Liver Foundation says [Be]:
"Non-alcoholic fatty liver disease (NAFLD) is the build up of extra fat in liver cells that is not caused by alcohol. It is normal for the liver to contain some fat. However, if more than 5% - 10% percent of the liver’s weight is fat, then it is called a fatty liver (steatosis)."
"NAFLD tends to develop in people who are overweight or obese or have diabetes, high cholesterol or high triglycerides."
"NAFLD affects up to 25% of people in the United States."
Here's a quote from a 2015 paper [Bf]:
"Excessive accumulation of triglycerides (TG) in liver, in the absence of significant alcohol consumption is nonalcoholic fatty liver disease (NAFLD). NAFLD is a significant risk factor for developing cirrhosis and an independent predictor of cardiovascular disease."
"Ingested carbohydrates are a major stimulus for hepatic de novo lipogenesis (DNL) and are more likely to directly contribute to NAFLD than dietary fat."
...
Prostate cancer does not typically use glucose for fuel. Radio-labeled glucose PET scans cannot be used for diagnostic purposes. Elevated glucose is a problem in PCa to the extent that insulin is also elevated. Diabetics have impaired insulin production &, ultimately, a lower risk for PCa (they have a higher risk for every other cancer type). Meanwhile, prediabetics are still over-producing insulin (in a futile attempt to overcome insulin resistance - higher levels merely reduce insulin sensitivity further.)
Non-diabetics at PCa diagnosis score higher in symptoms of the metabolic syndrome [MetS] than non-diabetics without PCa. Which no doubt explains why men with PCa have a greater risk for cardiovascular disease [CVD].
From a paper published in February [Bg]:
"The presence of MetS is associated with worse oncologic outcomes in men with PCa, in particular with more aggressive tumor features, and biochemical recurrence."
The medical profession seems strangely uninterested in connecting the dots, but Dr. Myers pushes the Mediterranean diet for his PCa patients, based on CVD studies. The Med diet is as high as 40% fat. He has mentioned that his low-fat diet patients do poorly. Without actually saying as much, he is treating PCa as a metabolic condition. This is certainly sensible for men on ADT, since loss of testosterone rapidly leads to prediabetes or worse. Myers, I believe, has now been in remission for 18 years, & remains an enthusiastic adherent of the Med diet. He even has a cookbook.
Our views on fat are still largely based on the ideas promoted by Ancel Keys sixty years ago. Dr. Dean Ornish & his 10% fat diet remains remarkably influential. He claims Bill Clinton as a patient. Clinton, meanwhile, is also a patient of Dr. Mark Hyman, author of "Eat Fat, Get Thin". LOL
If a 40% fat diet can reverse MetS & lower the risk for a number of diseases, including CVD, NAFLD & cancer, is there any value in going higher?
The ketogenic diet is the ultimatate low-carb diet. My feeling is that the difficulties involved in following it, precludes its use unless there is a serious medical condition, such as cancer.
With the ketogenic diet, there is a drop in two promoters of PCa: IGF-I & insulin.
The ketogenic diet is a very low-carb, very high-fat diet. Protein intake remains unchanged. In this diet (& variants), there is not enough carbohydrate to meet glucose needs, so energy requirements are met by fatty acids & ketones. If this seems too weird to countenance, the diet has been used for almost a century in very young children prone to seizures that do not respond to available drugs,'
The intro to an April paper [Bh]:
"High-fat, low-carbohydrate ketogenic diets have been used for almost a century for the treatment of epilepsy. Used traditionally for the treatment of refractory pediatric epilepsies, in recent years the use of ketogenic diets has experienced a revival to include the treatment of adulthood epilepsies as well as conditions ranging from autism to chronic pain and cancer. Despite the ability of ketogenic diet therapy to suppress seizures refractory to antiepileptic drugs and reports of lasting seizure freedom, the underlying mechanisms are poorly understood. This review explores new insights into mechanisms mobilized by ketogenic diet therapies."
The brain has a high energy requirement. In the absence of glucose, it readily adapts to ketones as fuel.
Those who suggest the ketogenic diet for cancer, argue that cancer is dependend on anaerobic glycolysis (the Warburg effect). That it cannot adapt to the loss of glucose. I'm not sure that I believe that, but PCa is the exception. It actually prefers fatty acids.
