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Oncology Douglas H. Thamm, VMD, DACVIM (Oncology) Colorado State University Animal Cancer Center, Fort Collins, CO Aftershocks of Cancer Therapy: Managing Adverse Events The majority of cytotoxic chemotherapy protocols in common veterinary use are designed to have a low risk of adverse effects. In general, less than 1 in 4 animals will have unpleasant adverse effects and only approximately 5% will have a serious adverse event, leading to hospitalization. With appropriate intervention, the risk of a treatment-associated fatality is less than 1 in 200. Should serious side effects occur, doses can be reduced, drugs can be substituted, or additional medications dispensed to minimize the likelihood of further adverse effects. These changes are effective 90% of the time. Even in practices where chemotherapy is not administered, referring and emergency/critical care practices are often called upon to deal with adverse effects resulting from cancer therapy that may have been administered at another clinic. Having a protocol in place for the treatment of these patients dramatically increases the likelihood of a good outcome should a serious adverse event be encountered. The most commonly encountered adverse effects, neutropenia and gastrointestinal disturbance, generally occur as a result of "collateral damage" done to rapidly dividing cells by the cytotoxic agent. Both bone marrow stem cells and gastrointestinal crypt cells are rapidly dividing and thus sensitive to the antiproliferative effects of chemotherapy. Neutropenia and Sepsis Neutropenia is a relatively common side effect of chemotherapy in companion animals and humans. In certain malignancies, bone marrow infiltration or other conditions can exacerbate myelosuppression. The severity of neutropenia and associated sepsis can be extremely variable, ranging from clinically silent to overwhelming and fatal. Presenting Complaints: Many animals may be mildly or moderately neutropenic, yet show no outward signs of illness. Most companion animals have a relatively low risk of infection if their neutrophil count remains greater than 1,000/uL. It is important to remember that likelihood of infection and subsequent treatment decisions should be made based on absolute neutrophil count, not total white blood cell count. Septic patients will typically present with vague, nonspecific signs of illness such as lethargy, weakness, and inappetance. They are often febrile, but a normal temperature does not rule out the presence of a serious or even life-threatening infection. An accurate medication history is very important, as the timing of the last chemotherapy treatment can help to determine if myelosuppression is likely. Neutropenia is likely to be seen 7-10 days after the administration of most chemotherapy drugs. Exceptions to this rule include vinblastine and paclitaxel, which can cause neutropenia as early as 4-5 days after administration, and lomustine (CCNU) and carboplatin, which can occasionally cause neutropenia as late as 2-3 weeks following administration. Diagnostics: Septic patients are often febrile, as mentioned above. Other physical abnormalities could include tachycardia, injected mucous membranes, slow or prolonged capillary refill, or weak pulses. Initial minimum database should include a CBC and platelet count with manual differential, serum biochemistry profile, and urinalysis. Common changes include neutropenia with or without a left shift or toxic changes, thrombocytopenia, hyper- or hypoglycemia, evidence of dehydration, or metabolic acidosis. Urinalysis may reveal a quiet sediment, however urinary tract infections cannot be ruled out as neutropenia can result in the absence of neutrophils in the urine. Many clinicians will empirically culture the urine of neutropenic, septic patients. A coagulation profile is indicated in an animal with unquestionable signs of septic shock, as varying degrees of disseminated intravascular coagulation can be seen and must be treated aggressively. In animals presenting with respiratory signs or with a history of vomiting prior to presentation, thoracic radiographs to identify a nidus of infection are indicated. Recent human studies suggest that there is no benefit to obtaining "screening" thoracic radiographs in the asymptomatic neutropenic, septic patient. Treatment: Asymptomatic patients with less than 1,000 neutrophils/uL can be managed on an outpatient basis. In these patients, the risk of nosocomial infection outweighs the benefit associated with hospitalization. A broad-spectrum oral antibiotic such as trimethoprim-sulfa (7.5 mg/kg BID), Clavamox (13.75 mg/kg BID) or enrofloxacin (5-10 mg/kg SID) should be prescribed for a 5-7 day course, and the owner should be instructed to monitor the patient's temperature once or twice daily at home. If the patient becomes clinically ill or the temperature exceeds 103.5oC, hospitalization may be required. Patients with mild neutropenia (>1,000/uL) generally require no treatment. Febrile or systemically ill patients should be hospitalized for 24-hour care. The first line of treatment for these patients is intravenous crystalloid therapy. Shock doses of fluids, or the addition of colloids should be considered in the hemodynamically unstable, critical septic patient. In the stable patient, a fluid rate of 1.5 times maintenance is reasonable after correction of any existing fluid deficit. It is quite common for fever and clinical status to improve significantly after several hours of fluid therapy. The second line of defense is appropriate antibiotic coverage. The most common organisms responsible for neutropenic sepsis are resident flora that are usually antibiotic-sensitive. Common bacteria include E. coli, Pseudomonas, Staph. epidermidis, and Staph. aureus. Thus, intravenous coverage for both gram-positive and gram-negative organisms should be employed. Typical drug combinations might include