Nutrition and Cancer: Frontiers for Cure!

This article from and reprinted from Gregory K. Ogilvie, DVM Diplomate ACVIM (Specialties of Internal Medicine and Oncology), Professor of Oncology and Internal Medicine, Animal Cancer Center, Medical Oncology Research Laboratory, College of Veterinary Medicine and Biomedical Sciences, Colorado State University

See your veterinarian for specific recommendations about the nutritional care of your pet with cancer or any other disease. If you have any questions about this material, contact your veterinarian.

Cancer is one of the most common diseases in dogs and cats in the United States, Western Europe and Japan.

Cancer cachexia is the most common paraneoplastic syndrome in veterinary medicine. This paraneoplastic syndrome of dogs and cats with a wide variety of malignancies results in profound alterations in carbohydrate, protein and lipid metabolism that subsequently results in anorexia, fatigue, impaired immune function, poor performance and weight loss in the face of adequate nutritional intake. These profound alterations in carbohydrate, protein and lipid metabolism have been documented in dogs and probably in cats with cancer, even before evidence of cancer cachexia was clinically apparent. The importance of cancer cachexia is underscored by the knowledge that animals and people with cancer cachexia have a decreased quality of life, poor response to treatment, and a shortened survival time when compared to those with neoplastic diseases but do not exhibit clinical or biochemical signs associated with this condition. Therefore, it is obvious that cancer and cancer cachexia are of tremendous importance to the practicing veterinarian.

Nutritional therapy is a key component for the treatment of cancer cachexia and for actually helping control malignant disease in some situations. Specific nutrients can be used as powerful tools to reduce toxicity associated with chemotherapy, radiation therapy, and is important to enhance healing subsequent to surgery. There is little question that nutritional intervention must begin early and must be followed through aggressively to gain maximum benefit....long before the patient exhibits evidence of weight loss, debilitation, or anorexia begin which can in turn enhance response to therapy and improve quality of life.

The purpose of this article is to answer the following questions:

1. What clinically significant alterations in metabolism occur in animals with cancer cachexia?
2. How can knowledge about the metabolic alterations in metabolism change the way you use nutrition to treat your cancer. In other words: what nutrients should you feed your cancer patient?
3. Does surgery, chemotherapy or cancer increase or decrease the energy needs and the amount you should feed your patient?
4. Are there any data on the efficacy of the nutrients my clients constantly ask me about: vitamins, minerals, proteases, garlic, tea and shark cartilage?
5. What are the indications for intervening aggressively with appetite stimulants, tube feeding or total parenteral feeding for your cancer patients?
6. When and how do I place these feeding tubes in my practice?

Metabolic Changes Associated with Cancer Cachexia

Clinically, in many patients there are three phases associated with cancer cachexia. The first phase is the preclinical "silent" phase is where the patient is not exhibiting any clinical signs of disease, yet there is evidence of biochemical changes such as hyperlactatemia, hyperinsulinemia and alterations in amino acid and lipid profiles. All of these alterations are of impending clinical importance, but the alterations in carbohydrate metabolism appear to be quite profound resulting in the production of tremendous amounts of lactate through energy inefficient anaerobic metabolism.

The second phase is the clinical phase where the patient begins to exhibit weight loss, anorexia, lethargy and early evidence of weight loss. These patients are more likely to exhibit side effects associated with chemotherapy, radiation therapy, immune modulation, and surgery.

The third and final phase of cancer cachexia is an accentuated form of the second phase; it is associated with marked debilitation, weakness and biochemical evidence of negative

nitrogen balance that is also associated with clinical pathologic changes such as hypoalbuminemia. Cancer patients begin to loose carbohydrate and protein stores within the body. Loss of fat depots is noted in this third and final stage of the disease. These patients literally waste away due to the physical effects of the malignancy and the resulting cancer-induced alterations in metabolism.

Carbohydrates, Proteins and Fats and Feeding the Cancer Patient

Carbohydrate Metabolism

Perhaps the most dramatic alterations in metabolism of animals with a wide variety of cancers occur in carbohydrate metabolism. For example, when dogs with a wide variety of malignancies without clinical evidence of cachexia were evaluated with an intravenous glucose tolerance test, lactate and insulin concentrations were significantly higher when compared to controls. The hyperlactatemia and hyperinsulinemia did not improve when these dogs were rendered free of all clinical evidence of cancer with either chemotherapy or surgery. Metabolic alterations result in part because tumors preferentially metabolize glucose for energy by anaerobic glycolysis forming lactate as an end product. The animal must then expend necessary energy via "futile cycling" to convert lactate to glucose by the Cori cycle resulting in a net energy gain by the tumor and a net energy loss by the host.

The inability of some tumor bearing animals to tolerate glucose parenterally may have some bearing on the dietary management of the cancer patient. Logically, it can be concluded that diets high in simple carbohydrates may increase the total amount of lactate produced and the need for the host to utilize energy unwisely for conversion of lactate.

This may have long-term detrimental effects on animals with cancer.

To test this hypothesis in the dog, a group of dogs with lymphoma were evaluated to determine if a diet high in simple carbohydrates is detrimental compared to a diet low in simple carbohydrates. In this study, dogs were randomized and fed isocaloric amounts of either a high fat diet, or a high carbohydrate diet before and after remission was attained with up to 5 dosages of doxorubicin chemotherapy. As hypothesized, the mean lactate and insulin levels from the dogs fed the high carbohydrate diet was significantly higher than the level from the dogs fed the fat diet after the dogs were fed the diets and put into remission with chemotherapy. Interestingly, dogs fed the high fat diet were more likely to go into remission. This study showed, therefore, that diet was effective for influencing response to therapy and select aspects of carbohydrate metabolism.

