Verónica Salazar School of Veterinary Medicine, Universidad Alfonso X El Sabio, Madrid, 28691, Spain Cancer is a major disease in animals of all ages and is the leading cause of death in older pet animals [1]. However, a precise estimate of cancer morbidity and mortality is difficult to obtain due to several limitations that differentiate animal from human populations. Comprehensive state‐based cancer registries are available in human medicine, while only a few, very limited attempts have been made in veterinary medicine to create them [1–7]. At the time of registry publication, the cancer incidence rates were 0.4–2% in dogs and 0.1–0.4% in cats, while cancer prevalence in a set population of veterinary patients was approximately 4% [2–5, 7]. Additionally, mortality rates for veterinary cancer patients are 20–56% depending on age and breed [1, 6]. However, it is entirely possible that these figures may continue to improve as more sophisticated and advanced oncologic diagnostic and therapeutic procedures become widely available. Despite the lack of accurate epidemiological veterinary cancer data, the prevalence of cancer in pets continues to rise for several reasons, but is, at least in part, related to animals living to increasingly older ages. The greater life span is the result of better preventive and therapeutic medical practices (including better nutrition and vaccination policies) and possibly the development of a stronger human–animal bond within the last 30 years [1, 8]. As such, veterinary care for oncological pets is currently demanded by society and veterinary professionals are expected to provide expertise and proficiency in the clinical management of the cancer patient. A cornerstone of their medical care is the anesthetic/analgesic management during different stages of their clinical management that ranges from diagnostic to therapeutic or palliative procedures. Unfortunately, cancer patients present with many pathophysiologic derangements that derive not only from the neoplasia and/or its metastases, but also from the coexisting paraneoplastic syndromes (PNS) and the secondary effects of their therapeutic management (e.g., secondary effects of chemotherapy or radiation therapy, aggressive and invasive surgical procedures, etc.). In order to perform a safe and adequate anesthetic/analgesic management of the oncologic patient, a thorough understanding of the underlying pathophysiology is warranted. PNS include neoplasm‐associated systemic alterations that occur distant to the tumor but can be directly linked to the neoplastic disease [9]. Tumors can produce and release several biologically active substances such as cytokines, hormones, and growth factors that lead to clinical conditions that may occasionally present a higher morbidity than the original tumor itself. PNS can be classified according to the systemic organ they target (Table 17.1). Cancer anorexia–cachexia syndrome (CACS) represents the most common paraneoplastic disorder in both human and veterinary patients. The incidence among veterinary patients is yet to be determined by appropriate clinical studies. However, the incidence has been estimated at only 4% [10], which may be significantly lower than the real figure [9]. Oncologic patients frequently show weight loss and metabolic alterations associated with both adequate nutritional intake (cancer cachexia) and/or poor nutritional intake (cancer anorexia). This PNS results in alterations in carbohydrate, lipid, and protein metabolism that, if left untreated, decrease the patients’ quality of life, their survival time, and sometimes their chances of being suitable candidates for a more appropriate therapy [11]. Clinically, CACS is characterized by nausea, anorexia, and weight loss that ultimately leads to severe wasting due to massive body fat depletion and a dramatic decrease in muscle protein mass (Figure 17.1) [12]. Table 17.1 Classification of common paraneoplastic syndromes in oncologic patients. Patients may also have alterations in food perception (i.e., smell and taste), which decreases the palatability of the food they are offered [12]. The metabolic disorders associated with the CACS may occur even before weight loss is first detected and they may often persist after the patient is successfully treated for the neoplastic disorder, making weight gain challenging. The underlying CACS pathophysiologic mechanism is mediated by the production and release of serotonin and cytokines that lead to alterations in the resting energy expenditure as well as in physiologic protein, fat, and carbohydrate metabolism (Table 17.2) [12]. Oncologic patients that suffer from CACS require aggressive nutritional support to limit the adverse effects of CACS and to enhance immune system function as well as the efficacy and tolerance of different therapeutic interventions (i.e., diets rich in omega‐3 fatty acids) [13]. Nasoesophageal, esophagostomy, or gastrostomy tubes are also recommended in those patients that are persistently anorexic. As a result of the aforementioned changes associated with PNS, a low fat‐to‐body mass ratio and a low muscle‐to‐body mass ratio are commonly found in these patients. Due to the decreased availability of drug protein binding, higher circulating levels of free‐fraction or active drugs (e.g., barbiturates) administered in the perianesthetic period may be present. To avoid overdose and prolonged and/or rough anesthetic recoveries, careful pharmacological choices and dosing regimens need to be applied. Additionally, due to their very low fat‐to‐body mass ratio, these patients may be more prone to hypothermia during the perianesthetic period. Active efforts to decrease as much as possible heat loss is warranted (i.e., insulation from cold surfaces, careful wrapping, use of heat and moisture exchange filters, warm water blankets, etc.). Figure 17.1 Severe wasting in a dog due to CACS. Source: Photo courtesy of Dr. Ana Cloquell. Table 17.2 Cancer anorexia–cachexia syndrome (CACS): major clinical signs and pathophysiologic mechanisms. Fever as a PNS is associated with a wide variety of neoplastic disorders and, although it is very common in human patients, its incidence in veterinary medicine is unknown [14]. The pathogenesis of paraneoplastic fever is mostly due to the production and release of pyrogenic cytokines by the host immune system and/or tumor itself [15]. A thorough preanesthetic evaluation is warranted to rule out the presence of an infectious process prior to formulating an anesthetic plan. Severe elevations in body temperature are associated with an increased metabolic state and degree of oxygen consumption that may even exceed oxygen delivery to tissues. This situation may eventually lead to the development of a series of multiorgan dysfunctions (i.e., acute renal failure, myocardial arrhythmias, and disseminated intravascular coagulation [DIC]). In addition, hyperthermia is related to an increase in inhalant minimum alveolar concentrations (MAC) [20]. Anesthetic maintenance with inhalant agents may necessitate higher end‐tidal inhalant concentrations. If infection is ruled out and the fever is severe or life‐threatening, nonsteroidal anti‐inflammatory drugs (NSAIDs) should be used to inhibit the chemical mediators responsible for fever production while still allowing for normal thermoregulation [16]. Although NSAIDs are relatively safe, they should be avoided in patients with renal disease, gastrointestinal ulceration, or bleeding disorders. Dipyrone is also an injectable NSAID with antipyretic properties via cyclooxygenase (COX‐3) inhibition [17, 18] not associated with the usual NSAID contraindications. At this time, dipyrone is not used widely in small animals in the United States; however, it was recently approved by the Food and Drug Administration (FDA) for use in horses. Dipyrone may induce blood dyscrasias in human patients; however, this has not been shown in animals [19]. Tumors and their metastases can alter hematopoietic cell lines after infiltration of the bone marrow, and anemia is one of the most common PNS in veterinary patients with an incidence from 30% to 69% [21]. The most common causes are anemia of chronic disease (ACD), immune‐mediated hemolytic anemia (IMHA) usually associated with hematopoietic tumors, blood loss anemia associated with paraneoplastic gastroduodenal ulceration, and microangiopathic hemolytic anemia (MAHA) most associated with microvascular tumors or any type of tumor that could lead to the development of DIC. In the case of acute or severe anemia, stabilization is desirable before general anesthesia is considered. In ACD, blood loss anemia, and MAHA, only the tumor removal can improve the condition; however, when IMHA is present, treatment with corticosteroids with or without immunosuppressive agents such as azathioprine or cyclophosphamide may significantly improve the condition before general anesthesia is undertaken [22–26]. In addition, supportive treatment with whole blood or packed red blood cell transfusion may be necessary where hypoperfusion and hypoxia are a