Metabolic Alterations and Nutritional Therapy for the Veterinary Cancer Patient
Gregory K. Ogilvie and David M. Vail
More thorough attention to the nutritional well-being and application of nutritional support modalities have substantially improved the quality of life of many veterinary cancer patients. Weight loss, often encountered in the tumor-bearing individual, may be due to the primary effects of the tumor (e.g., compression or infiltration of the alimentary tract), effects related to therapy (e.g., chemotherapy-induced anorexia, nausea, or vomiting), or the alteration of metabolic pathways comprising the paraneoplastic syndrome of cancer cachexia. The results of recent research suggest that many tumor-bearing animals have alterations in metabolism necessitating not only special methods for delivering nutrients but also specific types of fluid and nutrient support. Cancer cachexia is a complex paraneoplastic syndrome of progressive involuntary weight loss that occurs even in the face of adequate nutritional intake. People with cancer cachexia have a decreased quality of life, decreased response to treatment, and a shortened survival time when compared to those with similar diseases who do not exhibit the clinical or biochemical signs associated with this condition. The purpose of this article is to review briefly what is known about some of the metabolic alterations that occur with cancer and how this knowledge can be used to meet the unique dietary and parenteral fluid needs of veterinary cancer patients.
METABOLIC ALTERATIONS IN CANCER
Perhaps the most dramatic alterations in the metabolism of animals with cancer occur in carbohydrate metabolism. Abnormalities have been documented in peripheral glucose disposal, hepatic gluconeogenesis, insulin effects, and whole-body glucose oxidation and turnover. These abnormalities exist often before clinical evidence of cachexia are present. For example, when dogs with lymphoma without clinical evidence of cachexia were evaluated with a 90-minute 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 achieved remission with doxorubicin chemotherapy. Metabolic alterations result in part because tumors preferentially metabolize glucose for energy by anaerobic glycolysis forming lactate as an end product. The host must then expend the necessary energy to convert lactate to glucose by the Cori cycle, which results in a net energy gain by the tumor and a net energy loss by the host.
The clinical significance of the alterations in carbohydrate metabolism are just now becoming understood. A recent report documented the exacerbation of hyperlactatemia by infusion of lactated Ringer's solution (LRS) in dogs with lymphomas. During that study, blood lactate concentrations of relatively healthy, well-hydrated dogs with lymphoma were compared to control dogs and determined to be significantly elevated before, during, and after LRS was infused at a relatively modest rate (4.125 ml/kg/hr). This LRS-induced increase in lactate concentration may place a metabolic burden on the host to convert lactate back to glucose, further exacerbating the energy demands on the host. This may be even more important for septic, critically ill patients with cancer that require more intensive fluid therapy. It is also logical to assume that glucose-containing fluids would likely increase hyperlactatemia, as evidenced by glucose tolerance tests. Therefore, until further information is known about the effects of hyperlactatemia on critically ill animals with cancer, glucose- or lactate-containing fluids should be avoided.
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. Others have published data to support this hypothesis.
Cancer has been shown to result in decreased body muscle mass and skeletal protein synthesis and to alter nitrogen balance while concurrently increasing skeletal protein breakdown, liver protein synthesis, and whole-body protein synthesis. Tumors preferentially use energy stores at the expense of the host. For example, tumors often preferentially use amino acids for energy via gluconeogenesis. 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.
In one study, amino acid analyses were performed on the plasma of 32 dogs with cancer and 8 normal control dogs. Of the 25 amino acids evaluated, tumor-bearing dogs had significantly lower plasma concentrations of threonine, glutamine, glycine, valine, cystine, and arginine and significantly higher levels of isoleucine and phenylalanine. The results did not differ between the different types of tumors represented.
Providing high-quality amino acids or protein dietarily may be of critical importance for the veterinary cancer patient. A quality protein diet that is highly bioavailable may be ideal. Arginine and glutamine may be of specific value for therapeutic purposes. Arginine will stimulate lymphocyte blastogenesis, and its addition to total parenteral nutrition solutions has been shown to decrease tumor growth and metastatic rate in some rodent systems. Some amino acids may decrease toxicity associated with chemotherapy. For example, glycine has been shown to reduce cisplatin-induced nephrotoxicity.
