Wednesday, August 10, 2011

Advanced cancer and the ketogenic diet

A new pilot trial about cancer-ketogenic diet has recently been published (1). This german group evaluated specifically the feasibility of a KD and its influence on the quality of life of patients with advanced metastatic tumors. The full text is free, so anyone can go and check the details and methodology used. The nutritional intervention was basically an ad libitum KD (<70g/CHO/day), plus extra omega-3 fatty acids. 

Dietary guidelines for the patients were (Table 2):
  1. Avoid all types of bread, cake, processed snacks, sweets, potatoes, pasta,
    rice, polenta, vegetables rich in starch (corn, beans, peas) and cereals.
  2. Be aware of hidden sources of CHO in sugar sweetened drinks, candy,
    chewing gum with sugar, milk and milk products, lunch meat and some
    cheeses as well as in most “low fat” products.
  3. Fruits are rich in CHO, therefore always calculate the amount and select
    those which are low in CHO.
  4. Vegetables are often rich in CHO - but mainly in dietary fiber, therefore
    calculate the usable CHO only.
  5. If possible, prefer cold-water fish and meat from grazing cattle as protein
    sources, because of their preferable fatty acid pattern.
  6. Vegetables and the few fruits allowed should be grown organic
  7. As nibbles, select oil-rich nuts (walnuts, brazil nuts, macadamia nuts) and
    seeds (sunflower), and only occasionally chocolate with very high cacao
    content (min. 85%).
This guidelines look very paleoish to me (whatever that means). Some things I found interesting are points 5 and 6. Not seen emphasized commonly. Additionally, patients were told to drink two liquid meals as snacks. Components of this shake were provided to the patients and included: 250ml of highly fermented yogurt-drink, 8ml vegetable oil mixture and 10g of protein preparation. Ingredients of the components can be seen in Table 3. 

Because of problems with compliance to the diet, from 16 initial participants, only 5 remained until the end of the study (31%). Two patients dropped out during the first week, one because of inability to adhere to the diet and the other because of personal problems. Two patients died from their malignant disease during the study, one patient dropped out because he suffered excessive weight loss and weakness, one patient quit because he felt he wasnt able to stick to the dietary guidelines, one because resuming chemotherapy and four due to progress of their advanced cancer situation. The compliance problem is common. Adopting a ketogenic diet involves a lifestyle change. Something even advanced cancer patients can't do. This reminds me of a study in which some cancer patients wouldnt adopt a KD because that meant "giving up the candies and ice cream", despite the fact that it could improve their condition. To complicate things further, the acceptance of the diet varied greatly. One patient said that after 3 days on the diet it was not feasible at all and stopped the diet. Two patients rate feasibility as "very good", seven patients rate it "good", three "moderate" and one "poor". This was after 2 weeks of dieting so included the 16 initial participants.

Quality of life was measured by the EORTC QLQ-C30 questionnaire. Global scores remained relatively stable during the evaluation time. Physical and role functioning worsened slightly over time and constipation was reported by most patients. Because of the advanced cancer stage of the patients, fatigue, pain or dyspnoea increased over time. Nevertheless, emotional functioning increased slightly and insomina improved. 

Of those who completed the whole 12 weeks of dieting, 60% reached a stable ketonuria, predominantly being 1.5-4.0mM. Among blood parameters, only some patients had available data. Overall, CRP levels increased slighlty over time, considering the initial values were high. Two patients initially had elevated glucose, which returned to normal. In other patients, cholesterol levels were "normalized" (meant by reduced to conventionally accepted levels), as well as triglycerides in one patient and ALT in other patient. Total leukocyte count significantly increased during the intervention (even though one patient with initial low leukocyte counts showed a further reduction). 

Patients lost an average of 2kg. Progress of the disease occured in 5 patients who then discontinued the diet, while 5 patients who adhered to the diet had stable disease progression.

Overall, the percentage of days in ketosis (>0.5mmol/l) was not correlated with the results of the study. We can see in table 4 that for example, patient 6 reached 97% of days in ketosis, but because of impaired food intake only completed 6 weeks and showed progress in the disease. On the other hand, patient 16 reached 100% days in ketosis, completed the trial and showed no progress in the disease. Both patients 5 and 11 only reached 25% of days in ketosis, but completed the trial and maintained their condition. 

The limitations of this study were:

- Patients had advanced stage cancer. While a KD might help preventing and/or treating some cancers, there is no much left to do when the disease is too severe.