a penicillin/aminoglycoside combination such as ampicillin (22 mg/kg IV TID) and amikacin (10 mg/kg IV/IM/SQ SID) (assuming renal function is adequate) or first-generation cephalosporin/fluoroquinolone combination such as cefazolin (20 mg/kg IV TID) and enrofloxacin (5-10 mg/kg IV or IM SID). Antipyretics are almost never necessary, and may make interpretation of response to therapy difficult. The majority of patients will respond rapidly to therapy, and neutrophil counts may rise very rapidly as well. The majority of animals will be afebrile within 12-24 hours, and can be discharged when they are afebrile and have greater than 1,000 neutrophils/uL. In patients that do not respond clinically during the first 48-72 hours, further diagnostics to identify a potential nidus of infection and to collect samples for bacterial culture and antibiotic sensitivity should be performed. Additional tests might include thoracic radiographs, abdominal ultrasound and echocardiography, and at least 2 sets of blood cultures. In those patients that do not respond rapidly, antibiotic coverage can be broadened while waiting for culture results. Anaerobic coverage may be broadened with the addition of metronidazole (25 mg/kg IV BID), and/or a second- or third-generation cephalosporin can be considered. Should protracted (>72h) neutropenia be encountered, a bone marrow aspirate may be useful (especially in patients with hematopoietic neoplasia where there is the possibility of infiltrative disease). There is continued debate as to the clinical utility of recombinant human granulocyte colony-stimulating factor (G-CSF, Neupogen®). Some clinicians will routinely utilize G-CSF for febrile, neutropenic patients; others will utilize it in cases of severe neutropenia where neutrophil count is less than some arbitrary value (500/uL or 100/uL, for example). Others will utilize G-CSF only if neutropenia persists for longer than 72 hours. Although some human studies have suggested no benefit in terms of length of hospitalization or mortality rate if G-CSF is employed, a recent study showed that severely neutropenic (< 100/uL) patients had decreased duration of neutropenia and hospital stay compared to controls, although there was no significant difference in mortality. In the author's hands, G-CSF is almost never necessary. Gastrointestinal Effects Although the majority of veterinary patients undergoing chemotherapy will tolerate treatment well, a small number may experience unpleasant gastrointestinal side effects such as nausea/vomiting or diarrhea. The majority are mild and self-limiting, however more severe episodes are occasionally encountered. Just as chemotherapy can target the rapidly dividing tumor cells and bone marrow precursors, the rapidly dividing gastrointestinal crypt cells are likewise susceptible to chemotherapy effects. Presenting Complaints: There are certain drugs (cisplatin, for example) that have the potential to cause immediate nausea/vomiting due to the activity of the drug itself on the chemoreceptor trigger zone in the brain. During cisplatin administration, for example, many dogs will vomit during or immediately after drug administration unless they are premedicated with an antiemetic such as butorphanol or dolasetron. More commonly, damage to the GI mucosa can result in irritation and inflammation that can lead to vomiting and/or diarrhea, most commonly in the 2-5 day period following chemotherapy administration. Signs can range from mild inappetance and slightly soft stools to severe, intractable vomiting and profuse, hemorrhagic diarrhea. Animals with mild symptoms can often be managed at home with dietary modification and oral medications. Animals that are unable to keep water down, that are becoming depressed, dehydrated or lethargic, or animals experiencing severe hematochezia should be hospitalized. Diagnostics: Careful medical and medication history should help to determine if the signs are likely to be associated with chemotherapy administration. In a severely affected animal, minimum database should include PCV/total solids, BUN/creatinine, electrolytes and urine specific gravity. A full CBC and serum chemistry profile is reasonable in these cases, and a CBC should also be performed in animals with significant hematochezia. If the patient has a protracted history of vomiting, thoracic radiographs are reasonable to rule out aspiration pneumonia. In an animal that is refractory to symptomatic therapy, further investigation (e.g. abdominal imaging) to rule out other causes for vomiting such as obstruction, pancreatitis, GI involvement with neoplasia, etc. should be considered. Treatment: Many animals with mild signs may respond to conservative therapy (e.g. brief NPO followed by bland, high-fiber diet and time). Oral antiemetics (e.g. metoclopramide 0.2-0.5 mg/kg PO or SQ TID, prochlorperazine 0.3 mg/kg PO or SQ TID) may be utilized if vomiting is infrequent and the patient is bright and alert. Oral medications for diarrhea such as kaolin/pectin may be used as well. The author favors the use of the opiate antidiarrheals such as loperamide (0.08 mg/kg PO TID) when necessary. Some animals with chemotherapy-associated diarrhea may respond to oral metronidazole (25 mg/kg daily) for 5 days. We will also prescribe metronidazole for any dogs with hematochezia. Animals that are weak, lethargic, dehydrated, or with severe, refractory symptoms should be hospitalized so that fluid, acid-base and electrolyte disturbances can be addressed. These animals should be kept NPO until vomiting resolves, and parenteral antiemetics can be administered (See Table 1). Dehydration should be corrected over the first 8-12 hours, then patients can be maintained on a fluid rate of approximately 1.5 times maintenance. Some animals may be mildly or moderately hypokalemic - This should be corrected with potassium supplementation. Judicious re-feeding with bland food and transfer to oral antiemetics can