Diagnosis and Treatment of Cancer in Aged Animals

Geriatrics and Gerontology

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Diagnosis and Treatment of Cancer in Aged Animals

Wallace B. Morrison, DVM, MS*

Pets provide humans with companionship, physical contact, a focus of attention, a means of safety, and a stimulus for exercise. 12 When a diagnosis of cancer is made in a pet, intense emotions are generated within the owners who have formed very d eep attachments to the pet over many years of life together. The disease "cancer, " although no more life threatening than many other diseases, has a unique ability to generate fear and pathos among those associated with it. 12 The pet with cancer and the owners of pets with cancer have special needs. Those who seek to treat cancer patients need sensitivity, a caring attitude, and a thorough knowledge of what is possible and what is not, in one of the most rapidly changing fields of medicine.

DIAGNOSIS OF CANCER IN AGED ANIMALS In his 1908 book, The Cure of Tumors by Medicines, Dr. John H. Clarke wrote "Anybody can diagnose an apple tree when he sees apples on it, but the skilled botanist can distinguish between an apple tree, a pear tree, and a plum tree, even when there are no leaves on them. In the same way, the skilled physician should be able to diagnose a cancer organism before any lump has appeared. "7 The real challenge of cancer diagnosis comes not with the obvious, but with the occult tumor that may be causing nonspecific clinical signs. Unfortunately, there are few clinical findings that exclusively define a neoplasm; however, a careful and complete historical review in combination with clinical laboratory data, radiology, and physical examination findings may allow an occult neoplasm to be diagnosed. Establishing a correct and complete diagnosis is of fundamental importance in establishing a plan of therapy for the patient with cancer. In most *Diplomate, American College of Veterinary Internal Medicine (Internal Medicine); Associate Professor and Chief Oncologist, Purdue Comparative Oncology Program, Purdue University School of Veterinary Medicine, West Lafayette, Indiana Veterinary Clinics of North America: Small Animal Practice- Vol. 19, No. l , January 1989

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instances of illness in young animals, no matter how many major problems a patient may have, all of them will be referable. to a single, common disease process. It is less common for two or m(n~e totally independent major diseases to coexist in young patients. However, older animals with cancer are likely to have acquired associated conditions such as renal insufficiency, mitral valvular disease, and degenerative joint disease. These and other common aging problems may increase the morbidity and mortality that can be expected with many diagnostic and treatment activities. Therefore, all the historical, physical examination, and clinical laboratory problems of a patient must be identified so that the complete profile of problems can be evaluated. Beyond the recognition of the presence of a neoplasm in a patient, it is usually imperative to have histologic confirmation and identification of the tumor type. Cytologic diagnosis can provide an accurate diagnosis in some cases, but reliance on cytologic diagnosis without histologic diagnosis deprives the clinician of grading informatitm that may allow for more accurate prognostic predictions. For example, survival times for dogs with cutaneous mast cell tumors have been shown to vary significantly with histologic grade. 47 Once the full extent of the disease of a patient is known and characterized, appropriate staging of a patient's neoplasm should be done. Staging, when combined with tumor grade, may allow a more accurate prediction of prognosis and likely response to therapy. k. 21 Staging schemes for various tumors have been reported elsewhere. k. 2 L 44 When treating aged animals, it is especially important to have a complete profile of all the major organ systems of the patient before proceeding with any kind of therapy. Patients must be evaluated for whatever diagnostic or therapeutic procedures are anticipated. A complete blood count, serum biochemical profile, urinalysis, and thoracic and area radiographs are major components of a data base for evaluating and treating the aged animal with ca,ncer. The need for other type§ qf patient data will vary with the individual situation. · ·· . TREATMENT OF

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Clinical Relevance of Tumor Cell Heterogeneity The concept that every tumor consists of a mixed or heterogeneous cell population is an extremely important one. Until recently, the idea of heterogeneity of tumors was of minimal interest to the clinician and for the most part subpopulations of tumor cells were ignored. However, in many human tumors, prognosis clearly relates to the subtle characteristics not apparent histologically that define subpopulations of tumor cells. 53• 54· 68· 73 Even within an individual patient with a single histologic tumor type, different subpopulations of cells will be found . Cells within the same tumor vary enormously in such characteristics as surface antigens, DNA content, secretory granual content, volume, pH, and sensitivity to chemotherapy. 54 Different populations of tumor cells may have different growth patterns and may require different therapies.

