Three phases of cachexia have been identified in human subjects; it is presumed that the syndrome follows a similar pattern in dogs and cats. During the first phase, the patient does not exhibit clinical signs, but biochemical changes are evident. These include elevated blood lactate and insulin levels (peripheral insulin resistance) and alterations in amino acid and lipid profiles. ¹¹ Dogs with lymphoma have significantly higher serum lactate and insulin concentrations following intravenous dextrose infusion, compared with levels in healthy dogs. ¹² These changes occur even in dogs that are not showing clinical signs of cachexia. Clinical signs develop during the second stage. The patient begins to show anorexia, weight loss, and depression and has an increased risk of experiencing detrimental side effects of cancer therapy. The third and final stage is characterized by marked losses of body fat and protein stores, severe debilitation, weakness, and biochemical evidence of negative nitrogen balance. If left untreated, cancer cachexia can be the ultimate cause of death. Indirect calorimetry studies with rats have found that the three phases usually coincide with normal, increased, and decreased energy requirements, respectively. ¹³

The biochemical alterations of cancer cachexia involve the metabolism of carbohydrate, protein, and lipids, which in turn affect basal metabolic rate. Together, this collection of biochemical changes leads to inefficient energy utilization by the host animal and enhanced energy use by the tumor. Alterations in carbohydrate metabolism are dramatic and are at least partially related to the metabolic needs of the tumor. Tumor cells preferentially metabolize glucose through anaerobic glycolysis for energy, and most are incapable of obtaining significant amounts of energy from either aerobic glycolysis or fat oxidation. ^{12. and 14.} As a result, as a tumor grows, it uses the host’s supply of glucose for energy, generating large amounts of lactate, the end product of anaerobic glycolysis. The host animal’s hepatocytes convert this excess lactate to glucose via the Cori cycle, resulting in a shift in glucose metabolism from energy-producing oxidative pathways to energy-requiring gluconeogenic pathways. The end result is a gain of energy by the tumor and a net energy loss for the host. This alteration in carbohydrate metabolism occurs as early as the preclinical stage of cancer cachexia. Therefore nutritional intervention that is aimed at shifting metabolism to benefit the host over the tumor should begin as soon as a diagnosis is made.

In addition to elevated serum lactate, other biochemical abnormalities that occur in response to changes in carbohydrate use in tumor-bearing animals include altered serum insulin and glucagon secretion patterns, increased rate of gluconeogenesis and glucose turnover, and insulin resistance. ^{15.16. and 17.} Although the majority of studies have been conducted with human cancer patients or laboratory animal models, there is evidence that these changes also occur in dogs (and presumably cats). Dogs with lymphoma, a common form of cancer in many breeds, show altered responses to glucose tolerance tests, and many develop insulin resistance. ^{12. and 18.} These changes occur before and after the development of clinical signs and continue after remission is achieved. ¹⁸ It is hypothesized that insulin resistance in dogs with lymphoma is due to a post-receptor defect resulting in glucose intolerance. Regardless of the underlying cause, the prevalence of glucose intolerance and insulin insensitivity mandate the need to limit and carefully select the type of carbohydrate included in foods for pets with cancer.

Because both the tumor and the host have obligatory protein requirements, negative nitrogen balance is common in cancer patients. ¹⁹ Growing tumors require amino acids for protein synthesis and will also use host gluconeogenic amino acids for the production of glucose. Because tumors often have a high metabolic rate, this significantly affects host protein stores and can result in abnormal serum amino acid profiles. ²⁰ The host experiences an increased rate of whole body protein turnover, characterized by a decreased rate of protein synthesis in skeletal muscle and an increased rate of synthesis in the liver. ^{21. and 22.} In human cancer patients the shift in protein synthesis from muscle to liver is referred to as the acute-phase reactant response, and its onset is a negative prognostic factor for survival. If not corrected, this protein imbalance eventually leads to increased loss of skeletal muscle (muscle wasting), hypoalbuminemia, compromised immunity, impaired gastrointestinal function, and delayed wound healing.