From a March paper [Bi]:
"The predominant use of glucose anaerobically by cancer cells (Warburg effect) may be the most important characteristic the majority of these cells have in common and, therefore, a potential metabolic pathway to be targeted during cancer treatment. Because this effect relates to fuel oxidation, dietary manipulation has been hypothesized as an important strategy during cancer treatment. As such, the concept of a ketogenic diet (KD) in cancer emerged as a metabolic therapy (ie, targeting cancer cell metabolism) rather than a dietary approach. The therapeutic mechanisms of action of this high-fat, moderate-to-low protein, and very-low-carbohydrate diet may potentially influence cancer treatment and prognosis. Considering the lack of a dietetics-focused narrative review on this topic, we compiled the evidence related to the use of this diet in humans with diverse cancer types and stages, also focusing on the nutrition and health perspective. The use of KD in cancer shows potentially promising, but inconsistent, results. 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. However, the potential positive influences a KD may have on cancer treatment justify the need for well-designed clinical trials to better elucidate the mechanisms by which this dietary approach affects nutritional status, cancer prognosis, and overall health. The role of registered dietitian nutritionists is demonstrated to be crucial in planning and implementing KD protocols in oncology research settings, while also ensuring patients' adherence and optimal nutritional status."
Since the Warburg effect is not seen in PCa, what is the evidence that it may be helpful?
- Ketogenic Diet & IGF-I.
[Bj] (2008 - Sweden)
"To examine the influence of the ketogenic diet (KD) on linear growth and insulin-like growth factor I (IGF-I) levels in children with pharmacotherapy-resistant epilepsy."
"Weight, height, BMI, and height velocity decreased significantly during the KD."
"We found that the KD had profound influence on growth and IGF-I levels."
[Bk] (2016 - Multinational) Large pooled meta-analysis.
"Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development."
- Ketogenic Diet & Insulin.
[Bl] (2012 - Greece)
"Metabolic impact of a ketogenic diet compared to a hypocaloric diet in obese children and adolescents."
"Both groups significantly reduced their weight, fat mass, waist circumference, fasting insulin, and HOMA-IR ... but the differences were greater in the ketogenic group."
[Bm] (2008 - India)
"Insulin can influence cancer risk through its effect on cell proliferation, differentiation and apoptosis. Although hyperinsulinemia is considered as a risk factor in the pathogenesis of various cancers, the data related to insulin sensitivity, insulin secretion and lipid profile is lacking in non-diabetic prostate carcinoma cases."
"The present study concludes that hyperinsulinemia associated with reduced insulin sensitivity may play a role in the pathogenesis of prostate carcinoma."
C. Dr. Stephen Freedland.
Steve Freedland is a PCa researcher & physician. Affiliated with Duke University Hospital, Durham, NC, as well as Cedars-Sinai, Los Angeles, CA, he nonetheless has his name on 400 PCa papers. I always read each new paper that has his name on it.
[Ca] (2006 - U.S.)
Title: "Is there a role for a low-carbohydrate ketogenic diet in the management of prostate cancer?" No free text, alas.
[Cb] (2008 - U.S.) Mouse study.
"Recent evidence suggests carbohydrate intake may influence prostate cancer biology. We tested whether a no-carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low-fat diets in a xenograft model."
"Despite consuming equal calories, NCKD-fed mice lost weight (up to 15% body weight) relative to low-fat and Western diet-fed mice and required additional kcal to equalize body weight. Fifty-one days after injection, NCKD mice tumor volumes were 33% smaller than Western mice"
"While the current pre-clinical study found that a NCKD diet prolonged survival relative to a Western diet, there are several points to consider before beginning human clinical trials. The dietary composition of the NCKD diet used in the current study does not correlate with human studies of low-carbohydrate/ketogenic diets. Rather we modeled the NCKD on the diet traditionally used by neurologists to help manage seizures in pediatric patients, which serves to minimize glucose intake and thereby reduce serum insulin levels. We believed this to be a good starting point for an initial proof of principle study. It is unknown whether introducing a small amount of carbohydrate into the diet, while still maintaining ketosis and low serum insulin levels would diminish the anti-tumor activity of the diet. One concern with low-carbohydrate diets in humans is their potential impact on the liver and cardiovascular system. In the current study, NCKD mice actually had the least amount of hepatic fatty infiltration. This is consistent with human data in which low-carbohydrate diets significantly reduce triglyceride levels and raise HDL levels which would be predicted to reduce fatty infiltration in the liver. Moreover, both of these changes, in conjunction with the weight loss which accompanies such diets, would be predicted to reduce the risk of heart disease. This is important, since heart disease is the number one cause of death among men diagnosed with prostate cancer."
