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Susan M. Cotter DVM, DACVM (Oncology and Internal Medicine) Tufts University, School of Veterinary Medicine North Grafton, MA (Clarification: "I checked the Melphalan dose. The one that I have used most often is the one on the slide: 1.5 mg/m2/day for 1 wk then q3days. The second one was from Ogilvie and Moore, Managing the Veterinary Cancer Patient, published by Vet Learning systems. Either dose can be used. The second one is actually slightly more aggressive when you compare dose/size.") GENERAL PRINCIPLES OF CANCER CHEMOTHERAPY
More and more owners of pets with cancer are requesting treatment. Most localized tumors are treated surgically, sometimes followed by radiation, chemotherapy or combinations of these modalities. Systemic tumors like lymphoma, and others that may have spread beyond the local site may be treated with chemotherapy. Combinations of drugs have improved the response rate. The primary limiting factors of these approaches are cost and toxicity. Although we can do little to minimize cost, except by participating in funded studies, toxicity can be minimized through careful patient selection, drug dosage, administration, and monitoring.
Before chemotherapy can be considered, a histologic diagnosis must be made. Some historical claims of cancer cure have been based upon erroneous diagnoses. The natural history of an untreated malignancy must be known before a therapy can be evaluated. Anecdotal case reports describe response of an individual patient to some treatment, but caution is advised in interpreting these reports. For example multiple plasmacytomas may regress and recur spontaneously. Antibiotic treatment of a urinary tract infection secondary to transitional cell carcinoma may cause transient complete resolution of clinical signs.
Comparison of treatment results with those of historical controls may not be suitable if surgical or supportive treatment has improved since the time the controls were obtained. However, the behavior of some common malignancies such as lymphoma or osteosarcoma is somewhat predictable because of prior studies of animals treated.
Adjuvant therapy (treatment of presumed microscopic tumor remaining after surgery) may be difficult to evaluate unless the natural behavior is known for the same tumor treated with surgery alone. Randomization is often needed to answer these questions, but this may require large numbers of similar patients treated over a long period of time. Sometimes several institutions will cooperate in studies of less common tumors. Whenever a new treatment is to be evaluated, measurable tumors should be treated first to determine whether or not a decrease in tumor size could be achieved. If so, the treatment can be moved to the adjuvant setting where efficacy is expected to be even better since the smaller the number of tumor cells present, the less likely it will be that resistant cells are present.
Patient selection for treatment may be a major variable in comparison of treatment protocols from one institution to another. Staging of disease helps to minimize this variable. Minor variations in dosage or scheduling may affect treatment results. Small sample size has been a problem in veterinary chemotherapy trials since many animals with malignancies are not treated. Cancer chemotherapy is expensive with frequent visits and laborato-ry monitoring needed to treat aggressively but to minimize iatrogenic morbidity. Sup-portive care may vary from one institution to another and this affects survival data on the same protocol.
Results in chemotherapy trials should be reported as to number and percent of patients achieving complete or partial remission or no response. Duration of complete remission should be given as a range and median. Mean remission time may be misleading because one long-term survivor can cause the mean to be much longer than the median but not representative of response in most animals. Survival times are less representative of response than are remission times since survival times may vary with wishes of owners and veterinarians regarding the proper time for euthanasia.
Gompertzian growth curve for solid tumors - Initially cell growth is geometric and then decreases, as tumor becomes larger. If most of the cells in a tumor are dividing, the susceptibility to chemotherapy is likely to be larger. Normal tissues with high growth fractions are also susceptible to chemo-therapeutic drugs (bone marrow, intestinal epithelial cells, hair follicle cells in man and some dogs). In a tumor the growth fraction is generally higher than that of marrow stem cells. This provides an index of safety. Tumor cells are less efficient in repairing damage to DNA than normal cells. Drugs kill a given percentage of tumor cells regardless of the number present. Leukemias, lymphomas and most solid tumors become clinically detectable when approximately 109 cells are present. If 99.9% of the cells are killed, the tumor can no longer be detected even though 106 cells (1gm) remain. This is why long courses of therapy are needed to effect cure. Each treatment may diminish the tumor cell number by 2 or 3 logs. For a tumor to reach detectable size, approximately 40 doublings have occurred assuming minimal cell loss. Depending on the doubling time, the time from cell transformation to detectable cancer can range from 20 days in experi-mental murine leukemia with a doubling time of 12 hours, to around 6 years for a slow growing tumor with a doubling time of 60 days. Disease Factors Certain malignancies are highly responsive to chemotherapy. The best example is the transmissible venereal tumor of dogs that is almost 100% curable with 3-4 weekly doses of vincristine. Lymphoma of dogs responds well to combinations of drugs so that 1 year survival is a realistic goal. Certain prognostic features have been identified which allow the veterinarian to make some predictions of response. This will help owners to decide whether or not to proceed with treatment. Drug Factors When combination chemotherapy protocols are developed, each drug should have its own anti-tumor activity, so that the combination has additive or synergistic efficacy. If two drugs with similar toxicity such as myelosuppression are used they should be scheduled at different times, or dose reduction must be made in one or both drugs. By becoming familiar with toxicities of individual drugs, one will be able to prevent some adverse effects, and differentiate treatment-related problems from those caused by the disease being treated. For most tumors, a standard protocol can be borrowed from an institution seeing large numbers of cancer patients. Built into these protocols are situations requiring changes from standard doses or schedules. Reasons for Failure of Chemotherapy
Canine Lymphoma Lymphoma accounts for approximately 90% of canine hematopoietic tumors. Affected dogs are generally middle aged and of either gender. Breeds with reported increased prevalence are boxers, golden retrievers, and perhaps bullmastiffs. The cause is unknown. The most common physical finding is generalized lymphadenopathy, with or without splenomegaly, (Stages 3 and 4). Signs of illness may or may not be present, (substage a or b). The marrow or other extranodal sites may be involved (stage 5). Cutaneous lymphoma may be either a high-grade extranodal type, or mycosis fungoides, a more indolent disease with an epitheliotropic histologic appearance. Lymphomas are of T or B cell origin, and comprised of immunoblasts or lymphoblasts. Most are high-grade malignancies, but a few are well-differentiated lymphocytic (low-grade) types. Staging lymphoma by extent of disease helps determine prognosis. The stages have been defined by the World Health Organization (WHO) as:
Feline Lymphoma Feline leukemia virus (FeLV) probably causes most cases, although most cats test negative for virus. The mean age ranges from four to six years and any breed or gender may be involved. The WHO staging system is more difficult to use in cats because visceral involvement is more common than peripheral lymphadenopathy. Instead, feline lymphoma is often classified by anatomic site of involvement. Mediastinal lymphoma presents with an acute onset of dyspnea, which is rapidly progressive as tumor begins to occlude lymphatics and fluid fills the thorax. Findings on physical exam are an incompressible chest and a posterior-dorsal displacement of the cardiac sounds. Thoracic radiographs followed by thoracentesis with cytologic examination of the fluid usually confirm the diagnosis. The fluid lymphocyte count is usually greater than 4000/ul, with most appearing large and poorly differentiated. In cases where fluid cytology is not diagnostic, aspiration of the mass itself can be done. If one is uncertain as to the presence of a mass, ultrasound examination is helpful. Alimentary lymphomas are usually non-viremic and involve the stomach and intestines of older cats. Gastrointestinal tumors may be discrete or diffuse. The primary clinical signs are anorexia and weight loss. Fewer than 50% of cats with intestinal lymphoma are presented because of vomiting. Cats with diffuse tumors may have diarrhea. The condition most likely to be confused with gastrointestinal lymphoma is inflammatory bowel disease, especially when the lymphoma is well differentiated. The diagnosis is made by fine needle aspiration of abdominal masses, or by endoscopic or open biopsy. Renal lymphoma results in bilaterally enlarged irregular kidneys. Rarely, kidneys are large and smooth or only one kidney is involved. Small irregular kidneys are not likely to be caused by lymphoma. No clinical signs are present until renal insufficiency develops. Because the tumor is interstitial, tumor cells are not present in the urine. Renal biopsy is the best way to confirm the diagnosis. Spinal lymphoma causes posterior paresis or paralysis with or without back pain. Occasionally the cervical spine is affected, causing front-limb abnormalities. Most tumors are extradural, with no radiographic lesions. The bone marrow is involved in 70% of cases, even in the absence of changes in the hemogram. If a diagnosis cannot be made after examination of the marrow, a myelogram and laminectomy must be considered. Spinal lymphoma should be treated as an emergency since paralysis may be permanent if chemotherapy is delayed. Other relatively common sites of lymphoma are skin, nasal passages, and the retrobulbar area. Nasal lymphoma differs from that in other sites in that it often localized to the nose and sinuses, and radiation therapy may result in prolonged disease-free survival. Peripheral lymph node lymphoma is rare in the cat compared with the dog. Most lymphadenopathy in cats is reactive. Whole-node excision biopsies are preferable to aspirates since