Lipid MetabolismFat 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 lymphoma were studied to determine if alterations similar to those reported in other species were present. When compared to healthy controls, dogs with lymphoma had significantly higher concentrations of the cholesterol concentrations associated with very low density lipoprotein (VLDL-CH), total triglyceride (T TG), as well as the triglyceride concentrations associated with very low density lipoprotein (VLDL-TG), low density lipoprotein (LDL-TG), and high density lipoprotein (HDLTG). Significantly lower levels of cholesterol concentrations associated with high density lipoprotein (HDL-CH) were also noted. HDL-TG and VLDL-TG concentrations from dogs with lymphoma were significantly increased above pretreatment values after remission was lost and the dogs had developed overt signs of cancer cachexia. These abnormalities did not normalize when clinical remission was obtained.
The clinical significance of the previously mentioned lipid parameters 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. Mean nitrogen intake, nitrogen balance, in vitro lymphocyte mitogenesis, time for wound healing, the prevalence of wound complications, and the duration of hospitalization were significantly better in 85 surgical patients fed an omega-3 fatty acid supplement when compared to controls.
Energy ExpenditureCancer cachexia may in part be due to a negative energy balance secondary to decreased energy intake or altered energy expenditure. Alterations in basal metabolic rate (BMR) and resting energy expenditure (REE) have been observed in human patients with cancer cachexia, and these changes are associated with derangements in carbohydrate, protein, and lipid metabolism. This is in contrast to the adaptive decrease in metabolic rate observed to occur in healthy fasted individuals. This attenuation of adaptive response may be responsible in part for the increased energy demand and subsequent weight loss occurring in the cancer-bearing host. Because the thyroid gland and its constitutive hormones are intimately involved in the control of energy homeostasis, it is not unreasonable to speculate that perturbations in thyroid function or thyroid hormone concentrations may play a role in altering energy states in tumor-bearing cachectic individuals. It is plausible that abnormally high concentrations of active thyroid hormone may play a significant role in the hypermetabolic state often encountered in individuals suffering from cancer cachexia. This hypothesis did not hold true in a recent investigation of thyroid function in tumorbearing dogs. In this study of 83 dogs, serum concentrations of thyroxine (T4),3,5,3'-triiodothyronine (T3), free thyroxine (fT4), and free 3,5,3'-triiodothyronine (fT3) were compared among tumor-bearing dogs with and without chronic weight loss and non-tumor-bearing dogs with and without chronic weight loss. Diminished serum concentrations of T4,T3, and f T3 occurred in dogs under study in proportion to the degree of weight loss associated with their disease state, regardless of their tumor-bearing status. It appears that these declines are related to abnormal nutritional state or severity of illness rather than to a tumor-related phenomenon.
Indirect calorimetry, a method by which REE is estimated from measurements of oxygen consumption and carbon dioxide production, is evaluated to understand more about nutrient assimilation, substrate utilization, thermogenesis, the energetics of physical exercise, and the pathogenesis of diseases such as cancer. Indirect calorimetry was performed on 22 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 (REE/kgo.75) was significantly lower than 30 tumor-free controls. Six weeks after the start of the study, REE/kg 0.75 was significantly lower in both groups of dogs with lymphoma when compared to the controls and the pretreatment values from the dogs with lymphoma. The dogs fed the diet relatively high in fat maintained a more normal energy expenditure than the dogs fed a diet relatively high in carbohydrates.