Studies of human cancer patients have shown that serum levels of the gluconeogenic amino acids alanine, glutamic acid, aspartic acid, and glycine generally decrease, while concentrations of the branch-chain amino acids (BCAAs) (leucine, isoleucine, and valine) are normal or increased. ^{20. and 23.} This shift reflects the increased proteolysis of skeletal muscle as the three BCAAs make up approximately ⅓ of skeletal muscle protein. Studies of dogs with cancer have also found changes in serum amino acid profiles. A group of 32 dogs with a variety of cancers had decreased serum levels of glycine, glutamine, valine, cystine, and arginine and elevated levels of isoleucine and phenylalanine, compared with values that were reported in the group of healthy control dogs. ^{24. and 25.}

Although the biochemical pathways are complex and are not completely understood, the primary underlying cause of skeletal muscle protein breakdown in cancer patients appears to be the up-regulation of the ubiquitin-proteasome proteolytic pathway. ^{26. and 27.} Activation of this pathway is responsible for the muscle wasting that is seen in a variety of disease and trauma states, including diabetes, hyperthyroidism, and in response to fasting, sepsis, and burns. With cancer, several tumor-derived factors and cytokines have been identified that influence this proteolytic pathway. These include proteolysis induction factor, tumor necrosis factor-alpha, and interleukin-1-beta.

Loss of body fat accounts for the majority of the weight lost by humans and animals with cancer cachexia. ²⁸ Although reduced food intake is a significant contributor to this loss, humans and animals with cancer also experience decreased lipogenesis and increased lipolysis. This metabolic shift is a result of decreased lipoprotein lipase activity and appears to also be influenced by several specific tumor-derived cytokines. ^{29. and 30.} The result is elevated serum concentrations of free fatty acids (FFAs), very–low-density lipoproteins (VLDLs), triglycerides, acetoacetate, and beta-hydroxybutyrate. ^{31. and 32.} In human patients with cancer, altered lipid profiles have been associated with immunosuppression and decreased survival time. ³³ Similarly, dogs with untreated lymphoma had significantly elevated concentrations of serum triglycerides, FFAs, and VLDLs when compared with healthy controls. ^{24. and 34.} Although serum cholesterol concentration increased in response to chemotherapy, other lipid parameters did not normalize during treatment or when the dogs attained remission.

As discussed previously, tumors obtain energy primarily through the anaerobic metabolism of glucose, resulting in the production of lactate. The host must then recycle this lactate through the Cori cycle, which leads to a net loss of energy. Additional energy costs to animals with cancer may include cytokine-induced increases in glucose recycling, protein degradation, and energy expenditure. ^{35. and 36.} Therefore, at least theoretically, energy expenditure in cancer patients is expected to increase. However, studies using indirect calorimetry to measure energy expenditure in tumor-bearing subjects have reported varying results. ^{13.37.38. and 39.} Some investigators have reported increased energy expenditure in humans and animals with neoplastic disease. Conversely, others have found normal or reduced energy needs. These discrepancies are probably a result of several factors. Because cancer cachexia develops in stages and biochemical alterations typically precede clinical signs, animals that are in the preclinical stage of cachexia are expected to have normal energy requirements. Conversely, individuals with active, untreated cachexia may have elevated energy expenditure, while those in the final stages may be hypometabolic. Additional factors that significantly affect energy needs include the type and size of tumor and the patient’s phase of treatment, severity of clinical signs, and level of activity.

Several studies using indirect calorimetry have been conducted to determine whether there are significant changes in resting energy expenditure (REE) in dogs with cancer. 40.^{41. and 42.} In one study, 22 dogs with naturally occurring lymphoblastic lymphoma were fed isocaloric amounts of either a high-carbohydrate or a high-fat diet before and during chemotherapy. ⁴¹ The initial REE values in dogs with lymphoma before treatment were significantly lower than those of healthy control dogs. After 6 weeks of chemotherapy, REE values decreased further in the dogs with lymphoma, even after remission was achieved in the majority of dogs. Although there were no significant differences in mean REE between the two diet groups, the dogs fed the high-fat diet maintained slightly higher energy expenditures than those fed the high-carbohydrate diet. An important consideration in this study is the fact that the healthy control animals were slightly younger than the dogs with cancer (mean ages of 5.4 versus 7 years, respectively). Although slight, this age difference may account for the lower initial mean REE in dogs with lymphoma. However, it would not account for the further decreases seen during treatment and remission. A possible explanation for these decreases may be that the dogs with lymphoma were in the first silent phase of cancer cachexia at the start of the study. This was followed by a reduction in metastatically active tumor tissue in response to treatment or possibly in response to a decrease in host metabolism caused by a loss of lean body tissue. A common side effect of chemotherapy is decreased energy intake, which could lead to a loss of lean body tissue and a decreased metabolic rate.