typically start after a patient has been emesis-free for 12-24 hours. For antiemesis, the author will often start with metoclopramide as a constant-rate infusion, and then add prochlorperazine or other drugs if vomiting continues. Ondansetron, a 5-HT3 antagonist, is very safe and effective, however its cost makes it impractical for use as a first-line antiemetic. Recently, another 5-HT3 receptor antagonist, dolasetron, has become available and is less expensive than ondansetron. For very refractory vomiting cases, butorphanol or anti-inflammatory doses of corticosteroids may be added. The addition of an H2 blocker (e.g. famotidine 0.5-1 mg/kg IV or SQ) or proton pump inhibitor (e.g. pantoprazole 1 mg/kg IV) may be helpful in minimizing risks associated with continued vomiting/reflux esophagitis. Recent information suggests that the H2 blocker ranitidine may also have prokinetic and antiemetic activity due to concurrent inhibition of acetylcholinesterase activity. Maropitant (Cerenia , which targets the substance P/NK1 receptor pathway, is now available for the treatment of dogs with emesis due to a variety of etiologies. If hospitalization is necessary, most animals will need support for 24-72 hours. After this period of time, the GI mucosal cells have usually had sufficient time to regenerate and the vomiting should subside. Vomiting persisting for longer than 72 hours should be an indication to rule out other disease. Selected References Thamm DH, Vail DM. Aftershocks of cancer chemotherapy: managing adverse effects. J Am An Hosp Assoc 43: 1-7, 2007. Endicott M. Oncologic emergencies. Clin Tech Small Anim Pract. 2003;18(2):127-30. van de Wetering MD, de Witte MA, Kremer LC, Offringa M, Scholten RJ, Caron HN. Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials. Eur J Cancer 2005;41(10):1372-82. Berghmans T, Paesmans M, Lafitte JJ, Mascaux C, Meert AP, Jacquy C, Burniat A, Steels E, Vallot F, Sculier JP. Therapeutic use of granulocyte and granulocyte-macrophage colony-stimulating factors in febrile neutropenic cancer patients. A systematic review of the literature with meta-analysis. Support Care Cancer. 2002;10(3):181-8. Washabau RJ, Hall JA. Gastrointestinal prokinetic therapy: serotonergic drugs. Comp Cont Ed Pract Vet 1997; 19(4):473-480. Hall JA, Washabau RJ. Gastrointestinal prokinetic therapy: dopaminergic antagonist drugs. Comp Cont Ed Pract Vet 1997; 19(2):214-220. Hall JA, Washabau RJ. Gastrointestinal prokinetic therapy: acetylcholinesterase inhibitors. Comp Cont Ed Pract Vet 1997; 19(5):615-620. De la Puente-Redondo VA, et al. The anti-emetic efficacy of maropitant (Cerenia) in the treatment of ongoing emesis caused by a wide range of underlying clinical aetiologies in canine patients in Europe. J Sm An Pract 2007; 48(2): 93-98. Ogilvie GK. Dolasetron: a new option for nausea and vomiting. J Am Anim Hosp Assoc 2000;36(6):481-483. Table 1: Commonly Used Antiemetics
Advances in Lymphoma Diagnosis and Management Lymphoma (LSA) is a relatively common disease entity in veterinary medicine. Most small animal practitioners will encounter LSA in their practice, and will be asked to provide information and treatment recommendations for pets with this condition. Diagnosis and Staging - Dogs The typical dog with LSA will present with generalized (or less commonly regional) lymphadenopathy. Differential diagnoses for generalized adenopathy can include Ehrlichiosis or other immune-mediated diseases, systemic mycosis, severe pyoderma or other skin disease, and reactive hyperplasia. The most simple way do discern the cause for lymphadenopathy is via needle aspiration cytology of an affected lymph node. If possible, the submandibular lymph nodes should be avoided due to the likelihood of some component of reactive hyperplasia being present due to drainage from the mouth and ears. Although many clinical pathologists are able to confirm a diagnosis of canine LSA cytologically, excisional biopsy of an affected lymph node provides the most information. It is critical that empiric prednisone therapy not be employed prior to diagnosis if lymphoma is a differential, as this may mask the signs of illness and has the potential to induce resistance to other forms of chemotherapy (See below). Complete clinical staging helps to ascertain the extent of disease, ensures that other types of medical problems are not present, and can provide prognostic information for the client. Complete staging should include complete blood count, serum chemistry panel, urinalysis, thoracic radiographs, and a bone marrow aspirate. Imaging of the abdominal cavity is of limited use, unless abdominal palpation is extremely difficult, or if abnormalities other than cranial organomegaly are palpated or clinical signs consistent with primary gastrointestinal disease are present. The World Health Organization has developed a clinical staging system for dogs with multicentric LSA, which takes into account the number and location of involved lymph nodes, presence or absence of hepatosplenomegaly, and the presence or absence of disease in the bone marrow, central nervous system, or other extranodal sites. In addition, a substage is assigned, (a) representing a patient without clinical signs of illness, and (b) representing a patient with clinical signs (anorexia, lethargy/weakness/ depression, significant weight loss, vomiting, diarrhea, etc.) (See Table 1). Most dogs that present are WHO Stage IIIa or IVa. Complete staging allows a thorough assessment of factors that may help to predict the outcome with treatment for an individual patient. Factors that have historically carried the most prognostic significance for remission duration and survival include presence of clinical signs at presentation (substage b), presence of hypercalcemia, mediastinal lymphadenopathy, and significant bone marrow infiltration. It is probable that both hypercalcemia and mediastinal lymphadenopathy are actually surrogate markers for LSA