The bottom line is that simple carbohydrates may not be ideal for the cancer patient. Therefore, when considering a diet for a pet with cancer, a diet that has minimal amounts of simple carbohydrates may be ideal.

Protein Metabolism

Cancer has been shown to result in decreased body muscle mass, skeletal protein synthesis, and alter nitrogen balance while concurrently increasing skeletal protein breakdown, liver protein synthesis, and whole body protein synthesis. Tumors preferentially use protein for energy at the expense of the host. Tumors preferentially utilize certain amino acids for gluconeogenesis, which results in abnormal amino acid profiles. These abnormal profiles have been documented in pet animals with a wide variety of cancers. The use of amino acids by the tumor for energy becomes clinically significant for the host when protein degradation and loss exceed synthesis. This can result in alterations in many important bodily functions such as immune response, gastrointestinal function and surgical healing.

Knowledge that cancer preferentially utilizes amino acids and that some amino acids may be therapeutic may be of value when designing a diet for the cancer patient. Providing high quality amino acids or protein in the diet may be of critical importance for the veterinary cancer patient. A quality protein diet that is highly bioavailable may be ideal.

Arginine, glycine, cystine and glutamine may be of specific value for therapeutic purposes. Arginine may stimulate lymphocyte blastogenesis. The addition of arginine to total parenteral nutrition solutions has been shown to decrease tumor growth and metastatic rate in some rodent systems. Some amino acids my decrease toxicity associated with chemotherapy. For example, glycine has been shown to reduce cisplatin-induced nephrotoxicity.

Cystine has been shown to be effective for reducing Heinz body anemia in cats. Glutamine has been shown to be effective for reducing histologic and clinical evidence of methotrexate-induced gastrointestinal toxicity in cats.

The bottom line is that a diet that has moderate amounts of highly bioavailable protein may be of value to the cancer patient. Certain amino acids such as glutamine, cystine, and arginine may also be beneficial for some cancer patients.

Lipid Metabolism

Fat loss accounts for the majority of weight loss occurring in cancer cachexia. Therefore, it is not surprising that human beings and animals with cancer have dramatic abnormalities in lipid metabolism. The decreased lipogenesis and increased lipolysis observed in humans and rodents with cancer cachexia result in increased levels of free fatty acids, very low density lipoproteins, triglycerides, plasma lipoproteins, and hormone dependent lipoprotein lipase activity, while levels of endothelial derived lipoprotein lipase decrease. Recently lipid profiles in dogs with a lymphoma were studied. It was determined that many of the alterations seen in other species with cancer were also present in dogs. These abnormalities did not normalize when clinical remission is obtained. The clinical significance of these abnormal lipid profiles in dogs with lymphoma is not known, however, abnormalities in lipid metabolism have been linked to a number of clinical problems including immunosuppression which correlates with decreased survival in affected humans.

The clinical impact of the abnormalities in lipid metabolism may be lessened with dietary therapy. In contrast to carbohydrates and proteins, some tumor cells have difficulty utilizing lipid as a fuel source while host tissues continue to oxidize lipids for energy. This has led to the hypothesis that diets relatively high in fat may be of benefit to the animal with cancer when compared to a diet high in simple carbohydrates.

Further research may reveal that the type of fat, rather than the amount, may be of greater importance. In one study, mean nitrogen intake, nitrogen balance, in vitro lymphocyte mitogenesis, time for wound healing, the prevalence of wound complications, and the duration of hospitalization was significantly better in 85 surgical patients fed an omega-3 fatty acid supplement when compared to controls. Studies of polyunsaturated fatty acids (PUFA's) of the n-3 series, especially eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), indicate that these fatty acids may prevent the development of carcinogen-induced tumors, the growth of solid tumors, as well as the occurrence of cachexia and metastatic disease in experimental tumor models. Fatty acids of the n-3 series have been shown to normalize elevated blood lactic acid and insulin levels in non-malignant conditions . In contrast, PUFA's of the n-6 series appear to enhance tumor development and metastases. These data, along with the epidemiological findings of an inverse relationship between dietary n-3 fatty acid intake and incidence of some cancer, is the basis of research to evaluate the potential benefit of n-3 fatty acids in the prevention of cancer cachexia and therapy of malignancy in cancer patients.

One such study was recently completed in dogs with lymphoma. A double blind, randomized study was recently reported to evaluate the hypothesis that polyunsaturated n-3 fatty acids and arginine can improve metabolic parameters, decrease chemical indices of inflammation, enhance quality of life, and extend disease-free interval and survival time in dogs treated for lymphoma. In that study, dogs fed the experimental diet had significantly higher serum levels of polyunsaturated n-3 fatty acids docosahexaenoic acid (C22:6) and eicosapentaenoic acid (C20:5) as well as arginine when compared to controls. Both diets were formulated to be relatively low in simple carbohydrates, with moderate amounts of highly bioavailable proteins. This formulation is designed to enhance the effect of n-3 fatty acids. Higher serum levels of these n-3 fatty acids were associated with lesser plasma lactic acid responses to intravenous glucose and diet tolerance testing. Increasing C22:6 levels was significantly associated with longer disease free interval and survival time for dogs with stage III lymphoma fed the experimental diet.

