Clients of pets with cancer have recently begun to expect the same level of care for their pets as they receive from their physicians and oncologists. This predicates that veterinarians treating pets with cancer have an increased understanding of the possible complications of cancer therapy. This review will concentrate on developing an increased understanding of the side effects of chemotherapy in order to best prevent and treat these side effects, thereby leading to an increased quality of life for those pets.

Most chemotherapy agents have a "BAG" (Bone marrow suppression, Alopecia, and Gastrointestinal) of side effects. The reason why these side effects are so common after chemotherapy administration is because these tissues contain cells that are rapidly growing and therefore inherently sensitive to chemotherapy. Therefore, cells such as those found in the bone marrow, as well as gastrointestinal epithelial cells and hair follicle cells that rapidly turnover are quite sensitive to chemotherapy, whereas cells that slowly turnover, or do not turnover (e.g. spinal cord, muscle, etc.) are generally extremely resistant to most chemotherapy agents.

The "B" in a "BAG" of side effects stands for bone marrow suppression, or myelosuppression. Almost all chemotherapy agents are myelosuppressive, however, at standard doses, corticosteroids, L-asparaginase, vincristine and bleomycin are not myelosuppressive. After a myelosuppressive chemotherapy agent is administered, the neutrophil count and platelet count may decrease, and the low point of the count for either of these types of cells is called the "nadir." The neutrophil and platelet nadir for most myelosuppressive chemotherapy agents is ~ 7 days, and this can be predicted based on the half-lives of neutrophils and platelets. The half life of neutrophils, platelets and red blood cells is 6 hours, 6 days, and ~ 120 days, respectively. Therefore, after myelosuppressive chemotherapy administration, neutropenia is the first to occur, and then thrombocytopenia, whereas anemia due to chemotherapy is extremely rare, because of the longer half-life of red blood cells. There are exceptions to this ~ 7 day nadir rule, which include cisplatin in the dog (days 7 & 17), carboplatin in dogs (day 10-14) and cats (day 21; and such is why an every 28 day therapy cycle is recommended in cats), as well as those chemotherapy agents that are orally administered on a somewhat continual basis such as melphalan, chlorambucil and others.

In order to ensure that the nadir does not drop below safe levels, a pre-treatment cbc/platelet count is required within 12-24 hours before EVERY myelosuppressive chemotherapy administration. For most myelosuppressive agents, a good rule of thumb is the presence of > 3,000 neutrophils and > 75,000 platelets. Similarly, after the first administration of a myelosuppressive chemotherapy agent, a "nadir" cbc/platelet count is performed ~ 7-10 days after the drug is administered. If the neutrophil count is 1500-3000, this is to be expected and subsequent doses of this drug should continue at the same level. If the "nadir" neutrophil count is < 1500 but the pet is not sick and does not have a fever, prophylactic broad spectrum antibiotics (Clavamox, TMP-S, etc.) are instituted for 5-7 days and considerations are made for a 10% decrease in the next dosing of that chemotherapy agent. If the pet has < 1500 neutrophils, has a fever and/or is sick (vomiting, diarrhea, etc.), then this represents an oncologic emergency, and hospitalization, blood/urine cultures, emergency fluid support and IV antibiotics are indicated. In addition, the dose of that chemotherapy agent upon the next administration will typically be reduced by ~ 25-30% to reduce the chance of subsequent severe neutropenia. The astute clinician will also remember that neutrophils are necessary for the production of a fever, therefore, a lack of a fever does not rule out sepsis.

The "A" in a "BAG" of side effects stands for alopecia or hair loss. This is a rare side effect of chemotherapy, however, it can occur in any breed of dog. Chemotherapy-associated alopecia is primarily seen in breeds with continuously growing haircoats such as Old English Sheepdogs, Terriers, and Poodles. More commonly, dogs tend to have partial alopecia with hair loss over exposed areas such as the face, shoulders, and the back. It is important to remember that shaved areas are particularly slow to regrow while on chemotherapy, and therefore these areas should be minimal and squarely shaved. Cats do not generally experience alopecia while on chemotherapy; however, loss of whiskers is extremely common. The hair/whiskers begins to regrow over the course of weeks to months once chemotherapy is discontinued, and it is generally more coarse and of a slightly different color than originally seen.