with a T cell immunophenotype, a very powerful predictor of outcome. Most veterinary pathology laboratories are now capable of immunophenotyping lymphomas with the use of CD3 immunohistochemistry. Additionally, the University of California at Davis, Colorado State University and North Carolina State University can perform this evaluation on fine-needle aspirates using flow cytometry. These prognostic factors do not typically alter the likelihood that a patient will achieve a complete response (CR); they do however, affect the likely duration of that response. Diagnosis and Staging - Cats Generalized lymphadenopathy is an uncommon presentation for cats with LSA. Clinical signs are dependent on the body system affected. Due to the changes in FeLV testing and vaccination, there has been a shift in the anatomic distribution of feline LSA over the past 15 years. Whereas the mediastinal form, occurring in young FeLV+ cats previously predominated, we are now seeing a great deal more of the alimentary form in older, FeLV- cats. Given the anatomic distribution in cats, diagnosis is more often achieved through histopathology after exploratory laparotomy or endoscopy. Needle aspiration cytology of enlarged peripheral lymph nodes in cats can be difficult to interpret, as cats are subject to a variety of lymphoid hyperplastic conditions that can mimic LSA cytologically. Clinical staging in cats with LSA is very similar to that in the dog. However, addition of FeLV and FIV serology is reasonable, due to its impact n prognosis and husbandry. A pre-treatment abdominal ultrasound can be helpful to establish a pre-treatment baseline in cats with alimentary LSA. Treatment and Prognosis Chemotherapy is the mainstay of treatment for LSA. A large number of single-agent and multi-agent chemotherapy protocols have been investigated over the last 20 years. However, one optimal chemotherapy protocol has not been identified which can integrate positive outcome, toxicity and cost. In general, combination chemotherapy is considered more efficacious than single-agent chemotherapy. Corticosteroids alone have been shown to induce at least partial remission in many dogs with LSA by their direct cytotoxic effect on the tumor cells. In addition, dogs that are systemically ill will often show improvements in appetite, activity and attitude while receiving steroids. Finally, steroids may reduce the magnitude of hypercalcemia, if present. Oral corticosteroids (most commonly prednisone at 2 mg/kg/day initially, then tapered over time to 0.5-1 mg/kg/day) are an excellent treatment option for some owners if chemotherapy is declined. However, it is important that owners understand the ramifications of utilizing prednisone as a single agent before initiating treatment. I will commonly inform owners that "Prednisone is a one-way street". While most dogs will experience significant short-term improvement, the duration of that improvement is typically on the order of only 1-2 months, and prednisone appears to be a powerful inducer of chemotherapy resistance. In other words, multi-agent chemotherapy is much less likely to be efficacious if a patient has come out of remission after treatment with prednisone alone. Some owners may reject the notion of utilizing injectable chemotherapeutic agents, but may be willing to combine prednisone treatment with another oral chemotherapy drug. The most common drug utilized for this purpose is oral cyclophosphamide (CTX). This combination can be administered in much the same way as it might when treating a dog with immune-mediated disease. A typical weekly dose of CTX in this setting might be 200 mg/m2, divided into several daily oral doses. This approach may extend the median survival of LSA patients by 1 to 2 months over prednisone alone, however there is no firm information regarding to efficacy reported. It is important that CTX tablets not be broken or crushed, due to risks of client exposure. A relatively simple, non-toxic and inexpensive chemotherapy protocol with intermediate efficacy is the COP (CTX/Vincristine/Prednisone) protocol. Prednisone is administered orally as above, CTX is administered either orally or injectably at 200 mg/m2 every 3 weeks, and vincristine is injected weekly for several weeks, then every 3 weeks thereafter. Response rates of approximately 75% can be achieved, and the median survival times are in the range of 6-8 months in most reports. Another protocol with similar efficacy is single-agent doxorubicin (DOX). This has become more affordable for many clients since DOX has become available in a generic form, and has the advantage of requiring only one injection every three weeks. In addition, if a side effect is encountered the drug responsible is easy to identify. Two unique effects of DOX are its potential for cumulative cardiac toxicity in dogs and cumulative nephrotoxicity in cats, and its potential to cause severe skin necrosis if extravasated. Generally, the most successful chemotherapy protocols have been multiagent protocols that include doxorubicin. A protocol of this type (one of many published protocols), referred to here as LA-CHOP, is employed at the UW-VMTH and at the AEC. (It has also been referred to in publications as the UW-Madison protocol, UW-25, or L-ASP-VCAM.) This treatment utilizes sequential injections of vincristine, CTX, and DOX, combined with daily oral prednisone for the first 4 weeks. (See Table 2) Complete response rates are 85-90% with these protocols, and median survival times are approximately 12 months, with 20-25% of dogs living longer than 2 years. The likelihood of a patient experiencing some type of adverse side effect is approximately 20%. However, the vast majority of side effects observed are mild and self-limiting, and do not require hospitalization. The likelihood of a patient experiencing a severe side effect (usually refractory vomiting or diarrhea, or neutropenia severe enough to cause sepsis) is approximately 