Another study was recently completed that was designed to determine the effect of a diet supplemented with n-3 fatty acids and arginine on irradiated skin and oral mucosa, carbohydrate metabolism and quality of life in a group of dogs with nasal tumors. This study showed that fatty acids of the n-3 series normalize elevated blood lactic acid. In a dose dependent manner, n-3 fatty acids result in decreased histologic evidence of radiation damage to skin and mucosa and improve performance scores in dogs with malignant nasal tumors. This would obviously be of great benefit to the cancer patient receiving radiation therapy. These two studies confirm that diets supplemented with polyunsaturated n-3 fatty acids are of benefit for the cancer patient.

The bottom line is that n-3 fatty acids in moderate amounts appear to benefit the cancer patient. More specifically, a diet relatively high in n-3 fatty acids and relatively now in simple carbohydrates has been shown not only to improve alterations in metabolism associated with cancer, but also improve response to chemotherapy and decrease the adverse effects associated with radiation therapy.

Fiber

Soluble and insoluble fiber are both important to prevent cancer and to enhance bowel function. This can be especially important for the cancer patient that may undergo chemotherapy, radiation therapy and surgery. Fiber is important not only to treat disorders of the gastrointestinal tract, but also to prevent concurrent diseases such as clostridial colitis. Therefore, a diet with adequate amounts of soluble and insoluble fiber may be indicated for many dogs and cats with cancer.

Carbohydrate, Protein, Fat and Fiber, What Do I Feed My Dog with Cancer?

The data noted above suggest that a diet relatively low in simple carbohydrates, with moderate amounts of highly bioavailable proteins as well as soluble and insoluble fiber, and moderate amounts of polyunsaturated fatty acids of the n-3 series may be of value to the cancer patient. Research is needed to address the issue of optimum quantities of carbohydrates, proteins and fats, especially n-3 fatty acids. In addition, the ideal ratio of n-3 fatty acids to n-6 fatty acids also remains an unknown. The ideal diet is made of much more than carbohydrates, proteins and fats. A brief discussion about some of what is known about vitamins, minerals and other ingredients is listed below.

Vitamins, Minerals, Garlic, Tea, Shark Cartilage and the Cancer Patient

Nutrients such as vitamins, minerals, garlic, diet-generated protease inhibitors, tea and shark cartilage have been suspected as being important for the prevention, control and treatment of malignancies for decades, and in some cases, generations. This field of study is poorly documented with controlled studies, but is rapidly evolving into mature science that may improve the quality and quantity of life for human and animal patients with cancer. The news media and lay publications often distort or misinterpret the efficacy of vitamin therapy. While it is naive to believe that a single nutrient or set of nutrients will be effective for the treatment of cancer there is optimism to believe that one or more nutrients can be effective for preventing certain types of malignancies in people and in animals. Most veterinarians are asked by their clients if vitamins, minerals, garlic and other nutrients can be beneficial for their pet with cancer. Because there are very few studies in veterinary medicine, studies involving rodents or human cancer patients will be used as models for veterinary disease. While it is not possible to make solid recommendations from these data, it may be adequate to allow the veterinarian to provide some guidance to their clients about these nutrients.

Vitamins

Retinoids, beta carotene and vitamins C, D and E may influence the growth and metastasis of cancer cells via a variety of mechanisms. These vitamins fall into and out of popularity based on the results of select studies and the lay press. The weight of the literature would suggest, however, that many of these vitamins may be of value for some cancer patients. A few of many select examples of the impact of a few vitamins is included below for the interested reader.

Retinoids

Retinoids are not used as a mainstay of cancer therapy, however there is a growing body of knowledge about the anticancer effect of this vitamin in man and animals. In people, 13-cis retinoic acid prevents secondary tumors in patients treated for squamous cell carcinoma of the head and neck and can reverse the effects of cervical human papillomavirus infection. Retinoic acid when used in the adjuvant treatment of retinoblastoma (a childhood cancer), resulted in translocation of bound receptor vitamin complexes to the nucleus, which results in the regulation of the neuroblastoma gene. Melanoma in mice has been successfully treated with retinoids. The efficacy of retinoids is not confined to rodents and people. A study was recently completed to evaluate the synthetic retinoid isotretinoin and etretinate to treat dogs with intracutaneous cornifying epithelioma (ICE), other benign skin neoplasia, and cutaneous lymphoma. All tumors were diagnosed by histologic examination. Successful treatment with isotretinoin was achieved in dogs with ICE, inverted papillomas, and with epidermal cysts. Successful treatment was achieved with etretinate in dogs with ICE. In addition, remission was achieved in 6 of 14 dogs with cutaneous lymphoma. Adverse effects developed in about 25% of the dogs.

Vitamin C

Vitamin C has been studied continuously over the last several decades as an antioxidant and an agent that can effectively treat conditions such as colds, cardiovascular disease and cancer. There have been some data that vitamin C may be of value for the prevention and treatment of certain types of cancers. Water-soluble vitamin C has been widely reported to inhibit nitrosation reactions and prevent chemical induction of cancers of the esophagus and stomach. Processed foods high in nitrates and nitrites, such as bacon and sausage, are often supplemented with vitamin C to reduce the carcinogenic capability of the resultant nitrosamines.

