Supportive Care for the Cancer Patient

How Painful Is Cancer in Animals?

Not all tumors are painful, and the amount of pain is likely to vary considerably from one animal to another, even with similar tumor types. The author’s experience and the experience of others would suggest that, using a conservative estimate, 30% of tumors in dogs and cats are associated with significant pain at the time of diagnosis. Tumors most likely to be associated with pain include those at the following sites: oral cavity, bone, urogenital tract, eyes, nose, nerve roots, gastrointestinal tract, and skin (Table 15-1). The 30% estimate is likely conservative since pain is experienced by 20% to 50% of human patients when the lesion is diagnosed, by nearly half undergoing active treatment, and by up to 90% with far advanced or terminal cancer. An overall average of about 70% of human patients with advanced cancer suffer pain.¹⁸

In addition to pain caused by the tumor itself, pain in cancer patients can also be caused by chemotherapy, radiation therapy, or surgery (perioperative pain, postoperative pain, and conditions such as “phantom limb” associated with some amputations) and by concurrent noncancerous disease, most notably osteoarthritis, gingivitis, and dermatologic conditions.

General Approach to Cancer Pain Management

The incidence of pain in animals caused by cancer is very difficult to estimate, as is the effectiveness of analgesic therapy. Recent surveys have found that significant numbers of animals in the perioperative setting were not receiving analgesic drugs,^19-26 although an overview of these studies seems to suggest the situation is improving. Analgesics are even less likely to be used for cancer pain. Glucocorticoids do provide some analgesia, and their use may be more widespread,²² but the specific treatment of cancer pain in animals is still likely to be suboptimal.

Suboptimal treatment of cancer pain in animals probably results from a number of factors such as the following:

In large part, these factors associated with suboptimal treatment of cancer pain in animals result from a lack of published, scientifically sound information on the subject. Such information also stimulates presentation and discussion of the topic in continuing education forums. In many respects, continuing education in a topic is facilitated by having Food and Drug Administration (FDA)-approved drugs or proven treatments because industry then has a vested interest in improving knowledge of the subject. Unfortunately, there are no analgesics with FDA approval for cancer pain in animals.

Although drug treatment is the mainstay of cancer pain treatment, effective cancer pain treatment often involves a combination of drug therapy, nondrug therapies, and good communication between all parties involved. A basic approach to cancer pain management is summarized in Table 15-2.

The Importance of Alleviating Pain in the Cancer Patient

The alleviation of pain is important not only from a physiologic and biologic standpoint, but also from an ethical point of view.²⁷ To help in an evaluation of welfare, “five freedoms,” initially proposed by the Brambell Committee in reference to farmed animals,²⁸ have been suggested. They may be applied equally in the context of companion animals²⁷ and are as follows:

For each freedom, there should be a consideration of the severity, incidence, and duration. As an example, consider a dog undergoing a maxillectomy. With such a surgery, it is possible that thirst and hunger may result from interference with the dog’s ability to eat and drink. However, the dog could be hand-fed and gradually taught to eat and drink despite the facial alteration. If the dog was never able to eat or drink again on its own, the owners could hand-feed him for the rest of his life or the dog could be fed via a feeding tube. Although this may represent a compromise to his freedom to express normal eating behavior, he would not be hungry or thirsty. Such a surgery may result in a cure for the disease and eliminate pain. However, the surgery may also result in pain and distress. Fear and distress would result because of the unfamiliar surroundings and people during the hospital stay. With appropriate nursing care, the dog should not suffer any physical or thermal discomfort. It can be seen from this example how many factors are interrelated, and all need consideration in the cancer patient, including pain and consideration of the length and severity of pain.

Pain relief may affect survival in cancer patients. Immunosuppression has been shown to depend on the severity of surgery in clinical^29-31 and experimental animal studies.^32,33 Additionally, the severity of surgery has been shown to influence tumor metastasis.^34-37 In 2002, a human clinical study suggested that laparoscopic colectomy was associated with increased survival,³⁸ and although subsequent studies found no difference in long-term survival,³⁹ there is interest in the immunologic and oncologic implications of less-invasive surgery.⁴⁰ In 2001, Page and coworkers found that the provision of analgesics significantly reduced the tumor-promoting effects of undergoing and recovering from surgery in a rodent model.⁴¹ The reduction of the tumor-promoting effects of surgery by analgesics may result from maintenance of natural killer (NK) cell function, but it is likely that other unrecognized factors also play a role.^41,42 More recently, it was found that spinal analgesia attenuated the laparotomy-induced suppression of tumoricidal function of liver mononuclear cells and decreased metastasis compared to rodents undergoing laparotomy without spinal analgesia.⁴³ This was considered to be due to preservation of T helper 1/T helper 2 (Th1/Th2) cytokine balance. Thus the provision of adequate perioperative pain management in oncologic surgery may be protective against metastatic sequelae in clinical patients. It is quite possible that chronic pain experienced by animals with cancer may also affect metastasis.

Assessment of Cancer Pain

Assessment of pain in animals, while often difficult, is extremely important. It is likely that the tolerance of pain by an individual animal varies greatly and is further complicated by the innate ability of dogs and cats to mask significant disease and pain. Physiologic variables such as heart rate, respiratory rate, temperature, and pupil size are not reliable measures of acute perioperative pain in dogs⁴⁴ and are unlikely to be useful in chronic pain states. The mainstay of pain assessment in cats and dogs suffering from cancer is likely to be changes in behavior. Table 15-3 outlines behaviors that are probably indicative in certain situations of pain. In general, if a tumor is considered to be painful in humans, it is appropriate to give an animal with a similar condition the benefit of the doubt and treat it for pain.

One of the most useful ways of determining if a tumor is painful is to palpate the area and evaluate the animal’s response. This may not correlate precisely with the amount of pain the animal spontaneously experiences, but if a tumor is painful on manipulation or palpation, it is highly likely there is spontaneous pain associated with it. As veterinarians, we struggle to measure spontaneous pain. It is perhaps reassuring that there is tremendous debate in the research community on how to measure spontaneous pain in rodent models.