- Most patients werent from the author's hospital. Blood samples and laboratory parameters had to be provided by their family doctors or local oncologists.

- Short sample and short intervention time. 

Being fair, at the time the study was done (2007) guidelines to apply a KD for cancer treatment were scarce. The only premise was that reducing carbohydrates (hence sugar and cancer's fuel) would reduce progression of tumors. Since then, there is more information available which suggest how to implement the KD for these patients. Overall, evidence suggest that the diet should be not only ketogenic, but calorie restricted. This is for achieving low blood glucose levels and increased KB. In the study reviewed in this post, calories were ad libitum and with a carbohydrate intake limited to 70g/day. Glucose should be ideally around 55-65mg/dl and KB 4-7mM. Checking the study data, most patients had much higer BG (mean 93) and only mild ketosis. Therapeutic fasting is another valuable tool, but harder to comply with. Another factor to take into account is the cancer phenotype. A restricted KD should be more efficient in predominantely glucose-consuming tumors, which can be assessed using some phenotypic markers. Serum LDH levels, for instance, have been shown to be correlated with activation of HIF related genes (2), which include glycolytic enzymes (3). Or using the more conventional FDG-PET. Finally, utilization of gluconeogenesis and glycolysis inhibitors (ie. 2-Deoxyglucose or metformin) with the KD has also been proposed (4,5).

Recent evidence suggests that this metabolic therapy is promising. One case report (6) has shown a rapid regression of glioblastoma multiforme in an old patient using the guidelines proposed by Seyfried et al (7). This patient started the metabolic therapy with a water-only fast, switching then to a restricted KD which delivered 600kcal/day for 14 days. Dexamethasone was also eliminated (because high dosage steroid medication increases gluconeogenesis and blood glucose levels, while enhancing apoptosis resistance in tumor cells). Because of development of mild hiperuricemia, the KD was changed for a non-ketogenic calorie-restricted diet which also delivered 600kcal/day. Aside from the complete regression in such a short time (2-2.5 months), the most surprising finding in my opinion was the recurrence of the tumor after discontinuing the metabolic therapy, which strongly suggests that the therapy itself was the most infulential factor in cancer regression.

It seems that controlling blood glucose levels is the more important part of the metabolic therapy. Achieving blood glucose levels of 55-65mg/dl and 4-7mM of ketone bodies has been termed as "the zone of metabolic management":


This resembles the results from the study on the GB patient:


Although target blood glucose levels were not achieved, the reduction observed was sufficient for controlling disease progression. The other difference was the method of detection of ketosis, urinary ketones, which doesnt always correlate to blood ketone levels. 

ResearchBlogging.orgSchmidt M, Pfetzer N, Schwab M, Strauss I, & Kammerer U (2011). Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. Nutrition & metabolism, 8 (1) PMID: 21794124

16 comments:

  1. I know this is slightly unrelated, but do you have any idea what might influence the development of ovarian cancer? Two generations on my mothers side: my mothers mother, and her mother died of this disease. I would be very interested to in your thoughts. Great site by the way, very interesting.

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  2. Perhaps it is hard to go cold turkey with all non-keto diet foods. I don't feel restricted or stressed about food at all, but I gave things up slowly, and I can easily see how people struggle with it. I think the last time I ate "junk" was about six months ago, which was vanilla ice cream. I eat starch though if I feel like it or have had a tiring workout, so I'm not strict "keto" all the time I guess.

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  3. "Adopting a ketogenic diet involves a lifestyle change. Something even advanced cancer patients can't do."

    Indeed that is a sad thing. Many people I speak to irl are completely outraged at even the thought of giving up carbs.

    Lucas to what degree do you think straight up extended water fasting could reverse cancer?

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  4. Kindke, my grandmother went on 40 plus days of 'juice fasting' having been diagnosed with bowel cancer which had originally spread from her ovaries. She died though. She was very emaciated, not entirely sure whether water fasting would have had any greater success in that department. She was skin and bone, probably a fat fast would have been kinder; energy with some kind of nourishment. I can't believe how much discipline it must have took for her to stick to the juice fast for 40 odd days. The other thing was that the more advanced her cancer became the harder she was able to actually eat, it seemed to be that her appetite was diminished, but i'm not sure that that was because she didn't feel hunger, but that she was experiencing a lot of pain in her body, which meant that she couldn't eat; due to the nausea she felt also.