A human tissue culture subline resistant to vincristine that was established from a small cell lung cancer cell line was pretreated with ascorbic acid, resulted in potentiation of the vincristine effects on resistant but not the sensitive cell lines. Therefore, ascorbic acid may be one therapeutic alternative for overcoming a drug resistance in some cancer cells.

Vitamin E

Lipid-soluble vitamin E, or alpha tocopherol, can also inhibit nitrosation reactions, but in addition, vitamin E has a broad capacity to inhibit mammary tumor carcinogenesis and colon carcinogenesis in rodents. In addition to its chemopreventative properties, vitamin E may convey potential therapeutic efficacy against certain malignancies.

This vitamin does so due to its antiproliferative activity. In the study conducted in cooperation between the Comparative Oncology Unit at Colorado State University and the Harvard School of Public Health, Department of Dental Medicine, was done to evaluate the effect of injecting d,l-alpha tocopherol and beta carotene directly into dogs with a variety of oral malignancies. A total of 12 dogs were entered into the study where they received weekly injections of this combination to result in mediation of tumor cell growth. This study resulted in two dogs achieving a complete remission (50% reduction in the original size of the tumor- both soft tissue sarcomas) and minor reduction in tumor size in two other cases. There was no direct evidence of tumor cytolysis in this study. Additional studies have been initiated in humans at Harvard School of Public Health.

Minerals

Minerals that have been suggested as having chemopreventative or anti-cancer effects and that are of value as nutrients include selenium, copper, zinc, magnesium, calcium, lead, iron, potassium, sodium, arsenic, iodine and germanium. Selenium has been one of the most heavily studied minerals associated with the development of cancer. Low serum selenium levels have been seen in human patients with prostate and gastrointestinal cancer. In rodents, dietary supplementation of selenium has been shown to inhibit colon, mammary gland and stomach carcinogenesis. An additional study is essential to determine whether alteration of selenium levels would be of value for the treatment of veterinary or human cancer patients.

Iron transferrin and ferritin have been linked to cancer risk and cancer cell growth. Lung cancer, colon, bladder and esophageal cancer in people has been highly correlated with increased serum iron and increased transferrin saturation. This may be because many tumor cells require iron for growth.

Therapeutic enzymes

Enzymes have therapeutic potential although limited approval in the United States. L-asparaginase is probably the most valuable therapeutic modality for the treatment of lymphoma and leukemia in animals and people. Oral enzyme preparations are used for the treatment of chronic pancreatic insufficiency and disaccharidase deficiency.

Several enzyme preparations are available in Europe for oral adjuvant treatment of cancer and other diseases. Of those, Wobenzyme and Musal, contain a similar mixture of enzymes. Recent studies report efficacy for the treatment of cancer patients, the mechanism of which is not precisely known. One hypothesis is that these enzymes eliminate pathogenic immune complexes. Therefore, enzymes may indeed be of value for the adjuvant treatment of cancer.

Protease Inhibitors

Garlic in Cancer Prevention and Treatment

There is a great deal of information that suggests that soybean-derived Bowman-Birk inhibitor (BBI) can inhibit or suppress carcinogenesis both in vivo and in vitro. Extracts of the Bowman-Birk inhibitor have been shown to inhibit carcinogenesis in several animal model systems, including colon- and liver-induced carcinogenesis in mice, anthracene-induced cheek pouch carcinogenesis in hamsters, and lung tumorigenesis in mice and esophageal carcinogenesis in rats. Bowman-Birk inhibitor concentration has been shown to inhibit metastasis and weight loss associated with radiation-induce thymic lymphoma in mice. Irradiated rodents treated with dietary Bowman- Birk inhibitor concentration have fewer deaths, lower average grade of lymphoma, and larger fat stores than controls.

Therefore, this protease inhibitor from soybeans may be an important adjunct to cancer chemotherapy protocols and to prevent secondary cancers.

Epidemiological studies have suggested a correlation between high garlic consumption and reduced risk of cancer development. Each garlic extract and several garlics and thioalkyl compounds have been shown to inhibit the activation of carcinogens and the bonding of polyarene thiol epoxide to a DNA bases, which caused DNA lesions and initiates chemically-induced carcinogenic process. Garlic and the thioalkyl compounds inhibit carcinogen-induced aberrations in the cell nucleus. In addition, garlic extracts have an anti-promotion effect in animals exposed to carcinogens. Also, garlic exerts direct cytolytic effects against cancer cultured human breast cancer cells and human melanoma cells. Concentrations of garlic used in these studies to arrest cancer cell growth, there is no effect on normal cells. Pretreatment of animals with garlic protects rodents against subsequent induction of tumors by a variety of carcinogens. There are no studies demonstrating the safety and efficacy of garlic for the prevention or treatment of cancer in people or in veterinary medicine.

Tea

While it may be awhile before dogs and cats acquire the taste for tea, there is compelling data that suggests that green and black teas may have anti-cancer properties. Many clients ask about the potential efficacy of teas or tea extracts for their pet. Green tea extracts contain catechin, and black tea contains fermentation products, thioflavine and theorubigins. These active agents inhibit cancer-promoting agents, protect against oxidative damage, and enhance antioxidant enzymes. Black tea seems to have soothing properties to reduce the discomfort associated with radiationinduced oral mucositis. The tannic acid and other ingredients act as an astringent and a local anesthetic agent when the oral cavity of affected dogs is lavaged 2 to 3 times a day.