Veterinarians should involve technicians and other staff members in the assessment process because they are usually the ones spending the most time with the patients in the hospital and may have more time to converse in a relaxed and informal way with owners.

The most important people in the assessment process are the owners. The veterinarian must work closely with the owner to capture this information. Often, owners need to be educated as to what signs to look for and that certain behaviors may be indicative of pain. Once very specific changes in behavior can be identified and recorded, these behaviors can be used to monitor the effectiveness of analgesic therapy. Furthermore, these specific activities can be used to create goals and therapy tailored to try to meet these goals. The importance of patient-reported outcomes (PROs) in human medicine is widely recognized.⁴⁵ These PROs may refer to a large variety of different health data reported by patients, such as symptoms, functional status, quality of life (QOL), and health-related quality of life (HRQOL).⁴⁵ In humans, QOL is a complex, abstract, multidimensional concept defining an individual’s satisfaction with life in domains he or she considers important. The term HRQOL reflects an attempt to restrict this complex concept to those aspects of life specifically related to the individual’s health and potentially modifiable by healthcare.⁴⁶ Both QOL and HRQOL have been used in veterinary medicine. Questionnaires have been developed to assess HRQOL in dogs^47,48 and cats⁴⁹ with cancer. Although pain certainly appears to be assessed in these HRQOL tools, it is not known how specific or sensitive these tools are to changing pain status.

The author’s approach to the evaluation of pain at each visit is to evaluate each of the following three aspects:

Follow-up is important, and the assessment of activity and behavioral parameters can be evaluated over the telephone.

Principles of Alleviation of Cancer Pain

Drugs and Strategies Used for Management of Pain in Cancer Patients

The drugs that can be used for chronic cancer pain management are outlined in Tables 15-4 and 15-5. The following notes are not a comprehensive appraisal of each class of drug but are suggestions for their use for cancer pain.

Neuronal Ablation or Exhaustion Therapy

Several new approaches to pain treatment revolve around the use of mechanisms to destroy or exhaust neurons involved in pain transmission. One approach is to use targeted neurotoxins to cause neuronal death.¹¹⁴ An example of this is the combination of a neurotoxin (saponin) to substance P. Substance P, when administered, binds to the neurokinin receptor (NKR), and the conjugate is internalized (a normal phenomenon of the receptor-ligand interaction), resulting in cell death due to the neurotoxin.^115,116 Because sensory neurons are rich in NKRs, if the conjugate is targeted appropriately (e.g., given intrathecally), sensory neurons are killed. Basic science studies suggest that in models of chronic pain, general sensory function is left intact, whereas hyperalgesia associated with chronic pain is decreased. Some toxicity work has been performed in dogs,¹¹⁷ and clinical trials in dogs with naturally occurring bone OSA are underway, with these being used as a model of human OSA pain. Another approach uses the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1) to target neurons involved in pain. When drugs such as capsaicin and resiniferatoxin bind to TRPV1, the resulting calcium influx that is initiated results in an inability of the neuron to function. If the activation of TRPV1 occurs for long enough or is intense enough, the resulting calcium influx can cause the neurons to degenerate and undergo apoptosis. Capsaicin is used in humans for neuropathic pain, and resiniferatoxin has been evaluated in dogs with naturally occurring bone cancer pain in which it provided prolonged pain relief, despite significant hemodynamic effects.⁵

Radiation Therapy

Radiation therapy is considered to palliate pain in canine OSA, although the evidence is largely anecdotal. A 0-7-21 palliative regimen, using 8 or 10 Gy fractions, has been reported to result in pain relief lasting about 70 days.^4,118 Additionally, two 8 Gy fractions over 2 consecutive days was reported to result in pain relief for a duration of 67 days.¹³ The difficulty in interpreting the value of radiation therapy for pain relief in these studies is the lack of controls or objective measures. Indeed, the natural course of pain and lameness in dogs with appendicular OSA has not been determined. One study evaluating objective measure of limb use in dogs with OSA undergoing radiation therapy found no significant changes in kinetic parameters after one 8-Gy dose of radiation.²

Samarium is a radioisotope that has been evaluated for use in dogs.¹¹⁹ Although the use of samarium Sm153 lexidronam in veterinary medicine is still limited, results of a noncontrolled clinical study with subjective assessments suggested improvement in lameness scores in 63% of dogs, suggesting that this therapy may be useful in the palliation of pain in dogs with bone tumors in which curative-intent treatment is not pursued.³

Acupuncture

Acupuncture can be provided through simple needle placement or by needle placement combined with electrical stimulation (of high or low frequency, although most types of pain respond to low-frequency stimulation). Results of a study in normal experimental dogs demonstrated a weak analgesic effect of electroacupuncture in anesthetized patients as evaluated by a reduction in the minimum alveolar concentration (MAC) of inhaled anesthetic agent.¹²⁰ Recent data utilizing a rodent model suggest that electroacupuncture may have beneficial effects in treatment of pain associated with bone cancer.^121,122 As yet, there is no evidence that acupuncture provides pain relief in veterinary patients.

The Future: Toward a Mechanistic Understanding of Cancer Pain

Over the last few years, it has become evident that the pain transmission system is plastic (i.e., it alters in response to inputs). This plasticity results in a unique neurobiologic signature within the CNS and peripheral nervous system for each painful disease. Understanding the individual neurobiologic signatures for different disease processes should allow novel, targeted, and more effective treatments to be established.¹²³ This approach should also allow for a more informed choice to be made regarding which of the currently available drugs might be most effective.

The first relevant model of cancer pain has been established in rats—an OSA model.¹²⁴ Prior to this model, evaluation of mechanisms and treatments were undertaken in chronic pain models such as sciatic nerve ligation or injection of chronic irritants—models that did not involve cancer. The introduction of clinically relevant cancer pain models is allowing tremendous progress to be made in the translation to effective human cancer pain treatment.¹⁰⁴ It is likely that spontaneous cancer in veterinary species will play a significant role in the future in the development of new analgesic approaches for humans, with an obvious benefit to canine and feline patients. Indeed, we are starting to see this with an exciting example being the evaluation of resiniferatoxin in dogs with bone cancer.⁵

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97. Chew, DJ, Buffington, CA, Kendall, MS, et al. Amitriptyline treatment for severe recurrent idiopathic cystitis in cats. J Am Vet Med Assoc. 1998;213:1282–1286.