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Malignant tumors often behave unpredictably. It is not unusual for a primary tumor site to be sensitive to chemotherapy whereas metastatic sites of similar appearing cells are resistant. Tumors of a similar tissue type may appear to be sensitive in one patient but not in another or behave differently in different parts of the body. Tumor cell heterogeneity is the likely explanation for these and many other clinical observations of unexpected tumor behavior. Further evidence of tumor heterogeneity can be found by examining differences in cell surface receptors. Approximately 60 per cent of canine and 10 per cent of feline mammary tumors have surface receptors for estrogen. 29• 41 Progesterone receptors have also been found on some canine and feline mammary tumors. 29• 41 Other receptors, such as those for dexamethasone and testosterone, have been found with varying frequency among many different histologic tumor types. 34 Stimulation of these hormone receptors may promote tumor growth, but the complete role of these receptors in the disease process is unknown. 29 Phenotypic variation with respect to drug sensitivity is another manifestation of tumor cell heterogeneity that has enormous implications for cancer therapy. 53• 54• 68 A frequent clinical observation in cancer patients is initial regression with chemotherapy, followed by tumor regrowth in the presence of the same drug. Drug resistance occurs via many mechanisms, including mutations that may induce an inability for drug transport across cellular membranes, promote drug inactivation, repair drug-induced DNA damage, or increase production of the drug's target enzyme. 54 Resistant phenotypes are thus selected from among the original cell population. Genes that control intracellular processes can have their effects amplified by cellular oncogenes that modify a cell's phenotypic expression toward drug resistance. 54 Cancer cells "learn" to live in the bodies of the host they inhabit and evolve through the natural selection process where the most rapidly growing of those cells with the best ability to grow in the most diverse environments are the cells that will eventually kill the host. 73 Tumor heterogeneity appears to be a dynamic process with changes in the composition of the constituent cell population occurring in response to environmental selection pressures generated within the tumor by such factors as the host's immune system defenses or changes imposed by treatment. In veterinary medicine, we are only beginning to appreciate the impact of tumor heterogeneity on the treatment of cancer. Palliation Versus Cure Palliation, by definition means to relieve without curing. 31 Much of what we do as clinicians involves the relief of symptoms without the intent or ability to cure the underlying disease. Congestive heart failure , renal failure, and diabetes mellitus are not curable, yet many of their symptoms can be controlled with appropriate medications. Palliation is a legitimate and honorable goal for the clinician in many situations before euthanasia need be considered. Our perceptions of ourselves and the pet owner's perceptions of the veterinarian as a healer can lead to frustration, guilt, and ange r, especially

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in the field of cancer medicine, where many patients are not curable. Whenever possible, therapy with the goal of cure. or life prolongation is the proper focus for the clinician. However, when a patient presents with a disease that is by definition or stage not responsive to rescue, symptomoriented therapy aimed at comfort becomes the prime obligation of the attending clinician. 31 Frequently, disease-oriented therapy with the goal of cure and symptom-oriented therapy are given simultaneously but with varying relative priorities. 31 Patients with treatable disease should not simply be comforted. Patients whose disease are not treatable should not be subjected to unnecessary suffering. Symptomatic therapy for either type of patient requires an accurate diagnosis so that an accurate prognosis can be given and the cause of each symptom treated most effectively. It is also important to be aware of those clinical situations in which early palliative therapy will prevent a major complication. For example, early limb amputation of a bone malignancy may prevent pain-associated anorexia, lameness, or a pathologic fracture. Removal of a thoracic effusion can prevent or delay life-threatening respiratory compromise. Early palliation can spare the patient considerable morbidity.52 Cancer Pain Although the general topic of animal pain has been recently reviewed, the specific area of cancer-related pain in animals has not been addressed. 2 • 11 • 21 · 51 · 71 There appears to be a scientific void concerning pain among veterinary cancer patients. In discussing animal cancer pain it is, perhaps, inadequate simply to review the human literature and apply what appears to be relevant. Unfortunately, for animal cancer pain, there appears to be no alternative. Although realizing the dangers of direct extrapolation from human medicine, it is nevertheless useful briefly to review the human experience with cancer p~n . . -~ Humans with cancer frequently have mult,iple sources of pain, and pain is the most common symptom of patients with advanced cancer. 17 Physicians are taught to consider the concept of "total pain" to describe the etiologic components of emotional, social, bureaucratic, financial and spiritual influences that compound noxous physical stimulation. 17• 30 Human cancer pain has been categorized in many ways, but a useful organization for veterinary medicine is by pathophysiologic mechanism. Approximately 70 to 78 per cent of human cancer pain is associated with direct tumor involvement, such as that from metastatic bone disease, muscle spasm, rectal or bladder spasm, intestinal colic from obstruction, nerve compression or infiltration, and hollow viscus involvement. 17· 30 Cancer therapy (surgery, chemotherapy, or radiation therapy) causes about 15 to 25 per cent of pain syndromes. 17• 3° Coincidental conditions unrelated to cancer or cancer therapy cause 3 to 15 per cent of pain in human cancer patients. 17· 30 Nonnarcotic analgesics (aspirin, acetaminophen) are usually prescribed for mild to moderate pain and narcotic analgesics (morphine, oxymorphone, meperidine, butorphanol) are frequently prescribed for moderate to severe