Shark Cartilage

Cartilage has been shown to be antiangiogenic which may be of value for the cancer patient. Some time ago, two studies that were never published in a refereed journal were expounded upon by the lay press. The two studies conducted in Mexico and Cuba were soundly criticized by the medical establishment for lack of histologic confirmation of malignancies and poor quality control. Regardless, at least one well designed study was initiated in the United States to evaluate the efficacy of shark cartilage for the treatment of human malignancies. This study was recently suspended due to the lack of efficacy. This author is not aware of any data published in reviewed or refereed medical literature showing that shark cartilage is effective for treating spontanously occuring malignancies in an outbred species. Despite this fact, shark cartilage manufacturers have created a multi-million dollar industry and have placed shark numbers at a dangerously low level due to over fishing.

Energy Needs of the Cancer Patient

The standard dogma in most human and veterinary texts is that cancer, trauma, and the process of recovering from surgery induces an increase in the amount of energy substrates burned by the animal. While this is definitely true in some patients, recent research using indirect calorimetry to document the rate fuel is burned in the body has placed these statements in doubt.

In the studies below, data was acquired by indirect calorimetry, a non-invasive method of estimating the amount of food required by the cancer patient. Indirect calorimetry determines the energy expenditure (EE), or the amount of fuel consumed by the cancer patient. This equates to the amount of nutrients needed by that animal.

Does Surgery Increase Energy Expenditure?

Energy expenditure and caloric requirements have been reported to increase in animals with and without cancer that are recovering from surgery. A study was performed to determine if this occurs in dogs. Energy expenditure was in a group of apparently resting, client-owned dogs that had been given general anesthesia for the following surgical procedures: ovariohysterectomy, orchiectomy, localized malignant tumor resection, and repair of a major orthopedic problem. Each dog was evaluated before and after surgery and compared to apparently resting normal, client-owned dogs. These data in this study suggest that unlike what has been reported elsewhere, the energy expenditure of dogs that undergo anesthesia and surgery for malignant and non-malignant conditions does not increase from baseline values or when compared to normal client-owned pet dogs. These data may be of value when planning nutritional therapy for dogs recovering from anesthesia and surgery.

Do Dogs with Cancer have Increased Energy Expenditure?

Studies were initiated to determine if animals with cancer have altered energy expenditure and to determine if elimination of cancer with chemotherapy or surgery alters energy expenditure. In the first study, indirect calorimetry was performed on dogs with lymphoma that were randomized into a blind study and fed isocaloric amounts of either a high fat diet, or a high carbohydrate diet before and after chemotherapy. Surprisingly, during the initial evaluation period, resting energy expenditure was significantly lower than tumor-free controls. Six weeks after the start of the study, EE was significantly lower in both groups of dogs with lymphoma when compared to the controls and the pretreatment values from the dogs with lymphoma. Dogs fed the diet that is relatively high in fat maintained a more normal energy expenditure than dogs fed a diet relatively high in carbohydrates.

Another study was undertaken to determine energy expenditure of client-owned dogs with nonhematopoietic malignancies in an apparently resting state before and after each tumor was surgically excised.81 Surgical removal of the tumor did not significantly alter any parameter when all dogs were assessed as a single group, or when these animals were subdivided into the following groups: carcinomas and sarcomas, osteosarcomas and mammary. The values obtained prior to any treatment from the dogs in any group were not significantly different from controls.

These data suggest that energy expenditure, and presumably caloric requirements of dogs with non-hematopoietic malignancies, are not different from those obtained from healthy client-owned dogs. Furthermore, these parameters do not change significantly when the tumor is removed surgically and the patient is re-assessed after 4-6 weeks.

Do Critically Ill Dogs have Increased Energy Expenditure?

Determination of energy expenditure of critically ill human patients by indirect calorimetry has become a standard procedure in many hospitals. The energy expenditure of apparently resting dogs critically ill dogs were determined in one hundred and four postoperatative and severely traumatized dogs and compared to a group of 20 clinically normal, apparently resting client owned dogs (controls) and to published normals for normal dogs. The EE of critically ill dogs was not different from the measured values for the controls. The measured EE of the critically ill dogs was significantly lower than the calculated value using the illness/injury/infection energy requirement.