NUTRITIONAL SUPPORT FOR THE VETERINARY CANCER PATIENT
The ideal method of addressing cancer cachexia is to eliminate the underlying neoplastic condition; however, this is often not possible, and efforts to provide nutritional support become important. Specific recommendations for nutritional support of patients with neoplastic disease should be based on estimates of caloric requirements, the patients' current and past nutritional status, and a knowledge of the underlying disease. Not all cancer patients are candidates for nutritional support. Clinical judgment based on historical information regarding past, present, and anticipated nutrient intake and needs; on physical examination with attention to body condition; and on a working knowledge of underlying disease mechanisms has proven superior as a measure of nutritional status and the need for nutritional support in people. Consequently, this seems the simplest, most reliable method of assessment in veterinary patients and would also be clinically judicious. Additionally, as with any treatment modality, serial assessment of nutritional status and subsequent modifications in nutritional support are indicated as the patient's status changes.
Enteral feeding has been shown to be a practical, cost-effective, physiologic, and safe modality that may abate or eliminate cancer cachexia. Several studies have failed to document the possibility of increasing tumor growth by enhancing the nutritional status of the hoSt. Enteral dietary support of the cancer patient can result in weight gain as well as increased response to and tolerance of radiation, surgery, and chemotherapy. Other factors that improve with enteral nutritional support include thymic weight, immune responsiveness, immunoglobulin and complement levels, as well as the phagocytic ability of white blood cells. Although the optimum diet formulation is still unknown, the following guidelines may apply.As a general rule, mature dogs and cats with a functional gastrointestinal tract that have a history of inadequate nutritional intake for 3 to 7 days or have lost at least 10% of their body weight over a 1- to 2-week period of time are candidates for enteral nutritional therapy. A note of caution: the present dogma of allowing 2 or more days of inappetence to pass before considering nutritional support may not be appropriate for the feline patient who has a relatively higher metabolic rate. For example, daily adenosine triphosphate (ATP) turnover in an 80 kg man at rest is roughly 60% of body weight versus 136% in a 3.5 kg cat, and humans have approximately twice the energy storage capabilities per unit of metabolic body size. In light of this, we feel it is prudent to implement nutritional support earlier in those feline patients where it is clearly indicated.
All methods to encourage food consumption, including the use of chemical stimulants, should be attempted first. Enhancing the palatability of food is the simplest means of increasing voluntary intake. Offering a variety of freshly opened food and warming it to body temperature may help. Appetite stimulants of the benzodiazepam family (diazepam, oxazepam) used at low doses orally or intravenously while presenting a, variety of foods may result in the consumption of nearly 25% of daily requirements in responsive cats. This is usually reserved for short-term appetite stimulation to "kick-start" a patient likely to recover quickly. Many other pharmacologic compounds have or are undergoing scientific scrutiny for reversing or abating the metabolic alterations occurring in cancer-bearing patients. Carefully controlled studies with human cancer patients suggest that cyproheptadine, corticosteroids, and nandrolone decanoate have little or no impact on objective indices of nutritional status or clinical outcome. Megestrol acetate has been shown to be of benefit in patients with significant g0trointestinal morbidity. Several studies recently reviewed by Chlebowski have shown that the clinical use of megestrol acetate has resulted in substantial increases in weight gain in people with cancer; the clinical utility of this drug for the treatment of cancer cachexia in veterinary patients remains to be determined.
Routes of Enteral Feeding
Once the decision to provide nutritional support has been made, an appropriate method of feeding must be chosen. Enteral feeding should always be considered over total parenteral nutrition unless it is contraindicated because of an inability of the gastrointestinal tract to digest or assimilate nutrients in adequate quantities. A vast body of basic and clinical literature exists that supports the ad adage "If the gut works use it! " While parenteral nutrition is certainly a useful tool, maintenance of gut mucosal integrity and the complex neuroendocrine network that orchestrates nutrient digestion, absorption, and metabolism is paramount and best served by enteral nutrition. Additionally, enteral feeding tends to be more cost effective and associated with fewer complications. A number of enteral feeding routes are commonly used in veterinary patients. Simply put, the gastrointestinal tract should be accessed with a feeding tube as far proximal as possible in order to maximize normal digestion, thus minimizing complications associated with bypassing normal digestive processes. The anticipated duration of nutritional support, patient tolerance, overall expense, and familiarity of hospital staff with a specific tube type should be considered as well when choosing a feeding site.