architectural changes help to differentiate neoplasia from hyperplasia. Health Evaluation of Dogs and Cats with Lymphoma The general health of the animal is evaluated prior to beginning treatment. A minimum evaluation, in addition to a complete physical examination should include a complete blood count (CBC), urinalysis, chemistry profile, bone marrow aspirate, and thoracic radiographs. Evaluation of B and T cell markers can be useful as well. Cats should be tested for FeLV and FIV. Changes in the CBC that suggests infiltration of the marrow are anemia, neutropenia, thrombocytopenia, circulating nucleated red cells or immature lymphocytes. Marrow involvement changes the stage, prognosis, and possibly the treatment. Neutropenia not only predisposes to bacterial infection (at levels of approximately 1000/ul) but also limits the use of myelosuppressive drugs, thus compromising the efficacy of the chemother-apy. Thrombocytopenia is of less concern unless platelet counts are less than 75,000/ul, since most myelosuppressive drugs do not suppress platelets to the same degree as neutrophils. The chemistry profile should be examined carefully, with special attention paid to renal and hepatic function and serum calcium levels. Hypercalcemia occurs in 20-25% of dogs with lymphoma and predisposes to renal failure. Dogs with hypercalcemia at the time of diagnosis usually also have hypercalcemia at relapse. Alanine aminotransferase and alkaline phosphatase are often elevated at the time of diagnosis of lympho-ma in dogs. This might be caused by hepatic infiltration by lymphoma, although this is not often documented by biopsy. Significant renal or hepatic dysfunc-tion may require a decrease in drug dosage depending on the route of excretion. Any infections present at the time of diagnosis must be identified and treated. Infections may be generalized or localized such as chronic otitis, gingivitis, urinary tract infections, or pyoderma. Unless infections can be treated successfully they are likely to continue, and may become life threatening once myelosuppressive and immunosuppressive drugs are given. Whenever an infection is present at the time of diagnosis a culture should be taken and sensitivity tests run to determine optimal treatment. In most situations, simultaneous treatment with antibiotics and chemotherapy is the best approach. Prognostic Features Attempts have been made to identify factors that would predict response to chemotherapy. Whether or not the dog or cat is feeling well at the time of diagnosis (substages a and b) is subjective but perhaps the single most useful factor. Animals with coexisting anorexia, organ failure, neutropenia or infections have more difficulty tolerating chemotherapy. Dogs - Dogs with histologically high-grade tumors were more likely to achieve CR with chemotherapy, but overall remission and survival times were not changed. B cell lymphoma has a better prognosis than does T cell lymphoma even though both are high-grade tumors. Dogs with hypercalcemia (usually T-cell lymphoma) seem to experience more adverse effects during the induction period and may have shorter remissions. Stage and extent of tumor are somewhat predictive of rate and duration of remission. A single site or small tumor volume does seem to predict that remission will occur, whereas extensive marrow involvement is associated with only about 25-30% chance of complete remission (CR). In one published report, 90 percent of dogs in stage 1 achieved CR as compared to 83 percent of dogs in stage 3 and 4, and 47 percent in stage 5. Although stage 5 dogs had a lower CR rate, the remission duration did not differ between stages. Other adverse prognostic factors that have been observed in one or more canine studies included hypoalbuminemia and male sex. Small dogs did better in one study, but in another with a more aggressive protocol, small dogs suffered more toxicity. Whenever drugs are dosed per surface area, small dogs receive proportionally higher doses than do large dogs. Dogs over 10 years of age did not achieve CR as readily as did younger dogs. Dogs that have received corticosteroids before beginning chemotherapy had shorter remission durations than those not receiving steroids. This may be because initial steroid treatment resulted in a delay of combination chemotherapy, or cells resistant to steroids may have emerged that were also resistant to other drugs. While it is reasonable that some owners will refuse the option of combination chemotherapy, it is a mistake to offer corticosteroids first and begin other therapy if steroids fail. If combination chemotherapy is to be used, it should be the initial treatment. The CR rate for dogs treated with corticosteroids alone is approximately 20% with another 40% achieving a partial response. These responses are generally short, usually less than 8 weeks, although rarely dogs are encountered that achieve a long-term remission on steroids alone. Single agent prednisone can be given at 2 mg/kg/day for 2 weeks and if a response occurs, continued at 1 mg/kg every other day until relapse. Cats - The overall response rate in cats is lower than that in dogs. The effect of FeLV status of cats with lymphoma has been controversial, but may adversely affect prognosis. Viremic cats remain viremic even if their tumors respond to treatment. Cats with mediastinal lymphoma usually respond well to chemotherapy. Alimentary lymphoma appears to have a less favorable prognosis perhaps because cats are often debilitated from anorexia, vomiting, or diarrhea. If a diagnosis can be made by endoscopic biopsy or by biopsy of an involved mesenteric lymph node without opening the intestine, chemotherapy can be started as soon as biopsy results are known. If the clinical status of the cat can be helped by excising and involved segment of intestine, this should be done even though chemotherapy will have to be delayed for 7 to 10 days to allow healing of the enterotomy site. Some with well-differentiated morphology may survive for prolonged periods, even with only conservative treatment with chlorambucil and prednisone. Communication with the Owner After diagnostic testing is completed, the clinician must arrange for an unhurried discussion with the owner regarding schedule of treatment, goals, prognosis, potential complications, and cost. Strategies to deal with any problems that might occur are discussed along with what will be done to prevent recurrence of complications. The options - combination chemotherapy, palliative therapy with oral prednisone alone, and euthanasia - are presented objectively. An informed decision is necessary to avoid disappointments generated from unrealistic hopes of cure. The owner must understand the difference between remission and cure. Remission may be defined as the absence of clinical or histologic evidence of the disease. It only becomes synonymous with cure when sustained over 2 or more years. The owner must also realize that some complications of chemotherapy, such as sepsis with neutropenia, may be life threatening. If signs of illness occur when the granulocyte count is expected to be low, owners must know to take the temperature if possible, and contact the veterinarian immedi-ately. Owners must be educated about goals and potential problems prior to starting treatment; otherwise they may become discouraged before enough time has elapsed to observe the beneficial effects of the drugs. Whenever a patient is euthanized because of adverse effects of chemotherapy, that treatment is a failure, regardless of tumor response. An information sheet may be given to owners. This outlines a schedule of drugs given, potential problems, and what to do. Most informed owners who decide to proceed with chemotherapy are co-opera-tive, conscientious, and appreciative of efforts made to help their pets.
CHEMOTHERAPY DRUGS
USES AND COMPLICATIONS The art of medical oncology lies in being able to deliver maximal doses of drugs, and minimize adverse effects that may follow treatment. Recognition of potential problems with each drug, and knowing when to make dose or schedule adjustments helps improve the success of treatment. Most chemotherapeutic drugs have a steep dose-response curve, meaning that pushing the dose to the verge of toxicity can significantly improve the tumor response. The aim is to develop a "feel" for a protocol so as to be aggressive enough to get the best response possible, and to preserve a good quality of life. The pretreatment evaluation is important, to determine the extent of the tumor, and to identify coexisting problems that might increase the risk of toxicity. Commonly Used Drugs Prednisone is used primarily in treatment of lymphoma, myeloma, and mast cell tumors. Adverse effects include gastric toxicity, immunosuppression, polydipsia, polyuria and weight gain. Dogs are more likely than cats to become cushingoid and to develop steroid hepatopathy. Some dogs pant incessantly or are ravenously hungry, stealing food from the owner's table. Although most of these effects decrease over time, pancreatitis or diabetes mellitus has developed rarely. Depending on the severity of the problem, steroids may have to be stopped or doses reduced. Steroids do decrease the risk of cystitis from cyclophosphamide, and may stimulate the appetite of a finicky patient. Vincristine is used in treatment of lymphoma, lymphoid leukemias and transmissible venereal tumor. It is one of the safest chemotherapeutic drugs, however it can cause anorexia or vomiting. Because it is irritating if given extravascularly, it is best given through a temporary intravenous catheter. Peripheral neuropathy and constipation, common in human patients, are rare in dogs and cats. Although vincristine is minimally myelosuppressive, it may cause neutropenia if combined with another drug, such as l-asparaginase . Cyclophosphamide is used primarily in to treat lymphoma. It is myelosuppressive and, when given as a single large dose, uniformly causes neutropenia with the nadir 5 to 7 days later. Cyclophosphamide is not given if the NEUTROPHIL count is less than 3,000/ul. Subsequent doses are decreased by 25% if the neutrophil count drops below 1,000/ul seven days after treatment. Hemorrhagic cystitis is an adverse effect of cyclophosphamide in man and the dog, but unlikely to occur in cats. If it occurs, signs can be minimized by intravesicular infusion of 20 ml of 25% dimethylsulfoxide. Cyclophosphamide should be discontinued and chlorambucil substituted if cystitis develops. Chlorambucil, which is less myelosuppressive than cyclophosphamide, is also used to treat chronic lymphocytic leukemia. Doxorubicin is quite effective against canine lymphoma and may used for maintenance of remission of feline lymphoma. Doxorubicin also has efficacy against some solid tumors, such as osteosarcoma, hemangiosarcoma