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pain. 17• 30• 60 Routes of administration and individual patient response to a given dose vary. The nonpharmacologic management of cancer pain includes appropriate surgery, radiation therapy, anesthesia, neurostimulation procedures, and neuroablative surgery. 17· 30· 60 An obvious difference in the management of a human with terminal cancer and the pet with terminal cancer is the option of euthanasia in the case of the pet. Most pets with untreated or unsuccessfully treated cancer are euthanized at a point determined with some objectivity and considerable subjectivity by the pet owner and the veterinarian. Occasionally, an owner may refuse to consider euthanasia to terminate a hopeless situation and will insist on a natural death in the home environment and request a drug to allow death relatively free of pain. An awareness of potential or actual pain in veterinary practice requires a subjective sensitivity to a patient's clinical demeanor. The experienced veterinary clinician and the pet owner may have an intuitive awareness of a patient's pain. Once pain or the potential for pain is recognized, a decision should be made to address the problem promptly. Active and Palliative Chemotherapy Although rarely stated explicitly, most clinical trials of anticancer chemotherapy are conducted with the goal of providing palliation to patients with incurable malignant disease. 63 The hope, of course, is for cure, but the expectation in many cases is for prolongation of a good quality of life. Small and large variations are found among the specific tumor chemotherapy protocols in use by veterinary oncologists. The continuing search for a reliable cure of malignant cancer is a reflection of the lack of clear superiority of any of the contemporary protocols for various cancers. The individualization of protocols in response to a patient's changing clinical and laboratory findings further compounds the variations found among chemotherapy regimens. Rather than provide specific protocols for tumor types and lists of the drugs, doses, and precautions, working with and through a referral veterinary oncology center is recommended so that veterinarians in general practice will access the most current trends in chemotherapy. Chemotherapy that is given with the intent of tumor cure or palliation is within the capabilities of most veterinarians. As a knowledge of anatomy and aseptic technique are prerequisites for attempting surgery, a knowledge of drug mechanisms, toxicities, pharmacokinetics, and safe handling are necessary prerequisites for administering chemotherapy. 18• 19• 62 Knowledge of this kind allows the clinician to move beyond the bounds of rigid protocols for common tumors and be able to decide intelligently how to manage drug-resistant or uncommon tumors and to exploit potential drug synergism. For example, combining a drug that damages DNA (alkylating agent), with a drug that prevents DNA repair (antimetabolite), can have a result that is more than additive. Chemotherapy given with the primary intention of palliation rather than cure of cancer is common. However, clinical trials documenting the efficacy of many approaches are lacking and evidence for the appropriateness of some forms of palliative chemotherapy is often empirical.

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Corticosteroids are commonly and sometimes appropriately used in cancer patients for their antiinflammatory properties. Many tumors have a granulomatous or inflammatory component that rriay result in edema and pain. Virtually all human patients with symptomatic brain metastasis or epidural spinal cord compression are treated with corticosteroids. 69 The goal for the administration of the corticosteroids in these cases is to improve neurologic function by reducing brain or spinal cord edema. Approximately 70 per cent of humans with brain metastasis ultimately experience significant clinical improvement with corticosteroid therapy. 69 There is a theoretical aspect of corticosteroid use that is of importance to the veterinary oncologist who might be using active chemotherapy concurrently for a malignancy of the brain. The morphologic changes found in brain tumors are extensive enough that many water-soluble antineoplastic drugs can readily pass through a disrupted blood-brain barrier and provide clinically important palliation of the tumor. 69 Corticosteroids may reduce peritumoral brain edema by decreasing brain tumor capillary permeability and thus potentially reduce drug delivery into brain tumors. 69 It remains to be seen if corticosteroids actually inhibit concurrent chemotherapy of brain tumors. At present, however, there are no medical alternatives for chronic antiedema therapy of brain and spinal cord tumors. 69 Corticosteroids are frequently part of combination chemotherapy protocols of hematopoietic tumors such as lymphosarcoma, myeloma, and acute and chronic lymphocytic leukemia. As single agents, they are frequently employed for palliation of hematopoietic tumors and mast cell tumors. Short-term tumor control (remission or disease stabilization) is frequently possible with corticosteroids. Cancer patients are at risk for serious and varied side effects when corticosteroids are administered for long periods of time. Polydipsia, polyuria, polyphagia, urinary tract infection, and other problems related to cortisol excess are common with corticosteroid use. To reduce the risk of toxicity, each patient's dosage should be individualize.g w~th the dosage and duration of therapy kept to a minimum. · · Nonsteroidal antiinflammatory drugs have also been used successfully for palliation . Recently, Knapp26 reported on the use of piroxicam as palliation for a variety of malign::mt tumors .. Fifty-four dogs, having failed conventional therapy for a variety of solid tumors or having conventional therapy declined by the owners, were treated with piroxicam. Partial remission (at least 50 per cent regression of measurable disease) was reported in 7.4 per cent of the dogs whereas 35.1 per cent of the dogs had their disease stabilized for at least 60 days. A palliation dose of 0.3 mg per kg of piroxicam orally given once a day is recommended. In this series of dogs, the gene ral quality of life was judged by the authors to be enhanced while receiving piroxicam. 26 It is unclear if the partial remissions and enhanced quality of life were due to the antiinflammatory or potential (and as yet unproven) antineoplastic effects of piroxicam. As with other nonsteroidal antiinflammatory drugs, piroxicam use may lead to gastric and duodenal ulceration. 39 Nonsteroidal antiflammatory drugs should be used cautiously in a hypovolemic, dehydrated, or renal compromised patient and in patients

