Gregory K. Ogilvie, DVM, Diplomate ACVIM (Internal Medicine, Oncology)
Professor and Head of Medical Oncology, Animal Cancer Center, Colorado State University
Ft. Collins, CO, USA
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.1 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.1-11
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.1-8 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?
Metabolic Changes Associated with Cancer Cachexia
Clinically, in many patients there are three phases associated with cancer cachexia.5 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 the 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
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.19 The hyperlactatemia and hyperinsulinemia did not improve when these dogs were rendered free of all clinical evidence of cancer with either chemotherapy or surgery.15 Metabolic alterations result in part because tumors preferentially metabolize glucose for energy by anaerobic glycolysis forming lactate as an end product.2,16 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.14,16-19
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.20 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.
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. 16-18 Tumors preferentially use protein for energy at the expense of the host. 16-18,21-25 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.22,23
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.26-29 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.26,27 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.32,33
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.33-37 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.34 Recently lipid profiles in dogs with a lymphoma were studied.35 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.16,32,34
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.36 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.37,38 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.37 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.40 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.
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.
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.80,81 In the first study80, 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.89 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.
Enteral dietary therapy has been shown to be a practical, cost-effective, physiologic, and safe modality that may abate or eliminate cancer cachexia, decrease complications from therapy and actually improve response to therapy. Several studies have failed to document the possibility of increasing tumor growth by enhancing the nutritional status of the host. 83-88 The dogma is that mature dogs and cats with a functional gastrointestinal tract that have a history of inadequate nutritional intake for 3-7 days or have lost at least 10% of their body weight over a 1-2 week period of time are candidates for enteral nutritional therapy. There is no question that this philosophy is short sighted. Nutritional intervention must begin earlier than these guidelines suggest. The key is to prevent problems before they occur.
As a general rule, mature dogs and cats with cancer with functional GI tracts that require nutritional support should have some form of enteral feeding: If the gut works, use it!!! The first step is to enhance appetite. The owner should be given a short term and long range plan for the nutritional support of their pet. This plan allows the veterinary health care team and the owner to have a sequential plan for maintaining nutritional support by first enhancing appetite, second, using tube support in appropriate cases, and third, considering more advanced measures such as total parenteral nutrition for serious problems. The first step, enhancing appetite, begins with the basics: warming the food to just below body temperature; providing a selection of palatable, aromatic foods; and providing comfortable, stress-free surroundings. When these simple procedures fail, such chemical stimulants as benzodiazepine derivatives (e.g., diazepam and oxazepam) and antiserotonin agents (cyproheptadine and pizotifen) can be used. Cyproheptadine (2-4 mg daily or twice daily PO) generally is effective in stimulating appetite in cats, as are megestrol acetate (2.5 mg daily for 4 days, then every 2-3 days thereafter). These drugs can be used concurrently for maximal stimulation of the appetite. Diazepam (0.05-0.5 mg/kg IV) is great for short term therapy in the hospital, but is often not adequate for home therapy. Dogs and cats may have improved appetite when metoclopramide is given orally to decrease nausea associated with chemotherapy or surgery. When all the aforementioned fails, enteral nutritional support via nasogastric, esophagostomy, gastrostomy or jejunostomy tube feeding, designed to deliver nutrients to the GI tract should be considered because it is practical, cost-effective, physiologic, and safe.1-4
Enteral Feeding Methods
The type of nutrients to be used depends largely on the enteral tube that is used and on the status of the patient. 1-3,5,83,87,88 The big question is: what should you feed the cancer patient? The easy answer is, whatever the pet will eat, however, specific therapy is preferred. Blended canned pet foods may be adequate for feeding by esophagostomy and gastrostomy tubes. Whenever possible, consider diets that are relatively low in simple carbohydrates, easily digestible, and that have appropriate soluble and insoluble sources of fiber. The later can be accomplished by adding psyllium to a canned maintenance pet food diet or by using a weight maintaining diet such as Hills Prescription Diet W/D. Because the later has restricted calories, an increased volume of feeding may be needed. Human enteral feeding products are easily administered though nasogastric and jejunostomy tubes (e.g., Impact, Osmolite HN, Jevity), however, veterinary enteral products are now available that are specifically tailored for the nutritional needs of animals, especially cats (e.g, Clinicare). In any case, feeding usually is not started until 24 hours after the tube is placed except for pets with an esophagostomy tube. Once feeding is started, the amount of nutrients is gradually increased over several days and is administered frequently in small amounts, which allows the animal to adapt to this method of feeding. Continuous feeding may reduce the risk of vomiting caused by overloading the GI tract. Regardless, the tube should be aspirated 3 to 4 times a day to ensure there is not excessive residual volume in the GI tract. The tube should be flushed periodically with warm water to prevent clogging.