and feline mammary carcinoma. Perivascular administration of doxorubicin causes severe tissue damage. Vomiting may occur within the first few days after treatment, but enterocolitis occurring after five to seven days may be more severe, and is sometimes hemorrhagic. Doxorubicin is myelosuppressive, with the nadir 7 to 10 days after treatment. Small dogs (less than 10 kg) and cats have increased risk of toxicity when doses are calculated on the basis of surface area, and should receive 1 mg/kg instead of 25-30 mg/m2 as used in larger dogs. Cardiac toxicity is most likely to occur in Doberman pinchers, boxers and other large breeds predisposed to cardiomyopathy. Cardiac toxicity is life threatening and usually occurs at cumulative doses over 180 mg/m2. Early toxicity is not evident on physical examination or electrocardiography, but periodic echocardiography can detect changes in contractility so that the drug may be discontinued. Heart failure has not been observed clinically in cats, but characteristic histologic lesions have been seen at necropsy. Renal toxicity has been reported in cats. Doxorubicin should not be given if the neutrophil count is less than 3,000/ul and the next dose decreased if the neutrophil nadir is less than 1,000/ul. L-asparaginase is effective for treatment of canine lymphoma and lymphoblastic leukemia, but is less effective in cats. Since it is not myelosuppressive it is especially valuable in neutropenic patients. The most dangerous adverse effect of l-asparaginase is anaphylaxis, which occurs in 30-40% of dogs receiving repeated intravenous or intraperitoneal injections. The subcutaneous routes of administration should be used to minimize the risk. Other less common adverse effects of l-asparaginase are vomiting or pancreatitis. Stupor has been seen in association with elevated blood ammonia. CCNU (Lomustine) a nitrosourea has activity against lymphoma and mast cell tumor as well as some brain tumors. For lymphoma, it is used (90 mg/m2 q 3 wks for dogs and 60 for cats) primarily as a rescue drug after relapse. It is myelosuppressive, but it differs from other drugs in that thrombocytopenia may be progressive and irreversible in some patients. A platelet count should be done before each dose and the drug discontinued if the count drops below normal. Ideosyncratic hepatotoxicity has occurred in some dogs, so liver function should be monitored after the first few doses. Platinum drugs are not routinely used for treatment of lymphoma, but have efficacy against a range of solid tumors to be discussed later. Cisplatin (70 mg/m2 q 3 wks) a broad-spectrum drug, is useful in dogs for treatment of some tumors such as osteosarcoma. It should never be used in cats because life-threatening pulmonary edema routinely occurs even at low doses. For dogs the dose-limiting toxicity is renal damage, which can usually be prevented by concurrent fluid diuresis. Cisplatin is contraindicated in dogs with pre-existing renal insufficiency. Aminoglycoside antibiotics, which are also nephrotoxic should not be given concurrently to dogs receiving cisplatin. Vomiting during administration can usually be prevented by pretreatment with an antiemetic such as butorphenol. Cisplatin is minimally myelosuppressive. Carboplatin (300 mg/m2 q 3-4 wks for dogs and 160 for cats), a related but more expensive drug is not nephrotoxic and avoids the need for fluid diuresis. It can be used in cats. Myelosuppression with the nadir as late as 3-4 weeks is the dose-limiting adverse effect. A CBC should always be done before each dose is given. Piroxicam, (0.3 mg/kg/day) an oral nonsteroidal anti-inflammatory drug has been shown to have efficacy comparable to cisplatin (about 30%) against transitional cell carcinoma. It may also have some activity against squamous cell carcinomas. Concurrent administration of a prostaglandin, (misoprostyl) helps minimize gastric irritation seen in some dogs. General Toxicity One much search for any ongoing, clinical or subclinical bacterial infections when beginning chemotherapy. If these are overlooked, the risk of sepsis is increased when myelosuppressive drugs are used. Especially in dogs, a urinalysis should be examined, and if pyuria is noted, a culture is obtained, and antibiotics are given concurrently with chemotherapy. Septic neutropenic patients often have fever without localizing signs. Enteric gram-negative pathogens may invade when chemotherapeutic drugs cause damage to the intestinal mucosa at the same time that the neutrophil number is decreased. Blood cultures are usually negative. Dogs seem more prone than cats to become septic when they are neutropenic. The combination of fever and neutropenia is a life-threatening emergency. Bactericidal antibiotics such as a combination of gentamicin and cephalothin or fluoroquinolones are given intravenously until the neutrophil count rises, usually within 2-3 days. Overall the most common chemotherapy-related problem in cats is anorexia. Some will respond to coaxing and tempting with special foods; others will respond to appetite stimulants such as cyproheptadine. If anorexia persists, nasogastric or gastrostomy feeding may be necessary. Hair loss is not a major problem for most dogs and cats receiving chemotherapy, although clipped hair is slow to grow. Breeds such as poodles, terriers with wiry coats, and some old English sheepdogs and Afghan hounds will loose a significant amount of hair, and owners should be reassured that this will probably be more of a concern for them than for their pet. Cats will loose their whiskers, and a few will lose some of the hard outer coat, leaving a softer undercoat. All hair and whiskers will re-grow when therapy is stopped. With proper selection of patients and with good client communication, treatment of cancer in pets can be rewarding experience. Owners appreciate the extra effort on the part of the veterinarian and the additional time they may gain with their pets. Combination Chemotherapy: Choosing a Protocol Many protocols have been used to treat canine and feline lymphoma. Drugs with most activity are cyclophosphamide, vincristine, doxorubicin, l-asparaginase and prednisone. The protocol to which most others are compared is COP: Cytoxan (cyclophosphamide), Oncovin (vincristine), and prednisone. This protocol is relatively effective, nontoxic and inexpensive. It is probably the treatment of choice for those practices that only occasionally use chemotherapy and without a referral practice in the area. Overall, COP causes complete remission in about 70% of dogs with lymphoma for a median time of 4-5 months. In cats the remission rate was originally reported at 79% with a median time of 5 months, but with the same protocol 12 years later, the CR rate was 47% for a median time of 3 months. The change probably reflects the change in types of lymphoma being seen. For cats, our best results have been with a COP 4-week induction followed by 6 doses of doxorubicin (25 mg/m2 at 3-week intervals). In this protocol, the median remission time was 8 months.
The COP protocol; cyclophosphamide, round off dose on the low side of <250 mg/m2 PO; vincristine 0.75 mg/m2 IV, prednisone 2 mg/kg PO, daily in cats and 1 mg/kg PO daily for one week then every other day in dogs. Continued every three weeks until relapse or for 1 year of continuous remission. An alternative treatment for cats is to use COP for weeks one through 4. Then cyclophosphamide is stopped and doxorubicin substituted on the same q3wk schedule starting on week 7 for a total of 6 doses, at a dose of 25 mg/m2. For dogs, several protocols have been developed that incorporate doxorubicin and l,asparaginase. Our most successful canine protocol to date has been VELCAP (see figure). The VELCAP protocol for canine lymphoma produces a median remission time of approximately 12 months. Approximately 25% of dogs achieving CR will still be in remission at two years, and occasional animals are cured. This protocol originally extended for 18 months but later was shortened since prolonged treatment may not be necessary for every patient. For the shortened 12-week version, the median remission time was just 20 weeks, but with repeated treatment, the percentage of long-term survivors was the same as for the long protocol. If relapse occurs within 4 months of stopping treatment, the full protocol is given (not to exceed 240mg/m2 doxorubicin). If relapse occurs after 4 months, a second 3-month course is given. Dogs that relapse on treatment have a poor prognosis. A protocol previously used to treat human Hodgkin's disease has been adapted for use in dogs and cats with lymphoma. Known as MOPP, the protocol incorporates nitrogen mustard, vincristine, procarbazine and prednisone. Nitrogen mustard is an injectable alkylating agent with myelosuppression as the dose-limiting toxicity. Procarbazine is an oral agent, which inhibits nucleic acid and protein synthesis. The major toxicities are vomiting and myelosuppression. MOPP has been used as an induction agent in cats, and a consolidation or rescue therapy for dogs. Management of Relapse Relapse can occur at any time, and the chance for a second remission is less than for the first, and if achieved, is usually shorter. Animals with a long first remission have a better chance for a second remission than do those that relapse early. As a general rule, drugs used to treat relapsed lymphoma should be of different classes than drugs used initially. For example if a dog has relapsed on COP, then doxorubicin or l-asparaginase can be used. Animals that relapse off treatment can sometimes be re-induced into remission with the same drugs used to achieve the first remission.
VELCAP-L For Dogs
Please follow this protocol and write date of treatment as it is given. Cytoxan is given only if neutrophil count is over 3000/ul and is stopped if cystitis occurs. (Chlorambucil substituted on the same schedule at 15 mg/m2 daily for 4 days every 3 weeks). Dose of cytoxan and Adriamycin is decreased by 25% if neutrophil nadir is less than 1000/ul. Submit CBC with each treatment and on additional dates shown. For dogs over 1 m2, the maximum dose of L-asparaginase in 10,000 u.
If VELCAP-S is used, dogs relapsing within 4 months of week 12 should receive VELCAP-L. Those relapsing after 4 months should receive a repeat of VELCAP-S.
MOPP Chemotherapy Protocol
Repeat on day 28.
* Obtain CBC on day 0 +7
** Average cat can receive 10 mg Procarbazine OTHER HEMATOPOIETIC MALIGNANCIES LEUKEMIA
Leukemia is a malignant proliferation of any hematopoietic cell. Depending on the cell transformed, and the degree of differentiation of that malignant clone, the disease may be acute or chronic. Also leukemias have been divided into those involving lymphoid cells and those involving non-lymphoid (myeloid) cells. The classification is listed below.