5%. Despite the improvements made in recent years in extending disease-free interval and survival time in dogs with LSA, all but 5% of patients will eventually relapse. Older publications routinely include a single injection of asparaginase at the beginning of multi-agent treatment. Recently, 2 studies have demonstrated no improvement in any measure of outcome in dogs receiving asparaginase. For this reason, the author chooses to omit asparaginase from initial treatment and save it for use as a potential therapy at relapse. Treatment and Prognosis - Cats The basic tenets of treatment for feline LSA are very similar to canine. One important difference, however, is that single-agent doxorubicin appears to have less activity in feline LSA. Even with injectable multiagent chemotherapym response and survival rates are lower in cats than in dogs, with approximately 70% of cats achieving a complete response, and median survival times in the 6-8 month range, even with aggressive therapy. However, approximately 30% of cats may do well for a very long time, with survival times exceeding 2 years. A recent preliminary report suggests that cats with low-grade gastrointestinal LSA may respond favorably and enjoy comparably long survival times when a protocol employing oral chlorambucil (15 mg/m2 PO daily for four days, repeated every 3 weeks) and prednisone is employed. The most important prognostic factors for feline LSA are early clinical stage, clinical substage (the vast majority of cats, unlike dogs, are substage "b"), incorporation of doxorubicin into the chemotherapy protocol, and FeLV status. Maintenance vs. No Maintenance One of the debates among veterinary oncologists centers around the utility of "extended maintenance" chemotherapy for pets with LSA. In human medicine, treatment is rarely continued for longer than 6 to 10 months, and randomized trials have not demonstrated significant survival advantage for patients receiving extended maintenance chemotherapy. However, the dosages of chemotherapeutic agents that dogs with LSA can tolerate are less than half of what a human would receive of the same agents. Recently, we investigated the effect of discontinuing treatment after 25 weeks of standard-dose chemotherapy. Analysis of a cohort of 50 dogs treated with this protocol showed no statistical difference in survival time or disease-free interval when compared with dogs receiving a similar protocol including extended maintenance chemotherapy. There are no studies in the literature investigating the necessity for maintenance chemotherapy in feline LSA. Rescue When remission is lost (either after an interval with no chemotherapy or after treatment at 2 or 3 week intervals), a large number of patients may experience a second remission simply by returning to the "Top of the protocol", i.e. switching back to weekly treatments and re-initiating prednisone therapy. However, a rule of thumb is that the second remission is likely to be about half as long as the first. After a period of time, the tumor cells will acquire resistance to the initial drugs utilized, and "rescue" or "salvage" chemotherapy drugs or protocols can be considered. A summary of rescue agents/protocols that have been systematically evaluated is shown in Table 3. The take-home message is that while there are many different drugs that can be utilized in this setting, no one agent or protocol is uniformly superior over the others in terms of response rate and duration. Sometimes, attaining a second or third remission can be a matter of trial and error, until an efficacious drug is found. Radiation Therapy Since LSA is considered a systemic disease in most circumstances, radiation therapy (RT) is not used commonly. One exception is in cases of feline nasal LSA, which is often solitary at presentation. In this disease, RT can be very efficacious. LSA can be very sensitive to RT, and thus is can be useful as a palliative treatment in animals with clinical signs related to lymphoma at a specific site (e.g. pleural effusion from mediastinal disease). Several studies have been published recently evaluating the outcome of dogs treated with chemotherapy followed by half-body radiation therapy: definitive evidence of improvement in outcome is lacking however. In summary, although LSA is a disease that can rarely be cured, it can be managed effectively in the majority of cases. Therapy is typically very well tolerated, and patients experience an excellent quality of life. Significant improvements have been made in recent years with regard to the treatment of this common disease, and we are hopeful that the coming years will bring equally great improvements. Selected References Vail DM, Young KM. Canine lymphoma and lymphoid leukemia. In: Withrow SJ and Vail DM, eds. Small Animal Clinical Oncology (4th Ed). Philadelphia: Saunders, 2007. pp. 699-733. Vail DM. Feline lymphoma and leukemia. In: Withrow SJ and Vail DM, eds. Small Animal Clinical Oncology (4th Ed). Philadelphia: Saunders, 2007. pp. 733-756. Vail DM, Thamm DH. Hematopoietic tumors. In: Ettinger S, Feldman E (eds), Textbook of Veterinary Internal Medicine, 6th Ed. Philadelphia: Saunders, 2005. pp. 732-746. Cotter SM. Treatment of lymphoma and leukemia with cyclophosphamide, vincristine and prednisone: 1. Treatment of dogs. JAAHA 19: 159-165, 1983. Postorino NC, et al. Single agent therapy with adriamycin for canine lymphosarcoma. JAAHA 25: 221-225, 1989. Garrett LD et al. Evaluation of a six month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. JVIM 16: 704-709, 2002. Moore AS, et al. Evaluation of mitoxantrone for the treatment of lymphoma in dogs. JAVMA 205(12): 1903-1905, 1994. Moore AS, et al. Lomustine (CCNU) for the treatment of resistant lymphoma in dogs. JVIM 13: 395-398, 1999. Rassnick KM, et al. MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases (1989-2000). JVIM 16: 576-580, 2002. Kristal O, et al. Single-agent chemotherapy with doxorubicin for feline lymphoma: a retrospective study of 19 cases (1994-1997). JVIM 15: 125-130, 2001. Teske E, et al. Chemotherapy with cyclophosphamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: new results with an old protocol. JVIM 16: 179-186, 2002. Vail DM, et al. Feline lymphoma (145 cases): proliferation indices, CD3 immunoreactivity, and their association with prognosis in 90 cats. JVIM 12: 349-354, 1998. Saba CF, et al. Combination chemotherapy with L-asparaginase, lomustine, and prednisone for relapsed canine lymphoma. JVIM 21: 127-132, 2007. MacDonald VS, et al. Does L-asparaginase influence efficacy or toxicity when added to a standard CHOP protocol for dogs with lymphoma? JVIM 19(5): 732-736, 2005. Table 1: WHO Staging Criteria for Canine Lymphoma.