The "G" in a "BAG" of side effects stands for gastrointestinal. While gastrointestinal side effects of chemotherapy are not very common, when they occur it can be a serious side effect for the patient and client alike. Gastroenteritis manifesting as vomiting and or small bowel diarrhea is seen in ~ 15-20% of dogs and cats receiving most chemotherapy protocols (because the small bowel enterocyte is so rapidly turning over), whereas nausea is thought to be seen in ~ 50-75%. This side effect is generally seen 3-4 days after chemotherapy administration and lasts for 2-4 days. Chemotherapy-associated colitis is extremely rare because of the slower turnover of large bowel epithelial cells, however, 25-40% of dogs experience colitis after administration of Doxorubicin.

This author routinely sends home metoclopramide (Reglan) for all patients receiving chemotherapy, however, the client is instructed to use it on an as needed basis. In addition, dogs receiving Doxorubicin are sent home with sulfasalazine (potent anti-colitis medication) to also be used on an as needed basis. The clients are also educated to be better able to delineate when their pet is experiencing nausea, as this can be very difficult to discern when compared to overt vomiting or diarrhea. The table included below compares and contrasts the presently available anti-nausea/anti-emetic products.

1. Six month chemo for lymphoma(1)

The purpose of this study was to compare a maintenance-free chemotherapy protocol based on CHOP (H from hydroxydaunorubicin = doxorubicin, O from Oncovin = vincristine) to a similar protocol with a maintenance phase for the treatment of canine lymphoma. Fifty-three dogs with multicentric lymphoma were treated with a 6-month modified version of the University of Wisconsin (UW)-Madison chemotherapy protocol (UW-25). Disease-free interval (DFI) and survival were compared to a historical control group of 55 dogs treated with a similar protocol with a prolonged maintenance phase. Remission rate for the study dogs was 94.2% (complete remission = 92.3%, partial remission = 1.9%). DFI and survival between the 2 groups did not differ significantly, with median DFI and survival of the study dogs equal to 282 and 397 days compared to 220 and 303 days for the control dogs (P = .2835 and .3365, respectively). Univariate analysis identified substage b (P = .0087), German Shepherd breed (P = .0199), and body weight > 18 kg (P = .0016) as significant for worse survival. Longer survival was associated with thrombocytopenia (P = .0436). Multivariate analysis revealed that substage (P = .0388) and weight (P = .0125) retained significance for DFI, whereas substage (P = .0093), thrombocytopenia (P = .0150), and weight (P = 0 .0050) retained significance for survival. Overall, the protocol was well tolerated by the dogs, with 41.5% (22/53) requiring a treatment delay or dose modification, but only 9.4% (5/53) needing hospitalization. The 6-month chemotherapy protocol based on CHOP with no maintenance phase provides similar DFI and survival times when compared to a similar protocol with a prolonged maintenance phase.

2. FNA of non-palpable LN's(2)

OBJECTIVE: To determine sensitivity and specificity of physical examination, fine-needle aspiration, and needle core biopsy of the regional lymph nodes for evidence of metastasis in dogs and cats with solid tumors.

DESIGN: Case series

ANIMALS: 37 dogs and 7 cats

PROCEDURE: Regional lymph nodes were evaluated by means of physical examination (palpation), fine-needle aspiration, and needle core biopsy. Results were compared with results of histologic examination of the entire lymph node, the current standard.