concern. Administration of hemoglobin‐based oxygen‐carrying solutions (HBOCs) may be also considered if available. In addition, measures should be taken to optimize oxygen delivery to the tissues in the anesthetized patient such as preoxygenation before induction of general anesthesia, maintaining the inspired oxygen level (FIO2) of 1.0 throughout the procedure, and striving for optimal perfusion at all times. Polycythemia or erythrocytosis is uncommon in veterinary oncologic patients, and it is mainly associated with renal tumors in which an increased level of erythropoietin may be present [27, 28]. Patients present with clinical signs of tissue hypoxia, polyuria, bleeding, or thrombosis that result from hyperviscosity of the blood as well as decreased perfusion of small vessels. Stabilization via phlebotomy can be a useful temporary adjunct therapy. Serial phlebotomies of 10–20 ml kg−1 of blood may be carried out until clinical symptoms have resolved or the target hematocrit is reached (usually below 50% for cats and below 55% in dogs). However, repeated phlebotomies may result in thrombotic complications or iron deficits, as well as the need for concomitant aggressive fluid therapy and potential administration of plasma [29]. Consequently, if phlebotomies are required more frequently than every 6–8 weeks, myelosuppressive therapy is advised, and hydroxyurea may be used [30]. Definitive treatment of PNS erythrocytosis implies the removal of the erythropoietin‐producing tumor. The incidence of thrombocytopenia in veterinary cancer patients is high, occurring in up to 58% of dogs and 20% of cats [31–33]. Clinical signs are usually not evident until the platelet count decreases below 30 000 μl−1. Definitive treatment requires removal of the stimulating tumor. Anesthetic management of PNS thrombocytopenia includes a thorough physical exam and hematological evaluation; platelet‐rich plasma or plasma transfusions may be indicated. Fresh frozen plasma (FFP) transfusions of 10 and 15–18 ml kg−1 have been reported with favorable results [34, 35]. Transfusion reactions are rare and range from mild signs (i.e., pruritus, facial swelling, and rash) to more severe (i.e., anaphylactic reactions or even death). Patients being transfused should always be closely monitored. Corticosteroids (>2 mg kg−1 PO daily) and immunosuppressive drugs such as azathioprine (2 mg kg−1 PO daily then 0.5–1 mg kg−1 every other day) may be used in the case of immune‐mediated disease [36]. Additionally, the use of lyophilized platelets in thrombocytopenic dogs has recently been reported with favorable results [37]. Veterinary oncologic patients may present with hyperaggregability and thromboembolism. Pulmonary thromboemboli (PTE) usually present with unexplained sudden hypotension, tachycardia, tachypnea, hypoxemia, or bronchospasm. Arterial blood gas analysis may reveal hypoxemia, hypocapnia, and an increased alveolar–arterial oxygen gradient. A decrease in end‐tidal CO2 levels is also suggestive of pulmonary embolism, although it is not specific. Definitive diagnosis of intraoperative PTE may require selective pulmonary angiography or computed tomography with contrast angiography. However, these techniques are highly sophisticated and may not be readily available. Oxygen therapy should be instituted in a timely manner and definitive therapy may include thrombolytic therapy (streptokinase, 90 000 U as an IV infusion over 20–30 min, followed by 45 000 U as an IV infusion over 3–7 h) [38] as well as anticoagulation with heparin and warfarin therapy (low‐molecular‐weight heparin at 75–100 U kg−1 SC every 8 h followed by warfarin at 0.1 mg kg−1 every 24 h) [39]. Prophylactically, the selection of short‐acting or reversible anesthetic agents is warranted in patients prone to suffering PTE, as these protocols may allow early postoperative ambulation, therefore decreasing the incidence of additional thromboembolic episodes. Additionally, in animals considered at risk for PTE, prophylactic anticoagulant therapy may be instituted (low‐molecular‐weight heparin at 75–100 U kg−1 SC every 8 h) [39]. PNS coagulopathies may be present, especially if alterations in platelet number and functionality are also present and DIC is the most frequent clinical abnormality [40]. Thrombocytopenia, prolongation of activated partial thromboplastin time (APTT), increased levels of fibrin degradation products (FDPs and D‐dimers), hypofibrinogenemia, and decreased antithrombin III (AT III) levels may be clear indicators of the presence of DIC (Table 17.3) [41]. Appropriate stabilization of any coagulation disorders is warranted prior to undertaking of general anesthesia. Table 17.3 Disseminated intravascular coagulation (DIC). The DIC continuum as defined by the scientific subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) on DIC [41] and modification for DIC in dogs [410]. Hyperproteinemia occurs in animals with multiple myeloma, where monoclonal immunoglobulins are secreted in large quantities producing paraproteinemia [42, 43]. Clinical signs associated with hyperproteinemia are associated with bleeding disorders (as a result of poor platelet aggregation and interference with coagulation factors) [44] and by blood hyperviscosity (due to the protein–protein interactions of large, long molecules with high intrinsic viscosity) [43]. Clinical signs of hyperviscosity result from tissue hypoxia due to the sludging of blood and include ocular disturbances, severe central nervous system (CNS) deficits, and cardiac disease or failure [43, 45]. Stabilization prior to general anesthesia through plasmapheresis may be necessary to reduce protein concentrations [46]. Approximately two‐thirds of dogs and one‐third of cats that present with hypercalcemia are diagnosed with neoplasia [47, 48]. The most common neoplasia associated with hypercalcemia of malignancy (HM) is lymphoma, but it may also be seen with mammary gland (adeno)carcinoma, parathyroid gland neoplasia, thyroid carcinoma, bone neoplasia, anal sac apocrine gland carcinoma, multiple myeloma, thymoma, squamous cell carcinoma, melanoma, and primary lung neoplasia [49–54]. Hypercalcemia occurs via bone resorption by osteoclasts and subsequent release of circulating calcium [55]. However, additional differentials include acute renal failure, hypoadrenocorticism, granulomatous disease, hypervitaminosis D, or a laboratory artifact (due to hemolysis or lipemia) [56]. Additionally, in the case of acidemia, an increase in the free ionized fraction of calcium can occur [9]. Similarly, the relationship between calcium and serum albumin should be evaluated, and the following correction formula could be used: Total calcium levels >18 mg dl−1 should be approached as a medical emergency [57]. Systemic signs include twitching, shaking, weakness, hypertension, bradycardia, depression, stupor, or even coma. Deposition of calcium salts in the renal parenchyma leads to pre‐renal and renal azotemia, while severe vasoconstriction causes a decrease in renal blood flow and glomerular filtration rate [58]. Decreased responsiveness to the antidiuretic hormone (ADH) at the distal tubule is responsible for the inability to concentrate urine. The urinary epithelium may then undergo degeneration and, eventually, necrosis [57]. Vomiting, polydipsia, and polyuria may develop and lead to progressive deterioration and dehydration of the patient. Since some of the symptomatic therapies to treat hypercalcemia could impair the ability to reach a final diagnosis or a final resolution of the etiology (e.g., glucocorticoids), the primary goal when managing a patient with HM should always be to elucidate and treat the underlying cause (for this reason, the use of corticosteroids in cases of hypercalcemia with undiagnosed neoplasia is strongly discouraged) [9, 59, 60]. General anesthesia should be performed with caution when calcium levels are significantly above the normal range (total calcium >12 mg dl−1 or ionized calcium >1.5 mmol l−1 in dogs and 1.4 mmol l−1 in cats) due to hemodynamic and renal consequences (i.e., bradyarrhythmias, asystole and cardiac arrest, hypertension, azotemia, polyuria, polydipsia). Complete normalization of calcium levels may not be achieved prior to anesthesia, as excision of the tumor will likely be the only definitive treatment in many cases. Nevertheless, treatment should be directed at promoting external loss of calcium, increasing renal excretion of calcium, and inhibiting bone reabsorption [9]. For example, in the case of mild hypercalcemia (12–15 mg dl−1) and no clinical signs, rehydration with 0.9% saline could result in normocalcemia. With moderate hypercalcemia (15–18 mg dl−1), rehydration and consequent diuresis with 0.9% saline and furosemide (1–4 mg kg−1 every 8–24 h IV, in dogs; 1–2 mg kg−1 every 8–24 h IV, in cats) should be initiated to inhibit calcium reabsorption by the ascending loop of Henle. If the final diagnosis has been reached and lymphoma has been ruled out, prednisone (1 mg kg−1 every 12 h PO, both dogs and cats) could be administered. In cases of refractory