Acute leukemias are more common in cats than in dogs. The cause in cats is the feline leukemia virus, and is unknown in dogs. The clinical signs seen in acute leukemias of all cell types are the same, and are the result of the lack of normal hematopoiesis. The marrow is filled with blasts that do not mature or function, but interfere with production of normal neutrophils, red cells and platelets. As one might expect, patients are presented with signs related to anemia, neutropenia, and thrombocytopenia. Anemia is the most common presenting sign in acute leukemias of all types. Bacterial infections secondary to granulocytopenia or bleeding tendencies from thrombocytopenia may be seen as well. The peripheral white cell counts vary from severe leukopenia to severe leukocytosis with many circulating blasts. The white count is most commonly normal or low, and a bone marrow aspirate is needed to confirm the diagnosis. Definitive diagnosis of ALL or any of the subtypes of AML can occasionally be made by the morphologic appearance of the blasts, but cell surface immunologic markers provide the most accurate diagnosis. In human medicine, specific chromosomal changes aid in differentiation of subgroups of AML. Most important in veterinary medicine is to differentiate between ALL and AML, since some patients with ALL respond to treatment whereas those with AML rarely respond, regardless of the subtype. Partial or complete maturation and function of the malignant cell line characterize chronic leukemias. Since production of these cells is autonomous, the numbers produced are excessive and not subject to usual feedback inhibition of production. The normal marrow cells tend to remain so that cytopenias are less likely. As the name implies, the clinical course tends to be prolonged. Acute Lymphoblastic Leukemia (ALL) Acute lymphoblastic leukemia is more difficult to manage than lymphoma, and response is not as good. The marrow must be cleared of blasts before normal cells can repopulate. The complete remission rate in ALL is generally 20-30%. Treatment can be started with vincristine (day 1 and 10), l, asparaginase (day 1 and 10) and prednisone at doses previously described. When the granulocyte count reaches 3,000/ul after the second treatment, a lymphoma protocol can be continued. If granulocytopenia and anemia persist beyond three weeks, it is likely that remission has not been achieved. The interval from diagnosis to repopulation represents a period of high risk of life threatening infection, bleeding, and progressive anemia. Transfusions are usually needed during the first two to three weeks of treatment because of the delay in repopulation of normal cells after tumor cells are obliterated. Chronic Lymphocytic Leukemia (CLL) Chronic lymphocytic leukemia is distinct from (ALL) both in morphology and biological behavior. In CLL, the presenting problems vary from none to lethargy, mild anemia, and splenomegaly, without significant lymphadenopathy. Sometimes a diagnosis is made when a CBC is done on a dog present-ing for some unrelated problem. The CBC shows leukocytosis with an increase in small lymphocytes that appear normal. The bone marrow will usually contain an increased number of small lymphocytes, sometimes over 50 percent of the nucleated cells. In contrast to ALL, where the marrow is replaced by lympho-blasts, the normal hematopoietic cells remain in CLL. A monoclonal gammopathy may be present. Most canine CLL is a T cell disease, whereas B cells are involved in human cases. Some canine CLL involves large granular lymphocytes, but the prognosis appears to be similar for both canine subtypes. CLL tends to be a slowly progressive disease. Aggressive chemotherapy and a complete remission are not required for long-term survival. Treatment may not be necessary in the early stages of CLL. If the animal is asymptomat-ic, not anemic or granulocytopenic, and if the total lymphocyte count is under 50,000/ul, therapy probably can be safely withheld and the patient monitored. If signs of illness are present, if the PCV drops or the lymphocyte count continues to rise, therapy can begin with prednisone 1mg/kg every other day and chlorambucil 15 mg/m2 daily for 4 days repeated every three weeks. This treatment is continued beyond the time that the CBC returns to normal, which may take several months. The blood is monitored periodically for relapse and therapy reinstituted if needed. The median survival for dogs with CLL is over 1 year, with approximately 25% surviving over 2 years. A few cases of CLL have been seen in cats but the number treated has been too small to predict results. Well-differentiated lymphocytic lymphoma, characterized by lymphadenopathy with small lymphocytes occurs occasionally in dogs. The disease is slowly progressive, and may be treated like CLL. Myeloproliferative Diseases The myeloproliferative diseases are a group of nonlymphocytic hematopoietic disorders arising in the bone marrow. Acute Myelogenous Leukemia (AML) Included in this category are acute leukemias of granulocytes, monocytes, red cells, and megakaryocytes. Depending on which cell line is predominant, AML is subclassified as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia or megakaryocytic leukemia. Abnormal cells may be present in high numbers in the blood, or be totally absent. The bone marrow contains from 30% to almost 100% blasts. The various blasts have some distinguishing morphologic features that help in classification of the type of leukemia, but evaluation of cell surface markers has improved the accuracy of diagnosis greatly. Many cases of acute leukemia in dogs and cats have been incorrectly classified as ALL, when the correct diagnosis was really AML. Between 50-60% of canine and feline acute leukemia is now thought to be of myeloid origin. No successful veterinary treatment protocol for AML has been described to date, although humans may respond to high doses of anthracyclines and Ara C. Chronic Myelogenous Leukemia (CML) Seen in humans and dogs, CML is characterized by proliferation of granulocytes that maintain normal function and morphology. Clinically a marked leukocytosis with neutrophilia and significant left shift are seen with gradual progression over months to AML, sometimes called blast crisis. The term leukemoid reaction is used to describe a leukocytosis and left shift in situations of pyogenic inflammation so severe that the CBC resembles that seen in CML. Animals with leukemoid reactions from infection are usually are febrile and quite ill and the white blood count drops after a few days of successful treatment. In contrast CML causes minimal morbidity initially. A characteristic chromosomal translocation called Philadelphia chromosome is present in human CML patients. This translocation is present in all of the myeloid precursors in the marrow, even those that do not exhibit a malignant phenotype, suggesting that malignant transformation must have occurred at the pluripotent stem cell level. Treatment with hydroxyurea may successfully lower the white cell count for a time, but progression to AML still occurs. If severe splenomegaly is present, splenectomy may be warranted. Polycythemia Rubra Vera (P vera) This disease of humans, dogs and cats is characterized by an autonomous overproduction of functional, mature red cells. The total red cell mass is increased resulting in a high Hct, hemoglobin concentration, red blood cell count, and red mucous membranes. Sludging of the blood can cause congestive heart failure and neurologic signs from decreased oxygenation of the brain. The marrow shows increased erythroid production, exactly the same as that seen whenever increased erythropoiesis occurs for any reason, such as response to blood loss. P vera must be distinguished from relative polycythemia as in dehydration, and other causes of absolute polycythemia (increased red cell mass) which might occur from hypoxia or from kidney tumors that secrete erythropoietin. In P Vera, erythropoietin levels tend to be normal or decreased relative to those expected in situations with an elevated Hct. P vera responds well to treatment. Initially the Hct should be lowered by phlebotomy. Approximately 20 ml/kg blood may be removed and the volume re-placed by saline or autologous plasma. The phlebotomy and fluid replacement are repeated until the Hct is 45 to 50 percent. It is not necessary for this to be done gradually so long as plasma or fluid is replaced. When the Hct is normal the clinical signs should subside. Hydroxyurea (80 mg/kg every 3 days) has been successful in maintaining the Hct at a normal level. In cats, methemoglobinemia has occurred at high doses (500 mg once weekly). The white cell count and platelet numbers should be monitored along with the Hct. In humans with P. vera, the disease may change to acute leukemia after a period of months or years. Myelodysplasia Myelodysplasia, most commonly seen in cats, is sometimes referred to as myelodysplastic syndrome, dysmyelopoiesis, or preleukemia. Abnormalities occur in maturation, and cell division of the granulocyte, erythrocyte and megakaryocyte series, either singly or in combination. Myelodysplasia is a monoclonal disorder, and thus considered to be a stage in the evolution of AML. The bone marrow is usually normocellular or hypercellular despite the associated peripheral cytopenias (ineffective hematopoiesis). A refractory anemia is the most common finding in the blood. Thrombocytopenia, leukopenia or both may also occur. Frequent findings are increased nucleated red blood cell counts out of proportion to the degree of polychromasia, large bizarre platelets, immature granulocytes, and abnormal erythrocyte or granulocyte morphology. The marrow is frequently hypercellular with maturation defects in multiple cell lines. Erythroid hyperplasia with megaloblastoid erythrocyte precursors may be found. A maturation arrest, abnormal granulation or abnormal nuclei may represent defects in myeloid maturation. Megakaryocytes may be increased or decreased in number and often have abnormal morphology. Myelodysplasia evolves over time with gradually increasing numbers of blasts in the marrow. When the percent blasts in the marrow exceeds 30%, the diagnosis of AML is made. Currently no specific therapy is effective though erythropoietin injections have raised the hematocrit in some cats. Myelofibrosis Classically, myelofibrosis as described in humans, cats and dogs has been included in the myeloproliferative diseases on the basis that it may represent a malignant proliferation of fibroblasts filling the marrow and inhibiting hematopoiesis. It is probably more likely that it represents an "end stage" marrow, analogous to cirrhosis of the liver. Whatever the cause, the marrow is replaced by fibrous connective tissue. Clinically pancytopenia is present along with severe extramedullary hematopoiesis (EMH, myeloid metaplasia) in the spleen, liver and sometimes other organs causing splenomegaly usually with hepatomegaly. The EMH does not contribute significantly to effective hematopoiesis. When one attempts to aspirate marrow no cells can be obtained, so a core biopsy of the marrow is necessary to make a diagnosis.