RESULTS: Tumors included 18 sarcomas, 16 carcinomas, 7 mast cell tumors, and 3 other tumors. Carcinomas were more likely to have metastasized to the regional lymph node (7/16 animals) than were sarcomas (2/18). Sensitivity and specificity of physical examination were 60 and 72%, respectively. Sensitivity and specificity of cytologic examination of fine-needle aspirates were 100 and 96%, respectively. Sensitivity and specificity of histologic examination of needle core biopsy specimens were 64 and 96%, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that fine-needle aspiration may be a sensitive and specific method of evaluating the regional lymph nodes in dogs and cats with solid tumors, because results correlated well with results of histologic examination of the entire lymph node. Physical examination alone was not a reliable method and should not be used to decide whether to aspirate or biopsy the regional lymph nodes.

3. Surgical Debulking before definitive therapy

A. OBJECTIVE: To compare, for dogs with intracranial meningiomas, survival times for dogs treated with surgical resection followed by radiation therapy with survival times for dogs treated with surgery alone.

DESIGN: Retrospective study.

ANIMALS: 31 dogs with intracranial meningiomas.

PROCEDURE: Medical records of dogs with histologic confirmation of an intracranial meningioma were reviewed. For each dog, signalment, clinical signs, tumor location, treatment protocol, and survival time were obtained from the medical record and through follow-up telephone interviews.

RESULTS: Dogs that underwent tumor resection alone and survived > 1 week after surgery had a median survival time of 7 months (range, 0.5 to 22 months). Dogs that underwent tumor resection followed by radiation therapy had a median survival time of 16.5 months (range, 3 to 58 months).

CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that in dogs with intracranial meningiomas, use of radiation therapy as a supplement to tumor resection can significantly extend life expectancy.(3)

B. Naturally-occurring urinary tract transitional cell carcinoma (TCC) comprises approximately 1.5 to 2% of cancer in dogs and is the most common urinary tract neoplasm. Numerous treatment modalities have been used for TCC including surgery, radiation, chemotherapeutic agents, and non-steroidal anti-inflammatory drugs. Although surgical resection has been attempted in many cases, survival times have been low (usually less than 6 months), and cure is rarely possible due to the location, invasive nature, and metastatic behavior of this tumor. It is possible, however, that removing part of the tumor (i.e. surgical debulking) could have a beneficial effect. The purpose of this retrospective study was to compare the survival times of dogs with TCC who had surgical debulkment to the survival times of those not having surgical debulkment. A retrospective review of Purdue University Veterinary Teaching Hospital (PUVTH) records of all dogs with a diagnosis of transitional cell carcinoma (TCC) between 1985 and 1998 was conducted. Cases included in this study had histopathological confirmation of TCC, complete information on surgery type performed, information on subsequent treatment (if any), and known survival information. Dogs who had a diagnosis made by cystoscopy, catheter biopsy, or cystotomy with biopsy were categorized in the "nonsurgery" group. Dogs in which the bulk of macroscopic tumor was removed via cystotomy for the purpose of palliation as well as diagnosis were categorized in the "debulking surgery" group. Survival of dogs in the debulking surgery group was significantly longer (P = 0.002; n = 350 days) than survival of dogs in the nonsurgery group (n = 207 days), and surgical debulking prolonged survival regardless of tumor location. Tumor location was also associated with survival, which was significantly shorter for dogs with tumor in the urethra and trigone compared to dogs with no tumor in those locations, regardless of treatment. The results of this study strongly suggest a beneficial role of debulking surgery in prolonging survival times of dogs with TCC.(4)

4. Efficacy of RT for incompletely resected MCT & STS

A. OBJECTIVE: To evaluate efficacy of radiation for treatment of incompletely resected soft-tissue sarcomas in dogs.

DESIGN: Prospective serial study.

ANIMALS: 48 dogs with soft-tissue sarcomas.

PROCEDURE: Tumors were resected to < 3 cm3 prior to radiation. Tumors were treated on alternate days (three 3-Gy fractions/wk) until 21 fractions had been administered. Cobalt 60 radiation was used for all treatments.