Table 2: LA-CHOP (UW-Madison) Protocol for Canine Lymphoma
* 1 mg/kg furosemide is given concurrently with each cyclophosphamide injection to diminish the occurrence of sterile hemorrhagic cystitis Table 3: Response to Chemotherapy in Dogs with Relapsed Lymphoma.
DTIC: Also called dacarbazine. MOPP: Mechlorethamine (nitrogen mustard), vincristine, procarbazine, prednisone. D-MAC: Dexamethasone, melphalan, actinomycin D, cytosine arabinoside. NR: Not reported. Response rates refer to a combination of complete and partial responses. Demystifying Mast Cell Tumors INTRODUCTION Mast cell tumor (MCT) represents the most common malignant cutaneous tumor in the dog, and is commonly encountered in small animals. There is a large degree of variation in the histologic appearance and biologic behavior of canine MCT, ranging from histologically and behaviorally benign to histologically and behaviorally malignant. However, 65 to 80% of MCT will remain local diseases. Knowledge of the signs associated with worrisome prognosis, and the steps to take to address the potential for recurrence and/or metastasis, can help to simplify the approach to this sometimes frustrating neoplasm. Likewise, newer information regarding local and systemic treatment of MCT has increased the management options available for veterinarians and owners to consider. DIAGNOSIS Canine MCT have been referred to as "the great pretender", because they can look and feel like anything. This can include soft, subcutaneous masses that can feel exactly like lipomas. Thus, needle aspiration cytology should be offered for any lump or bump encountered. Cytology is sufficient to achieve a diagnosis of MCT in approximately 90% of dogs. The classic appearance is a population of large round cells with central nuclei and abundant cytoplasm, with characteristic blue-purple cytoplasmic granules Granules will not be visible in approximately 10% of MCT, which may confound the diagnosis in a small number of cases. It is common to see other inflammatory cells, such as eosinophils and neutrophils, admixed with the MCT cells. When a presumptive diagnosis of MCT is made, it is useful to perform needle aspiration cytology of the regional lymph node at the same time, whether or not it feels enlarged, to rule out early metastasis. TO STAGE OR NOT TO STAGE The majority of canine MCT, while locally aggressive, are unlikely to metastasize. Having an idea of which are likely to behave aggressively prior to surgery may help to identify those patients in which additional staging, to rule out disease elsewhere, should be undertaken preoperatively. Prior studies have identified several prognostic factors associated with MCT: (1) Histologic grade is one of the strongest -- dogs with high-grade (grade III) tumors may die of their disease rapidly despite appropriate local therapy; (2) Clinical stage - Dogs with metastasis to regional lymph nodes or other structures at presentation have a less favorable long-term prognosis; (3) Location - Tumors in the preputial, perianal, oral, subungual (nail bed) and other mucocutaneous sites classically have worse prognoses; (4) Recurrence following initial surgical excision is a negative prognostic indicator; (5) The presence of systemic signs (anorexia, vomiting, hematemesis, melena) is a strong negative prognostic indicator, as it often indicates systemic dissemination; (6) Recent rapid growth or tumor ulceration are also worrying signs. Animals with tumors displaying these criteria may have a higher likelihood of metastasis, and thus a thorough search for disease elsewhere is reasonable prior to undertaking definitive therapy. This may also be reasonable in lower-risk patients if very expensive or aggressive treatment is likely to be necessary, or if the tumor is in a location not amenable to wide surgical excision. In the absence of these factors, it is reasonable to proceed immediately to appropriately aggressive surgical excision (See below). Complete staging for canine MCT should include cytologic evaluation of the regional lymph node, abdominal ultrasound, and thoracic radiographs. Of these tests, abdominal imaging and lymph node cytology are the most likely to yield important results. Cytology of abnormal lymph nodes or organs in the abdomen is indicated, however aspirates of structurally normal liver and spleen are rarely useful. If radical, expensive or potentially disfiguring surgery is being contemplated, an incisional biopsy may also be considered for histologic grading. The utility of other tests such as bone marrow aspiration cytology and buffy coat smear is questionable at best, and they are not routinely performed in the author's practice. If no evidence of disease elsewhere is found, appropriate local therapy can be pursued. Identification of disease in the regional lymph node means that this should be removed as well at the time of surgery, and that additional systemic therapy should be considered irrespective of histologic grade. Identification of disease beyond the regional lymph node usually means that surgery will be of little or no benefit. SURGERY FOR MAST CELL TUMORS Even well-differentiated MCT are associated with aggressive local tissue