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  5. Hi Jenna,

    There is evidence that ovarian and breast cancer both have a genetic component (mutations on BRCA1 and BRCA2, for instance). Nevertheless, the primary triggers for proliferation and metastasis are growth factors and different anti-apoptotic stimuli. Most of ovarian cancers are derived from the epithelium surface, have almost no genetic influence, and are very agressive and proliferative; so controlling glucose levels and inflammation is key for prevention.

    Hi Kindke,

    I think the best preventative measure for cancer is therapeutic fasting, that being, 7 days of only distilled water. This produces a very strong metabolic pressure to cancer cells, and creates differential stress resistance, where normal cells increase their tolerance to mutagens, ROS and other types of stress, whereby cancer cells do not. This also promotes autophagy, key for removing damaged or misfolded/modified proteins.

    I wouldnt use the word "reverse" because these are all hypotheses which must be further tested. However, trials like the one in the post using the RKD look very promising. There is also evidence that short term fasting before/after chemotherapy reduces side-effects (PMID:20157582).

    In the case Jenna mentions, "Juice fasting" is nothing like true fasting. Its more like a "starve your body and feed the cancer" therapy.

    Appetite is generally reduced in cancer patients and associated with cancer cachexia. Chemo/Radiotherapy, surgical procedures and the localization of the tumor also contribute to lack of appetite and patient deterioration. Cachexia is characterized by excessive production of pro-inflamatory cytokines which have an anorexigenic effect in the hypothalamus.

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  6. Thanks Lucus,

    Within what range of glucose intake, do you think would be preventative?
    You mention inflammation; what dietary factors, do you think contribute to it's development? I vaguely remember reading a comment you left somewhere, about saturated fat's ability to also create inflammation; if so, is this just related to quality?

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  7. Great article, thanks for posting it

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  8. Thanks for bringing this study up. It's unfortunate that the study design included the two meal replacement drinks and that the drinks included 8 mL vegetable oil. I can't help but wonder if compliance would have been improved if all real food had been used via a Jaminet-type ketogenic diet (controlled carb, controlled protein, copious amounts of coconut oil, no fructose).

    http://perfecthealthdiet.com/?p=2479
    http://perfecthealthdiet.com/?p=2638

    He mentions in the comments that "eating fructose depletes liver ATP and so short-chain fats would be burned to generate energy instead of converted to ketones. So don’t eat fructose if you want to be ketogenic". BG and ketone measurements were not at target which makes me wonder how much of an impact even low CHO fruit may have had rather than simply disallowing fructose consumption.

    I always enjoy your blog posts and appreciate the time you take to make them happen.

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  9. Hi Jenna,

    Saturated fat can be inflammatory in a high glucose milieu. I would aim to no more than 100g of glucose per day, matched to physical activity. If you move less, eat less. Among cancer researchers, it is a well known fact that omega 6 is pro-carcinogenic. High glucose stimulates insulin, which also reduces IGFB3, increasing IGF-1 levels. This also stimulates leptin and other pro-inflammatory cytokines.

    For trying to prevent cancer, you must control growth factors. This is achieved both by regular fasting (which confers other benefits, as Ive mentioned) and calorie restriction.

    Hi Kat,

    Yes, I think the problem was the diet was not calorie restricted.

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  10. Hi Lucas!

    In your opinion, what is the ideal fasting blood glucose level for a KD _healthy_ person? I'am asking this because I've read many reports that at full keto-adaptation (1-2 years from starting KD), the FBG raises and remains stable at pretty high level of about 100. While adding even 20-30G of carbs lowers it down to 80-90.

    Best wishes

    Dmitry

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  11. Hi Dmitry,

    The only evidence of a KD raising BG levels I have seen is in the website. I havent seen any study that sees this phenomenon, but maybe because of the duration of the observation period (the longest being 3 years). Anyways, I think that anything below 100 is acceptable. A KD even with restricted carbs, if very high calories, can increase BG. You might want to check Peter's series on physiological insulin resistance.

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  12. I was wondering if a ketogenic type of diet would help someone with renal cancer. I know someone whose mother has recently been diagnosed (a 2nd time).

    I don't know the nature of her tumour, and whether it's a glucose feeding type or not. It would seem to me that KD would be beneficial regardless, but would like to know your opinion.

    Btw, they will operate and take her kidney out leaving her with none. She will be on dialysis for the rest of her life as a result.

    Thanks.

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