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concurrently receiving nephrotoxic drugs or diuretics because they reduce renal cortical blood flow and may precipitate renal failure in some situations. 28 Gastric and duodenal ulceration associated with mast cell tumors has been previously reported. 42 The pathogenesis of the ulcer formation is thought to be related to mast cell derived histamine excess and subsequent gastric hyperacidity. Antihistamines (H 2 blockers) such as cimetidine and ranitidine are useful in preventing and treating ulceration. Cromolyn sodium will stabilize mast cell membranes and prevent degranulation. 42 Its use in humans with systemic mastocytosis has had varying results. 42 It is unlikely that cromolyn sodium will find a prominent place in veterinary medicine as it is meant for inhalation use only. Sucralfate is an oral drug with antiulcer properties. Sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site that protects it against further attack by gastric acid, pepsin, and bile salts. 14 It has not been evaluated in dogs with mast cell associated ulceration, but it may have a role for this. Palliative Surgery In general, the patient receiving palliative surgery is at increased risk for morbidity and mortality. 4 • 32 However, palliative surgery may be useful in many patients with progressive or incurable cancer who have developed a variety of distressing symptoms. 4 Surgery may be considered early for relief of specific mechanical problems such as extensive local tumor, intestinal or biliary obstruction, and pathologic fractures. 4 The general comfort of the patient can be enhanced through drainage of both ascites and pleural effusion. 4 In other patients, securing venous access or creating feeding enterostomy sites can be extremely helpful in correcting progressive dehydration and malnutrition. 4 Patients with untreated or unsuccessfully treated cancers sometimes develop large, ulcerated, painful, and secondarily infected tumors. 4 • 72 If the patient's life expectancy is more than a few weeks and if the lesion is technically resectable, surgical removal of the entire tumor is usually desirable. 4 In addition to alleviating problems associated with chronic bleeding, odor, and infection, removal of such a tumor may be of some psychological benefit to the owner. For example, the owner of a dog with an ulcerated mammary tumor with metastasis may be less tempted to select euthanasia as a means of resolving the problem and may be more inclined to pursue systemic chemothe rapy or allow the patient to live out its life without the morbidity associated with a large ulcerative lesion. Large ulcerated lesions that are not easily resectable usually require some form of wound care with gentle cleaning of exudate, the use of nonadherent dressings, and protection from inadvertent trauma. Superficial bacterial infection may respond to topical or systemic antibiotics, and prompt drainage of any associated abscess is indicated. Although many of these secondary problems can be controlled, any attempt to promote actual healing of large ulcerated lesions is futile in the absence of effective antineoplastic therapy. 4 Destruction of cortical bone resulting in pathologic fractures can be

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seen with primary bone neoplasms such as osteogenic sarcoma. Painful stimuli from periosteal disruption may be debilitatin..,g. Amputation of such an affected limb can provide pain relief during the remaining period of the patient's life. A probable life expectancy of at least two months is a suggested criterion to justify amputation. The morbidity and the direct risks of surgery as well as the expected length of hospitalization and subsequent convalescence must be weighed against potential benefits of the procedure for each patient. Palliative Radiation Therapy For human beings with incurable cancer, palliative radiation therapy is effectively employed to obtain relief from pain, alleviate obstruction, control hemorrhage, and improve function in many cancer patients. 50 In humans, nearly half of all radiation therapy treatments are given with palliation as the primary goal. 50 The most common problems addressed with palliative radiation therapy include metastasis to bone, brain, and liver. 50 Although widely available as a therapeutic modality at veterinary teaching institutions, its use for palliation of pain is relatively infrequent in animal cancer patients. Significant reduction in bone pain associated with long bone tumors has been observed by many veterinary radiation oncologists, although the prime intent of radiation therapy has been for tumor control rather than pain relief. 25 Hormonal Palliation and Palliation of Common Endocrine Tumors Palliative therapy with hormones and palliative therapy of endocrine tumors is common in veterinary medicine. Many examples of this can be found. Prednisone is frequently used as palliative therapy of hypoglycemia caused by insulin-secreting tumors of the endocrine pancreas when cost or toxicity of diazoxide or streptozocin limit their use. 16 The anti-insulin effects of prednisone can be very helpful in maintaining normoglycemia. Inoperable adrenal and pituitary tumors that result.. in hyperadrenalcorticism are routinely treated with mitotane. Re~ults ofsuch therapy have been reviewed extensively elsewhere. 16 Ketaconazole has recently been advocated for treatment of some forms of hyperadrenalcorticism. 6 Ketoconazole is an immidazole derivative with antifungal properties. It is known to blunt cortisol responses to ACTH, possibly through inhibition of 14-demethylation oflanosteral to cholesterol. 6 Ketoconazole administration (15 mg per kg twice a day) to dogs with hyperadrenalcorticisms results in a rapid decrease in plasma cortisol concentration, suppression of plasma cortical response to ACTH, lack of compensatory increase in plasma ACTH concentration, minimal side effects, and remission of clinical signs. 6 Feline plasma cortisol concentrations are unaffected by ketoconazole. 70 Because ketoconazole also blocks testosterone production, it has found a role in the palliation of prostate carcinoma in humans. 40 Prostatic carcinoma is an androgen-responsive tumor in men, and castration or estrogen therapy will enhance survival in many cases.4° Ketoconazole also blocks canine testosterone synthesis, so a similar role in temporary palliation of canine prostate carcinoma might be expected, although its value for this in