infiltration. Thus, it is necessary to include a generous margin of normal-appearing tissue on all sides of the tumor (including deep) to insure that any microscopic nests of tumor are removed. The standard recommendation is to remove a minimum of 3 cm of normal-appearing tissue 360 degrees around the tumor, and at least one normal fascial plane deep. The entire specimen should be submitted in one piece, preferably with the margins inked, so that the pathologist can assess all margins for adequacy of excision. There is accumulating information, however, that surgical margins less than 3 cm may be sufficient in "tight spots". This seems especially true for low/intermediate grade tumors, and those that are fairly small in diameter. When necessary, very aggressive or radical surgical procedures, such as amputation or body wall resection, are reasonable to consider. Prior to contemplating procedures such as these, complete staging is recommended, and incisional biopsy for determination of histologic grade may be helpful. When dealing with a low or intermediate-grade tumor, very aggressive surgery is reasonable because the likelihood of metastasis is low. The question of whether or not to administer perioperative histamine blockers is a matter of personal choice. The risk of a serious degranulation reaction is very small unless the tumor is extensively handled (which should not happen if 3 cm of normal tissue is removed!). INTERPRETING THE PATHOLOGY REPORT Two equally important pieces of information need to be gleaned from the pathology report: (1) Histologic grade; and (2) Adequacy of surgical margins. If only a representative piece of the tumor is submitted, margins cannot be evaluated and the utility of the report is cut in half. Pathologists often utilize a numeric grading scheme, where "Grade I" is well-differentiated and "Grade III" is poorly differentiated, however some pathologists will now utilize words such as "low, intermediate or high-grade" or "well, poorly or intermediately differentiated" in place of a numerical scale. If information regarding grade or margins is not provided, it should be requested from the pathologist. Low or intermediate grade MCT with complete surgical margins usually require no further therapy, as the risk of recurrence or metastasis is only approximately 10%. However, regular rechecks for recurrence, metastasis, or new cutaneous masses is indicated. Low or intermediate grade tumors with incomplete surgical margins have a high chance of recurrence, but a low chance for metastasis. Thus, further aggressive local therapy is reasonable. When possible, immediate re-excision of the surgical scar (and an additional 3 cm tissue in all directions and another fascial plane deep) is the most useful treatment. The entire excised tissue should be inked and re-submitted for histopathology. When this is not possible, the next best option would be the use of radiotherapy. Chemotherapy may be useful to delay or prevent recurrence in cases where additional surgery or radiotherapy is not possible or has been declined. High grade MCT with complete surgical margins have a low chance for recurrence, but a high chance for eventual metastasis. Systemic therapy (e.g. chemotherapy) can be offered in an attempt to delay or prevent this. High grade MCT with incomplete margins have a high likelihood of both recurrence and metastasis: Therapy designed to address both of these possibilities (e.g. additional surgery or radiotherapy, with chemotherapy) is indicated. There is new information that assessment of mitotic index (a measure of the rate of proliferation, which can be assessed on any histology slide), may be a strong predictor of outcome, identifying intermediate grade tumors at high risk of spread and, potentially, high-grade tumors at lower risk of spread. CAUTION OWNERS AGAINST A "WAIT AND SEE" APPROACH The importance of addressing the potential for local recurrence the very first time the tumor appears cannot be overstated. Owners should be strongly cautioned against adopting a "wait and see" attitude, with the intent of becoming more aggressive if/when the tumor grows back. Recurrent tumors are likely to grow more quickly, invade more deeply, and are more likely to ulcerate or become painful. In a recent study, dogs with MCT that were locally recurrent at the time systemic therapy was started were more than 4 times more likely to die as a result of MCT than dogs that started therapy at the first occurrence. In addition to aggressive local surgery, several other local therapeutic modalities have been investigated for the adjuvant treatment of canine MCT. Radiation therapy (RT) has proven to be a very effective local treatment modality when combined with "marginal" surgical excision. 2-year control rates of 85 to 90% can be expected when incompletely excised low- or intermediate-grade MCT are treated with RT. Radiation therapy to bulky tumors is consistently less effective than RT to microscopic disease, with a one-year control rate of approximately 50%. Animals with undifferentiated MCT, MCT that have metastasized, or tumors in a historically unfavorable location (see above) may benefit from the addition of some form of systemic therapy to appropriate local therapy. In addition, aggressive surgery or RT may be cosmetically unappealing or financially impossible for some owners. Recently, several studies have been published investigating various systemic therapies for measurable canine MCT, the results of which are summarized in Table 1. Two studies have been published evaluating the efficacy of chemotherapy in the prevention of recurrence or metastasis in the post-surgical setting. These utilized oral prednisone and injectable vinblastine. Prednisone and vinblastine administration - Prednisone is administered orally at an initial dose of 2 mg/kg SID, for the first week, and this dose is tapered and discontinued over approximately 3 months. VBL is given as a rapid