Since plasma cells are differentiated B cells, the malignancies of plasma cells may be grouped with the lymphoproliferative malignancies. Myeloma has also been referred to as plasmacytoma, plasma cell myeloma, or multiple myeloma. The disease usually begins in the marrow and invades and lyses bone to produce punched-out, well circumscribed, lytic lesions, which are diffuse in flat bones and are less common in long bones. The disease may be detected because of bone pain or pathologic fracture. If vertebrae are involved, paraplegia may occur. In some cases, tumors arise from non-osseous sites. The tumor cells are primarily immature plasma cells, which usually secrete immunoglobulin. Serum protein electrophoresis is a screening test to evaluate serum proteins. The malignant plasma cells secrete a single species of immunoglobulin ("paraprotein"). Because all of these molecules are synthesized by progeny of a single clone (and are, therefore, monoclonal). They are chemically identical, travel together and appear as a tight band on electrophoresis. In individuals without myeloma stimulation of multiple B-cell clones to increase antibody production leads to a broad-based elevation of globulin, designated as a polyclonal gammopathy. This pattern follows exposure to several antigens simultaneously, as in most infections. Myelomas, usually secrete IgG or IgA, and are the most common cause of monoclonal gammopathy. Other less common causes include lymphomas and Waldenstrom's macroglobulinemia, a malignancy of "plasmacytoid" B-cells which produce high concentrations of IgM. Representative patterns of gammopathies are shown in the following figure.
Anemia, bleeding tendencies, and recurring infections are reasons for presentation. Cytopenias may result from infiltration of the marrow interfering with hematopoiesis. Bleeding may also result from abnormal platelet function caused by coating of platelets by immunoglobulin, which interferes with aggregation. This coagulopathy can only be detected by determining the bleeding time. Hyperviscosity syndrome occurs with macroglobulinemia (IgM), but may also occur with polymerized IgA myeloma or with very high hematocrits as occurs with polycythemia. The flow characteristics of blood are determined by interactions between red cells and the proteins of the suspending plasma. Blood viscosity, a measure of internal resistance to flow, increases rapidly with increasing concentration of red cells and/or of the larger molecules of the plasma, such as fibrinogen and IgM. Because plasma proteins serve as electrical insulators, elevated concentrations allow red cells (normally negatively charged) to come closer to each other and form weak agglutinates, a phenomenon known as rouleau formation. Rouleaux appear as microscopic "stacks of coins" in blood smears or the test tube, and settle more rapidly in plasma than single red cells and consequently elevate the "erythrocyte sedimentation rate" (ESR). Hyperviscosity leads to hypertension and heart failure with impaired circulation to the eyes, brain, kidneys and other organs. Neurologic signs and dilated retinal vessels with hemorrhage may be seen. The mechanism of clinical signs is probably sludging of blood in small vessels and tissue hypoxia. The blood volume is increased in many patients with hyperviscosity syndrome because of increased osmotic pressure in vessels. These findings in the presence of a relative serum viscosity of 4 or more represent a hematologic emergency. Viscosity, as measured by a viscometer, measures the serum viscosity relative to water (normally 1-2). Diagnosis of myeloma is generally made when several of the above findings are present. A bone marrow aspirate showing infiltration by immature plasma cells, lytic bone lesions and monoclonal gammopathy are the most typical findings. Occasionally ehrlichiosis may cause plasmacytosis in the marrow and monoclonal gammopathy, but not bone lesions. Treatment is a combination of prednisone (2mg/kg/day for the first week, then 1 mg/kg every other day) and melphalan (0.1 mg/kg/day for 10 days then 0.05 mg/kg/day after that). The CBC must be monitored and the dose adjusted if neutropenia is a problem. Rarely aplastic anemia has occurred in dogs on chronic treatment. Less is known about treatment of cats, but the same combination may be used. Treatment of hyperviscosity should include plasmapheresis or manual removal of plasma with replacement by crystalloids, possibly with normal plasma added depending on the amount of plasma removed. Thymoma Thymomas arise from ectodermal epithelium rather than from the lymphoid elements of the gland. Middle aged to old animals are most likely to be affected. The most common presenting sign is dyspnea, but some show coughing, vomiting, or regurgitation. The onset of signs is often more gradual than that seen with mediastinal lymphoma. Radiographically, a mediastinal mass is visualized, with or without effusion. Most are radiographically difficult to distinguish from lymphoma, but a few thymomas seem to be located more posteriorly in contact with the heart, and look like pericardial effusion (large globoid cardiac silhouette). When pleural effusion is present, small, mature lymphocytes, and occasional mast cells are usually seen. Some animals show signs of polymyositis or myasthenia gravis, and dogs sometimes have esophageal paralysis. Most feline thymomas are benign, and surgery may be curative. In dogs the tumor tends to be more invasive and difficult to remove. Chemotherapy has been ineffective, but steroids may be of palliative benefit for inoperable tumors. Radiation therapy has been reported to be helpful for inoperable tumors of both dogs and cats.
CANINE AND FELINE SOLID TUMORS
The overall incidence of tumors is lower in cats than in dogs, but a higher percentage of feline tumors are malignant. Skin Tumors Tumors involving the skin and subcutis are second in frequency to hematopoietic tumors in cats, and are the most common site of canine tumors. In the cat, most are malignant, whereas in the dog, most are benign. Middle aged and old animals are at greatest risk for the development of skin tumors. Mast cell tumors - The origin of mast cells is still open to question. They originate as hematopoietic cells and are most closely related to basophils. They are most numerous in connective tissue, especially skin, intestine, and respiratory tract. The cells are 7-10u in diameter with a round nucleus and many granules. The granules are visible on giemsa, new methylene blue and toluidine blue stains, but not on H and E stain. The granules contain several active substances, including heparin, histamine, proteolytic enzymes, dopamine, eosinophil chemotactic factor, leukotrienes, and pros-taglandins. Mast cells function in inflammatory and allergic reactions. They have receptors for the FC portion of IgE. When they bind to IgE, the mast cells degranulate and release the substances mentioned above. Canine cutaneous mast cell tumors - Cutaneous mast cell tumors vary greatly in appearance. They are most often soft, raised, broad-based, and hairless. They may appear well circumscribed grossly, but individual cells infiltrate into the surrounding tissues microscopically. For this reason it is important to identify a mast cell tumor before surgery, so that a wide surgical margin can be planned. Fortunately, a cytological diagnosis is easily made in most cases by a fine needle aspirate. Mast cell tumors are variable in behavior, from relatively benign to very malignant. The grading (and prognosis) varies with the degree of differentiation and depth of invasion, and must be determined on histologic biopsy. Well-differentiated (grade 1) tumors have approximately a 20% rate of recurrence after excision. Grade 2 tumors 50%, and poorly differentiated (grade 3) tumors have a 75-80% chance of recurrence after excision, and are more likely to metastasize. For each grade the chances for recurrence is lower if excision is complete. Multiple tumors are often individual tumors, rather than spread of a single tumor, so they can have a good prognosis after complete excision. When metastasis occurs, it is usually to regional lymph nodes. Spread to the lungs is very rare. Pre-surgical thoracic radiographs are not necessary, but regional nodes should be carefully palpated, and aspirated if enlarged. Occasional mast cells may be present in a reactive node of a patient without mast cell tumor, so the number necessary to be certain of nodal involvement can be difficult to determine. In most cases where tumor is present in the node, the number of mast cells seen is great enough to avoid confusion. Feline cutaneous mast cell tumors - Feline cutaneous mast cell tumors may be single or multiple and occur most commonly on the head and neck. They are usually raised, firm, hairless, but may be white, yellow, erythematous or ulcerated. They are usually indolent, and not routinely graded. Systemic mastocytosis - A CBC should be done to look for circulating mast cells. If greater than 2-3 mast cells are seen on a buffy coat smear, the tumor may be systemic. An aspirate of an enlarged spleen of the bone marrow may provide evidence of systemic disease. Approximately 25% of feline mast cell tumors are systemic, and this appears to be a distinct disease. In one study, only 4 of 160 cats with cutaneous tumors eventually developed systemic disease. Visceral tumors may involve the spleen, marrow, liver or lymph nodes, alone or in combination. Splenomegaly is most commonly present and may be severe. The substances contained in the granules cause complications. Edema from histamine and hemorrhage from heparin may make it difficult to determine the margins of a tumor, or in severe cases, a mass may not even be palpable within the swelling. Duodenal ulcers are a serious problem caused by histamine release by the granules. Clinical signs may not be shown until perforation and peritonitis occur. In one necropsy study, GI ulceration was present in 83% of dogs with mast cell tumors, and 15% had perforated. Delayed wound healing after surgical removal or biopsy of mast cell tumors is sometimes noted, especially with incomplete excisions. Treatment of mast cell tumors - For solitary (grades 1 and 2) mast cell tumors the chance for cure depends of wide and deep (3 cm margins) surgical excision. If the tumor is well differentiated and does not extend to the edge of the surgically excised tissue, further treatment is not needed, and the prognosis is good. If the tumor is inoperable, or if microscopic tumor remains, or if the tumor is poorly differentiated (grade 3), follow up therapy is indicated. Radiation therapy can be effective if localized residual tumor is present. Medical treatment with prednisone sometimes combined with other drugs such as CCNU or vinblastine is often used. In addition, an H2 blocker such as ranitidine is given so long as gross tumor is present to reduce the risk of duodenal ulcers. Diphenhydramine is sometimes useful in reducing swelling in acutely edematous tumors. Other skin tumors - Basal cell tumors are common in cats. These tumors are well circumscribed, round or oval, raised, sometimes cystic, and often hairless or ulcerated. They may be heavily pigmented