SEARCHING FOR A COMPLIMENT FOR CANCER Part 1 Nutrition and Cancer

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1 SEARCHING FOR A COMPLIMENT FOR CANCER Part 1 Nutrition and Cancer Donna M. Raditic DVM, DACVN, CVA Clinical Assistant Professor Integrative Medicine Nutrition Service The University of Tennessee College of Veterinary Medicine C247 Veterinary Teaching Hospital 2407 River Drive Knoxville, TN Veterinarians face multiple questions and challenges in approaching a patient with cancer that is being given supplements with the most important being safety and efficacy. We need to rely on scientific evidence yet at the same time we cannot overlook the client s perspective. It has been reported that human oncology patients use nutrition and natural products to empower themselves, attempt to take control of their health, and increase quality of life. With the strength of the human animal bond, it is logical to respect these same emotions when an owner is facing cancer in their pet. If a veterinarian is not responsive and knowledgeable about appropriate nutrition, supplements, and other complementary and alternative veterinary medicine (CAVM), advice from friends, non-professional literature, popular magazines, and the Internet provide an ample, but possible incorrect source of information for pet owners. In an unpublished 2005 survey, 60% of veterinarians reported that they required the skills or knowledge of CAVM on a weekly or monthly basis, whereas 7% indicated that situations arose daily and 33% reported this occurred once a year or never. It was noted in this report that CAVM is incorporated less into veterinary medical curricula than CAM in medical schools. It has been reported that 40% of human cancer patients use herbal preparations, supplements or some other non-herbal preparation. In a study of colon rectal cancer patients more than half took more than one supplement. A third study revealed 80% of human cancer patients used vitamin supplements mostly multivitamins, vitamin C, or vitamin E. The high prevalence of using supplements, nutraceuticals, and vitamin supplements suggest that this same use is probably common in pets with cancer. From clinical experiences, the use of multiple supplements, herbal preparations and diet changes are commonplace for pets with cancers. Owners are highly motivated to be a part of the health care of their pet with cancer and they are often looking for supplements, herbs, and diets that will cure their pet of cancer. It is critical that the veterinarian and health care team addresses this at the time of diagnosis. These products are expensive and they may preclude a client s ability to afford conventional therapies or logical nutritional and/or supplements programs that may truly result in an integrative approach to their pet s cancer. This is an opportunity for a veterinarian to formalize the veterinarian and health care team-owner- patient bond. Regardless of final 1

2 outcome, owners are grateful and more satisfied when their pet with cancer is treated with a plan that integrates thoughtful nutrition, supplements with conventional therapies. PATIENT ASSESSMENT Four phases of metabolic and clinical alterations have been described in cancer patients. Phase 1 or the preclinical silent phase is where patients do not exhibit overt signs, but subtle behavior changes are noted. The owner may describe the patient as older, slowing down, less active, or not following normal routines. Phase 1 & 2 Phase 1 has metabolic changes including hyperlactatemia, hyperinsulinemia, and alterations in blood amino acid profiles. The next phase is the observation of clinical signs including lethargy, weight loss, and/or anorexia. When these patients are undergoing chemotherapy, radiation or other conventional treatment they may have side effects that may alter nutrient intake and use, and thus the nutrition support plan. Phase 3: Cancer Cachexia Marked debilitation, weakness and biochemical evidence of negative nitrogen balance such as hypoalbuminemia characterizes Phase 3 or cancer cachexia. The patients begin to lose protein and body stores while owners report chronic vomiting, diarrhea, weakness, and weight loss. It is known in the human literature that most cancer patients experience weight loss at some time as their disease progresses. Malnutrition increases risk of treatment complications and may lead to poor treatment response and/or tolerance, reduced quality of life, and poor outcomes. Differentiation between malnutrition and cachexia must be identified. Malnutrition (under nutrition) is defined as a state of nutrition in which a deficiency of energy, protein and other nutrients adversely affects body composition, function and clinical outcome. The most common cause of malnutrition is reduced food intake. Cancer patients may have a reduced food intake as a consequence of treatments causing nausea and vomiting, malabsorption, anorexia, fatigue, and pain. Strong evidence supports nutritional intervention to maintain the patients weigh with high energy, high protein diets or texture modification, supplements, and/or enteral feeding. However, a major hurdle in implementing an appropriate treatment for the weight-losing patient is differentiating between simple malnutrition and cancer cachexia. Progressive weight loss in cancer cachexia, as per definition, is in excess of that explained solely by reduced food intake; therefore it is unlikely to be effectively treated by satisfying any deficit in intake alone. Cancer cachexia requires a multi- modal approach. It is imperative to use clinical judgment when evaluating weight loss, as there are no precise biochemical cutoffs in cachexia versus malnutrition and the definitions vary. Irrespective of malnutrition or cancer cachexia, nutrition intervention should play a pivotal role in any multimodal management plan. Owners should be counseled to monitor patient intake and report any change in eating behavior and gastrointestinal dysfunction. 2