98. Challapalli, V, Tremont-Lukats, IW, McNicol, ED, et al. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev. 4, 2005. [CD003345].

99. Fleming, JA, O’Connor, BD. Use of lidocaine patches for neuropathic pain in a comprehensive cancer centre. Pain Res Manag. 2009;14:381–388.

100. Ko, J, Weil, A, Maxwell, L, et al. Plasma concentrations of lidocaine in dogs following lidocaine patch application. J Am Anim Hosp Assoc. 2007;43:280–283.

101. Ko, JC, Maxwell, LK, Abbo, LA, et al. Pharmacokinetics of lidocaine following the application of 5% lidocaine patches to cats. J Vet Pharmacol Ther. 2008;31:359–367.

102. Weiland, L, Croubels, S, Baert, K, et al. Pharmacokinetics of a lidocaine patch 5% in dogs. J Vet Med A Physiol Pathol Clin Med. 2006;53:34–39.

103. Weil, AB, Ko, J, Inoue, T. The use of lidocaine patches. Compend Contin Educ Vet. 2007;29:208–210. [212, 214–206].

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105. Jimenez-Andrade, JM, Mantyh, WG, Bloom, AP, et al. Bone cancer pain. Ann N Y Acad Sci. 2010;1198:173–181.

106. Sabino, MA, Mantyh, PW. Pathophysiology of bone cancer pain. J Support Oncol. 2005;3:15–24.

107. Milner, RJ, Farese, J, Henry, CJ, et al. Bisphosphonates and cancer. J Vet Intern Med. 2004;18:597–604.

108. Fan, TM. Intravenous aminobisphosphonates for managing complications of malignant osteolysis in companion animals. Top Companion Anim Med. 2009;24:151–156.

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110. Farese, JP, Ashton, J, Milner, R, et al. The effect of the bisphosphonate alendronate on viability of canine osteosarcoma cells in vitro. In Vitro Cell Dev Biol Anim. 2004;40:113–117.

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114. Wiley, RG, Lappi, DA. Targeted toxins in pain. Adv Drug Deliv Rev. 2003;55:1043–1054.

115. Wiley, RG. Substance P receptor-expressing dorsal horn neurons: lessons from the targeted cytotoxin, substance P-saporin. Pain. 2008;136:7–10.

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Metabolism of Cancer: Substrate Utilization

Numerous neoplastic cell lines have been successfully propagated in culture allowing examination of cell biology. A fundamental observation is that the majority of neoplastic cells propagate better in a high glucose media, which is likely the result of limited fatty acid metabolism coupled with increases in metabolic pathways that utilize glucose. This has traditionally been termed the Warburg effect after Otto Warburg’s seminal work suggesting that glycolysis is the primary pathway for energy production in neoplastic cells.^1,2 Studies in humans have shown that certain cancer patients liberate excessive lactate from solid tumors,^3,4 providing evidence that glycolysis and pyruvate production are critical to neoplastic cell metabolism. This has led to the Cori cycle hypothesis of neoplasia, whereby neoplastic tissues, much like skeletal muscle tissue, appear to undergo regeneration of glucose from lactate through hepatic resynthesis of glucose.⁵ Unfortunately, this regeneration of glucose is an energy costly cycle and is thought to contribute to increases in resting energy requirements.

In veterinary medicine, there is a significant body of work examining metabolism and cancer, often through the application of indirect calorimetry assessments to study whole body metabolism. These studies have interrogated oxygen consumption and carbon dioxide liberation and such data provide an estimate of energy consumption (resting energy expenditure [REE]) and substrate utilization (respiratory quotient [RQ]). Healthy dogs display higher REE than dogs with stage III and IV lymphoma.⁶ RQ values between the groups were not different, suggesting that all dogs were using similar substrate, and dogs with lymphoma were not preferentially consuming more glucose than their control counterparts.⁶ In a separate study, dogs with lymphoma fed either a high-fat or high-carbohydrate diet during doxorubicin chemotherapy did not differ in remission times, survival times, or tumor burden, suggesting that dogs with lymphoma under treatment were not sensitive to this basic dietary alteration.⁷ During this study the REE and RQ assessed during treatment did not change significantly when the tumor burden was eliminated with chemotherapy suggesting no significant changes in energy expenditure or metabolism. These data collectively indicate that there is no fundamental difference observed between normal healthy dogs and dogs with lymphoma and that removal of the tumor burden does not alter the resting energy requirement.

Canine nonhematopoietic malignancies were also examined before and 4 to 6 weeks after excision of their primary tumors, including mammary carcinoma, OSA, high-grade mast cell tumors, and lung carcinoma. As in dogs with lymphoma, REE was not different from control dogs nor was there any difference in REE between preexcision and postexcision of the primary tumor, suggesting no futile cycling of energy in these patients.⁸ Interestingly, in this study the RQ values were above 0.8 for all control and tumor-bearing dogs, suggesting that the resting energy was not from lipolysis, which was contradictory to a follow-up study performed in dogs with OSA. In that follow-up study, there was an increase observed in the REE in dogs with OSA compared to control dogs but a RQ of 0.7 in both affected and control dogs.⁹ This increased REE persisted after excision of the primary lesion, suggesting that the modest increase in REE was due to factors other than the primary neoplasia and may be associated with micrometastasis, inflammation associated with neoplastic disease, or heightened pain response associated with the primary tumor and surgical procedure.⁹ These findings were surprising in light of the previous studies mentioned but were likely more valid considering that the REE calculations in the OSA study were based on lean mass rather than total kilograms of body weight.⁹ It is well known that fat mass is relatively metabolically inert; therefore REE based on lean body mass is more appropriate. The previous studies in nonhematopoietic malignancies and lymphoma did not adjust for body condition or lean body mass in tumor-bearing or normal populations under study,^7,8 and the inability to document differences in REE noted in these two studies may have been confounded by a lack of body condition assessment.

