Cancer nutrition: evidence-based approaches (Proceedings)

Many clients whose pets are being treated for cancer are interested in potential benefits from nutritional modifications. Some owners blame a diet for causing the cancer while others want to home-cook so they can feel like they are actively contributing to their pet's care. Still another group has done "research" online and in various books and would like to modify or supplement their pet's diet in the hope that these changes will help cure their pet.

Despite large volumes of information in lay sources touting various nutrients, diets, or supplements for treating cancer in pets and humans, there is little published research addressing nutrition and cancer in dogs and virtually none in cats. The goal of this presentation is to discuss some of the commonly recommended nutritional strategies for veterinary cancer patients and to review the evidence to support these recommendations.

It should be stressed to clients that the most important nutritional goals for cancer patients are to maintain an appropriate caloric intake and ensure that all essential nutrient needs are met. These goals can be accomplished with a commercial diet or a home-cooked diet, but the latter requires much more careful planning and institution to ensure nutritional balance. It is important to keep in mind and stress to clients that there is absolutely nothing wrong with simply continuing cancer patients on the diet that they have been doing well on, provided they will eat an appropriate amount to maintain weight and the diet is complete and balanced and made by a reputable company.

Low carbohydrate

One of the more prevalent recommendations, online and within the veterinary community, is that pets with cancer should be fed as low a carbohydrate diet as possible because carbohydrates "feed" the cancer. It has been known for over 50 years that cancer cells obtain most of their energy via anaerobic fermentation of glucose to lactate rather than via aerobic respiration as in most normal cells1 and it has been reported that dogs with lymphoma have higher insulin and lactate levels than normal dogs2. Thus, the suggestion has been made that dogs with cancer may do better on lower carbohydrate diets. However, this theory has not been proven in-vivo. A published study that investigated the use of high carbohydrate (55% of calories) versus low carbohydrate (7.5% of calories) diets in dogs with lymphoma did not show an obvious difference in remission times (survival time was not assessed and statistics were not performed) or energy requirements3. The author is unaware of any additional published studies in dogs or any published studies investigating the effect of dietary carbohydrate content on cancer in cats. There continues to be a need for well-designed controlled clinical trials to further investigate the role of dietary carbohydrates in cancer treatment of companion animals. Despite the current lack of evidence to support low carbohydrate diets, this recommendation continues to be enthusiastically embraced by clients and veterinarians alike.

If, after being educated on the lack of evidence to support a benefit, an owner would still like to try a low carbohydrate strategy (< 20% of calories from carbohydrates), he or she should be advised to be sure to pick a diet made by a reputable manufacturer that is designed to be complete and balanced. Many commercial high meat diets are not designed to be fed as the majority of the diet and will result in nutrient deficiencies if fed alone. Low carbohydrate diets (not to be confused with "grain free" diets which may be quite high in simple carbohydrates) are generally high in fat and may lead to pancreatitis (dogs), gastrointestinal disturbance or weight gain in sensitive animals.

In summary, if low carbohydrate diets are already being fed and are well-tolerated, there is no evidence to suggest that they are harmful to otherwise healthy animals; however, there is little evidence to suggest any benefits of switching a cancer patient from a balanced diet with a more typical carbohydrate concentration to a low carbohydrate diet.

Amino Acids

There has been increasing interest in potential anti-neoplastic benefits of certain amino acids. Two commonly discussed amino acids are leucine and arginine. Both are involved in regulation of muscle protein metabolism.

Leucine has been shown to bind the mTOR (mammalian target of rapamycin) receptor, which is a very hot area of research currently. Supplementation with leucine has been shown to increase skeletal muscle protein synthesis via an mTOR mediated pathway. Experimental models in rodents suggest that leucine supplementation may reduce muscle loss (cachexia) associated with neoplasia. However, data in naturally occurring disease or in larger mammals is lacking, as is dosing information.