RESULTS: Five-year survival rate was 76%, and survival rate was not different among tumor types or locations. Four (8%) dogs developed metastases. Eight (17%) dogs had tumor recurrence after radiation. Development of metastases and local recurrence were significantly associated with reduced survival rate. Median survival time in dogs that developed metastases was 250 days. Median disease-free interval for all dogs was 1,082 days. Median time to recurrence was 700 days. Dogs that developed recurrence after a prolonged period responded well to a second surgery. Acute radiation toxicosis was minimal; osteosarcoma developed at the radiation site in 1 dog.

CONCLUSIONS AND CLINICAL RELEVANCE: An excellent long-term survival rate may be achieved by treating soft-tissue sarcomas in dogs with resection followed by radiation. Amputation is not necessary for long-term control of soft-tissue sarcomas in limbs. Development of metastases and recurrence of local tumors after radiation treatment are associated with decreased survival rate. Acute and delayed radiation toxicosis was minimal with the protocol used in this study.(5)

B. The records of 56 dogs treated with megavoltage radiation for mast cell neoplasia were reviewed to determine the efficacy of this treatment modality. Total radiation dose ranged from 45 to 57 Gray (Gy), dose per fraction ranged from 3.0 to 4.0 Gy, and radiation treatment time ranged from 14-28 days. Median disease free interval (95% CI) was 32.7 (19-70) months. Median disease free interval for dogs older than 7.5 years was 15 (lower limit 7) months as compared to 62 (lower limit 20) for dogs younger than 7.5 years of age (p = 0.006). Median disease free interval for dogs with measurable disease was 12 (lower limit 5) months as compared to 54 (32-70) months for dogs with microscopic disease (p = 0.006). Radiation treatment time was also significantly related to disease free interval. Median disease free interval for dogs treated longer than 22 days was 12 (7-19) months as compared to greater than 50 (lower limit 20) months for dogs treated in 22 or fewer days (p < 0.001). This appeared to be due to more recurrences in dogs treated with 3-per-week fractionation and suggests that tumor proliferation in the interfraction interval may be important. Sex, tumor location, histologic grade, WHO clinical stage, number of radiation fractions, total radiation dose, and dose-per-fraction, as well as the following "yes/no" variables: steroids given, surgery prior to radiation, lymph nodes irradiated, and development of another mast cell tumor did not appear to influence median disease free interval or survival. Data presented herein support megavoltage radiation as an effective treatment for canine mast cell neoplasia, and suggest that disease free interval in dogs treated with daily fractions may be longer than that achieved with alternating day fractions.(6)

5. LSA Rescue Protocols

A. The purpose of this retrospective study was to evaluate the efficacy and toxicity of the MOPP chemotherapy protocol (mechlorethamine, vincristine, procarbazine, and prednisone) as a rescue regimen in dogs with lymphoma. One hundred seventeen dogs that had resistance to previously administered chemotherapy were evaluated. Before treatment with MOPP, all dogs received a median of 6 chemotherapy drugs for a median duration of 213 days. Thirty-one percent (36 of 117) had a complete response (CR) to MOPP for a median of 63 days, and 34% (40 of 117) had a partial response (PR) for a median of 47 days. Sixteen percent (19 of 117) had stable disease (SD) for a median of 33 days. Predictors for response to MOPP were not identified. Gastrointestinal (GI) toxicity occurred in 28% (33 of 117) of the dogs, and 13% (15 dogs) required hospitalization. Five dogs developed septicemia, and 2 died as a result. MOPP was an effective treatment for dogs with resistant lymphoma and was well tolerated by the majority of affected dogs.(7)

B. Forty-three dogs with lymphoma that had relapsed or had failed to achieve complete remission to previous chemotherapy were treated with lomustine (1-(2-chloroethyl)-3-chyclohexyl-1-nitrosourea [CCNU]) at a dosage of 90-100 mg/m2 body surface area PO every 3 weeks. Durable complete or partial responses occurred in 11 dogs for a median of 86 days. The acutely dose-limiting toxicosis was neutropenia 7 days after administration, resulting in a recommended dosage of 90 mg/m2. Cumulative thrombocytopenia occurred in dogs receiving continued CCNU treatment, and a dose interval of 3 weeks may be too short for continued administration of this drug. Toxicoses evident as fever or central nervous system signs or renal damage were uncommon or rare. CCNU is effective in the treatment of relapsed lymphoma.(8)