Specific metabolic changes have been reported in dogs with several types of cancer. Alterations in glucose metabolism (potentially higher glucose turnover), increased protein turnover, and urinary protein losses in dogs with OSA have been observed.⁹ In addition, studies in dogs with lymphoma identified alterations in carbohydrate metabolism such as increased serum lactate and insulin concentrations during glucose tolerance testing that suggest insulin resistance.^6,10,11 This may be partially explained by aberrant interleukin-6 (IL-6) and other cytokine influences on glucose metabolism resulting in insulin resistance in dogs with lymphoma.¹² Insulin insensitivity and serum lactate did not change once remission was achieved in one of these studies.⁶ Mild alterations in lipid metabolism in dogs with lymphoma were suggested by higher basal triglyceride and cholesterol concentrations compared to control dogs,¹³ and treatment with doxorubicin lowered serum cholesterol, perhaps due to hepatic effects of chemotherapy.¹³ However, the dyslipidemia present was not ameliorated once the primary tumor burden was eliminated, which is logical in light of the insulin resistance observed.

Cancer Anorexia and Cachexia

Anorexia or hyporexia (inadequate food intake) in cancer patients is a common occurrence and can be one of the presenting clinical signs of cancer. Inadequate appetite is often due to an enhanced inflammatory cytokine response (i.e., IL-6 and IL-1) associated with the tumor, resulting in hypothalamic arcuate nucleus suppression of appetite. In the case of gastrointestinal cancer, pain associated with eating, obstruction, or dysfunctional transit mechanisms can lead to anorexia. In patients undergoing treatment, anorexia may be partially explained by adverse events associated with the use of chemotherapy. Chemotherapeutics can cause a variety of alterations in olfactory and taste sensorium. Since dogs and cats rely heavily on olfactory cues, the loss of olfactory bulb stimulus diminishes palatability of foods.^13,14 Additionally, the loss or alteration of taste (ageusia or dysgeusia) can further complicate anorexia and may last for several months before neuronal regeneration can take place at the olfactory bulb and tongue.^13,14

Cachexia, on the other hand, although identified in many human cancer patients, does not appear to be common in dogs with nonhematopoietic malignancies other than a predisposition toward insulin resistance.^6,10,15,16 Evidence in humans and mouse models suggests that the most prominent influence inciting the cachectic phenomenon may be excessive cytokine stimulation, which leads to insulin resistance, extensive lipolysis, and proteolysis of tissue stores.^17,18 The three primary cytokines thought to be involved in promoting enhanced proteolysis are TNF-α, IL-1β, and IL-6.^17,18 TNF-α and IL-1β have both been directly associated with anorexia and upregulation of mitochondrial uncoupling protein, whereas IL-6 and TNF-α have been observed to increase myofibrillar degradation machinery, all of which may play a role in the anorexia/cachexia syndrome associated with neoplasia.^19,20 IL-6 and c-reactive protein, both markers of inflammation, have been observed to increase in canine lymphoma patients.^12,21,22 Yet, it does not appear that cachexia is a common occurrence in dogs diagnosed with neoplasia since dogs examined 6 months prior to diagnosis of cancer showed no difference in body weight or body condition than at presentation for various neoplasms.¹⁵ This may be partially explained by differences in common tumor types between species. Cachexia in humans is often associated with epithelial cancers such as pancreatic, colon, mammary, and prostate cancer. Additionally, human patients undergo dramatically different and more aggressive treatment protocols over lengthy time periods, which we typically do not encounter in veterinary medicine due to owner financial constraints and QOL considerations.

Cats on the other hand may show a more typical cachectic response involving excessive lean body mass wasting. Recent evidence suggests that approximately 56% of cats with lymphoma and other solid tumors have body condition scores of less than 5 out of 9.²³ More intriguing is that the survival time for cats with lymphoma with a body condition score of 5 or greater was 16.9 months, compared to those with lower scores (3.3 months).²³ This warrants monitoring of caloric intake and aggressive implementation of nutritional interventions in feline cancer patients.

Epidemiology, Prevention, and Risk Factors

In humans, the two major nutritional factors associated with risk of developing cancer are excess body weight (obesity) and low fruit and vegetable consumption.^24-27 Although these parameters may be interrelated, both appear to play a direct role in the risk of cancer development. Convincing data suggest that the westernized diet and lack of fruit and vegetable matter are linked to increased relative risk of nearly all types of neoplasia, including prostate, colon, breast, lymphoma, and leukemia.^28-30 Although the evidence is compelling, the data do not support a causal association, and it may be a combination of factors associated with diet, as well as confounding lifestyle differences in humans consuming higher amounts of fruits and vegetables, that may be important in deterring cancer.

In veterinary medicine, there are few studies examining the effects of dietary substrate (protein, fat, carbohydrate) and plant-based dietary intake and cancer incidence. Two epidemiologic studies using validated food frequency questionnaires examined the effect on survival of calories coming from fat, protein, and carbohydrate for 1 year prior to and after diagnosis of mammary carcinoma.^31,32 These data were contradictory to human findings, showing that dogs with increased protein intake had increased survival times and that fat and carbohydrate intake did not play a role in progression of disease.^31,32 Another study suggested that risk of neoplasia was increased in dogs receiving nontraditional, poorly balanced diets (i.e., table foods as primary consumption).³³ Further examination of this group showed no association between blood selenium concentration and mammary carcinoma when compared to healthy age-matched and hospitalized control dogs. Serum retinol (vitamin A) values were also decreased in dogs with mammary carcinoma in this study.³³ Whether the lower serum retinol was a reflection of poor retinol intake or a reflection of the disease manifestation was not determined. A diet high in red meat was also identified as a risk factor in this study. In many cases, a high-protein food may be evaluated as higher quality because protein is an expensive ingredient; however, many variables in addition to ingredients are important. Ingredient quality, digestibility, and socioeconomic factors such as veterinary care should be considered. It does suggest that feeding an incomplete diet is associated with increased cancer risk and provides justification for a complete and balanced diet (Association of American Feed Control Officials [AAFCO]-approved commercial dog food) throughout the life of a dog.