References

1. Ogilvie GK, Vail DM. Metabolic alterations and nutritional therapy for the veterinary cancer patient. In Withrow SJ, MacEwen EG, Clinical Veterinary Oncology, Philadelphia, WB Saunders, 1996.
2. Ogilvie GK, Vail DM. Unique metabolic alterations associated with cancer cachexia in the dog. In: Current Veterinary Therapy XI, Kirk RW (ed), WB Saunders, Philadelphia, 433-438, 1992.
3. Ogilvie GK, Moore AS. Nutritional Support, In: Managing the Veterinary Cancer Patient: A Practice Manual. Veterinary Learning Systems, 124-127, 1995.
4. Shein PS, Kisner D, Haller D, et al. Cachexia of malignancy. Cancer 43:2070-2076, 1976.
5. Ogilvie GK. Paraneoplastic sundromes. In Ettinger S, Feldman E (eds). Textbook of Veterinary Internal Medicine (fourth edition). WB Saunders, Philadelphia, In Press 1998.
6. Theologides A. Cancer cachexia. Cancer 43:2004-2012, 1979.
7. Buzby GP, Steinberg JJ. Nutrition in cancer patients. Symposium of Surgical Nutrition 61:691-699, 1981.
8. Landel AM, Hammond WG, Mequid MM. Aspects of amino acid and protein metabolism in cancer-bearing states. Cancer 55:230-237, 1985.
9. Bray GA, Campfield LA. Metabolic factors in the control of energy stores. Metabolism 24:99-117, 1975.
10. Vail DM, Ogilvie GK, Wheeler SL: Metabolic alterations in patients with cancer cachexia. Compendium of Continuing Education for the Practicing Veterinarian 12:381-387, 1990.
11. Ogilvie GK, Vail DM: Advances in nutritional therapy for the cancer patient. Veterinary Clinics of North America [Small Animal], Couto G (ed), Philadelphia, WB Saunders Co, 20:4, 1990.
12. Ogilvie GK, Vail DM: Advances in nutritional therapy for the cancer patient. Veterinary Clinics of North America, Couto G (ed), Philadelphia, WB Saunders Co, 20:4, 1990.
13. Vail DM, Ogilvie GK, Wheeler SL, Fettman MJ t al: Alterations in carbohydrate metabolism in canine lymphoma. J of Vet Intern Med 4:8-11, 1990.
14. Vail DM, Ogilvie GK, Fettman MJ, Wheeler SL: Exacerbation of hyperlactatemia by infusion of lactated Ringer's solution in dogs with lymphoma. J Vet Intern Med 4:228-232, 1990.
15. Ogilvie GK, Vail DM, Wheeler SJ. Effect of chemotherapy and remission on carbohydrate metabolism in dogs with lymphoma. Cancer 69:233-238, 1992.
16. Heber D, Byerley LO, Chi J, et al. Pathophysiology of malnutrition in the adult cancer patient. Cancer 58:1867- 1873, 1986.
17. Bozzetti F, Pagnoni AM, Del Vecchio M. Excessive caloric expenditure as a cause of malnutrition in patients with cancer. Surg Gynocol and Obstetrics 150:229-234, 1980.
18. Dempsey DT, Mullen JL. Macronutrient requirements in the malnourished cancer patients. Cancer 55:290-294, 1985.
19. Ogilvie GK, Walters LM, Salman MD, et al. Alterations in select aspects of carbohydrate, lipid and amino acid metabolism in dogs with non-hematopoietic malignancies, Am J Vet Res, 8:62-66, 1994.
20. Ogilvie GK, Walters LM, Salman MD, et al. Treatment of dogs with lymphoma with adriamycin and a diet high in carbohydrate or high in fat. Am J Vet Res, In Press.
21. Chory ET, Mullen JL. Nutritional support of the cancer patient: delivery systems and formulations. Surgical Clinics of North America 66:1105-1120, 1986.
22. Langstein HN, Norton JA. Mechanisms of cancer cachexia. Hematol/Oncol Clin N Amer 5:103-123, 1991.
23. Kurzer M, Meguid MM. Cancer and protein metabolism. Surg Clin N Amer 66:969-1001, 1986.
24. Teyek JA, Bistrian BR, HehirDJ, et al. Improved protein kinetics and albumin synthesis by branched chain amino acid-enriched total parenteral nutrition in cancer cachexia. Cancer 58:147-157, 1986.
25. Oram-Smith JC, Stein TP. Intravenous nutrition and tumor host protein metabolism. J Surg Res 22:499-503, 1977.
26. Barbul A, Sisto DA, Wasserkrug HL et al. Arginine stimulates lymphocyte immune response in healthy human beings. Surgery 90:244-251, 1981.
27. Tachibana K, Mukai K, Hirauka I, et al. Evaluation of the effect of arginine enriched amino acid solution on tumor growth. J Parenter Enteral Nutr 9:428-434, 1985.
28. Heyman SN, Rosen S, Silva P, et al. Protective action of glycine in cisplatin nephrotoxicity. Kidney International 1991;40(2):273-179.
29. Brennan NF. Uncomplicated starvation versus cancer cachexia. Cancer Res 37:2359-2364, 1977.
30. Marks SL, Cook AK, Griffey S, Kass PH, and Rogers QR: Dietary modulation of methotrexate-induced enteritis in cats. Am J Vet Res 58(9):989-996, 1997.
31. Yoshida S, Kaibara A, Yamasaki K, Ishibashi N, Noake T, Kakegawa T. Effect of glutamine supplementation on protein metabolism and glutathione in tumor-bearing rats. J Parenter Enteral Nutr 19(6):492-497, 1995.
32. Chlebowski RT, Heber D. Metabolic abnormalities in cancer patients: carbohydrate metabolism. Surg Clin N Amer 66:957-968, 1986.
33. Dewys WD. Pathophysiology of cancer cachexia: Current understanding and areas of future research. Cancer Res 42:722-726, 1982.