hypercalcemia, administration of salmon calcitonin (4–10 MRC units kg−1 every 24 h SC) and bisphosphonates such as zoledronate (0.25 mg kg−1 IV, every 4–5 weeks) or pamidronate (1–1.5 mg kg−1 IV in dogs and 1.5–2 mg kg−1 IV in cats, every 2–4 weeks) should be considered [61–63]. Hypoglycemia is mainly associated with insulin‐producing islet cell pancreatic tumors [64]. However, it has been described in patients suffering from leiomyoma, leiomyosarcoma, hepatoma, hepatocellular carcinoma, and hemangiosarcoma [65]. Pathophysiologic mechanisms include increased tumor utilization of glucose, decreased hepatic gluconeogenesis, secretion of insulin‐like growth factors I and II, or upregulation of insulin receptors [66], and the most common clinical signs include weakness, disorientation, seizures, and coma. With severe hypoglycemia, IV bolus of 50% dextrose (1 ml kg−1 diluted 1:2–1:4 over 5 min) and an IV infusion of 2–2.5% dextrose or glucagon should be initiated [67]. However, care must be taken when treating hypoglycemia in patients with suspected insulinoma or other tumors secreting insulin‐like analogs, since IV dextrose may stimulate the release of even larger amounts of insulin from the tumor, further aggravating the hypoglycemic state. Dextrose infusions should be formulated by adding the appropriate amount of 50% dextrose to an isotonic crystalloid fluid (such as Lactated Ringers, 0.9% NaCl, or Plasma‐Lyte) and then administered at fluid therapy maintenance rate (40 ml kg−1 d−1). Care must be taken to not administer 5% dextrose in water, since the solution is hypotonic and devoid of electrolytes. Glucagon can also be administered. It should be reconstituted and diluted in 0.9% saline, resulting in a 1000 ng ml−1 solution. It may be first administered as a 50 ng kg−1 bolus followed by a 5–40 ng kg−1 min−1 constant rate infusion. Some oncologic patients may be already receiving various treatments aimed at fighting hypoglycemia such as diazoxide (10–60 mg kg−1 every 12 h PO, in dogs), as it increases glucose levels by enhancing epinephrine‐induced glycogenolysis and by inhibiting insulin release and uptake by cells [68]. Others may be receiving hydrochlorothiazide (2–4 mg every 12 h PO, in dogs and cats) to potentiate the effects of diazoxide, or somatostatin (5–20 g every 8–12 h PO or SC) [9, 68, 69]. Gastroduodenal ulceration is associated with mast cell tumors (MCTs) or gastrinomas (gastrin‐secreting non‐islet cell pancreatic tumor) [70]. Mast cell granules contain several biologically active substances such as histamine, heparin, and proteolytic enzymes and are associated with gastric mucosal damage and ulceration due to increased gastric acid secretion [70–72]. Oncologic patients diagnosed with MCT or gastrinoma should be treated with a histamine‐2 receptor antagonist such as famotidine (0.5–1 mg kg−1 slow IV or PO every 12 h, dogs and cats) or ranitidine (2 mg kg−1 slow IV, every 12 h, dogs and cats) to prevent gastrointestinal complications [70]. The use of NSAIDs or corticosteroids should be avoided whenever possible due to the adverse effects on gastrointestinal mucosa. PNS alopecia is usually bilaterally symmetrical and nonscarring and has been associated with pancreatic carcinomas with metastasis to the liver [73–75]. Patients that suffer from PNS alopecia are clinically anorexic, lose weight, are lethargic, and have difficulties standing or walking [73–75]. During the preanesthetic evaluation, several differential diagnoses should be ruled out such as hyperadrenocorticism, self‐induced alopecia, or symmetrical alopecia. Oncologic patients may suffer glomerulonephritis due to precipitation of tumor‐related immune complexes on the glomeruli as well as hypercalcemic nephropathy in those patients that suffer hypercalcemia [9, 70]. Careful renal function evaluation during the preanesthetic evaluation is warranted to stabilize an oncologic patient that may need general anesthesia for different diagnostic and therapeutic procedures. Acquired myasthenia gravis (MG) can occur in oncologic patients diagnosed with thymoma, osteosarcoma, lymphoma, and bile duct carcinoma [76–80]. Antibodies to nicotinic acetylcholine receptors are produced because of the tumor, and, as a consequence, failure of transmission across the neuromuscular junction occurs. Clinical signs include exercise intolerance, episodic muscular weakness, dysphagia, megaesophagus, and secondary aspiration pneumonia. Improvement of this tumor‐associated disorder may be observed after surgical removal of the tumor itself. However, the occurrence of megaesophagus is a negative prognostic factor [76]. The administration of immunosuppressive doses of prednisone (over 2 mg kg−1 every 24 h PO, dogs and cats) may be attempted if surgical therapy is not an option. Since these patients frequently present with skeletal muscle weakness, perianesthetic concerns may include diaphragm insufficiency requiring ventilator support and/or megaesophagus (see Chapter 15). Patients may show resistance to depolarizing neuromuscular blockers (i.e., succinylcholine) [81]. On the other hand, acute sensitivity to the effects of nondepolarizing blockers (i.e., vecuronium, rocuronium, or atracurium) may also occur [82]. Consequently, approximately one‐tenth of the initial dose is advised in these patients. Assessment of the neuromuscular block using a nerve stimulator with or without acceleromyography or electromyography should always be established in patients requiring neuromuscular blockade. Peripheral neuropathy affects both human and veterinary oncologic patients with lymphoma, multiple myeloma, primary lung neoplasia, mammary neoplasia, hemangiosarcoma, and MCTs [83–86]. The underlying pathophysiologic mechanism is due to autoantibodies targeting antigens expressed both on the tumor and the peripheral nerves [70]. Clinical signs range from weakness and progressive paraparesis to tetraparesis with lower motor neuron symptoms with or without polyneuropathy. Pain management is particularly important with these patients. Administration of gabapentin or pregabalin as adjuvant analgesics in addition to the standard pain management plan may be extremely beneficial in treating the neuropathic component of pain [87–93]. The most used dose of gabapentin in dogs is 10 mg kg−1 PO every 8 h, while in cats the dose is of 10 mg kg−1 PO every 12 h [94, 95]. Pregabalin dosages recommended by pharmacokinetic studies in both canine and feline patients are 4 mg kg−1 PO every 12 h [96, 97]. Hypertrophic osteopathy (HO) is characterized by progressive periosteal proliferation of new bone along the shafts of long bones of the appendicular skeleton and is commonly associated with primary lung tumors, although HO has also been described in tumors that metastasize to the lungs (Figure 17.2) [98–102]. The precise pathophysiologic mechanism is unknown; however, it is partly related to afferent neurologic stimulation through irritation of the vagal and/or intercostal nerves which subsequently enhances blood flow to the limbs [103]. Clinical signs include shifting leg lameness and reluctance to move when several limbs are affected. The extremities are usually warm, swollen and manipulation is painful. Diagnosis is usually achieved by radiography of the affected limb, and thorough screening for the tumor responsible for the development of this PNS should be initiated in a timely manner. Management of pain associated with HO relies on the administration of NSAIDs, opioids (e.g., fentanyl transdermal patches), tramadol (not as a sole agent due to questionable efficacy following PO administration), and bisphosphonates [104, 105]. Other treatments include vagotomy or intercostal nerve resection to disrupt the neurologic afferent input that causes blood flow to increase [106]. However, these therapeutic options have not been extensively studied in veterinary patients. Figure 17.2 Primary lung tumor (white arrow in left picture) in a patient suffering hypertrophic osteopathy with periosteal proliferation in the same patient (white arrow in right picture). Source: Photo courtesy of Dr. Sergio Monteagudo. The increased incidence and prevalence of cancer in the small‐animal population has led to an expansion in knowledge and availability of sophisticated treatment options for cancer patients. Currently, most of these therapeutic options depend on complex chemotherapeutic interventions that are associated with several complications. Since most chemotherapy drugs exert their effects in the active phases of the cellular cycle [107], their toxic effects take place most commonly in tissues with a constant cellular turnover. As some normal tissues present a growth rate that resembles that of tumoral tissue (i.e., mucosa, gametes, epidermis, or hematopoietic cells) [108], chemotherapeutic agents will therefore affect not only tumoral tissues, but some normal tissues as well. Additionally, most chemotherapeutic drugs present a very narrow therapeutic margin, as their desired effect is cellular toxicity. These effects can alter the way anesthetic plans are formulated, since