Nutritional risk factors examined in Scottish terriers, who have a genetic predisposition to develop transitional cell carcinoma (TCC), showed that the addition of vegetables to a dog’s diet resulted in a lower incidence of the disease.³⁴ However, there are confounding lifestyle factors that cannot be accounted for in this epidemiologic investigation, including better health care, variation in nutrition supplied as commercial food, and other associated environmental exposures. Yet, this study is provocative and suggests further study is warranted.

Specific vitamins and their relationship to cancer development have received significant attention in humans, including retinol, ascorbic acid, vitamin E, selenium, and vitamin D. In veterinary medicine, these nutrients have not been thoroughly studied in relation to cancer risk. Human metaanalyses examining oral supplementation for single nutrients such as ascorbate, selenium, and vitamin E have been inconclusive or negative when examining protective, anticarcinogenic effects.^35-37 Other nutrients like β-carotene, the precursor to retinol, is currently thought to be ineffective as a chemopreventive agent and in some instances has proved to be harmful in certain populations (i.e., smoking populations).^38-40 Currently, vitamin D (25-hydroxyvitamin [OH] D₃) status and supplementation has been an area of vigorous epidemiologic investigation due to an increased relative risk of various neoplastic diseases associated with low serum vitamin D status.^41-43 In dogs and cats, unlike humans, vitamin D status is directly dependent on dietary intake since they cannot convert 7-OH-dehydrocholesterol to pre-vitamin D. One would expect that serum vitamin D concentrations would not fluctuate tremendously in dogs being fed commercial dog food.⁴⁴ A recent investigation suggests that Labrador retrievers with mast cell disease have lower serum vitamin D status than healthy Labrador retrievers, making vitamin D status an interesting area of future investigation.⁴⁵ Whether this is a direct reflection of dietary intake or a reflection of the biochemical disposition in affected dogs with cancer remains to be determined.

In humans, obesity has been associated with an increased risk of many cancers, including breast, prostate, colon, leukemia, lymphoma, and pancreatic neoplasia.^24-27 In companion species, studies examining this association are limited. The largest retrospective study in dogs showed no association between body condition and neoplastic disease,¹⁵ whereas other epidemiologic studies suggested that obese cats and dogs may have a slightly higher rate of neoplastic disease.^46,47 Two other investigations revealed a more definitive link between obesity in female dogs and the onset of mammary carcinoma.^31,33 The risk of mammary carcinoma was greater in obese spayed dogs in one study, although obesity was an increased risk factor but independent of spay status in another.^31,33 Both studies suggest an increased risk when obesity is present at 1 year of age, and one suggested that obesity at 1 year before diagnosis also increased risk.⁴⁷ The question of whether early onset obesity, much like early spaying, epigenetically predisposes mammary glands to an altered risk of cancer remains to be addressed.

Implementing a Nutritional Plan for the Oncology Patient: Nutritional Assessment

To fully assess the cancer patient, information regarding body weight, body condition score, and diet history are crucial. Dietary history, before and during treatment, should be obtained to appropriately assess the kilocalorie intake. This information will allow the practitioner to feed the patient appropriately during hospitalization and, more importantly, to recognize hypophagic behaviors, allowing for proactive interventions. A typical diet history should include the forms of food (wet or dry), amounts fed daily, as well as treats, human table foods, and additional supplements provided. A food diary has been helpful for humans attempting to understand energy and nutrient intake and is likely to also be helpful for dogs in particular as a wide variety of food stuffs are offered to dogs.

Serial assessment of body weight is important, particularly where malnutrition is a consideration. Malnutrition is often associated with cachexia and/or anorexia. Anorexic behavior can be deduced from the diet history and can be treated aggressively with nutritional and/or pharmacologic intervention; however, if cachexia is suspected, then alternative treatments can be sought. The difficulty in clinically differentiating cachexia from anorexia is our inability to measure loss of lean versus fat mass. The loss of fat mass is typical during anorexia, and equal loss of lean and fat mass suggests cachexia. Although this cannot be deciphered efficiently in veterinary practice, overall weight loss guidelines have been offered in the human literature whereby body weight loss of 5% in 1 month or 10% in 3 months without conscientious dieting suggests cancer cachexia.⁴⁸ Two body condition scoring (BCS) systems have been adopted as a means of nutritional assessment in companion species; however, the 1 to 9 BCS system (Figure 15-2) has been more thoroughly validated in the literature.^49,50 Modest differences in BCS between dogs and cats exist due to preferential deposition of body fat along the inguinal and abdominal areas in cats, whereas dogs tend to have no preferential deposition. These differences may justify a muscle condition scoring system in cats (Table 15-6).²³

The final component of nutritional assessment consists of a routine physical examination, complete blood cell count, and serum chemistry evaluation. Physical examination findings consistent with malnutrition include poor hair coat, chronic gastrointestinal disturbance, seborrhea, lethargy, and pallor. The first signs of chronic nutrient deficiency are often manifested in areas of rapid cellular turnover leading to skin, gastrointestinal, and hematologic signs and should be considered in cases of prolonged anorexia. Chronic malnutrition can result in low hemoglobin and red blood cell counts, as well as hypoproteinemia and hypoalbuminemia. Additionally, with the trend toward nontraditional feeding practices, there is the potential for diets that lack sufficient mineral content (e.g., calcium, iron, and copper) resulting in bone and hematologic manifestations. Many homemade diets lacking supplementation with bone meal can lead to secondary hyperparathyroidism and clinical osteopenia.^51,52 Clients using nontraditional diets should be educated through consultation with a veterinary nutritionist.

In dogs, excess body condition (i.e., obesity) may be more of a concern than malnutrition or deficiency. Treatment of obesity is not a priority in many cancer patients, considering metabolic changes that may occur during chemotherapy and the potential for treatment-related eating pattern changes. One study suggests that body condition does not change from 6 months prior to diagnosis to the day of diagnosis,¹⁵ whereas another study suggests that over 68% of dogs lose weight during treatment⁵³; however, loss was less than 5% of body weight and nearly 30% of dogs were scored as obese prior to treatment. The occurrence of obesity in dogs with neoplasia appears to follow the national trends in canine obesity.