34. McAndrew PF. Fat metabolism and cancer. Surg Clin N Amer 66:1003-1012, 1986.
35. Ogilvie GK, Ford RD, Vail DM et al: Alterations in lipoprotein profiles in dogs with lymphoma. J Vet Intern Med. 1994;8:62-66.
36. Shein PS, Kisner D, Haller D, et al. the oxidation of body fuel stores in cancer patients. Annals of Surgery 204:637-642, 1986.
37. Tisdale MJ, Brennan RA, Fearon KC: Reduction of weight loss and tumour size in a cachexia model by a high fat diet. Br J of Cancer 56:39-43, 1987.
38. Daly JM, Lieberman M, Goldfine J, et al. Enteral nutrition with supplemental arginine, RNA and omega-3 fatty acids: A prospective clinical trial. Abstract, 15th Clinical Congress, American Society for Parenteral and Enteral Nutrition, J Enter Parenteral Nutr 15:19S, 1991.
39. OgilvieGK, Fettman MJ, Mallinckrodt CH, Walton JA, Hansen RA, Davenport DJ, Gross KL, Richardson KL, Rogers Q, Hand MS. Effect of fish oil and arginine on remission and survival time in dogs with lymphoma. Cancer, Submitted 1998.
40. Anderson CR, Ogilvie GK, LaRue SM, Powers BE, et al: Effect of fish oil and arginine on acute effects of radiation injury in dgos with neoplasia: A double blind study. Proceedings, Veterinary Cancer Society, 1997, pp33-34.
41. Weisburg JH. Interactions of nutrients in oncogenesis. Am J Clin Nutr 53:2265:1991.
42. Quillin P. An overview of the link between nutrition and cancer. In Quillin P, Williams RM. Adjuvant Nutrition Cancer Treatment. Arlington Heights, IL, Cancer Treatment Foundation, 1993:1-17.
43. National Academy of Sciences. Diet, Nutrition and Cancer, National Academy Press, Washington, DC, 1982.
44. National Academy of Sciences, Diet and Health: Implications for Reducing Chronic Disease Risk, National Academy Press, Washington, DC, 1989.
45. Diet, Nutrition, and Cancer: A Critical Evaluation, vol II. Micronutrients, Nonnutritive Dietary Factors and Cancer, Reddy, BS and LA Cohen (eds), CRC Press, New York, New York, 1986.
46. Boutwell RK. An overview of the role of diet and nutrition in carcinogenesis. in, Nutrition, Growth and Cancer. Alan R. Liss, Inc, New York, New York, 1988.
47. Bertram JS, Kolonel LN, Meyskens FL. Rationale and strategies for chemoprevention of cancer in humans. Cancer Res 47:3012-3018, 1987.
48. Chance WT, Balasubramainiam A, Sheriff S, Fischer JE. Possible role of neuropeptide Y in experimental cancer anorexia. In, Diet and Cancer: Markers, Prevention and Treatment, MM Jacobs (ed), Plenum Press, New York, New York, 1993 pp109-134.
49. Hong WK, Lipman SM, Itri LM, Karp DD, Lee JS, Byers RM, Schantz SP, Kramer AM, Lotan R, Peters LJ, Dimery IW, Brown BW and Goepfer H: Prevention of secondary primary tumors with isotretinoin in squamous cell carcinoma of the head and neck. N Eng J Med323:796-805, 1990.
50. Vitamins and Mineral in the Prevention and Treatment of Cancer. Jacobs MM (ed), CRC Press, Boca Raton, FL, 1991, pp 127-141.
51. Mirvish SS. Effects of vitamins C and E on N-nitroso compound formation, carcinogenesis, and cancer. Cancer 58:1842-1855, 1986.
52. Lamm DL, Riggs DR, Shriver JS, et al. Megadose vitamins in bladder cancer: A double blind clinical trial. Journal of Urolology 151:21-26, 1994.
53. Li J, Sartorelli CA. Synergistic induction of the differentiation of WEH1-38 D+ myelomonocytic leukemia cells by retinoic acid and granulocyte colony-stimulating factor. Leuk Res 16:571-577, 1992.
54. Pirisi L, Batova A, Jenkins GR, Hodam JR, Creek KE. Increased sensitivity of human keratinocytes immortalized by human papillomavirus type 16 DNA to growth control by retinoids. Cancer Res 52:187-192, 1992.
55. Yen A, Chandler S, Forbes ME, Fung YK, T'Ang A, Pearson R. Coupled down-regulation of the RB retinoblastoma and c-Myc genes antecedes cell differentiation: Possible role of RB as a "Status-Quo" gene. Europ J Cell Biology 57:210-215, 1992.
56. Niles RM and Loewy BP. Induction of protein kinase C in mouse melanoma cells by retinoic acid. Cancer Res 49:4483-4492, 1989.
57. White SD, Rosychuk RA, Scott KV, et al: Use of isotretinoin and etretinate for the treatment of benign cutaneous neoplasia and cutaneous lymphoma in dogs. J Am Vet Med Assoc 1993; 202(3):387-91.
58. Branda RF. Effects of folic acid deficiency on tumor cell biology. In, Vitamins and Minerals in the Prevention and Treatment of Cancer. Jacobs MM (ed). CRC Press, Boca Raton, FL, 1991, pp167-185.
59. Kline K, Sanders BG. Modulation of immune suppression and enhanced tumorigenesis in retrovirus tumor challenged chickens treated with vitamin E, In Vivo; 3:161-185, 1989.
60. Kline K, Cochran GS, Sanders BG. Growth inhibitory effects of vitamin E succinate on retrovirus-transformed tumor cells in vitro. Nutr and Cancer 14:27-35, 1990.
61. Kline K, Rao A, Romach EH, Kidao S, Morgan TJ, Sanders BG. Vitamin E effects on retrovirus-induced immune dysfunction. Annals of the New York Academy of Science 587:294, 1990.