and resemble melanomas. About 75% are located on the cranial half of the body, often over the head, neck, and thorax. Despite the fact that these are sometimes called "carcinomas", most basal cell tumors are benign. Cutaneous melanomas occur occasionally in dogs and cats, and generally behave in a benign manner. One exception is that melanomas occurring at the base of the canine toenail tend to be malignant. Cutaneous squamous cell carcinomas occur primarily around the ears, eyes and nose of white cats and at the toenail base in black dogs. The tumors are slow to spread, but may be ulcerated and confused with infections. Histiocytic tumors may vary from benign, single masses that spontaneously regress in young dogs, to aggressive systemic malignancies in dogs and cats. Soft Tissue Sarcomas Tumors such as fibrosarcomas, neurofibrosarcomas (nerve sheath tumors), malignant fibrous histiocytomas, hemangiopericytomas, and myxosarcomas are referred to as soft tissue sarcomas. All tend to be solitary, invasive, subcutaneous masses occurring in middle aged or old animals. Most are relatively slow to spread, but frequently recur after local excision. The tissue of origin of some sarcomas may be difficult to discern, so the diagnosis of undifferentiated sarcoma is made. Fibrosarcomas of cats may be caused by chronic inflammation related to certain injectable drugs or especially vaccines. Adjuvented rabies and leukemia vaccines have been most implicated, but no specific adjuvant, preservative, or brand of vaccine has been associated with tumor development. The incidence of post-vaccine fibrosarcomas has been estimated to be in the range of 1 per 10,000 vaccines given, so the risks and benefits of vaccination must be considered for each cat. The rate of growth is variable, but time from surgical removal to recurrence ranges one or two weeks to than a year later. Cats with surgical margins free of tumor had a median time to recurrence of 16 months, whereas in those with "dirty" margins, the median time to recurrence was 4 months, and their median survival was only 9 months. Preoperative biopsy is recommended so that the surgery can be planned to be curative. Studies in both dogs and cats have shown that degree of differentiation and mitotic index (number of mitoses per 10 high power fields) may be prognostic. Cats with mitotic indices <5 had a median survival of 128 weeks, whereas those with an index >5 survived a median of 16 weeks. A pre-surgical CT scan can help to determine the true extent of the tumor. Treatment is wide and deep surgical excision, but in the case of large masses, treatment should be coordinated between the surgeon and radiation oncologist. Radiation can significantly prolong the time to recurrence. Cats are less likely than dogs to suffer from acute skin reactions from radiation. For this reason, larger doses can be given to cats. In one study of cats with residual microscopic tumor after surgery, the median time to tumor recurrence after radiation was 18 months. Fibrosarcomas, caused the feline sarcoma virus (FeSV) occurs rarely in young cats. It may be multicentric, grows quickly, and metastasizes widely. The presence of FeLV is required for replication of FeSV. Bone Tumors The most common bone tumor of dogs and of cats is osteosarcoma. Large dogs are most commonly afforded. The rate of metastasis is much greater in the dog than in the cat. Amputation is curative in 90% of cats, compared to only less than 5% of dogs. The most common sites of canine osteosarcoma are the distal radius, proximal humerus, distal femur, and proximal tibia ("away from the elbow and towards the knee"). Cats are most likely to develop osteosarcomas of the axial skeleton and hind limbs. Canine osteosarcomas involving bones of the skull are slower to metastasize than those in other sites. The prognosis has been improved in dogs with adjuvant chemotherapy with cisplatin or carboplatin. The median survival in treated dogs is approximately 1 year and 25% are still alive at 2 years. Doxorubicin has also shown efficacy when used after amputation. Radiation may be of palliative benefit for pain relief in patients for whom amputation is not an option. Although most treated dogs are more comfortable, they are at risk for pathologic fracture since they may put weight on the affected leg. Other tumors that commonly involve bone are chondrosarcoma, fibrosarcoma, and hemangiosarcoma. Metastatic tumors to bone more typically involve the area of the nutrient foramen, and may be multiple. Chondrosarcomas most commonly involve the axial skeleton, are slow to metastasize and less sensitive to chemotherapy. Wide surgical excision or amputation is the treatment of choice. Synovial sarcomas arise around joints especially in middle aged male dogs. Tumors with a high mitotic rate, nuclear pleomorphism, and necrosis have a poor survival (210 days compared with 1080 days for less aggressive tumors. Treatment is amputation. Osteochondromas in cats may be multiple and often involve bones of the axial skeleton. They are often associated with FeLV infection, and, are difficult or impossible to remove because of their location. Tumors of the Respiratory System Tumors of the nasal cavity are malignant, and are more common in dogs than in cats. The most common ones are adenocarcinoma and squamous cell carcinoma. Sarcomas, arising from bone, cartilage, or fibroblasts, may also occur in the nasal cavity. Nasal lymphoma, more common in cats, may occur as a solitary mass or may be part of a multicentric disease. Lymphoma commonly will extend to involve the sinuses and retrobulbar area. Cryptococcosis frequently arises in the feline nasal cavity and mimics neoplasia in that the fungus may erode nasal bones and cause deformity very much like that seen with tumors. Other nasal infections are much less likely to erode bone. Signs may begin gradually with sneezing, nasal discharge, noisy breathing, and later, epistaxis. The early signs may be confused with those of a respiratory infection. Diagnosis can usually be made with a small biopsy forceps or by cytology of nasal flushes. Nasal tumors, with the possible exception of lymphoma, are relatively slowly growing and slow to metastasize. Surgery is not curative, and radiation therapy is a better approach to treatment, with a median survival of about one-year. Primary lung tumors are rare in dogs and cats (since they do not smoke), most being adenocarcinomas, arising from bronchi or bronchoalveolar cells. Radiographically, primary lung tumors may be solitary masses, but frequently take a diffuse, mottled appearance, and may be confused with inflammatory lesions. If pleural effusion is present, a cytologic diagnosis may be possible. Reactive mesothelial cells must be differentiated from malignant cells. If a solitary mass is present, lobectomy may be curative, but diagnosis is seldom made at that stage unless the tumor is discovered as an incidental finding when thoracic radiographs are taken for another reason. Metastatic tumors occur more commonly in the lungs than do primary tumors. Metastatic tumors are typically multiple and well circumscribed although occasionally they may be diffuse as is often seen with hemangiosarcoma. Vascular Tumors Hemangiosarcoma arises from vascular endothelial cells, and can occur anywhere where there are blood vessels. The most common sites are spleen, right auricular appendage, subcutis and in the abdominal or thoracic cavities. Cats sometimes develop hemangiosarcomas with presenting signs similar to those seen in dogs. Bleeding into the abdomen or pericardial sac may occur. Bleeding may be difficult to control partly because the abnormal vessels in the tumor do not contract, as would a normal vessel when traumatized. In addition, coagulopathies are often present. Nucleated red cells and fragmented red cells may be seen in the peripheral blood. Neoplastic cells are usually not present in the hemorrhagic effusions, so diagnosis requires surgical excision. Ultrasound evaluation is useful in detecting pericardial effusion, cardiac masses, as well as hepatic metastases. Prognosis is poor after surgical removal, with the median time to recurrence of tumor being about 2-4 months. Some response to doxorubicin has been seen in dogs. Tumors of the Gastrointestinal Tract One of the most common tumors of older cats is oral squamous cell carcinoma. The ventral aspect of the tongue is the most frequent site. Since the base of the tongue is invaded early, it seems to be impossible to diagnose them early enough for surgical excision. Routine physical examination on every cat should include observation of the ventral surface of the tongue, both to find the occasional swallowed string, or a very early tumor. Other sites for oral squamous cell carcinomas include the mandible and maxilla, usually along the dental arcade. The first sign may be halitosis, salivation, or difficulty eating. Teeth in the region of the tumor may become loose, and a frequent history includes a recent extraction of a "bad" tooth with failure to heal. Whenever dental disease appears localized, especially with proliferation or ulceration of adjacent gingiva, a biopsy should be taken at the time of dentistry. Squamous cell carcinomas are very invasive, and quickly involve bone. They are slow to metastasize, and aggressive surgery such as mandibulectomy may be curative if the tumor is small enough and in a site that is accessible. In the dog, the most common oral malignancy is the melanoma, which invades aggressively and metastases early to regional nodes and to the lungs. The dog may also develop squamous cell carcinomas, which behave like those in cats except that the tongue is less likely and the tonsil more likely to be involved in dogs. Tonsilar carcinomas metastasize early to submandibular lymph nodes and lungs. Other oral tumors include fibrosarcoma, epulides, and ameloblastomas. Nasopharyngeal polyps develop secondary to otitis media in cats, and may travel down the eustachian tube. Clinical signs are similar to those seen with nasal or oral tumors. Polyps are easy to remove by pulling the soft palate forward and using a slow twisting and pulling motion. Salivary gland carcinomas occur in older animals, usually starting as a palpable nodule in the region of any of the salivary glands. They are invasive and quickly cause difficulty in eating, salivation, and sometimes obstruction of the external ear canal. Surgery is indicated if the tumor is small, and the tumors are moderately radiosensitive. Esophageal tumors are rare except for the occasional squamous cell carcinoma in dogs with Spirocerca. Gastric neoplasia is also infrequent in cats except for lymphoma. Gastric tumors in dogs are most commonly adenocarcinoma or lymphoma. Contrast radiography is helpful in the diagnosis, but definitive diagnosis requires endoscopic or open biopsy. Intestinal tumors include lymphoma, adenocarcinoma, mast cell tumors and smooth muscle tumors. Lymphoma in both dogs and cats may be localized, but more commonly is diffuse, often associated with mesenteric lymphadenopathy. Sometimes low-grade (well-differentiated) intestinal lymphoma in cats seems to have followed inflammatory bowel disease, but misdiagnosis may be the