Feeding the Hospitalized Oncology Patient

Hospitalization of debilitated cancer patients undergoing evaluation or therapy has unique nutritional opportunities and challenges. Hospitalization during some fractionated radiation therapy is common, and the provision of more than the resting energy requirement (RER) during this period is often unnecessary unless extreme circumstances exist where extensive tissue repair is ongoing (e.g., postoperatively, epithelial mucositis). This increased energy requirement is known as the illness energy requirement (IER) and is often considered to be between 1.1 to 2 times the RER, particularly when transudates or exudates are involved with the repair process and protein losses are excessive. Energy requirements postdischarge may also be increased above hospitalization RER due to increased activity and neuter status, which is represented as the maintenance energy requirement (MER). Table 15-7 presents starting calculations for MER based on the linear equation used in veterinary patients taking into account the activity status. Exponential equations are preferred in dogs and cats under 2 kg or over 30 kg to derive a more accurate estimate of the RER:

Evidence suggests that the exponent of the equation may be different for cats (e.g., 0.67).⁵⁴ Once a patient returns home, its RER typically increases slightly due to increased activity. Therefore clinicians should adjust the energy intake on discharge.

Coax Feeding and Pharmacologic Appetite Stimulation

Ensuring full energy requirement intake enterally may be difficult due to a diminished appetite in canine and feline cancer patients. There are many considerations when trying to promote adequate intake, and these may be different in dogs and cats. Hand-feeding in dogs and cats that enjoy this approach should be considered rather than putting a bowl in the cage and leaving it there. Hand-feeding may be best achieved during owner visits when the animal is most comfortable and often away from the busy atmosphere of most intensive care units or oncology wards.⁵⁵ For cats, having a quiet place away from distractions that create a fearful environment may be helpful to achieve adequate intake. Making one cage an eating cage that is covered and away from the litter box is ideal as some cats will not eat near the litter box during hospitalization.⁵⁵

Addition of flavorings may also be helpful. Dogs have salt and sweet receptors, and the addition of sugar, syrups, or other sweeteners can sometimes improve appetite.⁵⁵ Cats do not have the lingual receptors to appreciate sweet flavors. Therefore salt can be used to entice cats to eat; however, they tend to be more averse to oversalted foods.⁵⁵ Additional protein added to the diet of both dogs and cats can improve appetite and enhance intake since dogs appear to prefer higher protein diets and cats have increased density of lingual amino acid receptors, making high protein choices logical.⁵⁵ The supplementation of animal-based or vegetable-based fat may increase palatability but must be monitored as additional fat can dilute the nutrient content of the feed. In the presence of nausea, introducing multiple foods can create long-term aversions limiting choices of form and texture once the nausea has resolved.⁵⁵ Using one or two foods to coax feed is ideal, rather than an entire array of products from the kitchen.

Pharmacologic approaches to improve enteral support may be attempted; however, many of the purported effects are anecdotal with little evidence of their true utility in veterinary medicine. Human studies suggest several approaches, including pharmacologic alterations in serotonergic stimulation in the brain, decreased cytokine stimulation, and the promotion of hypothalamic satiety center signaling.^56,57 Approaches in veterinary medicine have focused on the use of the antiserotonergics (e.g., cyproheptadine and mirtazapine). Unfortunately, no definitive clinical studies documenting the efficacy of these drugs in dogs and cats with cancer exist.⁵⁵ Of some interest is the use of valium to stimulate appetite in cats and the recommended dosing of 1 mg by mouth (PO) daily has proved useful.⁵⁸ However, the use of valium does not come without the potential for severe side effects (e.g., hepatic necrosis), making long-term use of valium ill advised.⁵⁹ In dogs, low-dose propofol is used to briefly stimulate eating behavior to test the integrity of the bowel (i.e., vomiting) when unsure about enteral functional status, although more prolonged use of propofol is not attempted.⁶⁰

Assisted Enteral Support

In many instances, the use of assisted enteral nutrition should be considered, particularly if the animal is not consuming appropriate kilocalorie requirements. In the hypophagic cancer patient, it may be essential to provide assisted feeding through various techniques, including syringe, nasogastric, esophagostomy, or gastrostomy feeding. Syringe feeding is the easiest and requires the least attention to detail by owners and clinicians. In the nauseous and anosmic patient, this can be difficult to implement due to patient resistance. Nasogastric tubes can be easily placed without anesthesia and can be useful in hospitalized animals but are often problematic to manage at home and are limited to the use of liquid enteral products due to tube diameter. The two most widely accepted means of implementing long-term enteral support is the placement of an esophagostomy or gastrostomy tube. The esophagostomy tube is typically placed under anesthesia; techniques for placement have been described elsewhere.⁶¹ Once secured, the tube site is typically wrapped, and the insertion site should be examined every 24 to 48 hours for signs of cellulitis and discharge. These tubes are typically recommended for intermediate to long-term feeding for a period of 2 to 3 weeks up to 2 to 3 months.

Gastrostomy tube placement should be considered when tube placement is required for longer than 6 to 8 weeks.^61,62 Advantages include direct gastric delivery of nutrients and prevention of tube eversion if emesis is encountered. Anesthesia is required for either surgical or percutaneous endoscopic placement approaches. The endoscopic approach is generally safe and effective, although associated with a higher risk of complications.⁶² The author prefers surgical placement in large breed dogs because they may be predisposed to separation of the stomach from the body wall after endoscopic placement. Peritonitis is the most serious complication following tube placement since the peritoneum is disturbed with this approach and leads to a permanent stoma from the stomach to the outside of the body.^61,62 After successful gastrostomy tube placement, the tube can be used within 24 hours of placement but should not be removed before 2 weeks, allowing for adhesion and fibrosis of the gastric wall to the abdominal wall. Once a stoma has formed, the original surgically placed tube may be replaced with a low profile or “button” feeding device. Owners should be aware that these low profile devices need replacing every 6 to 8 months and will require mild sedation for replacement.⁶³

Esophagostomy and gastrostomy tubes allow for a diverse number of products to be used for feeding beyond the liquid veterinary diets. Many over-the-counter and veterinary therapeutic diets can be blended for feeding; however, when some products are blended with water, they result in less than 1 kcal/mL. Diets that provide higher caloric density that can be passed through a 7 French or greater diameter catheter are listed in Table 15-8. These products tend to be higher in protein and fat and can be fed at reduced volumes and rates when nausea or food volume is an issue. A typical dog or cat receiving a slurry of food at 1 kcal/mL will also be meeting their fluid requirements.⁶⁴ Similarly, providing 1 kcal/mL for dogs and cats that are not actively consuming water at home is also advised.