many patient systems, including the bone marrow, gastrointestinal, dermatologic, neurologic, and urologic systems, are affected; hypersensitivity reactions and acute tumor lysis syndrome (TLS) can also occur. Myelosuppression is commonly associated with the cytotoxic effects of chemotherapeutic agents. Anemia is rarely seen secondary to chemotherapy, as the life span of red cells is longer than other cells. However, certain drugs such as doxorubicin can cause recurrent bone marrow suppression and consequent exhaustion after longer periods of chemotherapy. Thrombocytopenia resulting from chemotherapeutic toxicity is rare, although rebound thrombocytosis can be observed. Neutropenia is often present after the administration of cytotoxic chemotherapeutic agents 7–21 days post‐treatment, especially at the nadir of the treatment [107]. Frequently, treatment is not necessary, as patients are asymptomatic and cell counts return to normal limits within a few days, but prophylactic antibiotic therapy may be used when neutrophil counts drop below 1000 cells μl−1. Anorexia, vomiting, and cachexia are the most common side effects of chemotherapy on the gastrointestinal tract due to its cytotoxic effects. Depending on the severity of the symptoms, fluid therapy, antibiotics, and hospitalization for close observation are recommended. Hydration and volume status should be optimized prior to general anesthesia. Extravasation of the chemotherapeutic agents is a viable concern. Severe local tissue reactions may lead to necrosis of the area; doxorubicin is the agent that most commonly causes the most severe reactions due to large extravasated volumes. Clinical signs may include moist dermatitis, erythema, pruritus, pain, and eventually necrosis of the area within 7–10 days after extravasation; veins should be evaluated prior to administration for catheterization viability (Figure 17.3). Local tissue reactions should be treated symptomatically by applying topical antibiotic or steroid preparations. Within 3 h of doxorubicin extravasation, dexrazoxane should be administered IV at a dose 10 times the extravasated dose and then daily for 3 days. If a vinca alkaloid is acutely extravasated, the area should be infiltrated with sterile saline ± 8.4% sodium bicarbonate and dexamethasone SP. Peripheral neuropathies are the main signs of neurotoxicity after administration of chemotherapeutic agents. These include partial paralysis, hind limb weakness, and even ileus that could lead to abdominal pain and constipation, especially if vinca alkaloids are being administered. Platinum products have been reported to cause cortical blindness. Nephrotoxicity and renal failure have also been reported secondary to cisplatin and doxorubicin administration, respectively, and stabilization of the patient may be necessary if azotemia or electrolyte derangements are present. Figure 17.3 Forelimb necrosis in a canine patient after doxorubicin treatment (left) and surgical repair in the same patient (center and right). Source: Photo courtesy of Dr. Cavadonga Sanchez‐Mellado. Acute, type I hypersensitivity reactions have been reported secondary to administration of certain chemotherapy agents such as L‐asparaginase or etoposide, while other agents such as doxorubicin have been associated with anaphylactoid reactions due to direct stimulation of mast cell degranulation [107]. Emergency treatment should include epinephrine administration if severe vasodilation and bronchoconstriction are present, as well as fluid therapy, histamine‐2 receptor antagonists (i.e., diphenhydramine), and steroids (i.e., dexamethasone), if necessary. TLS may also occur secondary to chemotherapy and is associated with rapid tumor cell destruction leading to release of intracellular ions and metabolic byproducts into the extracellular environment and intravascular space [109]. The most common metabolic derangements of TLS include hyperkalemia, metabolic acidosis, azotemia, and hyperphosphatemia that could secondarily induce hypocalcemia. Clinical signs of TLS include vomiting, diarrhea, lethargy, bradyarrhythmias (secondary to hypocalcemia), and pale mucous membranes (secondary to decreased cardiac output). Initial treatment should include restoration of tissue perfusion with aggressive fluid therapy and hemodynamic stabilization, correction of electrolyte and acid–base disturbances, and renal stabilization [109]. Current radiation therapy is based on the use of ionizing radiation for local and regional eradication of malignant and, occasionally, benign tumors while preserving normal healthy tissue structure and function. The biological effect of ionizing radiation is based on its ability to cause ionization and excitation of atoms and molecules in cells that lead to the synthesis of a number of short‐lived ions and unstable free radicals capable of causing molecular damage [110]. This molecular damage compromises cell survival by interaction of free radicals with cellular DNA, causing tumoral cells to enter mitosis with unrepaired DNA damage. This type of cell death is particularly relevant for tumors, as tumoral cells possess a characteristic ability to divide indefinitely. The side effects of radiation therapy on normal tissues are usually restricted to the treatment site, and they are classified chronologically into acute (during or immediately after treatment) and late effects (months to years after completion of treatment). Acute effects occur primarily from radiation‐induced stem cell depletion that exceeds cell production in rapidly proliferating parenchymal tissues and usually affect mucous membranes and skin. These lesions are commonly self‐limiting and resolve naturally after treatment; however, they may be temporarily painful and require supportive treatment. Late effects are considered true complications of radiation therapy and are mainly due to lesions of the vasculoconnective stroma in slowly proliferating parenchymal tissues of organs such as lungs, heart, bone, cartilage, spinal cord, or kidneys. These lesions are not self‐limited and tend to irreversibly progress to severe fibrosis, necrosis, loss of function, or even death. They are usually treated conservatively, although occasionally extremely severe complications may require surgical treatment. Mucositis usually presents in the oral cavity, pharynx, and/or esophagus when tumors of the neck and head are irradiated; colitis may be present when caudal portions of the gastrointestinal system receive radiation therapy. Clinical signs include tender mouth and thickened saliva that lead to dysphagia and eventually anorexia, dehydration and malnutrition with mucositis, and severe large intestine diarrhea with colitis. Symptoms usually develop 1–2 weeks after the beginning of therapy and reach maximum development by the end of therapy, although oral mucositis should resolve 2–3 weeks after the end of therapy. Owner compliance is essential during these weeks and interventions such as hand‐feeding low‐salt diets and detailed instruction on caloric and fluid requirements of the animal may be helpful. Placement of an esophagostomy/gastrostomy tube (Figure 17.4) or administration of subcutaneous fluids may be necessary in some instances to preserve the patient’s hydration and nutritional status. The preanesthetic evaluation should assess hydration and electrolyte status, body condition score (BCS), and the degree of oral mucositis. Oral lesions should be evaluated carefully, and special care should be taken when endotracheal intubation is performed by thoroughly lubricating the endotracheal tube (ETT), handling the laryngoscope with care, and securing the ETT in a gentle way, avoiding lesion areas. Dermatological early side effects are usually restricted to the radiation field and their severity is dose related. They include several lesions such as erythema, subcutaneous fibrosis, pigmentation abnormalities, epilation, moist desquamation, and even self‐mutilation of the lesion areas if care is not taken. Pain management strategies should focus on pain relief for these lesions and every effort should be made to provide padded and careful positioning to avoid the development of decubitus ulcers. Special care should be taken to avoid burning lesions by the warming devices in those sensitive areas that have radiation side effects. Ophthalmological consequences are dose‐related and vary in severity depending on the proximity of the eyes to the radiation field. Every effort is usually made to keep the eyes out of the radiation field; however, depending on the location of the tumor, it is not always possible. Acute effects include blepharitis, blepharospasm, conjunctivitis, keratoconjunctivitis sicca (KCS), and ulceration. Care must be taken to provide excellent lubrication of the eyes during the anesthetic period in those patients that suffer from KCS. Figure 17.4 Esophagostomy tube placement in a dog. Pain is not just a sensation, but rather an “experience” that includes both sensory‐discriminative and motivational‐affective components [111]. Cancer‐related pain results from one