reason. Intestinal adenocarcinoma, seen most commonly in old dogs and cats, appears as a napkin-ring lesion, because fibrosis in the tumor slowly constricts the lumen, causing partial obstruction. It also has a tendency to spread to mesenteric nodes and to implant in the mesentery, resulting in multiple nodules throughout the peritoneum, and ascites, with malignant cells in the fluid. Ulceration of the mucosa may result in chronic bleeding and iron deficiency. If the tumor appears localized, resection of the involved segment of intestine and some normal margins is warranted. The risk of recurrence or spread is high however, and most animals survive only a few months postoperatively. The quality of life during that time is good. The most common clinical signs with stomach or intestinal tumors of all types are vomiting, anorexia, and weight loss. Diarrhea is less common, and constipation may occur if the tumor is in the colon. Anal sac carcinomas frequently cause hypercalcemia, and also spread early to the sublumbar lymph nodes. A large sublumbar mass may be present with only a tiny primary tumor. A rectal exam must be part of every physical exam in a hypercalcemic dog. Liver tumors are relatively uncommon, most being carcinoma of hepatocytes or bile ducts, and occasionally hemangiosarcoma. Lymphoma rarely affects the liver as a primary site, but invasion as part of multicentric disease is relatively common. Ultrasound examination of the liver is helpful prior to biopsy or surgery to differentiate solitary from diffuse lesions. Pancreatic adenocarcinoma is relatively common in the cat, and less so in the dog. It is very malignant and spreads quickly throughout the mesentery and to distant sites. Occasionally a single tumor is palpated, but most commonly the diagnosis is made when ascites develops with tumor cells in the fluid. Tumors of the Urinary System The most common renal tumor of the cat is lymphoma, whereas adenocarcinoma is most common in the dog. The kidneys in cats with lymphoma usually are both enlarged and nodular, resembling those in feline infectious peritonitis. Clinical signs associated with renal tumors are usually vague: weight loss and anorexia. Hematuria, a common sigh in adenocarcinoma, is rarely seen with lymphoma, which typically involves the interstitium. A mass may be palpable, but ultrasound and contrast radiography help to determine whether one or both kidneys were involved. Nephrectomy is the treatment of choice for renal carcinomas. A careful evaluation of renal function and involvement of the opposite kidney is obviously important, as is a search for metastases prior to surgery. Polycythemia from ectopic erythropoietin produced by the tumor has been reported in dogs with renal neoplasia. In the cat renal tumors outnumber bladder tumors; in the dog, the reverse is true. The rarity of bladder carcinomas in cats was ascribed in one report to their ability to metabolize tryptophan without producing phenol metabolites, which have been implicated as a cause of bladder tumors in man and the dog. Bladder tumors are most commonly transitional cell carcinomas, with leiomyosarcomas and lymphomas less common. Clinical signs are stranguria and hematuria, and dogs some have co-existing cystitis. If a transitional cell carcinoma is suspected, one should avoid cystocentesis since spread of tumor cells along the needle track has occurred. Since most of these tumors involve the trigone or urethra, they are rarely operable. Ureteral obstruction may cause hydronephrosis. Piroxicam has been as successful as chemotherapy in reducing the size of the tumor in about 30% of cases, and in relieving clinical signs in an additional 30%. Tumors of the Reproductive System The most common testicular tumors in dogs are Sertoli cell tumors, seminomas and interstitial cell tumors. Sertoli cell tumors and seminomas are more common in retained testicles. About 60% of Sertoli cell tumors and rare seminomas produce estrogen, which causes feminization and sometimes aplastic anemia. Testicular tumors are slow to grow and to metastasize, and most are cured by castration. Prostatic carcinoma occurs with equal frequency in intact and castrated male dogs. Castration or hormonal manipulations are of no value for treatment. Many prostatic tumors arise from transitional cells rather than the glandular prostatic tissue. Testicular and prostatic cancer is very rare in cats. Ovarian tumors, most commonly adenocarcinomas and granulosa cell tumors, are occasionally seen in unspayed female dogs and cats. Although they may spread, most are relatively benign and are cured by surgery. Mammary gland tumors are common in older intact females. Spaying prior to the first heat period greatly decreases the risk of later tumor development. In dogs roughly 50% are malignant, whereas over 80% of feline tumors are malignant. A particularly malignant variant seen in dogs is the inflammatory carcinoma. This tumor spreads rapidly along lymphatics and is often ulcerated and very painful; it may be mistaken for mastitis. Estrogen receptors are rarely present in feline tumors, but progesterone receptors are usually present. In dogs, 50-60% of mammary carcinomas contain estrogen receptors. This information has not yet been translated into any useful treatment option. An increased incidence of mammary carcinomas has occurred in bitches and in both male and female cats, neutered and intact, treated with progestational agents such as medroxyprogesterone acetate. Mammary carcinomas spread both by hematogenous and lymphatic routes. Anterior glands are affected somewhat more frequently in cats than posterior glands, whereas the opposite is true for dogs. In dogs the degree of malignancy increases from complex to simple carcinoma to sarcoma. Over half of the dogs with mammary carcinomas are cured by surgery. Most tumors that recur or metastasize will do so within one year. In cats, prognosis is most correlated with the size of the tumor at the time of removal. The average survival time for cats with mammary adenocarcinomas removed surgically is reported to be 12.7 months. For tumors less than 2 cm in diameter, the median survival time was 4.5 years, but for tumors 3 cm or greater in diameter, the median survival was only 6 months. All mammary nodules should be assumed to be carcinomas and excised quickly and completely. Thoracic radiographs should always precede surgery since lung metastases are common. Simple mastectomy is acceptable treatment for a single nodule, but complete removal of all mammary tissue is indicated for dogs or cats that present with multiple nodules. In this case, surgery may have to be done in two stages, one side at a time. Radical mastectomy, removal of all of the normal glands as well as the affected one, increased disease-free survival, but may not increase overall survival provided that the original tumor was completely excised. Opinions vary as to whether ovariohysterectomy should be done at the time of mastectomy. Tumors of the Endocrine System Tumors of the pituitary or adrenal glands in dogs most often cause signs of hyperadrenocorticism. Pheochromocytomas are less common, but secrete catacholamines, which cause hypertension. Thyroid carcinomas occur in both dogs and cats, but are much less common in cats than hyperplasia. In dogs, hyperthyroidism essentially always indicates the presence of thyroid carcinoma. Most canine carcinomas do not cause hyperthyroidism, and some may be cured by surgery if diagnosed early. Those that cannot be cured by surgery may respond to chemotherapy and/or radiation. Laryngeal paralysis is a common complication of either the tumor or the surgical excision. Feline thyroid carcinomas tend to infiltrate the adjacent tissue, and may coexist with thyroid hyperplasia. They are slow to metastasize, and may be treated by surgery, and if residual tumor is present, radioactive iodine may eradicate remaining tumor. Parathyroid tumors, usually adenomas, should be considered in either dogs or cats presenting with hypercalcemia. In cats, parathyroid adenomas are more likely to cause hypercalcemia than is lymphoma. Most of these masses are too small to palpate, but they may be seen with ultrasonography. Exploratory surgery may be necessary for diagnosis as well as treatment. Pancreatic islet cell tumors are more common in dogs than in cats and should be considered whenever hypoglycemia is diagnosed. Abdominal ultrasound may identify a primary tumor, but insulinomas are often too small to visualize. The liver should be evaluated for metastases. Surgery is difficult and postoperative pancreatitis or diabetes mellitus is common. Metastasis occurs early, but palliation with corticosteroids, sometimes with diazoxide is usually possible. Other agents sometimes used are hydrochlorothiazide, which potentiates the effects of diazoxide, and propranolol, which inhibits insulin release. A median of one-year survival is a reasonable expectation. Tumors of the Nervous System Meningiomas are the most frequent intracranial tumor of the cat, also occurring occasionally along the spinal cord. Clinical signs depend on the location. The most common signs in cats are behavior change, followed by seizures or focal neurologic deficits. Some large meningiomas have been found at necropsy as incidental findings. Signs tend to be slowly progressive, and some tumors are removable surgically. The MRI has allowed for accurate localization to determine the feasibility of surgery. In the dog, gliomas, especially astrocytomas predominate. Clinical signs depend on the location, but include seizures, mental dullness from increased intracranial pressure, and localizing signs such as cranial nerve deficits or long tract signs. In both dogs and cats, many tumors in the brain are metastases from malignancies elsewhere in the body. Since tumors metastasize to the lungs as well, thoracic radiographs may be helpful in detecting them. Most canine tumors occur deep in the brain making removal impossible. Radiation therapy has produced some remissions in glial and pituitary tumors. Lymphoma is the most common spinal tumor in the cat. Dogs may develop spinal lymphoma, but are more likely to develop tumors arising in the vertebrae or extending into the spinal canal from a peripheral nerve, especially neurofibromas arising in the brachial plexus. Initially lameness and pain are present, but later paresis of the affected limb is noted. Tumors of the Eyes and Ears The most common tumor of the feline external ear canal is the inflammatory polyp. This was discussed earlier in the section of oral tumors. Some polyps exit from the middle ear through the eardrum. Of the benign neoplasms in cats, the most common are the adenomas of ceruminous glands. These are irregular grape-like, dark, firm masses, usually seen in the presence of chronic otitis. Adenocarcinomas of ceruminous glands or squamous cell carcinomas in cats and dogs tend to be poorly circumscribed, sometimes ulcerated, and spread to regional nodes, or occasionally to distant sites. Radiation may be effective for palliation of inoperable masse The most common ocular tumor is the melanoma of the iris. In the cat, this tumor is likely to spread to submandibular lymph nodes, and sometimes beyond.