Nasogastric tube feeding is one of the most common methods used for short-term nutritional support of dogs and cats. The use of small-bore, silastic, or polyurethane catheters have minimized complications associated with this delivery system. To decrease any discomfort associated with the initial placement of the catheter, tranquilization may be indicated and lidocaine is instilled into the nasal cavity, with the nose pointing up. The tube is lubricated and passed to the level of the thirteenth rib in dogs and the ninth rib in cats. In cats, the tube should be bent dorsally over the bridge of the nose and secured to the frontal region of the head with a permanent adhesive. In dogs, the permanent adhesive or a suture should be used to secure the tube to the side of the face that is ipsilateral to the intubated nostril.
Gastrostomy tubes are being used more and more in veterinary practice for those animals that need nutritional support for longer than 7 days. These tubes can be placed surgically or with endoscopic guidance. If surgery is used, a 5 ml balloon-tipped urethral catheter "is usually inserted, or a "mushroom"-tipped pezzer proportionate head urological catheter+. The reader is referred to other sources for a detailed description of this surgical procedure. In this author's practice, endoscopically placed gastrostomy tubes are considered ideal for many cancer patients and are described later.
The percutaneous placement of a gastrostomy tube by endoscopic guidance is quick, safe, and effective. A specialized 20 French tube* is used for placement in both dogs and cats. First, the stomach is distended with air from an endoscope that is placed into the stomach. Once the stomach is distended, an area just caudal to the last left rib below the transverse processes of the lumbar vertebrae is depressed and then located by the person viewing the stomach lining by endoscopy. A polyvinylchloride over-the-needle IV catheter is then placed through the skin and into the stomach in the area previously located by the endoscopist. The first portion of a 5-footlong piece of 8-pound test, nylon filament, or suture is introduced through the catheter into the stomach and then grabbed by a biopsy snare passed through the endoscope. The attached nylon and endoscope is then pulled up the esophagus and out the oral cavity. The end of the gastrostomy tube opposite the "mushroom" tip is trimmed so that it has a pointed end that will fit inside another polyvinylchloride catheter, after the stylet has been removed and discarded. This second polyvinylchloride IV catheter is then placed over the nylon suture so that the narrow end points toward the stomach. The free end of the nylon that has just been pulled out of the animal's mouth is then sutured to the end of the tube. The catheter-tube combination is then pulled from the end of the suture located outside the abdominal wall until the pointed end of the IV catheter comes down the esophagus and out the abdominal wall. The tube is then grasped and pulled until the mushroom tip is adjacent to the stomach wall as viewed by endoscopy. To prevent slippage, the middle of a 3- to 4-inch piece of tubing is pierced completely through both sides and passed over the feeding tube so that it is adjacent to the body wall and then glued or sutured securely in place. The tube is capped and bandaged in place. An Elizabethan collar is recommended. Once the tube has been in place for 7 to 10 days, the tube just below the bumper is severed to allow the mushroom tip to fall into the stomach. This piece may need to be removed by endoscopy in all but very large dogs.
Needle catheter jejunostomy tubes should be considered for dogs and cats with functional lower intestinal tracts that will not tolerate nasogastric or gastrostomy tube feeding. This method is especially valuable in cancer patients following surgery to the upper gastrointestinal tract. In this procedure, the distal duodenum or proximal jejunum is located and isolated by surgery (Fig. 12-7). A purse-string suture of 3-0 nonabsorbable suture is placed in the antimesenteric border of the isolated piece of bowel. A number 5 French polyvinyl infant nasogastric infant feeding tube is passed through a small incision in the skin and abdominal wall, through a piece of omentum (referred to as an omental patch) and then into the lumen of the bowel through a small stab incision in the center of the area encircled by the purse-string suture. An ideal placement site is in the bowel 20 to 30 cm from the enterostomy site or neoplastic lesion. The purse string is tightened and secured around the tube. The loop of bowel with the enterostomy site is then secured to the abdominal wall with four sutures that later will be cut after the tube is removed when feeding is complete in 7 to 10 days. Complications with this method, as with the gastrostomy tubes, include peritonitis, diarrhea, and cramping.