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the dog is speculative because no clinical trials proving this have yet been reported. Feline testosterone concentrations are unaffected by ketoconazole. 70 In dogs, recent reports that castration has no influence on the development of prostatic carcinoma has raised two interesting possibilities. 40 Either the etiology of prostatic carcinoma in dogs is different than in men and is not under testicular androgen influence or nontesticular hormones influence the development of the disease. 40 There are indications that nontesticular androgens have significant influence on the canine prostate. The adrenal glands influence the prostate by secreting weak androgens or androgen precursors that are converted to dihydrotestosterone intraprostatically. 40 Adrenal estrogen may also play a role in the etiology of canine prostatic carcinoma because atrophic prostate cells are known to be stimulated by estrogens in vitro. 40 The in vitro observation that estrogen are capable of stimulating atrophic prostatic cells from castrates to differentiate raises doubts about the wisdom of the traditional use of estrogen for palliation of prostatic carcinoma in dogs. The proper role of hormonal or antihormonal therapy in prostatic carcinoma is further obscured by the finding and unknown significance of prolactin and growth hormone binding sites in the canine prostate. 40 Tamoxifen is a drug that blocks cellular estrogen receptor sites. It is considered to be an effective adjunctive treatment for many women with breast cancer. 49 Although up to 61 per cent of malignant canine mammary tumors have estrogen receptors (which when stimulated may promote growth or differentiation), the benefit of tamoxifen therapy in dogs has not been established. 29 Although personal experie nce using tamoxifen in dogs with mammary gland malignancies has been limited , the drug seems to be well tolerated except for a frequent occurre nce of apparent drug-induced vaginitis. Tamoxifen therapy should be considered experimental at this time. The use of tamoxifen in dogs with malignant mammary gland tumors needs to be investigated further. Feline hyperthyroidism, which has bee n well described, is frequently treated with agents such as methimazole, propylthiouracil, and iodine 131. 16 Both methimazole and propylthiouracil inhibit synthesis of thyroid hormones by preventing iodine from being incorporated into the tyrosal groups of thyroglobulin. Methimazole has been found to cause fewer side effects than propylthiouracil. 48 Propylthiouracil is no longer recommended for use in cats. 48 Iodine 131 treatment is an excellent choice for a non stressful treatment of hyperthyroidism in elderly cats. 16 Iodine 131 treatment requires no anesthesia, solution, oral medication, or surgery. It is expensive, however, and it is not widely available. 16 Recombinant Technology A new field of cancer medicine has emerged with the availability of highly purified products of recombinant DNA technology such as interferons (IF), interle ukin-2 (IL-2), and tumor necrosis factor (TNF). An investigational trial in dogs with soft-tissue neoplasms using IL-2 and TNF had variable but encouraging results. 37 Toxicities of TNF were primarily gastrointestinal. 37 Toxicities of IL-2 included inappetance, weight loss, and weakness. 37

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Interferons increase natural killer cell activity, antibody synthesis, phagocytosis by macrophages, and antitumor ceU activity. 24· 55 They may arrest cell division and inhibit cell differentiati.on. 24• 55 There are several major types of IFs (alpha, beta, and gamma), and their effects and activity vary. 24 Alpha IF has apparent activity in a wide range of human malignancies. 55 Its use in human medicine and its availability have led to its inevitable empiric use in veterinary medicine. Generalizations from the human alpha IF experiences are: continuous dosing appears to be more effective than intermittent dosing, alpha IF is more likely to be effective if the tumor burden is small, a delayed response is common, and an optimum dose remains unknown with contradictory results in both in vitro and clinical reports. 55 Toxicities of alpha IF appear to be dose related and include fever, nausea, vomiting, diarrhea, mental depression, hypotension, and tachycardia. 55 Alpha IF has been advocated for use in cats with nonregenerative anemia associated with feline leukemia virus infection. There are two recent reports of IF treatment involving small numbers of feline leukemia virus infected cats with anemia that recovered and had long-term survival. 59 · 66 However, all the cats in one report had concurrent Hemobartonella f elis infection, which was also treated, making an assessment of the cause of recovery from the anemia difficult. 59 A controlled clinical trial of treatment of feline leukemia virus infected cats with oral bovine beta IF and intramuscular subcutaneous or oral human alpha IF found no discernable toxicity or benefit. 1 Interferon's value over more traditional approaches of treating clinical manifestations of feline leukemia virus infection remains speculative.

MORBIDITY ASSOCIATED WITH COMMON CANCER TREATMENTS It is not the purpose of this article to discuss in detail all aspects of morbidity associated with cancer treatment. Rather, the goal is for the reader to have increased aware.ness about .the •potential for complications, especially in the aged patient. Clinical maturity and an individual patient assessment should help the clinician to weigh the relative risks of a procedure or treatment against the anticipated clinical behavior of an untreated tumor.

Morbidity Associated with Chemotherapy Chemotherapeutic age nts used in cance r affect virtually every organ and tissue. 36 Toxicity from these agents can be delayed in onset and longterm in duration. Because of their toxicities, preexisting organ system disease may limit the use of many drugs.