Parenteral Support

If enteral support is not an option, then parenteral nutrition (PN) should be considered. Parenteral support can be either partial PN (PPN) or total PN (TPN). PPN has also been termed peripheral parenteral nutrition considering it is typically delivered through peripheral veins. Prospective studies examining outcome following parenteral support have not been performed in clinical veterinary medicine and only a handful of retrospective investigations characterize complication rates.^65-70 In veterinary patients, particularly cats, the metabolic complication most often encountered is hyperglycemia. Mechanical complications are also prevalent (i.e., feeding line problems, inadvertent patient removal). A common misconception is that sepsis is a common complication, but in fact it is quite rare.^65-70 Parenteral support should only be considered when enteral support is not an option due to medical complications; enteral support is considered superior as it prevents transmigration of bacteria to the portal blood and improves the immunologic status of patients.⁷¹

Parenteral support is not well studied in veterinary medicine, and the relative use and utility of the three main substrates (glucose, amino acid, and lipid) differ, depending on the source of information.^72-74 Some advocate using glucose and lipid to meet the energy requirements and then add in amino acids to the formulation based on the protein needs per kilogram of body weight. Others advocate adding just above the minimal protein requirement as amino acids making up part of the REE. The protein requirements for ill cats and dogs are currently unknown, and we can only assume the requirements are similar to those of healthy normal animals. Extrapolation from human data suggests that protein turnover may be higher during catabolic illness, and we often add slightly more protein than required. In an elegantly designed study, it was found that approximately 2.3 g protein/kg body weight is sufficient for IV amino acid solution in normal dogs.⁷⁵ This suggests that adding 2.5 to 3 g/kg amino acid solution for a dog appears sufficient and 4 g/kg is often used as a starting point for cats. Amino acids come in several different formulations and strengths (e.g., 5.5%, 8.5%, and 10%). Additionally, amino acid solutions come with and without electrolytes. Amino acids with electrolytes typically provide basal sodium, chloride, magnesium, phosphorus, and potassium when used at 1.5 to 2.5 g/kg body weight of protein; however, these are used less often in veterinary species, particularly in cats whose protein requirements are higher. When using amino acids with electrolytes, the electrolytes provided should be considered before supplementing additional electrolytes in fluids. Figure 15-3 describes a typical TPN feeding program for a cat or dog using a 10% amino acid solution without electrolytes. During the first day of TPN, it is recommended to provide only half of the calorie requirement, particularly if there has been a history of anorexia. This recommendation is due to the potential for refeeding syndrome, whereby rapid glucose metabolism can lead to hypophosphatemia, hypokalemia, and hypomagnesemia. This also illustrates the need to assess electrolyte status every 12 to 24 hours for the first 48 to 72 hours when implementing TPN.

PN formulation should be done in a laminar flow hood with appropriate aseptic procedures to prevent contamination of solutions. A sterile catheter should be used, and PN should be administered through its own port in a multilumen catheter with the most distal port reserved for PN. Avoid the addition of other medications or treatments because some medications are not compatible with PN. The typical osmolality and pH of a TPN solution will be far different than plasma osmolality (around 1000 to 1300 mOsmol and pH less than 7). This may be irritating to the vascular endothelium and requires a large vessel for administration.⁷⁴ Such high osmolar solutions cannot be used in a peripheral vein as they may induce thrombophlebitis, and this is the reason that 5% glucose is used to dilute PPN rather than the 50% glucose solution used in TPN solutions.^66,72 Using 5% dextrose creates an osmolality of less than 700 mOsmol, which is a guideline from human medicine that has been adopted by many veterinary nutritionists and internists.⁷⁶ Figure 15-4 describes guidelines for PPN formulation for dogs and cats.^66,72 Addition of B-complex vitamins should also be considered when using TPN and PPN. Most preparations do not include folate, and cobalamin may be insufficient or absent and should be considered separately if long-term support is required Furthermore, if chronic use of TPN is required, the addition of calcium to separate fluids and the use of amino acids with electrolytes and trace mineral additions to the TPN should be considered.

The proportions of glucose and lipids in parenteral solutions is a subject of much debate, particularly in the cancer patient, because of suggestions that neoplastic tissues utilize glucose more readily and the possibility of mild insulin resistance.^10,11 However, increasing lipid content to meet energy requirements has also been met with some trepidation due to lipid’s potential to mildly suppress the immune system.⁷⁷ Lipid has also been incriminated as the cause of microemboli,⁷⁸ and some suggest placing a 1.5 to 2 µm filter in the line to remove lipid particles and microbes; however, recent evidence suggests that in a typical veterinary-formulated TPN solution the lipid particles remain well emulsified—no bacterial growth was evident for 3 days following formulation when kept refrigerated.⁷⁹ PPN, with its lower osmolality, is at an increased risk of sequestering microbial growth.

Nutritional Support in the Cancer-Bearing Patient

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A Paradigm Shift: Paternalism to Partnership

Recent societal changes have caused a paradigm shift in the veterinarian-client-patient relationship. Growing client expectations, the strong attachment between people and their pets, and increasing consumer knowledge demand a shift in communication style from the traditional paternalistic approach to a collaborative partnership.^5,21,22 Many clients are no longer content with taking a passive role in their animal’s healthcare, preferring to take an active role in the decision-making process.⁵

Paternalism is characterized as a relationship in which the oncologist sets the agenda for the appointment, assumes that the client’s values are the same as the veterinarian’s, and takes on the role of a guardian for the patient.^23,24 Traditionally, paternalism is the most common approach to medical and veterinary visits. In general practice, the veterinarian used a paternalistic approach in 31% of wellness visits and 85% of problem visits.²¹ The topic of conversation is primarily biomedical in nature, focusing on the medical condition, diagnosis, treatment, and prognosis.²¹

In a paternalistic relationship, the oncologist does most of the talking and the client plays a passive role. This approach is often referred to as the data dump and symbolized by a shot-put.²⁵ Throwing a shot-put is unidirectional, the intent is on the delivery, the information to be delivered is large in mass and scale, and it is challenging to receive the message. Intuitively, it seems like this directive approach enhances efficiency and promotes time management. The challenge is that the agenda and subsequent diagnostic or treatment plan may not be shared between the oncologist and client, compromising the ability to reach agreement, move forward, and achieve full compliance. This could result in a roadblock and the need to take steps backward to recover and regain client understanding, commitment, and trust.