Arginine, via its conversion into nitric oxide, has been shown to have both pro-neoplastic and anti-neoplastic properties at the molecular level. In-vivo, arginine has been associated with improved immune function in healthy patients. In critically ill patients, supplementation trials have been equivocal. In-vivo data in humans and animals with neoplasia are still inconclusive.

Omega-3 fatty acids

Omega-3 polyunsaturated fatty acids (PUFAs) have been demonstrated to have anti-inflammatory effects in numerous species, including dogs. They are increasingly being investigated for potential anti-neoplastic activity as well. Clients are likely to be interested in supplementing or already supplementing various omega-3s when their pet is diagnosed with cancer.

There are two main sources of omega-3 fatty acids: terrestrial plants and marine algae and fish. Flaxseed is an excellent source of alpha-linoleic acid (ALA, 18 carbon, 3 double bonds), a short chain omega-3 fatty acid. The two other well-known omega-3s, docosahexaenoic acid (DHA, 22 carbon, 6 double bonds) and eicosapentaenoic acid (EPA, 20 carbon, five double bonds) are only found in marine algae and the cold water marine fish that eat it. Although ALA can theoretically be converted to EPA and then DHA through enzymatic means, a sizable percentage of dietary ALA intake is oxidized4 for energy and the conversion rates in mammals are generally poor. Cats, for example, are essentially unable to convert ALA to EPA.

The literature is ambiguous when it comes to benefits of ALA for neoplasia, despite the enthusiastic embracement of this fatty acid on the internet (i.e. Budwig cancer diet). Research in human breast and prostate cancers, mostly correlation studies, has suggested both positive and negative associations between ALA intake and tissue concentration and cancer.

The evidence for potential benefits for EPA and especially DHA is more impressive in humans and animal models, although not overwhelming enough to make supplementation the standard of care in human oncologic practices. Hundreds of studies are currently on-going to more accurately discern the potential anti-neoplastic effects of long chain omega-3 fatty acids in humans and laboratory animals as well as to determine the appropriate doses to optimize these effects in-vivo.

The DHA and EPA research in companion animals has mostly been directed towards demonstrating anti-inflammatory effects in dogs with kidney disease, osteoarthritis and heart disease. There has been little work published in cats. Only one controlled study has investigated a diet high in EPA and DHA on outcome in dogs with cancer5. This study looked at dogs with Stage IIIa and IVa lymphoma fed a diet supplemented with fish oil and arginine or a similar diet with no fish oil or added arginine. Overall disease free interval and survival time were not different between the diets, although when the dogs were divided by stage, stage III dogs eating the supplemented diet had longer disease-free interval and survival time. Many aspects of this study have been criticized, including the post hoc subgroup analysis and the method of initial staging. There is a veterinary therapeutic diet that resulted from this work, Hill's Prescription Diet canine n/d, but it seems to be rarely utilized in oncology practices, at least in academia.

Despite the lack of definitive evidence for benefit of EPA and DHA supplementation in dogs or cats with cancer and the lack of a defined appropriate dose, the sum total of the human and animal literature is suggestive of a benefit, and it is therefore very reasonable to feed a diet high in EPA and DHA or to supplement a low omega-3 commercial diet with these fatty acids. Although appropriate doses have yet to be determined, the author generally uses a total daily dose of 300 g EPA and DHA per 10 pounds body weight. There is minimal evidence at this point to support a benefit of flax (ALA) supplementation as a source of omega-3 fatty acids in dogs, and it should not be used as a source of omega-3 fatty acids for cats. Clinicians should keep in mind that there is an upper limit to how much omega-3s can be supplemented, although it remains rather undefined. High concentrations may tax antioxidant systems and can lead to increased clotting times. Additionally, fat of any kind adds 9 kcal/g to the diet and care must be taken to ensure that fish oil supplementation plus all treats, table food, food for medication administration, etc, totals less than 10% of the pet's total daily caloric intake to minimize the risk of nutrient deficiency secondary to nutrient dilution.