3 Phase 4: Recovery and/or remission is where the cancer is eliminated. It is known that metabolic alterations persist in some patients despite elimination or control of the cancer. Cancer patients can develop food aversions in this phase and at any time because of treatment-induced alterations in taste and smell. Warming foods, paper plates, feeding or flavoring with strong smelling foods may be useful to encourage normal intake. ASSESSING NUTRITIONAL STATUS Currently no single gold standard test exists for determining a cancer patient s nutritional status. Body condition scoring, muscle scoring, and body weight changes are the most practical tools for monitoring the overall nutritional effects of cancer and cancer treatment in dogs and cats. TUMOR STAGING Veterinarians can use tumor staging which may correlate with clinical behavior in certain types of cancer and help determine whether a tumor will respond to nutritional management. In known tumor types, grading the degree of malignancy histologically predicts biologic behavior. Although a direct relationship between tumor grade and nutritional status including cancer cachexia has not been established, it is logical to consider aggressive cancers to cause more pronounced systemic effects on body condition and weight. Aggressive nutritional therapies may be applied to higher grade tumors. It is important though to realize even a benign tumor can significantly affect the nutritional status of a dog or cat if it interferes with intake or assimilation. Oral tumors such as SSC in cats may inhibit food intake, and intestinal tumors such as lymphomas, can cause poor nutrient absorption, decreased appetite and diarrhea. CANCER METABOLISM The progress of cancer research has been increased with the metabolic concept that cancer cells use reprogramming of energy metabolism. Understanding cancer metabolism provides novel therapeutic targets for inhibiting tumor growth. Early studies in the 1920 s demonstrated the high rate of glucose uptake and lactate production by cancer cells compared to normal tissues even in the presence of oxygen called the Warburg effect. It has been demonstrated cancer cells use glycolytic pathways as it produces ATP more rapidly than oxidative phosphorylation. Although glycolysis is a less efficient pathway for energy production it is thought the faster rate of ATP production may provide for rapid cell proliferation. Glycolysis It is also know that the glycolytic pathway may provide for other molecules that are beneficial for cancer cell survival including lipids, nucleotides, NADPH, and amino acids. The glycolytic products lactate and H + provide a constant acidic extracellular environment which favors cancer proliferation and invasion. A high rate of aerobic glycolysis is now considered the hallmark of cancer cell metabolism. This dependence on aerobic glycolysis offers attractive potential therapeutic targets that can selectively kill cancer cells. 3

4 Metabolic targeting Unfortunately normal cells utilize this type of metabolism; therefore the challenge is to selectively target cancer cells without harming normal proliferating cell populations. Potential candidates for targeting include GLUT 1 receptors, Hexokinase II, pyruvate kinase, lactate dehydrogenase A, and glucose 6 - pyruvate dehydrogenase, which are all overexpressed in cancer cell metabolism. Increasing interest and research into cancer cell metabolism has already generated new potential therapies, but concern has been low selectivity and specificity along with toxic effects on normal cells. The question now is what is the best way to target the metabolism of cancer cells? Metabolic profiling Identifying the different metabolic profiles of different cancers may allow for effective targeting of the predominant energy pathway to produce effective metabolism- target agents. Finally the development of specific delivery systems to allow metabolic- target agents to be delivered to exact tumor sites may increase specificity. An example of this is the nanoparticle intervention which has been shown to be effective in mouse and human cancer cell lines. In conclusion, altered energy metabolism in cancer cells provides a unique opportunity to develop new and more effective anticancer therapies. KEY NUTRIENTS OF CONCERN Studies demonstrate that carbohydrate, lipid and protein metabolism is altered well before clinical disease and certainly in patients with cachexia. This altered metabolic state persists in patients in remission or those who have recovered from their disease. Human survivors report many changes in dietary preferences, food intake, digestive functions, skin, hair, and nail growth as well as other body systems after chemotherapy, surgery and/or radiation treatment protocols. We have yet to recognize, appreciate, and address these potential changes in veterinary oncology. Cancer cell metabolism Understanding cancer cell metabolism determines key nutritional factors in cancer patients. These would include soluble carbohydrates, fat, specific fatty acids, proteins, and specific amino acids, notably arginine. Nutritional factors identified in human cancer include polyphenols, flavonoids, fiber, and specific vitamin and minerals. More research is needed in veterinary medicine to identify other nutritional factors for cancer patients. Despite limited veterinary studies, critical evaluation of the data combined with known nutritional requirements of dogs and cats allows the use of translational research and extrapolation from human data to improve the nutritional status of our patients. NUTRIENT RECOMMENDATIONS Soluble Carbohydrates Nutrient composition of the diet should be altered to potentially minimize the physiological response of stress and slow tumor progression. Studies demonstrate poor utilization of soluble carbohydrates due to peripheral insulin resistance and feeding high levels can cause hyperglycemia, hepatic dysfunction, hyperlactatemia, glucosuria, and hyperosmolarity. Utilization of glucose- and lactate-containing fluids should generally be avoided in the critically 4