"In an animal model of prostate cancer growth, an NCKD resulted in reduced tumor growth and significantly prolonged survival relative to mice fed a Western diet. This was associated with a reduction in serum insulin and IGF-1 levels and increased IGF-BP3 levels. The diet was well-tolerated and no toxicity was seen. These results lay the foundation for future studies of low-carbohydrate diets for the management of prostate cancer."
[Cc] (2010 - U.S.)
"Low-carbohydrate diets and prostate cancer: how low is "low enough"?"
"Previous studies indicate that carbohydrate intake influences prostate cancer biology, as mice fed a no-carbohydrate ketogenic diet (NCKD) had significantly smaller xenograft tumors and longer survival than mice fed a Western diet. As it is nearly impossible for humans to consume and maintain NCKD, we determined whether diets containing 10% or 20% carbohydrate kcal showed similar tumor growth as NCKD."
"LAPC-4 xenograft mice fed a low-carbohydrate diet (10-20% carbohydrate kcal) had similar survival as mice consuming NCKD (0% carbohydrate kcal)."
[Cd] (2014 - U.S.)
"The Effect of Carbohydrate Restriction on Prostate Cancer Tumor Growth In a Castrate Mouse Xenograft Model"
"Worldwide regional disparities in the occurrence of prostate cancer (PCa) have been attributed in part to the effect of diet, with Asian men having up to a six fold decreased incidence over their western counterparts. Epidemiologic observations, however, have been inconclusive about which specific dietary components contribute to PCa. A logical extension is that if diet can affect the development of cancer, it can also influence the growth of an established tumor, and indeed this has been demonstrated in animal studies. While traditionally a low fat diet was thought to be optimal, we previously hypothesized that a reduced carbohydrate diet was likewise beneficial. In a prior study we found that mice consuming a no-carbohydrate ketogenic diet (NCKD) had increased overall survival and slower tumor growth, compared to mice on a western diet, a benefit not observed in mice consuming a low fat diet. ... The favorable effect in the NCKD mice was thought to be from decreased signaling of the insulin/ insulin-like growth factor (IGF) axis, a pathway integral in the progression of PCa"
"While these dietary changes appear to be promising for slowing tumor growth, the best established therapy for stunting PCa involves chemical or surgical castration. The deleterious effects of androgen deprivation on weight, diabetes and cardiovascular health make dietary decisions under this circumstance of particular interest. Thus we sought to explore the effect of low- and no-carbohydrate diets on tumor growth and survival as an adjunct to androgen deprivation therapy in a PCa xenograft model."
"In the present study, no difference in tumor growth, IGF-axis, and survival was found among mice fed 3 different carbohydrate restricted diet, varying in proportion from 0% to 20%. In fact, those consuming a 20% carbohydrate diet had the slowest tumor growth, which was significantly slower than mice fed a western diet."
-Patrick
[Ba] google.com/search?q=U.S.+fo...
[Bb] diabetes.org/newsroom/press...
[Bc] cdc.gov/features/diabetesfa...
[Bd] ncbi.nlm.nih.gov/pubmed/271...
[Be] liverfoundation.org/aboutth...
[Bf] ncbi.nlm.nih.gov/pmc/articl...
[Bg] ncbi.nlm.nih.gov/pubmed/282...
[Bh] ncbi.nlm.nih.gov/pubmed/281...
[Bi] ncbi.nlm.nih.gov/pubmed/283...
[Bj] ncbi.nlm.nih.gov/pubmed/187...
[Bk] ncbi.nlm.nih.gov/pubmed/269...
[Bl] ncbi.nlm.nih.gov/pubmed/231...
[Bm] ncbi.nlm.nih.gov/pubmed/183...
[Ca] ncbi.nlm.nih.gov/pubmed/168...
[Cb] ncbi.nlm.nih.gov/pmc/articl...
