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. 

Schmidt 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