1. What clinically significant alterations in metabolism occur in animals with cancer cachexia? Dogs and cats with cancer have significant alterations in carbohydrate, lipid and protein metabolism that can result in cancer cachexia. These alterations in metabolism have the potential to decrease quality of life, reduce response to therapy and shorten survival times.
2. How can knowledge about the metabolic alterations in metabolism change the way you use nutrition to treat your cancer patients? While the ideal anticancer diet is not known, research to date would suggest that any nutritional support is better than none. Normal feeding practices should begin early before evidence of cachexia are noted, and plans should be designed to support the patient when voluntary feeding is not optimum. In addition, the following guidelines may be considered early for each patient:
a. Arm clients with appropriate information, dietary plans and appetite stimulants such as cyproheptadine and megesterol acetate from the very beginning. The goal is to prevent anorexia and weight loss from ever happening.
b. Consider foods that are highly bioavailable, easily digested, and highly palatable with a good smell and taste
c. Consider foods that are relatively low in simple carbohydrates, moderate amounts of good quality sources of proteins and soluble and insoluble fiber, and moderate amounts of fats; fats of the n-3 fatty acid series may be effective in reducing or eliminating some of the metabolic alterations associated with cancer cachexia. Antioxidants are essential whenever n-3 fatty acids are used. Hills prescription diet nd is one good example.
d. Enhanced quantities of arginine, cystine and glutamine may be of value in maintaining a more normal immune, hematologic and gastrointestinal tract.
e. Fiber, both soluble and insoluble, is essential to maintain normal bowel health. A diet with adequate amounts of fiber is essential to prevent or to treat various problems of the gastrointestinal tract.
3. Does surgery, chemotherapy or cancer increase or decrease the energy needs and the amount you should feed your patient? Each patient should be assessed as an individual and the nutritional profile, including the amount to be fed should be prescribed for each animal on a daily basis based on reassessments. As a general rule, with the exception of septic animals, dogs and cats with cancer, critical care illnesses, or that are recovering from surgery do not have energy needs that exceed those of normal animals. A formula that approximates the need for many animals with cancer in a resting state is as follows: 1.1[30(wt in kg) + 70]= kcals required per day.
4. Are there any data on the efficacy of the nutrients my clients constantly ask me about: vitamins, minerals, proteases, enzymes, garlic, tea and shark cartilage? What nutrients should you feed your cancer patient? Data exist demonstrating that many antioxidants, minerals, proteases, garlic, enzymes, and tea all have some potential for reducing the risk of cancer, or the growth and metastases of established malignant diseases. Research must be done to establish ideal dosages, and optimum applications of these nutrients. The lay press and word of mouth can bypass the presence of any research data demonstrating efficacy as it has for shark cartilage. To date, little if any data exist demonstrating that shark cartilage is effective for treating spontaneously occurring cancer in an outbred species. Despite this lack of proof, the public does believe that shark cartilage does have some efficacy.
5. What are the indications for intervening aggressively with appetite stimulants, tube feeding or total parenteral feeding for your cancer patients? For maximum benefit, intervention should begin early in the course of the disease. The owner must have a clear plan for dietary intervention beginning first with the choice of nutrients, followed by appetite stimulants, and then on to feeding tubes for those patients that cannot or will not support themselves.
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 syndromes. 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-nitrosodiethylamine-induced 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. 80. Ogilvie GK, Walters LM, Fettman MJ, et al. Energy expenditure in dogs with lymphoma fed two specialized diets. Cancer 1993;71:3146-3152
80. 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.
81. 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.
82. Wheeler SL, McGuire BM. Enteral nutritional support. In Kirk RW (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp 30-36.
83. Copeland EM, Daly JM, Dudrick SJ. Nutrition as an adjunct to cancer treatment in the adult. Cancer Res 37:2451-2456, 1977.
84. Dempsy DT, Mullen JL. Macronutrient requirements in the malnourished cancer patient. Annals of Surg 55:290-294, 1985.
85. Lawson DH, Nixon DW, Kutner MJ, et al. Enteral versus parenteral nutritional support in cancer patients. Cancer Treatment Report 65:101-105, 1981.
86. Donohue S. Nutritional support of hospitalized patients. Kallfelz FA (ed), Veterinary Clinics of North America [Small Animal] 19(3):475-495, 1989.
87. Allen TA. Specialized nutritional support. In Ettinger SJ (ed): Textbook of Veterinary Internal Medicine, ed 3. Philadelphia, WB Saunders, 1989, pp 450-455.