5 ill cancer patient. And the recommended soluble carbohydrate level in the diet for canine and feline cancer patients should contain no more than 25% DM. Protein The data and focus on protein metabolism is less compared to research in fat and fatty acids in cancer patients. Most studies are in dogs with cancer despite the unique protein requirements of cats. From limited veterinary research and extrapolation from non -veterinary species published recommendations are dietary protein levels in foods for cancer patients should exceed levels normally used for maintenance of adult animals. This assumes normal renal and/or liver function from diagnostic testing. The protein levels in foods for dogs with cancer are 30 to 45% DM suggested protein levels in foods for cats with cancer are 40 to 50% DM. Fats and Fatty Acids More studies are needed to determine specific to match fat levels, amounts of N-6 and N-3, N-6 to N-3 ratios to different tumor types and tumor staging in dogs and cats. Current published recommendations continue to be focused on foods with increased fat calories (25 to 40% DM fat); increased levels of dietary omega-3 fatty acids (>5.0% DM) and an N-6: N-3 fatty acid ratio approximating 1:1. These recommendations should be critically evaluated in cancer patients with gastrointestinal disease either primary or secondary as high fat diets can be problematic. FEEDING PLAN Conventional treatments in dogs and cats result in a range of metabolic/nutritional abnormalities and known metabolic derangements are common to most types of cancer. Understanding these principles provide the basis for development of a feeding plan for cancer patients. To identify the key nutritional factors veterinarians should combine patient assessment including history, physical examination and diagnostics with known etiopathogenesis of the cancer. This summation will provide nutritional support of cancer patients that is individualized. The veterinarians should outline nutritional therapy with the overall prognosis of the patient clearly in mind so that the aggressiveness of dietary intervention (e.g., supportive, adjunctive, definitive) can be adjusted as needed. Owner education about the integral role nutrition plays in the total management of their pet s disease is required. Expectations and limitations of dietary management should be discussed as an integral part of the overall treatment plan. KEYPOINTS FOR CANCER DIETS Strong evidence that nutrition counseling increases dietary intake, maintains bodyweight, nutritional status and quality of life in cancer patients We recommend dietary counseling for owners with pets with cancer to improve nutrition, impact symptoms, improve treatment response, quality of life, and possibly increase survival times There continues to be a paucity of nutrition intervention studies in patients with cancer cachexia in both the human and veterinary literature Regardless of whether patients are experiencing reduced dietary intake resulting in malnutrition or due to cachexia, nutrition is the cornerstone of multimodal treatment The use of N-3 fatty acids may have some positive effects in patients (Diets should contain >5.0% DM and a 1:1 N-6 to N-3 ratio) 5

6 Cancer diets nutrient content recommendation: Carbohydrate 25% or less; Protein 30 to 45% DM for the dog and 40 to 50% DM for the cat; Fat 25 to 40% DM SPECIFIC NUTRIENT THERAPY IN VETERINARY CANCER PATIENTS A discussion of specific nutrients in cancer therapy will be discussed and include as follow: Iron, B12, B complex Calcitriol (1,25-dihydroxycholecalcifero; 1α25-dihydroxycholecalciferol) Retinoids Antioxidants 6

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