Paraneoplastic syndromes are often divided into endocrine, hematologic and miscellaneous. These are listed in the attached tables. A few are discussed here in more detail. Hypercalcemia Lymphoma is the most common cause of hypercalcemia in the dog, and parathyroid adenoma is the most common in the cat. About 20% of dogs with lymphoma present with signs of hypercalcemia, sometimes without other overt signs of lymphoma. Whenever hypercalcemia is found, a search for malignancy should ensue. A rectal exam should always be done in dogs since a small carcinoma of the anal sac may be the cause. These metastasize early to sublumbar nodes, which may become much larger than the primary tumor. Thoracic radiographs might disclose a mediastinal lymphoma. A bone marrow aspirate might show a lymphoblastic leukemia. Serum globulins, if elevated, should be further evaluated to see if a monoclonal spike is present. Abdominal ultrasound exam or radiographs might show an abdominal mass. Some parathyroid adenomas have been visualized by ultrasonography. A serum parathormone evaluation might be useful provided that results can be obtained soon since renal tubular damage occurs quickly of hypercalcemia is not corrected. One should avoid trial doses of corticosteroids until everything possible has been done to diagnose an occult lymphoma. Intravenous saline diuresis can be done while tests are in progress but the best treatment for hypercalcemia is treatment of the underlying cause. For example when chemotherapy is begun for lymphoma, calcium drops in 24-48 hours, occasionally below normal transiently, but usually to normal. Hypoglycemia Insulinoma is the most common cause of hypoglycemia in dogs, ferrets and occasionally cats. Increased insulin is present in this tumor, but usually not in tumors such as hepatocellular carcinomas which occasionally cause hypoglycemia. Neurologic signs predominate in hypoglycemia since the brain requires glucose for its function. Persistent fasting hypoglycemia or an amended insulin/glucose ratio is useful in confirming a diagnosis of insulinoma.
Serum insulin uU/ml x 100 = ratio. If the ratio is > 30 this is highly suggestive of an insulin producing tumor. Abdominal ultrasound may identify a primary tumor, but insulinomas are usually too small to visualize. The liver should be evaluated for metastases. Surgery is difficult and postoperative pancreatitis or diabetes mellitus is common. Surgery is usually not curative since metastasis occurs early, but palliation with corticosteroids, sometimes with diazoxide (10-40 mg/kg divided BID) is usually possible. Other agents sometimes used are hydrochlorothiazide which potentiates the effects of diazoxide, and propranolol which inhibits insulin release. A median of one-year survival is a reasonable expectation. Erythrocytosis Clinical signs associated with increased red cell mass are hyperviscosity, mental dullness, lethargy, and occasionally heart failure or polydipsia. When erythrocytosis is secondary to hypoxia, as in right to left cardiac shunts, cardiac and respiratory signs usually predominate. Blood gas determination would confirm this but usually is not necessary. Erythrocytosis secondary to erythropoietin-secreting tumors may be more difficult to diagnose. One might start by ultrasound or radiographic contrast evaluation of the kidneys, the most likely site. Erythropoietin concentrations are increased when erythrocytosis is secondary to hypoxia or erythropoietin secreting tumors, but normal or decreased in polycythemia vera. Anemia Anemia may be caused by chronic blood loss from gastrointestinal neoplasia, from decreased production in primary hematopoietic malignancy or anemia of chronic disease or from hemolysis in tumors such as hemangiosarcoma that cause microangiopathic hemolysis. Cancer Cachexia Alterations in carbohydrate, lipid and protein metabolism have been documented in cancer patients. These alterations may persist even after remission is achieved. For example, dogs with lymphoma have been shown to have increased insulin and lactate concentrations. Lactate levels increase further if lactate-containing fluids are given. Energy requirements in dogs with lymphoma are not increased; contrary to prior suggestion that stressed patients in general have increased energy requirements. Adequate calories must be provided with a diet containing a moderate amount of protein, fat and complex carbohydrates and minimal simple carbohydrates. If anorexia is present, tempting foods are offered. Sometimes cyproheptadine or megestral acetate may help. Cats more than dogs are likely to become anorexic when chemotherapy is started. Disseminated Intravascular Coagulation (DIC) Malignancy is a relatively common cause of DIC, especially in dogs with hemangiosarcoma. Occasionally bleeding may be the first clinical sign and prompt a search for a tumor. More commonly, DIC is a complication of extensive malignancy with or without sepsis. Unless the tumor can be removed or treated, it is unlikely that the coagulopathy can be corrected. In normal individuals, circulating levels of clotting factors are in excess of those needed, and additional extravascular distribution of most factors is present. Except for factors V, VIII and fibrinogen, most of the factors are roughly the size of albumin and share its 40% intravascular and 60% extravascular distribution. In DIC factors are consumed by excessive thrombosis and clot lysis. Always a secondary disease process, DIC results in depletion of platelets, coagulation factors, and antithrombin. Fibrinogen degradation products (FDPs) accumulate and inhibit coagulation. A complication of DIC is the seeding of microthrombi in tissues leading to localized hypoxia and necrosis. Under normal circumstances, microthrombi are eliminated by fibrinolysis and by tissue macrophages. In DIC, fibrinolytic enzymes are depleted and macrophages are overwhelmed. Tissues most often affected by microthrombi are the liver, kidneys, and lungs. Clinical signs associated with each of these organ systems may complicate the clinical picture making diagnosis of primary diseases difficult. A diagnosis of DIC may be made if one observes multiple abnormalities such as increased prothrombin time (PT), partial thromboplastin time (PTT), activated clotting time (ACT), fibrin degredation products (FDPs), thrombocytopenia, hypofibrinogenemia, decreased antithrombin, and the presence of schistocytes on a blood smear. The laboratory diagnosis of DIC has been overemphasized and may be confusing. Tests may change rapidly and the classic picture of low platelets and fibrinogen, prolonged PT and PTT, and elevated FDP levels may not be present. Whenever the fibrinogen level is decreased below 80-100 mg/dl, the PT and PTT will be prolonged because fibrinogen is needed for fibrin formation in both tests. Thrombocytopenia is so consistent that a diagnosis of DIC cannot be certain without it. The platelet count returns to normal slowly over several days as DIC resolves. The fibrinogen level however, rapidly returns to normal. FDPs are cleared primarily in the Kupffer cells of the liver and some are excreted in the urine. Elevated FDPs may sometimes be seen in hepatic or renal failure or after hemorrhage into a body cavity. By the time DIC is clinically evident, clotting factors are severely depleted. Once a patient is bleeding and fibrinogen is low, and the PT and PTT are prolonged, replacement of clotting factors with fresh frozen plasma (FFP) is needed in addition to supportive care. In addition to coagulation factors, FFP contains antithrombin a potent inhibitor of thrombin formation. The endogenous production of antithrombin in dogs was shown to increase rapidly beginning within 6 hours of induction of DIC by endotoxin injection. Production was able to surpass consumption after 1-2 days despite ongoing DIC. If one can eliminate the underlying cause of DIC and if bleeding is not evident, it is not necessary to "treat" the laboratory abnormalities; they can simply be monitored along with the patient. In the most severe cases of DIC with excessive blood loss, replacement of red cells, clotting factors and platelets may be needed. Here fresh whole blood is indicated initially with individual components added as needed. Heparin is sometimes used in conjunction with FFP and controversy exists as to when and how it should be used. There is general agreement that heparin used alone in the bleeding patient is risky and unlikely to be successful. Heparin is a specific activator of antithrombin and requires its presence for its anticoagulant effect. Heparin is most likely to be beneficial in cases diagnosed early before clotting factors are depleted and before bleeding begins. In cases of DIC where clotting factors have been depleted and bleeding is ongoing, FFP can be given first and heparin added to try to minimize additional formation of microthrombi if the patient continues to bleed or shows evidence of thrombosis afterwards. Some have advocated incubating heparin with FFP before administering to activate antithrombin III to help prevent further thrombosis. In low doses (5-10 units/kg, Tid, SQ) its main effect is to bind to antithrombin and increase its activity. In higher doses (75-100 u/kg IV every 4-6 hours) it has a stronger anticoagulant effect. Patients that are actively bleeding or require surgery should have factors replaced, and not receive heparin. Monitoring for signs of improvement can be difficult when heparin is given. A rise in the platelet count and fibrinogen concentration is favorable prognostic signs. Despite the controversy, heparin has never been shown to increase survival in gram-negative sepsis or other states where DIC is encountered. Other therapeutic agents such as inhibitors of fibrinolysis (epsilon amino caproic acid) and steroids are not likely to help and may be dangerous. Steroids slow the clearance of FDPs, bacteria and immune complexes, but may be indicated in septic shock from gram negative bacteria. Antithrombin concentrates have recently been used with some success in human patients, but are not available for animals.
Table 2: Hematological and hemostatic paraneoplastic syndromes
Modified from Gorman NT, Clinical management of tumors in geriatric dogs and cats: systemic effects of tumors and paraneoplastic syndromes, Veterinary Record (1990), 126, 395-398 and Gaschen FP: Paraneoplastic Syndromes in Dogs and Cats. Proc. 13th ACVIM Forum (1995) 254-257. Table 3: Miscellaneous paraneoplastic syndromes
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