or more of the following: (i) tumor‐related pain from direct invasion of different organs, bones, and nerves, (ii) treatment‐related pain following surgical intervention, chemotherapy, or radiation therapy, (iii) indirect etiologies including metabolic imbalances due to PNS, vascular obstruction, and by secondary infection, and/or (iv) unrelated factors associated with inactivity and deconditioning [112–115]. Combinations of these different etiologies result in complex pain patterns that are difficult to accurately diagnose in the veterinary cancer patient. In addition, processes related to chronification of pain such as hyperalgesia, central sensitization, synaptic remodeling, novel gene expression, and behavioral adjustment develop rapidly after persistent tissue injury, making pain management complex and challenging [116, 117]. Neoplastic‐associated pain can be either neuropathic, nociceptive, or a combination of the two. Neuropathic pain is related to central or peripheral neural tissue lesions and is characterized by aberrant somatosensory processing [113]. Nociceptive pain is associated with unhealed injury to either visceral or somatic tissues and can be dull and diffuse (visceral or deep somatic) or sharp, pricking, and well‐localized (superficial somatic). Neuropathic pain in cancer patients is very complex, as tumor involvement of the peripheral nervous system presents many different clinical manifestations that may range from local invasion or compression of nerves to direct infiltration or perineural spread. Some of these lesions may also be associated with inflammatory changes that may lead to additional pain. The pathophysiologic mechanism underlying nerve infiltration or compression includes reparative and reactive biochemical changes that affect dendrites, soma, and axons of the entire primary afferent neuron so that it will eventually lose its neuropeptides and atrophy, and degenerate [118, 119]. In addition, tumors contain endothelin and inflammatory substances that may sensitize or directly or indirectly (through tissue acidosis) excite the nociceptors of primary afferent neurons [120]. Following repeated stimulation at both peripheral and central levels, sensitization can occur, and manifest as an enhanced response to noxious stimulation or a newly acquired responsiveness to a wider range of stimuli that includes non‐noxious stimuli. Peripheral sensitization occurs when nociceptors are sensitized. Central sensitization occurs when activated N‐methyl‐D‐aspartate (NMDA) receptors increase excitability of secondary afferent neurons in the dorsal horn. This phenomenon is also known as “central wind‐up” and has two main consequences: (1) pain is more difficult to manage; larger doses and multiple drugs need to be administered, and (2) patients perceive heightened levels of pain due to the altered interpretation of stimuli (see Chapter 22). One of the most challenging aspects in management of the veterinary oncologic patient is related to the identification, evaluation, and quantification of pain, since, unlike humans, self‐report is not an option in veterinary patients. Additionally, the tolerance of pain varies greatly from one individual to another, and the innate ability of animals to mask significant disease and pain on certain occasions complicates things further. Therefore, in veterinary medicine, the recognition of pain relies heavily on the interpretation of the animal’s behavior by an observer as well as the physiological responses. Although behavioral changes vary between species, a number of changes have been identified and are used in a vigorously validated animal pain scoring system for hospitalized patients called the Glasgow Composite Measure Pain Scale (CMPS), for dogs, and the Glasgow Feline Composite Measure Pain Scale (CMPS‐Feline), for cats (Figures 17.5 and 17.6) [121, 122]. They include the assessment of spontaneous and evoked behaviors, interactions with the animal, and clinical observations. These two scales were developed to assess acute pain in canine and feline patients, respectively, and should only take a few minutes to perform. The behaviors and interactions listed in the CMPS will obviously vary with animal nature and temperament, but these assessments are relevant in most patients. Analgesia should never be withheld due to the difficulty recognizing pain in an animal. Both clinicians and technicians must be proactive in looking for signs of pain in patients, and, if in doubt, the administration of analgesia with subsequent assessment of response to treatment is recommended. Moreover, if a type of tumor and/or its location is painful in humans, it is appropriate to assume that it is so in animals as well. Since pain is not a static process, a pain assessment should be performed prior to a procedure and frequent postprocedure assessments are necessary, including home assessments. During the past decades, many efforts have been devoted to the assessment of quality of life in human patients, and several methods have been developed and validated in clinical trials. However, validated, and standardized criteria for measuring quality of life in animals are rare. Any assessment of the quality of life of an animal must come indirectly from a proxy informant, most commonly, the owner. In 2005, Yazbek and Fantoni validated a health‐related quality‐of‐life scale for dogs with signs of pain secondary to cancer which can be used to evaluate the cancer management plan (Table 17.4) [123]. Tumor pain characteristics differ according to the type and stage of tumor development. Osseous tumor infiltration is the most common cause of pain in oncologic patients (Figure 17.7) [113]. The pathophysiologic pain mechanisms elicited by infiltrative bone or bone marrow tumors are associated with lesions causing periosteal elevation, release of chemical mediators that sensitize nociceptors, increased intraosseous pressure, or loss of stability. Nociceptive pain originates from nociceptors located in the bone itself, but also in the bone marrow and in the periosteum. Tumors of encapsulated organs such as kidneys, spleen, liver, or brain can enlarge the organ to several times the organ’s normal size (Figure 17.8). As the organ capsule grows less rapidly than the tumor, pain ensues from increased intracapsular pressure, direct capsule infiltration, or from traction or pressure on the tissue suspending the organ. Figure 17.5 Guidance for use of the CMPS‐SF. The short form composite measure pain score (CMPS‐SF) can be applied quickly and reliably in a clinical setting and has been designed as a clinical decision‐making tool which was developed for dogs in acute pain. It includes 30 descriptor options within 6 behavioral categories, including mobility. Within each category, the descriptors are ranked numerically according to their associated pain severity and the person carrying out the assessment chooses the descriptor within each category which best fits the dog’s behavior/condition. It is important to carry out the assessment procedure as described on the questionnaire, following the protocol closely. The pain score is the sum of the rank scores. The maximum score for the 6 categories is 24, or 20 if mobility is impossible to assess. The total CMPS‐SF score has been shown to be a useful indicator of analgesic requirement and the recommended analgesic intervention level is 6/24 or 5/20. Source: Adapted with permission. Figure 17.6 Guidance for use of the Glasgow Feline Composite Measure Pain Scale (CMPS‐Feline), which can be applied quickly and reliably in a clinical setting, has been designed as a clinical decision‐making tool for use in cats in acute pain. It includes 28 descriptor options within 7 behavioral categories. Within each category, the descriptors are ranked numerically according to their associated pain severity and the person carrying out the assessment chooses the descriptor within each category which best fits the cat’s behavior/condition. It is important to carry out the assessment procedure as described on the questionnaire, following the protocol closely. The pain score is the sum of the rank scores. The maximum score for the 7 categories is 20. The total CMPS‐Feline score has been shown to be a useful indicator of analgesic requirement and the recommended analgesic intervention level is 5/20. Source: Adapted with permission. Tumors and metastases in digestive and urogenital hollow organs are frequently painful (Figure 17.9). Pain results from intestinal dilation, motility disorders, ulcerations, and blood flow impairment. Pain in urogenital organs may be caused by arteritis, perineural tumor infiltration, or perineural inflammatory reactions. Solid organs such as the pancreas suffer specific pain symptoms subsequent to tumor‐induced necrosis that results in autodigestive pancreatitis. The autodigestion most likely results from tumorous destruction of the parenchyma as well as from tumor infiltration and stenosis of the excretory ducts. Tumor infiltration of soft tissues elicits pain by compressing individual nerves and plexus, as