Myelotoxicity Bone marrow suppression is a major toxicity seen with many chemotherapeutic agents. 18 Myelosuppression most commonly occurs between 7

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and 10 days after treatment and is characterized by a rapid decrease in neutrophils followed by a decrease in platelets. Life-threatening sepsis and or bleeding are possible when profound neutropenia and thrombocytopenia occur. Effects on the red cell population take longer to become manifest because of the longer life span of erythrocytes, but mild anemia commonly occurs when myelosuppressive drugs are used for prolonged periods of time. Cardiotoxicity Acute and chronic cardiotoxicity may occur with the use of anthracycline derivatives such as doxorubicin hydrochloride. Cardiotoxicity is a major dose-limiting factor of doxorubicin use, and a variety of benign and life-threatening arrhythmias have been reported. 18• 33• 61 Chronic administration of doxorubicin to a cumulative dose greater than approximately 180 to 200 mg per M2 in many dog~ is associated with an increased risk of congestive heart failure and sudden death on the basis of a drug-induced cardiomyopathy or fatal arrhythmia. 61 Cats exposed to long-term doxorubicin therapy also show microscopic evidence for myocardial damage, which, until recently, was not appreciat~d. 9 All dogs and cats in whom doxorubicin therapy is anticipated should have a pretreatment electrocardiogram and echocardiogram or a radioriucleotide-ventriculogram to assess ventricular performance. If there is evidence of cardiac dysfunction, doxorubicin therapy may be contraindicated. Prior radiation to the mediastinum or concurrent therapy with cyclophosphamide may increase this risk. 33 Cutaneous Toxicity Hypersensitivity reactions during administration of doxorubicin occur approximately 30 per cent of the time in dogs. 61 The angioneurotic edema and urticaria are transient and are not considered a contraindication for future use. Pretreatment with antihistamine and corticosteroids have had variable success in preventing hypersensitivity reactions. 61 · 64 Alopecia may occur in any dog given doxorubicin, but the hair loss is frequently much worse in long-haired dogs. 61 The rate of hair loss is variable; some dogs experience severe hair loss even after a single dose. Histologically, the skin becomes characterized by marked atrophy of the epidermis, hair follicles, and sebaceous glands.61 Several intravenous agents (doxorubicin, vincristine) will produce severe perivascular sloughing if extravasation of the drug occurs. 18 If doxorubicin is extravasated, the area should be flooded with normal saline and a small amount of 8.4 per cent sodium bicarbonate and dexamethasone. 13• 18· 64 · 74 The sodium bicarbonate is thought to prevent interaction between the drug and tissue DNA. 13· 74 If vincristine is extravasated, the manufacturer advises that the area should be injected with hyaluronidase and moderate heat and topical dimethylsulfoxide should be applied to the area of leakage to help disperse the drug. 18· 43 Ice packs for 48 to 72 hours have been suggested as an alternative to local heat to confine the extravasated drug by inducing vasoconstriction and thus limiting tissue damage to a smaller area. 13

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The drug most commonly associated witlt pulmonary toxicity in veterinary medicine is cisplatin. 13• 27 Cisplatin's pulmonary toxicity appears to be specific for cats. 13• 27 Its use in cats at the canine dose led to unanticipated fatalities. Postmortem findings in cats with cisplatin toxicity include severe hydrothorax, pulmonary edema, and mediastinal edema. 27 Microscopic changes of the pulmonary parenchyma include thickening of alveolar septae and thrombi and small foci of necrosis and fibrin with fibrin exudation into the alveolar spaces. 27 The mechanisms of lung injury are not clearly defined. A safe dose for cisplatin in cats has not been established. Cats appear to tolerate a dose of 20 to 25 mg per M2 if it is accompanied by intravenous saline diuresis at a rate of 20 ml per kg per hour for 4 hours preceding and 4 hours following cisplatin administration. This drug should be used very cautiously in cats. Other less commonly used antineoplastic agents with a potential for pulmonary toxicity include bleomycin and the nitrousureas. Urinary Tract Toxicity Nephrotoxicity is a dose limiting side effect of cisplatin administration in dogs and cats. 18• 19• 22 • 45 Abnormalities in renal function induced by cisplatin use may be mitigated to a large extent with intravenous saline diuresis prior to and following drug administration. Patients to be treated with cisplatin should have a complete urinalysis, evaluation of serum electrolytes, creatinine, and urea nitrogen prior to drug administration. Methotrexate may also induce nephrotoxicity, especially when used in high-dose regimens. 18 Toxicity of methotrexate may be related to its precipitation in the renal tubules and collecting ducts. The concurrent use of other potentially nephrotoxic agents such as nonsteroidal antiinflammatory drugs, diuretics, or aminoglycoside antibiotics should be done with great caution in patients receiving nephrotoxic chemotherapeutic agents. 28 Great caution sh6uld also be exercised in the :''u~e of any of these drugs alone or in combination in patients that evidbnce dehydration or preexisting , renal insufficiency. Doxorubicin can cause delayed nephrotoxicity in cats, and the upper limit of safe cumulative dosage in cats is. imknown. 8 · 35 Renal failure may occur from 4 to 6 months following doxorubicin administration. 9 All cats in whom the use of doxorubic:in is anticipated should have ample clinical laboratory evidence for adequate renal function. Hemorrhagic cystitis from cyclophosphamide use in dogs and cats is well recognized. 18• 57• 64 The excretion of irritating cyclophosphamide metabolites can induce fibrosis of the bladder wall, telangiectasia of the bladder mucosa, and hematuria. 57 Cystitis usually occurs with long-term use and is most common in female dogs, followed in frequency of occurrence by neutered male dogs, and is least common in cats. 57 If detected early and if the drug is withdrawn, the cyclophosphamide-induced hemorrhagic cystitis is reversible.57 If the drug is continued in the presence of clinical signs, irreversible damage to the bladder may ensue. If secondary infection exists, then appropriate antibiotics are indicated.