A second study examined the effects of surgical excision of various types of tumors on energy expenditure in dogs. ⁴² Removal of tumors did not significantly affect REE, regardless of tumor type. In addition, the energy expenditure of tumor-bearing dogs prior to surgery was not significantly greater or less than that of a control group of healthy dogs. In contrast to the previously described study of dogs with lymphoma, this study indicated that REE and energy needs of dogs with other types of cancer are not significantly different from healthy dogs of the same age.

Although studies of the energy requirements of dogs with cancer are limited (no studies have been published for cats), results thus far indicate that the energy needs of cancer patients do not significantly increase, and they may decrease slightly with some types of cancer. In addition, removal of the cancer through surgery or chemotherapy does not appear to appreciably affect energy needs. These data do not support the standard tenet that patients with neoplastic disease have increased energy requirements. Rather, it seems that the energy needs of dogs and cats with cancer must be addressed on an individual basis and may vary with the type of cancer, stage of the disease, and method of treatment.

Current data indicate that food selected for cancer patients should take advantage of the differences in metabolic needs between the host animal and the tumor. The food’s caloric distribution should emphasize calories originating from fat and protein, rather than from carbohydrate, because fatty acids and amino acids are not the preferred fuel source for most tumors. A diet that contains reduced carbohydrate and elevated protein and fat may supply a readily available source of energy, meet the host’s protein needs, and limit the supply of carbohydrate to tumor cells. 28. ^{and 43.} Human cancer patients with cachexia have shown improvements in body weight, adipose stores, energy and nitrogen balance, and ability to metabolize glucose when dietary fat is increased. ^{44. and 45.} Similarly, dogs with lymphoma fed a high-fat diet had lower mean lactate and insulin levels after remission when compared with dogs fed isocaloric amounts of a high-carbohydrate diet. ⁴¹ A food that contains 50% to 60% of total calories from fat, 30% to 50% of calories from protein, and the remaining portion of calories from soluble carbohydrate is recommended for dogs and cats with cancer. ⁴⁶ In addition to shifting metabolism away from carbohydrate and toward fat, another benefit of feeding a high-fat diet to cancer patients is the increased energy density and palatability of these foods.

The type of fat that is included in foods for pets with cancer is also an important consideration. In recent years, the importance of omega-3 fatty acids for human and pet cancer patients and the effects of this class of fatty acids on tumor development and metastasis have been studied. (A complete review of these fatty acids and their use in pet foods is included on pp. 387-395.) The antiinflammatory effects of omega-3 fatty acids on multiple systems of the body suggest a role in treating cancer patients. There is an increasing body of evidence showing that omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), limit tumor growth. ^{47.48.49. and 50.} Studies using animal models have shown that supplementation with EPA and DHA helps to prevent cachexia and metastatic disease. ⁵¹ There is also indirect evidence that omega-3 fatty acids may be metabolically helpful in preventing the recurrence of cancer after remission has been achieved. ⁵² Although the underlying mechanism is not completely understood, the effect appears to be related to incorporation of long-chain omega-3 fatty acids into tumor cell membranes. This alters membrane fluidity and permeability, potentially increasing tumor cell susceptibility to both chemotherapeutic agents and to the host’s own immune system. Increasing cell membrane omega-3 fatty acids also shifts prostaglandin synthesis away from prostaglandin E ₂ (PGE ₂) and toward PGE ₁. Cyclooxygenase metabolites such as PGE ₂ play a role in the progression of several forms of cancer, and blocking their production can inhibit tumor growth. ⁵³