well as by affecting organs that are responsible of the patient’s movement, such as tendons or muscles (Figure 17.10). Infiltration of the interstitium and destruction of lymphatic vessels, nerves, and blood vessels prevent these organs from normal function. Tumor infiltration and inflammation of serosa and mucosa also cause pain. Although pleural carcinomas do not usually cause pain (most likely due to the development of pleural effusion that prevents the pleurae from rubbing against each other), peritoneal carcinosis does. Pain results from either direct contact of the metastases with peripheral nerves or from the inflammatory reaction resulting from tumor‐induced perforation or penetration of an abdominal hollow organ. Peripheral nerve pain usually arises due to entrapment of individual nerves and plexus by tumor growth. However, pain can also result as tumor infiltration causes the neural cleft to widen, and infiltration of the tumor into the nerve itself takes place. Table 17.4 Questionnaire for evaluating health‐related quality of life in dogs with signs of pain secondary to cancer. Source: Adapted with permission. Scores (values in parentheses) for all 12 questions were summed to determine the health‐related quality‐of‐life score. Possible scores ranged from 0 to 36 [123]. Figure 17.7 Osteosarcoma in the mandible of a feline patient (white arrow on radiograph). Source: Photo courtesy of Dr. Ana Ríos. Figure 17.8 Splenic hemangiosarcoma in a canine patient. Source: Photo courtesy of Dr. Sara Colopy. Figure 17.9 Transitional cell carcinoma invading the entire bladder of a canine patient. Source: Photo courtesy of Dr. Hilde de Rooster and Dr. Alejandro Rubio. Figure 17.10 Fibrosarcoma in the interscapular region of a feline patient. Blood and lymphatic vessels are invaded as malignant neoplasia begins to metastasize. Although small vessel infiltration and obstruction are rarely painful, when large veins are affected, edema and pain in the affected area of venous drainage are often present (Figure 17.11). Treatment of acute pain should be a priority not only for obvious ethical reasons, but also to minimize its negative influence on postoperative morbidity and mortality (such as decreased rate of healing, hypertension, tachycardia, or ileus). Treating perioperative pain significantly reduces the tumor‐promoting effects of surgery, as surgery itself suppresses natural killer (NK) cell activity which may enhance metastasis [124, 125]. Although drugs are the mainstay of cancer pain management, nonpharmacologic interventions are becoming increasingly popular. Overall, cancer pain management therapeutic interventions may be divided into two categories: pharmacologic and nonpharmacologic. Figure 17.11 Facial edema as part of superior vena cava syndrome in two canine patients. Source: Photos courtesy of Dr. Noemi del Castillo and Dr. Sonia Fernandez. Multimodal analgesia should be used to alter more than one point along the nociceptive pathway including nociceptive transduction, transmission to the CNS, modulation within the CNS, or perception at the cortex (see Chapter 22). This analgesic approach reduces individual drug doses, thereby reducing the potential for adverse effects. The use of preemptive analgesia should also be used to reduce central hypersensitivity or wind‐up pain. Additionally, providing effective multimodal and preemptive analgesia will not only reduce postoperative pain, but will also form part of a balanced anesthesia plan that may allow significant reductions in anesthetic agent requirements. All these interventions may ultimately lead to a smoother plane of anesthesia and optimal recovery characteristics. The first line of analgesia should be the use of “traditional” analgesics such as opioids, NSAIDs, and local anesthetic techniques. Recently, other “adjunctive” analgesics such as NMDA receptor antagonists (i.e., ketamine, amantadine), alpha‐2‐adrenergic receptor agonists, bisphosphonates, and anticonvulsant (i.e., gabapentin) drugs have gained popularity. The World Health Organization (WHO) has outlined a ladder or general approach to cancer pain management in humans based on these drug groups: nonopioids, opioids for mild‐to‐moderate pain, opioids for moderate to severe pain, and adjuvant drugs [126]. However, “WHO is discontinuing these guidelines considering new scientific evidence that has emerged since the time of their publication in 2019. And although WHO remains fully committed to ensuring that people suffering severe pain have access to effective pain relief medication, including opioids, it also recognizes that the need for access to pain relief must be balanced with concerns about the harm arising from the misuse of medications prescribed for the management of pain, including opioids. Scientific evidence indicates there are risks associated with the use of these medications, such as the development of dependence, overdose, and accidental death. Recent research in the fields of palliative care and pain management has identified many strategies for managing pain, beyond drug treatment alone” [127]. In fact, at the end of 2019, a task force for the reevaluation of pain management guidelines was appointed by WHO [128]. Regardless of all the recent reevaluation of this therapeutic management in human medicine, there are two potential problems with the use of the WHO analgesic ladder in veterinary medicine. First, there is a lack of information on which drugs are most effective on which type of cancer pain in veterinary patients. Second, this approach may not be appropriate for many veterinary cancer patients, as they often present at an already advanced stage of disease and may already be in a moderate to severe state of pain. Once pain has been allowed to become chronic, central sensitization and hyperalgesia are already taking place. To manage this very complex type of pain, an analgesic reverse pyramid approach may be required, which relies on the use of multiple different classes of drugs until the intensity of pain decreases, at which point the amounts and types of drugs may be minimized. Opioids such as morphine, hydromorphone, methadone, fentanyl, buprenorphine, and butorphanol exert their analgesic effects and their side effects through actions on the different opioid receptors (μ, δ, and κ). The most frequent side effects of opioids include dose‐ and drug‐dependent cardiovascular depression due to a reduction in sympathetic tone. This often results in varying degrees of bradycardia, while no direct effects on systemic blood pressure or myocardial contractility are commonly seen [19]. Vasodilation from histamine release can also be observed, mainly after IV administration of morphine and meperidine [129]. Dose‐ and drug‐dependent respiratory depression may be described after opioid administration and may be especially noticeable when given in conjunction with anesthetic induction agents and volatile anesthetics. Ileus decreases gastric emptying time and constipation may be observed as well as short‐term urinary retention. Dysphoria may occur after opioid administration; however, it is infrequent if administered to animals in pain or in combination with sedatives or tranquilizers. Finally, alterations in thermoregulation, such as hypothermia and/or panting, are usually observed, while cats may exhibit hyperthermia after opioid administration. All the previously mentioned parenteral opioids may be administered by an intermittent IV or IM route [19]. However, with intermittent dosing, patients often feel pain before their subsequent dose and may become sedated after dose administration. Alternatively, continuous rate infusions (CRI) of a shorter‐acting, potent opioid analgesic agent can be used (e.g., fentanyl, alfentanil, remifentanil). Fentanyl administered as a CRI provides constant and reliable plasma levels that provide excellent analgesia and allow sparing of inhalant agent; therefore, reducing its systemic adverse effects [130–134]. Fentanyl may also provide postoperative analgesia; due to potential respiratory depression, patients should be under constant and vigilant observation. Intramuscular, slow IV bolus, or CRI administration of morphine is efficacious, although histamine release may limit its use in MCTs [129]. Fentanyl transdermal patches provide another route of opioid administration and analgesia can be provided for several days [135–137]. However, the degree of analgesia can be unpredictable, especially in cats, probably due to failure of patch application or inappropriate dosing, and frequent patient monitoring is essential [138, 139]. Since plasma levels do not reach peak values until 12–24 h post placement, additional analgesia should be provided in the immediate postoperative period. Fentanyl patches are a suitable option for patients that may need prolonged opioid administration and for those that do not tolerate oral medication. Fentanyl patches should not be prescribed when young children are in the household, since potential removal and ingestion are of concern [140, 141]. Finally, opioids such as morphine