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Hepatotoxicity Although many chemotherapeutic agents are metabolized in the liver, relatively few of them are associated with hepatotoxicity. 13 In most situations, toxicity associated with these drugs is manifest by elevations of hepatic enzyme concentrations although hepatic failure rarely follows . The group of chemotherapeutic agents most likely to induce hepatic dysfunction are the aritimetabolites. This group of chemotherapeutic agents acts on cells by limiting various enzyme pathways that are usually involved in the production of purine and pyramidine bases that are in turn involved in the synthesis of DNA. Hepatic dysfunction may alter the metabolism of systemic and inhaled anesthetics. Therefore, patients exposed to antimetabolic drugs should have an evaluation of liver function prior to the use of anesthesia. Gastrointestinal Toxicity Vomiting and diarrhea are occasionally associated with the use of antineoplastic agents. 18 In most cases, when the doses used are accurate, gastrointestinal disturbances are minor and transient. On rare occasions, gastrointestinal disturbances are severe. Emesis associated with chemotherapy can usually be mitigated by the use of antiemetics. 10• 23 Diarrhea associated with chemotherapy can usually be addressed with symptomatic measures. All gastrointestinal disturbances can potentially result in dehydration, azotemia, and acid-base and electrolyte abnormalities. The prevalence of emesis with each individual chemotherapeutic drug shows a high degree of interpatient variability. 10 The occurrence of emesis is affected by multiple factors, including dose and frequency of administration, concurrent drug therapy, and associated medical complications. 10 Certain drugs, such as cisplatin, cause emesis very frequently whereas other drugs, such as vincristine rarely induce symptoms. Emesis in dogs caused by cisplatin therapy can usually be controlled with metoclopramide (3.0 mg per kg subcutaneously) or butorphanol (0.4 mg per kg intramuscularly before and after drug infusion). 23 Dexamethasone is considered a useful antiemetic in humans given cisplatin, and it will enhance the antiemetic activity of metoclopramide in dogs. 3 • 10 Cirrietidine and phenothiazine derivatives are unreliable antiemetic drugs for cisplatin-induced emesis in dogs . 3 Antihistamines are considered to be ineffective in controlling chemotherapy-induced emesis. 10 Neurotoxicity Although periphenil neuropathies are a common side effect of vincristine in humans, they are not considered a risk of vincristine use in dogs and cats. I am aware of one cat in which the owners reported a voice change following vincristine therapy. The relationship, if any, between the voice change and the vincristine use is unclear, but it might represent a manifestation of a peripheral neuropathy. The vast majority of dogs and cats tolerate vincristine very well. Severe neurotoxicity is associated with the use of 5-fluorouracil in dogs, cats, and humans. 64 Neurotoxicity may be transient in dogs and humans, but it is frequently fatal in cats. Cats should not be given 5fluorouracil because of their extreme sensitivity. 64

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Tumor lysis syndrome can occur in some human cancer patients following chemotherapy for lymphoblastic lymph<;>ma, Burkitt's lymphoma, acute lymphoblastic leukemia, and, occasionally; ~other tumor types. 18 • 46· 58 Tumor lysis syndrome consists of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, which may develop separately or in any combination. 46· 58 These changes are the result of rapid cytolysis following chemotherapy, which may cause obstructive nephropathy or acute cardiac decompensation. The incidence and potential significance of tumor lysis syndrome in veterinary medicine is unknown. 46 Dogs receiving chemotherapy for lymphoma have been suggested to be at risk for tumor lysis syndrome if they have a large tumor burden or renal insufficiency. 46 Definitive documentation of this syndrome in veterinary medicine is lacking. Teratogenic and Oncogenic Effects Pregnant animals receiving cyclophosphamide (Cytoxan) have an increased risk of teratogenic effects in their offspring. The use of cyclophosphamide and other alkalating agents may also induce a second neoplasm. 57· 64 In humans and in dogs there are several reports of a patient receiving alkylating agents such as cyclophosphamide to treat one tumor and the patient subsequently develops a second tumor (usually of the urinary tract). 18• 57 The carcinogenic potential of cyclophosphamide is not one that should limit its use. However, use beyond 8 to 10 months should only be undertaken when there is clear-cut advantage to the patient in prolonged exposure to this agent. Morbidity Associated with Surgery Most surgeries happen without complications. 32 Some problems such as infection and dehiscence of the surgery site may follow any surgery, and each type of operation has its own special problems. Thorough perioperative patient evaluation, strict aseptic technique, appf.QPr.iate fluid therapy, surgical finesse, and good postoperative nursing ··c~te will reduce the incidence of complications from surgery. Complications common to many surgical procedures include hypovolemia, hemorrhage, and infection. 32 Irritation from intravenous catheters or periv~scular infiltration of drugs may cause phlebitis, pain, and local swelling. 32. Animals that will be recumbent for long periods of time following surgery are at risk for developing decubital ulcers. 32 Hypostatic congestion of the pulmonary parenchyma may lead to bacterial pneumonia. Postoperative pain may be severe enough to warrant analgesic use. 11 Interpretation of pain by the veterinarian is subjective, and clear guidelines are difficult to establish. Morbidity Associated with Anesthesia A large number of complications associated with anesthesia have beeri extensively reviewed elsewhere. 32• 67 Although cancer is more common in older animals, operative anesthetic deaths are no more common in older animals than in young ones. 72 Complications and anesthetic effects arise from the interactions of the physical status and individual sensitivity of the