Enteral Feeding Formulations
The type of nutrients to be used depends largely on the enteral tube that will be used and on the status of the patient. Blended canned pet foods may be adequate for feeding by gastrostomy tubes while human enteral feeding products are easily administered though nasogastric and jejunostomy tubes. In any case, feeding usually is not started for 24 hours after the tube is placed. Once feeding is started, the amount of nutrients is gradually increased over several days and administered frequently in small amounts or continuously to allow the animal to adapt to this method of feeding. Either way, the tube should be aspirated 3 to 4 times a day to ensure there is not excessive residual volume in the gastrointestinal tract and should be flushed periodically with warm water to prevent clogging.
Additional research is necessary to determine if recent studies are correct in determining that standard texts overestimate the caloric requirements of normal dogs, including those with cancer. Until that time, the recommendation for determining the amount of enteral nutrients should be followed Briefly, the basal energy requirement (BER, Kcal/day) is calculated by multiplying 70 times the animal's weight in kg°.75 and then multiplying by a factor to derive the illness energy requirement (IER, Kcal/day as nonprotein calories). For normal dogs that are at rest in a cage, the BER is multiplied by 1.25. For those that have undergone recent surgery or that are recovering from trauma, the BER is multiplied by 1.2 to 1.6. If the dog is septic or has major burns, the BER is multiplied by 1.5 to 2.0. The IER has not been determined for dogs with cancer; however it may be high even in the absence of sepsis, burns, trauma, or surgery. The protein requirement for dogs is 4 gm/kg/day for normal dogs and 6 gm/kg/day in dogs that have heavy protein losses. Dogs and cats with renal or hepatic insufficiency should not be given high-protein loads (<_ 3 gm/100 Kcal in the dog; <_ 4 gm per 100 Kcal in the cat). Since most high-quality pet foods can be put through a blender to form a gruel that can be passed through a large-bore catheter, the IER of the animal is divided by the caloric density of the canned pet food to determine the amount of food to feed. The same calculation can be done with human enteral feeding products; the volume fed may need to be increased if the enteral feeding product is diluted to ensure it is approximately iso-osmolar before it is administered.
Total Parenteral Nutrition
Indications for total parenteral nutrition (TPN) include those previously discussed for enteral gastrointestinal tract to retain, digest, or absorb adequate quantities to meet the animal's nutritional needs. The benefit of long-term TPN in cancer patients is questionable at best. While the theoretical gains of TPN are similar to those espoused for enteral support, few have been realized to date in the scientific literature. Metaanalysis of large numbers of clinical trials for TPN in tumor-bearing people has revealed no significant benefit with respect to nutritional parameters, survival, treatment tolerance, or tumor response. Bone marrow transplant recipients are one important exception to the rule, as they appear to enjoy sigpificant improvement with TPN. At the same time, tumor-bearing patients receiving TPN are much more likely to develop serious systemic infections and are slightly less likely to achieve a response to their antineoplastic therapy. The authors recommend TPN in our cancer patients only when we anticipate recovery from the underlying circumstances. This includes postoperative gastrointestinal surgery patients, those with chemother- apy-induced anorexia, and patients with tumors for whom remission or cure is likely. The reader is directed to, several excellent reviews of TPN principles and. procedures in the veterinary literature.
As mentioned earlier, cancer cachexia is a common paraneoplastic syndrome that is associated with many of the alterations in metabolism noted in dogs with this condition. Cancer cachexia may have more clinical significance than the underlying malignancy. The clinical manifestations of cancer cachexia can impact a patient's quality of life, response to therapy, and overall survival time. Nutritional support is of paramount concern for the patient with cancer; the considerations are