and fentanyl have been administered epidurally to prolong perioperative analgesia [142–145]. With placement of an epidural catheter, epidural opioids can be administered for days to weeks in patients suffering from peritoneal or pancreatic pain, as well as following amputations. NSAIDs such as meloxicam or carprofen are used widely to treat mild‐to‐moderate pain associated with inflammation and to reduce opioid consumption. However, they possess a much lower therapeutic index than opioids and are not reversible. NSAIDs inhibit COX enzymes, thereby preventing the production of prostaglandins (PG), thromboxanes, and prostacyclin from membrane phospholipids. However, the isoenzyme COX‐2 is also related to the pathogenesis and progression of certain types of tumors. The synthesis of PGE2 by COX‐2 has been associated with the promotion of tumorigenesis, and COX‐2 overexpression inhibits apoptosis, facilitates the adhesion and invasiveness of tumor cells, increases cell growth, suppresses the immune system, and enhances angiogenesis [146, 147]. Overexpression of COX‐2 has been implicated in a number of canine carcinomas, such as those affecting the bladder, kidneys, mammary tissues, and intestines, squamous cell carcinoma, and some sarcomas such as osteosarcoma [148–152]. As a result, the use of selective COX‐2 inhibitors is widespread not only for their analgesic effects in patients with these types of tumors, but also for their beneficial effects on the tumor therapy [153–165]. The most common side effects of NSAIDs include impairment of gastrointestinal protection, inhibition of platelet aggregation and vasoconstriction, and impairment of renal perfusion [166]. Oncologic patients are at greater risk of toxic effects due to their potential for pre‐existing renal disease or the concurrent administration of nephrotoxic oncologic therapies. The use of NSAIDs is not recommended in patients, regardless of their tumor, that present with gastrointestinal disorders, coagulopathies, impaired renal and hepatic function, patients that are dehydrated or hypovolemic, and those that are already receiving other NSAIDs or corticosteroids. Additionally, it should be remembered that cats have longer and inconsistent rates of metabolism and excretion of NSAIDs compared to other species (particularly through glucuronidation), and chronic dosing (longer than 5 days) is likely to be associated with greater risks in cats than other species and therefore should be used cautiously [167]. Renal monitoring of the patient that is receiving NSAID‐based therapy is warranted. The owner should be informed of the potential for toxicity as well as instructed for monitoring of adverse events (depression, lethargy, vomiting, melena, and polyuria). Baseline blood work and urinalysis should also be performed at the beginning of therapy and repeated every 2–4 weeks and up to 1–4 months depending on the individual patient and evolution of the case. Local anesthesia is the only effective way of providing complete analgesia, as the main mechanism of action is via blockage of sodium channels. Perineural administration completely blocks transmission of nociception, thereby minimizing central sensitization for the duration of block. Local anesthetics (LAs) can be used by topical application, local infiltration, IV administration, interpleural administration, body cavity instillation, through wound‐soaker catheters, by transdermal patches, and through epidural catheters. Neurological side effects are biphasic, first shown as excitatory signs (tremors, visual disturbances, and eventually seizures) and then signs of neurological depression (coma and apnea). Cardiovascular side effects include direct myocardial depression from blockade of cardiac sodium channels. The use of topical LAs as a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) cream has been suggested to minimize pain and discomfort during venipuncture or intravenous catheterization [168, 169]. LAs may be deposited directly over selected nerves prior to transection during surgical procedures. Ring blocks around the distal end of affected limbs or around a mass that needs to be excised may also be performed through infiltration of tissues. Ideally, the infiltration should be performed prior to surgery, paying attention to a gentle and cautious application if dealing with aggressive tumors (i.e., sarcoma); however, infiltrative blocks can also be employed during closure of surgical wounds, applying the traditional or liposome‐encapsulated local anesthetic at various levels during wound closure. Finally, administration of the local anesthetic adjacent to the wound during closure has been shown to reduce pain postoperatively and reduce opioid requirements following laparotomy [170]. Figure 17.12 Surgical placement of wound‐soaker catheter (left) with drainage and analgesic administration through the same soaker catheter (right). Source: Photo courtesy of Dr. Hilde de Rooster and Dr. Alejandro Rubio. Wound diffusion catheters (also known as wound‐soaker catheters) may be used to provide analgesia to large surgical wounds (e.g., amputations, tumor resection, mastectomies; Figure 17.12). They are usually well‐tolerated and, if correctly placed, may not only improve patient comfort but significantly decrease opioid requirements. The incidence of wound infections or breakdown appears to be the same as in dogs where wound‐soaker catheters are not placed [171]. Occasionally, catheters may fail to provide analgesia for the full extent of the surgical site; this may be due to uneven distribution of local anesthetic, incorrect placement, or catheter blockage. LAs may be administered every 6–8 h (1–2 mg kg−1 ropivacaine or bupivacaine) [171]. The catheters can be removed 48 h after placement or remain in place for longer, if required. LAs may be administered interpleurally to provide analgesia post thoracotomy and to manage pain in a variety of pleural conditions. After drainage of the chest is performed, a 0.25% solution of bupivacaine (1.5 mg kg−1) may be slowly administered through the drain (Figure 17.13). This technique will usually provide up to 6 h of analgesia, while the pleural cavity may still be drained every hour if necessary, without affecting the efficacy of analgesia [172–176]. LAs may also be administered intraperitoneally. It has been found that the combination of intraperitoneal bupivacaine administered preoperatively with subcutaneous wound infiltration with bupivacaine postoperatively provided improved analgesia in dogs [170]. Similarly, sprayed, and injected intraperitoneal bupivacaine relieves postoperative pain behavior and biochemical stress responses after surgery in dogs [177, 178]. Newer techniques such as IV lidocaine infusions are efficacious and safe in dogs while decreasing isoflurane MAC [179]. In addition, longer‐term epidural analgesia may be preferable for pain management of certain procedures and conditions (e.g., pancreatic pain, extensive hind limb surgery, amputations) and an epidural catheter may be placed to allow repeated administration of LAs (Figure 17.14). Drugs may be epidurally administered intermittently as a bolus or as an infusion using a syringe pump. Preservative‐free morphine (0.1 mg kg−1) may be administered every 12–24 h, while bupivacaine (0.06–0.12 mg kg−1) can be administered intermittently as required. Alternatively, a CRI into the epidural catheter of morphine (0.0125 mg kg−1 h−1) and bupivacaine (0.03 mg kg−1 h−1) has been reported [180]. Figure 17.13 Chest drain and interpleural administration of local anesthetic in a cat. Source: Photo courtesy of Dr. Hilde de Rooster and Dr. Alejandro Rubio. Lidocaine 5% patches may be applied alongside wounds that present allodynia. Studies in both dogs and cats suggest that local skin lidocaine concentrations are high while plasma levels are low, suggesting that the analgesia seen following placement is most likely due to the local effect rather than to a systemic effect [181–184]. The use of subanesthetic doses of NMDA antagonists such as ketamine and amantadine may reduce the chances of central sensitization developing postoperatively and may also be particularly helpful for the management of pain derived from nerve damage. Side effects of this drug class include dose‐dependent cardiovascular stimulation via sympathetic activation, increased salivation and respiratory tract secretions, cerebral vasodilation, and elevated systemic blood pressure that may lead to significant increases in cerebral blood flow and intracranial pressure. However, at the doses used for analgesia, these effects are minimized. Bolus administration of ketamine and low‐dose ketamine infusions for adjunctive analgesia have become common practices in the perioperative setting (e.g., hemilaminectomies, amputations). Several studies have proven the MAC‐sparing properties of ketamine; however, only few studies evaluate the analgesic effects of ketamine which suggest that ketamine decreases postoperative wound hyperalgesia and pain scores and rescues analgesic requirements [185–187]. Amantadine is