Antioxidants

Antioxidant supplementation is controversial in cancer patients, both human and animal. While there is evidence that some antioxidants may help prevent certain types of cancers, there is also evidence that some antioxidants increase the risk of certain cancers (e.g. beta carotene and lung cancer). Studies in humans with active tumors have shown variable results from high-dose antioxidant supplements including beneficial, no observable, and detrimental effects. Common recommendations in humans include avoiding antioxidant supplements within a few days of chemotherapy and throughout a course of radiation. These recommendations apply to antioxidant supplements, rather than antioxidants naturally occurring in whole foods (or commercial diets for our pets). Two antioxidant sources commonly (and controversially) supplemented in human and animal cancer patients are green tea extract and vitamin C.

Green tea contains active compounds called polyphenols and there is some data (mostly epidemiological) to suggest that polyphenols may help prevent cancer. The assumption has thus been made that green tea extract may also be helpful to treat existing cancer. However, polyphenols are known to up-regulate cytochrome p450 drug metabolism pathways, which may alter chemotherapeutic metabolism, potentially leading to enhanced toxicity or cancer cell resistance in cancer patients. Recent cell culture studies in human tumor lines have also shown that concentrated green tea polyphenols directly antagonize cell killing by some chemotherapeutics6 as well as up-regulate certain transcription factors in cancer cells, leading to decreased sensitivity to doxorubricin7, a commonly used chemotherapeutic in both humans and animals. Overall, the current data suggests that green tea supplements are potentially harmful in cancer patients and the use of these supplements should be discouraged.

Vitamin C is often recommended for cancer patients by complementary and alternative medicine practitioners. Although high doses of vitamin C are commonly reported to be beneficial anecdotally in human cancer patients, there is little evidence to support a benefit from controlled trials in humans or animals. Additionally, high doses of vitamin C may predispose susceptible pets to developing calcium oxalate urolithiasis as vitamin C is metabolized to oxalic acid endogenously.

Other Supplements

There is little evidence to support the use of shark cartilage or Co Q10 in people or animals with cancer.

While resveratrol has shown potentially beneficial effects in experimental models, its low bioavailability makes appropriate dosing in vivo outside of the laboratory impractical.

Summary

In summary, the best evidence supports feeding pets with cancer commercial or home-cooked diets designed to meet both their energy and essential nutrient requirements. Low carbohydrate diets are of no proven benefit but supplementation with EPA and DHA should be considered. Supplementation of leucine and arginine remains equivocal. Antioxidant supplementation is controversial and until it becomes less ambiguous, it is likely best to avoid exogenous supplementation outside of the levels provided by a well-balanced diet, especially during chemotherapy or radiation. Green tea extract and high doses of vitamin C should be avoided.

References

Warburg O. On the origin of cancer cells. Science 1956;123:309-314.

Vail DM, Ogilvie GK, Wheeler SL, et al. Alterations in carbohydrate metabolism in canine lymphoma. J Vet Intern Med 1990;4:8-11.

Ogilvie GK, Walters LM, Fettman MJ, et al. Energy expenditure in dogs with lymphoma fed two specialized diets. Cancer 1993;71:3146-3152.

Cunnane SC, Ryan MA, Nadeau CR, et al. Why is carbon from some polyunsaturates extensively recycled into lipid synthesis? Lipids 2003;38:477-484.

Ogilvie GK, Fettman MJ, Mallinckrodt CH, et al. Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and survival time for dogs with lymphoma: a double-blind, randomized placebo-controlled study. Cancer 2000;88:1916-1928.

Golden EB, Lam PY, Kardosh A, et al. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood 2009;113:5927-5937.

Hu L, Miao W, Loignon M, et al. Putative chemopreventive molecules can increase Nrf2-regulated cell defense in some human cancer cell lines, resulting in resistance to common cytotoxic therapies. Cancer Chemother Pharmacol 2010;66:467-474.