In contrast, partnership or relationship-centered care represents a balance of power between veterinarian and client and is based on mutuality.^23,24,26 In the relationship-centered model, the relationship between oncologist and client is characterized by negotiation between partners, resulting in creation of a joint venture, with the veterinarian taking on the role of advisor for the client. Respect for the client’s perspective and values and recognition of the role the animal plays in the life of the client are incorporated into all aspects of care. In general practice, 69% of wellness visits and 15% of problem visits were characterized as relationship-centered.²¹

The conversation content of relationship-centered visits is broad, including biomedical topics, lifestyle discussion of the pet’s daily activities (e.g., exercise regimen, environment, travel, diet, and sleeping habits) and social interactions (e.g., personality or temperament, behavior, human-animal interaction, and animal-animal interactions) that are key indicators of patient quality of life.²¹ In addition, a relationship-centered approach encompasses building rapport, establishing a partnership, and encouraging client participation in the animal’s care, all of which have the potential to enhance clinical outcomes.

This collaborative relationship is symbolized by a Frisbee.²⁵ In playing Frisbee, the interaction is reciprocal; the intent is on dialog; the delivery is airy, light, and free; small pieces of information are delivered at a time; and the deliverer and receiver adjust their message to stay on target. The emphasis of the Frisbee analogy is on eliciting client feedback to assess how the client perceives, processes, and understands the information presented.

Relationship-Centered Care

Combining several frameworks, Mead and Bower²⁷ identified the following five distinct dimensions of relationship or patient-centered care in the human medical setting:

These principles translate readily to the veterinary context.^21,22 Expanding data gathering to explore the broader lifestyle of the client and pet enhances the understanding of the animal’s illness. Discussing unique details such as financial resources, the role of the primary caregiver, feasibility of implementing the plan, and recent life events (i.e., new birth, death, new job, or moving) promotes compliance. With increased recognition of the human-animal bond, it is important to assess the level of attachment and the impact of the animal’s illness on the family. Eliciting information on the client’s expectations, thoughts, feelings, and fears about the pet’s illness fosters client participation and satisfaction and promotes shared decision making.

Based on medical communication studies, the following principles of relationship-centered care are associated with significant clinical outcomes:

In veterinary medicine, a study investigating the use of patient-centered communication in euthanasia discussions with undisclosed standardized clients identified that veterinarians did not fully explore client feelings, ideas, and expectations.²² In these visits, veterinarians did not involve clients in defining the problem and identifying treatment goals. Shared decision making is a key component of relationship-centered care, in which there is two-way exchange between the veterinarian and client, identifying preferences and working toward consensus to achieve significant clinical outcomes for the veterinarian, client, and patient.

Core Communication Skills for Cancer Communication

The Calgary-Cambridge Guide²⁵ is an evidence-based communication model that provides structure to the clinical interview, describing the tasks and identifying key communication skills to help veterinarians achieve clinical outcomes. Defining and demonstrating specific skills and behaviors are instrumental first steps to enhancing communication approaches.^14,15 The communication tools described next were identified as core communication skills¹⁵ in human cancer communication literature^7,13,18,20 and are highly applicable to veterinary oncologist-client-patient interactions.

“I Don’t Have Time for This…”

Before moving on to how to use these skills in crucial cancer conversations, one of the most common concerns expressed in communication training is that there is not enough time in the clinical interview. It seems like the facilitative approach (i.e., Frisbee) of relationship-centered care takes more time; however, it was found in veterinary general practice visits that relationship-centered care appointments were shorter in length because the veterinarian and the client achieved common ground.²¹ In human medicine, when patients are left to tell their story uninterrupted, their average talking time was 92 seconds, sharing key clues to the diagnosis.²⁵ Empathy can be expressed as well without prolonging the appointment time; in one study, as little as 40 seconds of empathy decreased the patient’s anxiety level.^38,39 Although counterintuitive, evidence suggests that using the core communication skills actually saves time and allows for a more efficient veterinarian-client-patient interaction. In addition, spending time to build a relationship at the beginning of the evaluation process creates trust, which will pay dividends as the management process progresses through the diagnostic and treatment phases.

Approaches to Cancer Conversations

As presented in the introduction, cancer communication is a series of conversations over time, starting with delivering the diagnosis (i.e., delivering bad news), discussing prognosis, making decisions about treatment options, assessing QOL, transitioning to palliative or supportive care, and ending with preparing families for euthanasia, dying, and death.¹⁸ These difficult conversations are spread throughout multiple visits. This step-by-step approach is guided by the veterinarian’s expertise, the client’s agenda and perspective, and the patient’s condition, response to treatment, and QOL.

Conclusion

Given the growing expectations of clients, the strength of the human-animal relationship, and the resultant emotional impact of cancer communication on pet caregivers and the oncology team, relationship-centered care is integral to providing quality cancer care.^5,21,22 Extrapolating from evidence in human medicine, compassionate cancer communication is related to significant clinical outcomes for the oncologist, client, and the patient, including enhancing client^28-30 and veterinarian satisfaction,^31,32 improving adherence to recommendations,³³ working through emotions,^38,39 and promoting patient health.³⁴ Effective techniques for cancer communication can be taught and are a series of learned skills.^15,25 Through supportive approaches, cancer communication can be made less distressing to the client, fostering client relationships and optimizing patient care while promoting professional fulfillment for the veterinarian.

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