an antiviral drug that was originally approved to treat influenza A in people. It is also used clinically to reduce symptoms of Parkinson’s disease and other drug‐induced extrapyramidal syndromes. Similar to ketamine, it is an NMDA receptor antagonist. However, it differs from ketamine, as it does not block the flow of current through open channels, but it stabilizes channels in the closed state. Numerous laboratory animal studies suggest that amantadine’s NMDA antagonist activities may make it a useful adjunctive analgesic agent [188–190], but there are a limited number of controlled trials documenting its safety and efficacy in dogs and cats. It has been included in a multimodal analgesic regimen for the alleviation of refractory canine osteoarthritis pain and dogs had activity and lameness scores [191]. Amantadine may come to play a key role in managing chronic pain in dogs in the future and it may be an interesting therapeutic option for oncology patients. Alpha‐2‐adrenergic receptor agonists such as dexmedetomidine are commonly used as adjunctive analgesics, although they are not considered first‐line analgesics. Alpha‐2‐adrenergic receptors and opioid receptors appear to interact and coadministration of these two classes of drugs may achieve synergistic analgesic effects. However, the alpha‐2 receptor‐mediated analgesic effect is of shorter duration than the sedative effects [192, 193]. They are particularly useful in cardiovascular stable patients that require anxiolysis in addition to analgesia. Side effects include vasoconstriction, decreased cardiac contractility, reflex bradycardia and atrioventricular blocks, nausea and vomiting, polyuria, hyperglycemia, and increased myometrial contractility. Figure 17.14 Epidural catheter placement in a cat. Source: Photo courtesy of Dr. Veronica Vieitez . Dexmedetomidine CRIs may help manage both intraoperative and postoperative pain and have been found to be equally effective as morphine CRIs at providing postoperative analgesia, with no significant adverse clinical effects [194]. In addition, the incorporation of low‐dose medetomidine or dexmedetomidine into an epidural protocol may achieve additive or synergistic analgesic effects when combined with standard doses of opioids or LAs due to actions at spinal alpha‐2‐adrenergic receptors [195–198]. In addition to the epidural route, alpha‐2‐adrenergic receptor agonists may be administered intraarticular and perineural, where they contribute to analgesia by inhibition of norepinephrine release and by enhancing peripheral nerve block intensity. Tramadol is a synthetic codeine analog that exerts weak agonist properties at all opioid receptors (particularly at μ‐opioid receptors). In addition, it stimulates presynaptic serotonin release and inhibits the reuptake of serotonin and noradrenaline [199]. Its analgesic potency is one‐tenth that of morphine; however, recent studies comparing the effects of IV tramadol and morphine administered before ovariohysterectomy concluded that IV tramadol was comparable to morphine in its analgesic efficacy for this type of surgical pain [200, 201]. On the other side, oral administration of tramadol has shown to provide an unreliable degree of absorption as well as low concentrations of the pharmacologically active metabolite (O‐desmethyltramadol, ODM) [202]. In fact, pharmacokinetic studies in dogs have shown that dogs do not produce ODM as a substantial metabolite after tramadol administration; therefore, dogs are not expected to have substantial opioid effects after tramadol administration [203, 204]. However, pharmacokinetics in cats are different, since they produce high concentrations of ODM after tramadol administration and, as a result, can show significant opioid effects. Common side effects include sedation and dysphoria (especially in cats), while constipation and respiratory depression seem to be generally milder than those caused by opioids. Its administration is contraindicated in patients with hepatic insufficiency and in those that are seizure‐prone, as it decreases the seizure threshold in humans. Because of its inhibitory effect on serotonin uptake, tramadol should not be administered to patients that may have received monoamine oxidase inhibitors, such as selegiline. Neuromodulating drugs, such as anticonvulsants, have become the mainstay of neuropathic pain treatment in human patients in the past decades. Both pregabalin and gabapentin share a similar mechanism of action by binding to the α2δ subunit of the voltage‐gated calcium channels and inhibiting the release excitatory neurotransmitters involved in pain transmission. Side effects are minimal, and they are limited to mild ataxia and sedation. Although gabapentin is widely used in the treatment of human patients [205–207], only a few investigations have documented its effectiveness to treat chronic neuropathic pain, chronic cancer pain, chronic osteoarthritis pain, and perioperative pain in veterinary medicine [87–89, 92, 94,208–211
17
Neoplastic Disease
Introduction
Pathophysiologic Considerations
Paraneoplastic Syndromes
General Manifestations
Cancer Anorexia–Cachexia Syndrome
Organic system
Manifestations
General manifestations
Cancer anorexia–cachexia syndrome (CACS)
Fever
Hematologic manifestations
Anemia
Leukocytosis
Thrombocyte Hyperaggregability
Pancytopenia
Erythrocytosis
Thrombocytopenia
Coagulation disorders
Hyperproteinemia
Endocrine manifestations
Hypercalcemia
Hypoglycemia
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Gastrointestinal manifestations
Gastroduodenal ulceration
Cutaneous manifestations
Alopecia
Nodular dermatofibrosis
Cutaneous flushing
Neuromuscular manifestations
Myasthenia gravis
Peripheral neuropathy
Renal manifestations
Glomerulonephritis
Miscellaneous manifestations
Hypertrophic osteopathy
Affected system
Pathophysiologic mechanism
Clinical signs
Protein metabolism
Decreased protein anabolism
Increased protein catabolism
Muscle atrophy
Poor body condition score
Carbohydrate metabolism
Altered insulin receptors
Anaerobic glucose metabolism
Hyperlactatemia
Lipid metabolism
Increased lipolysis
Increased lipid mobilization
Decreased fatty acid extraction
Body fat loss
Poor body condition score
Resting energy expenditure (REE)
Abnormal glucose metabolism
Increased REE
Fever
Hematologic Manifestations
Anemia
Erythrocytosis
Thrombocytopenia
Thrombocyte Hyperaggregability
Coagulation Disorders
Stage
Controlled non‐overt DIC
Controlled overt DIC
Noncontrolled overt DIC
Pathophysiologic mechanism
Activated but compensated coagulation
Thrombin generation contained or balanced by inhibitors
Platelet activation
Activated and uncompensated coagulation
Thrombin‐inhibitors overwhelmed
Inflammation–hemostasis feedback loop
Platelets and coagulation factors are consumed
Clinical signs
Microvascular thrombosis
Macrovascular thrombosis
Organ dysfunction
Hemorrhage
Diagnosis
Predisposing disease
Altered trend in PT
Altered trend in fibrinolytic products (FDP and D‐dimers)
Increased PT, PTT
Increased FDP and D‐dimers
Low fibrinogen
Increased PT, PTT
Increased FDP and D‐dimers
Low fibrinogen
Severe thrombocytopenia
Hyperproteinemia
Endocrine Manifestations
Hypercalcemia
Hypoglycemia
Gastrointestinal Manifestations
Cutaneous Manifestations
Renal Manifestations
Neuromuscular Manifestations
Myasthenia Gravis
Peripheral Neuropathy
Osseous Manifestations
Treatment
Chemotherapy
Radiation Therapy
Cancer Pain
Pain Pathophysiology
Pain Evaluation
Specific Pain Characteristics
Questionnaire
How much do you think that the disease is disturbing your dog’s quality of life?
Very much (0)
Much (1)
A little (2)
Not at all (3)
Does your dog still do what it likes (e.g., play or go for a walk)?
No (0)
Rarely (1)
Frequently (2)
In a normal way (3)
How is your dog’s mood?
Totally altered (0)
Some episodes of alteration (1)
Changed a little bit (2)
Normal (3)
Does your dog keep its hygienic habits (i.e., clean itself)?
No (0)
Rarely (1)
Less than before (2)
Yes (3)
How often do you think that your dog feels pain?
All the time (0)
Frequently (1)
Rarely (2)
Never (3)
Does your dog have an appetite?
No (0)
Only eats when forced; will eat more of what it likes (1)
Little (2)
Normal (3)
Does your dog get tired easily?
Yes, always (0)
Frequently (1)
Rarely (2)
No (3)
How is your dog sleeping?
Very badly; not sleeping at all (0)
Badly (1)
Almost normally (2)
Normally (3)
How often does your dog vomit?
Always (0)
Frequently (1)
Rarely (2)
Never (3)
How are the intestines of your dog functioning?
Very badly (0)
Badly (1)
Almost normally (2)
Normally (3)
Is your dog able to position itself to defecate and urinate?
Never (0)
Rarely (1)
Sometimes (2)
Urinates and defecates normally (3)
How much attention is your dog giving to the family?
Indifferent (0)
Little attention (1)
Increased attention; the dog is needy (2)
Has not changed (3)
Cancer Pain Management
Pharmacologic Interventions
Opioids
Nonsteroidal Anti‐Inflammatory Drugs
Local Anesthetics
NMDA Antagonists
Alpha‐2‐Adrenergic Receptor Agonists
Tramadol
Anticonvulsants
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