62. Shamberger RJ, Rukovena E, Longfield AK, Tytco SA, Deodhar S, Willis CE. Antioxidants and cancer, I. Selenium in the blood of normals and cancer patients. J Natl Cancer Inst 50:867-887, 1973.
63. Ip C. Factors influencing the anticarcinogenic efficacy of selenium in dimethylbenzanthracene-induced mammary tumorigenesis in rats. Cancer Res 41:2638-2644, 1981.
64. Jacobs MM, Jansson B, Griffin AC. Inhibitory effects of selenium on 1,2-dimethylhydrazine and methylazoxymethanol acetate induction of colon tumors. Cancer Lett 2:133-144, 1977.
65. Vernie LN. Selenium in carcinogenesis. Biochemistry Biophysics Acta 738:203-110, 1984.
66. Jacobs MM, Griffin AC. Effects on selenium on chemical carcinogenesis: Comparative effects on antioxidants. Biol Trace El Res 1:2-21, 1979.
67. Asselin BL, Ryan D, Frantz CN, Bernal SD, Leavitt P, Sallan Se, Cohen JH. In vitro and in vivo killing of acute lymphoblastic leukemia cells by L-asparaginase. Cancer Res 49:4363-4369, 1989.
68. Weed H, McGandy RB, Kennedy AR. Protection against dimethylhydrazine induced adenomatous tumors of the mouse colon by the dietary addition of an extract of soybeans containing the Bowman-Birk protease inhibitor. Carcinogenesis 6:1239-1241, 1985.
69. Messadi DV, Billings P, Shklar G, Kennedy AR. Inhibition of oral carcinogenesis by a protease inhibitor. J Natl Cancer Inst 76:447-452, 1986.
70. St. Clair W, billings P, Carew J, Keller-McGandy C, Newberne P, Kennedy AR. Suppression of DMH-induced carcinogenesis in mice by dietary addition of the Bowman-Birk protease inhibitor. Cancer Res 50:580-586, 1990.
71. Kennedy AR. Effects of protease inhibitors and vitamin E in the prevention of cancer. In, Nutrients and Cancer Prevention. Prasad KN and Meyskens FL (eds). The Humana Press, Inc, Clifton, New Jersey 79-98, 1990.
72. Witschi H, Kennedy AR. Modulation of lung tumor development in mice with the soybean-derived Bowman-Birk protease inhibitor. Carcinogenesis 10:2275-2277, 1989.
73. Billings PC, Habres JM, Kennedy AR. Inhibition of radiation-induced transformation of C3H10T1/2 cells by specific protease substrates. Carcinogenesis 11:329-332, 1990.
74. Wargovich MJ, Sumiyoshi H, Baer A, Imada O. Chemoprevention of gastrointestinal cancer in animals by naturally occurring organosulfur compounds in allium vegetables. In, Vitamins and Minerals in the Prevention and Treatment of Cancer. Jacobs MM (ed), CRC Press, Boca Raton, Florida, 1991.
75. Wang ZY, Hong JY, Huang MT, Reuhl K, Conney AH, Yang CS. Inhibition of N-nitrosodiethylamine and 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tumorigenesis in A.J mice by green tea and black tea. Cancer Res 52:1943-1954, 1992.
76. Wang ZY, Agarwal R, Khan WA, Mukhtar H. Protection against benzo(a)pyrene and N-nitrosodiethylamineinduced lung and forestomach tumorigenesis in A/J mice by water extracts of green tea and licorice. Carcinogenesis 13:1491-1496, 1992.
77. Khan SG, Kartiyar SK, Agarwal R, Mukhtar H. Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hairless mice: Possible role in cancer prevention. Cancer Res 52:4050-4056, 1992.
78. Fettman MJ, CA Stanton, LL Banks, DW Hamar, DE Johnson, RL Hegstad, S Johnston. Effects of neutering on body weight, metabolic rate, and glucose tolerance in domestic cats. Res Vet Sci 1996;in press.
79. Ogilvie GK, Salman MD, Fettman MJ et al. Effect of anesthesia and surgery on energy expenditure determined by indirect calorimetry in dogs with malignant and non-malignant condition. Am J Vet Res, 1996;57:1321-326.
80. Ogilvie GK, Walters LM, Fettman MJ, et al. Energy expenditure in dogs with lymphoma fed two specialized diets. Cancer 1993;71:3146-3152
81. Ogilvie GK, Salman MD, Fettman MJ et al. Resting energy expenditure in dogs with nonhematopoietic malignancies before and after excision of tumors. Am J Vet Res, 1996;57:1463-1467.
82. Lagutchik MS, Wingfield WE, Ogilvie GK et al. Energy Expenditure in 104 postoperative and traumatically injured dogs with indirect calorimetry. J Vet Emerg and Crit Care 1996; 6(2):71-80.
83. Wheeler SL, McGuire BM. Enteral nutritional support. In Kirk RW (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp 30-36.
84. Copeland EM, Daly JM, Dudrick SJ. Nutrition as an adjunct to cancer treatment in the adult. Cancer Res 37:2451- 2456, 1977.
85. Dempsy DT, Mullen JL. Macronutrient requirements in the malnourished cancer patient. Annals of Surg 55:290- 294, 1985.
86. Lawson DH, Nixon DW, Kutner MJ, et al. Enteral versus parenteral nutritional support in cancer patients. Cancer Treatment Report 65:101-105, 1981.
87. Donohue S. Nutritional support of hospitalized patients. Kallfelz FA (ed), Veterinary Clinics of North America [Small Animal] 19(3):475-495, 1989.
88. Allen TA. Specialized nutritional support. In Ettinger SJ (ed): Textbook of Veterinary Internal Medicine, ed 3. Philadelphia, WB Saunders, 1989, pp 450-455.