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patient, undetected disease, choice and dose and route of administration of anesthetic agent, interactions with other drugs, and the length of anesthesia. As with surgery, complications of anesthesia vary. Hepatic and renal blood flow are reduced by anesthesia. 32· 67 Prolonged hypovolemia can result in decreased renal blood flow; this may lead to acute renal failure. 32· 67 Acidbase and electrolyte abnormalities, neuromuscular blockade, hypothermia, aspiration pneumonia, hypotension, and arrhythmia have all been associated with anesthesia. Morbidity Associated with Infection Patients with cancer and those receiving chemotherapy are considered to have compromised immune systems. Infection in cancer patients is associated with improperly placed or maintained intravenous and urinary catheters, surgical technique, and tissue viability, but more commonly with endogenous enteric organisms. The use of antibiotics in cancer patients is common but is only justifiable if a bacterial infection is known to exist or one is anticipated by the clinician. Selection of antibiotics should be based on culture and sensitivity testing. In the absence of culture and sensitivity information, staining and morphologic characteristics of the bacteria, a knowledge of previous infection, or anticipation of the common pathogenic flora from a particular body site can be used as guides in drug selection. Sepsis with the patient's own enteric flora is uncommon unless peripheral neutrophil counts fall below 1000 cells per f.LL. Prophylactic use of widespectrum antibiotics such as trimethoprim-sulfa or a penicillin familyaminoglycocide combination are justified when a patient has profound neutropenia. Morbidity Associated with Radiation Therapy Radiation complications are usually seen either early (before or shortly after completion of irradiation) or late (weeks or months following irradiation). 65 Obvious evidence of the effects of irradiation will be observed in most patients. Acute complications of irradiation include epilation, changes in pigmentation, and mucositis and moist epithelial desquamation that result from the death of the rapidly proliferative cells of the skin or mucous membranes. 65 Early complications of radiation therapy usually heal quickly. Delayed complications involve necrosis of slowly or nonproliferating tissues such as muscle or bone. 65 The incidence of normal tissue necrosis is directly related to the total dose given and the size of the dose per fraction . 65 SUMMARY Considerable morbidity can be associated with cancer and the diagnosis and treatment of cancer. Knowledge of a tumor's likely clinical behavior and an awareness of the benefits and morbidity associated with treatment will help the clinician and the owner find the most appropriate plan of action for the aged pet with cancer. Tumor cell heterogeneity is a concept of enormous importance in our understanding of neoplasia. Phenotypic variations within cancer cell popu-

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'· lations often confound our attempts to cure a patient's cancer. Frequently, we are forced to settle for palliative therapy when\()ur patient's cancer has advanced beyond our ability to rescue. ·

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60. Sundaresan N, Di Giacinto GV: Antitumor and antinociceptive approaches to control cancer pain. Med Clin North Am 71:329, 1987 , 61. Susaneck SJ: Doxorubicin therapy in the dog. J Am Vet M~d Assoc 182:70, 1983 62. Swanson LV: Potential hazards associated with low dose exposure to antineoplastic agents. Part I. Evidence for concern. Compend Contin Ed Pract Vet 10:293, 1988 63. Tannock IF: Treating the patient not just the cancer. N Eng! J Med 317:1534, 1987 64. Theilen GH, Madewell BR: Clinical complications of cancer chemotherapy. In Theilen GH, Madewell BR (eds): Veterinary Cancer Medicine, ed 2. Philadelphia, Lea & Febiger, 1987, p 183 65. Thrall DE, Denhirst MW: Application of radiotherapy in control of neoplasia. In Gorman NT (ed): Oncology. New York, Churchill Livingstone, 1986, p 7l 66. Tompkins MB, Cummins IM: Response offeline leukemia virus-induced nonregenerative anemia to oral administration of an inteferon-containing preparation. Feline Pract 12:6, 1982 67. Trim C: Anesthesia and the kidney. Compend Contin Ed Pract Vet 1:843, 1979 68. Von Hoff DD: Implications of tumor cell heterogeneity for in vitro drug sensiti~ity testing. Semin Oncol 12:327, 1985 69. Weissman DE: Glucocorticoid treatment for brain metastasis and epidural spinal cord compression: A review. J Clin Oncol 6:543, 1988 70. Willard MD, Nachreiner RF, Howard VC, et a!: Effect of long-term administration of ketoconazol in cats. Am J Vet Res 47:2510, 1986 71. Willis WD, Chung JM : Central mechanisms of pain. JAm Vet Med Assoc 191:1200, 1987 72. Withrow SJ: Surgical oncology: Old and new ideas. Semin Vet Med Surg [Small Animal] 1:17, 1986 73. Yarboro JW: Introduction: Tumor heterogeneity and the new biology. Semin Oncol 12:201, 1985 74. Zueig JI, Kabakow B: An apparent effective counter measure for doxorubicin extravasation. JAMA 239:2116, 1978 Purdue Comparative Oncology Program School of Veterinary Medicine Purdue University West Lafayette, IN 47907