intravenous bolus at 2 mg/m2 every 1-2 weeks. The standard postoperative protocol consists of weekly injections for 4 weeks, followed by 4 biweekly injections. Side Effects - Adverse effects are noted in approximately 20% of patients, usually after the first dose of VBL. These are mild in most. Mild side effects include self-limiting vomiting, neutropenia without evidence of sepsis (7-day neutrophil count less than 1,000/µL), or lethargy/soft stool. Severe side effects occur in only approximately 5% of patients. Efficacy - As an adjuvant therapy to incomplete surgical resection ("microscopic disease"), VBL and prednisone treatment conferred a 57% one and two-year disease free rate in one report. In another report, postsurgical VBL and prednisone were able to prevent local recurrence in the large majority of incompletely excised, grade-II MCT treated. Although probably not as efficacious as "appropriately aggressive" surgery or cytoreduction and RT, many feel that this represents a significant improvement over incomplete resection alone. As adjuvant therapy to prevent metastasis in patients with "high-risk" disease (i.e. high grade tumor, lymph node metastasis, unfavorable location), prednisone and vinblastine results in 2-year disease-free intervals of 60%. Interestingly, there seems to be a profound difference between the outcome of a high-grade tumor and an intermediate-grade tumor with lymph node metastasis. Despite the presence of lymph node metastasis, 90% of patients with grade II tumors with positive lymph nodes are disease-free at one year. Patients with grade III tumors treated in the adjuvant setting have 2-year survival rates of 60%. This appears to be a significant improvement over historical data employing surgery alone, which report a median survival of 8 months and a 2-year survival percentage of less than 15%. Other clinicians recommend postoperative treatment with lomustine (CCNU), an oral alkylating agent, or alternating lomustine and vinblastine. At this time, there is no information regarding the efficacy of these treatments in the peer-reviewed literature. New Directions Perhaps the most important recent finding with potential to translate into new and exciting forms of therapy is the discovery that the majority of canine (and human) mast cell neoplasms express alterations in the expression of, or genetic mutations within, the gene that encodes the tyrosine kinase growth factor receptor c-KIT. This gene codes for a transmembrane protein that serves as the receptor for the growth factor stem cell factor, important in the maturation of normal mast cells and other hematopoietic cells. It has been shown that the majority of canine MCT either aberrantly express KIT or contain mutations that render KIT active even in the absence of bound stem cell factor. In other words, these mutations mean that the cells are receiving signals to proliferate and survive when they normally would not, leading to unchecked growth. New molecules have been developed that inhibit signaling through the c-kit tyrosine kinase, and there is now information that some of these compounds are able to interfere with the proliferation of canine MCT in vitro. Furthermore, evidence of antitumor activity has been documented in dogs with MCT treated with these compounds. It is hoped that an orally available inhibitor of c-kit may be approved for the treatment of canine MCT in the near future. Summary While recent advances in the medical treatment of MCT are very exciting, it is important to remember that, aggressive surgery remains the mainstay of treatment for canine MCT, and is sufficient to successfully treat the majority of MCT encountered in practice. Selected References Thamm DH, Vail DM. Mast cell tumors. In: Withrow SJ, Vail DM (eds), Small Animal Clinical Oncology, 4th Ed. Philadelphia: W.B. Saunders, pp. 402-424, 2007. LaDue T, Price GS, Dodge R, et al. Radiation therapy for incompletely resected canine mast cell tumors. Vet Rad Ultrasound 39: 57-62, 1998. Frimberger AE, Moore AS, LaRue SM, et al. Radiotherapy of incompletely resected, moderately differentiated mast cell tumors in the dog: 37 cases (1989-1993). J Am An Hosp Assoc 33: 324-324, 1997. Gerritsen RJ, Teske E, Kraus JS, et al. Multi-agent chemotherapy for mast cell tumours in the dog. Vet Quarterly 20: 28-31 1998. McCaw DL, Miller MA, Ogilvie GK, et al. Response of canine mast cell tumors to treatment with oral prednisone. J Vet Intern Med 8: 406-408, 1994. Rassnick KM, et al. Treatment of canine mast cell tumors with CCNU (lomustine). J Vet Intern Med 13(6): 601-605, 1999. Thamm DH, Mauldin EA, Vail DM. Prednisone and vinblastine chemotherapy for canine mast cell tumor: 41 cases (1992-1997). J Vet Intern Med 13: 491-497, 1999. Thamm DH, Turek MM, Vail DM. Outcome and prognostic factors following adjuvant prednisone/vinblastine chemotherapy for high-risk canine mast cell tumour: 61 cases. J Vet Med Sci 68(6): 581-587, 2006. Liao AT, Chien MB, Shenoy N, et al. Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors. Blood 100: 585-593, 2002. Pryer NK, Lee LB, Zadovaskaya R, et al. Proof of target for SU11654: inhibition of KIT phosphorylation in canine mast cell tumors. Clin Cancer Res 9: 5729-34, 2003. London CA, Hannah AL, Zadovoskaya R, et al. Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies. Clin Cancer Res 9: 2755-68, 2003. Davies DR, Wyatt KM, Jardine JE, Robertson ID, Irwin PJ. Vinblastine and prednisolone as adjunctive therapy for canine cutaneous mast cell tumors. J Am Anim Hosp Assoc 40: 124-30, 2004. Table 1: Response to Chemotherapy in Dogs with Mast Cell Tumors
CR: Complete Response. PR: Partial (>50%) Response. ORR: Overall Response Rate. P/C/V: Prednisone/Cyclophosphamide/Vinblastine. COP-HU: Cyclophosphamide/ Vincristine/Prednisone/Hydroxyurea. NR: Not Reported * Excludes patient that experienced CR - Euth. without evidence of disease after 440 days | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