6. Chemotherapy for canine MCT

A. Prednisone alone. Twenty-five dogs with naturally occurring mast cell tumors were treated with daily oral prednisone (1 mg/kg) for 28 days. Five dogs (20%) had reduction in tumor volume and were considered responders. Four of these underwent partial remission and one underwent complete remission. Survival times for the five responders were 3, 5, 6, 7.5, and greater than 28 months, respectively. We therefore conclude that prednisone is effective in some canine mast cell tumors. Further studies are indicated to determine the most effective dose of prednisone, the appropriate duration of treatment, and the efficacy in more benign mast cell tumors, and in combination with other forms of therapy.(9)

B. Prednisone & Vinblastine. Forty-one dogs with mast cell tumors (MCTs) were treated with oral prednisone and injectable vinblastine (VBL), both in the adjuvant setting (23 dogs) and in dogs with gross disease (18 dogs). Adverse effects were noted in 20% (8/41) of the patients, usually after the 1st dose of VBL. Adverse effects were considered mild in 6, and severe, necessitating treatment discontinuation, in 2 (5%). Overall response rate in the evaluable dogs with gross disease was 47% (7/15), consisting of 5 complete responses and 2 partial responses. Median response duration was 154 days (24 to >645 days). As adjuvant therapy to incomplete surgical resection, prednisone and VBL conferred a 57% 1- and 2-year disease-free rate. Median survival time (MST) for the entire patient population was not reached with a median follow-up of 573 days; however, the MST for dogs with grade III MCT was 331 days, with 45% of dogs alive at 1 and 2 years. This is an apparent improvement over historical survival data employing surgery alone. Upon univariate analysis, significant prognostic factors (P < .05) for survival included presence of a locally recurrent tumor, presence of gross disease, argyrophilic nucleolar organizer region frequency, lymph node status, histologic grade, previous chemotherapy, and ulceration of the tumor. Similar criteria were significant when analyzed for time to treatment failure. Response to therapy was also predictive of survival in the gross disease group. Upon multivariate analysis, histologic grade (P = .012) and presence of a locally recurrent tumor (P < .001) were significant factors for survival.(10)

C. CCNU alone. 1-(2-Chloroethyl)3-cyclohexyl-1-nitrosourea (CCNU) is an alkylating agent in the nitrosourea subclass. A prospective evaluation of CCNU was done to determine the maximally tolerated dosage of CCNU in tumor-bearing cats. Response data were obtained when available. Twenty-five cats were treated with CCNU at a dosage of 50-60 mg/m3 body surface area. Complete hematologic data were available for 13 cats. Neutropenia was the acute dose-limiting toxicity. The median neutrophil count at the nadir was 1,000 cells/microL (mean, 2,433 cells/microL; range, 0-9,694 cells/microL). The time of neutrophil nadir was variable, occurring 7-28 days after treatment, and counts sometimes did not return to normal for up to 14 days after the nadir. Based on these findings, a 6-week dosing interval and weekly hematologic monitoring after the 1st treatment with CCNU are recommended. The nadir of the platelet count may occur 14-21 days after treatment. The median platelet count at the nadir was 43,500 cells/microL. No gastrointestinal, renal, or hepatic toxicities were observed after a single CCNU treatment, and additional studies to evaluate the potential for cumulative toxicity should be performed. Five cats with lymphoma and 1 cat with mast cell tumor had measurable responses to CCNU. Phase II studies to evaluate antitumor activity should be completed with a dosing regimen of 50-60 mg/m3 every 6 weeks.(11)

7. Diagnostic Imaging Advances

To be reviewed at the lecture with special emphasis on importance to feline vaccine-associated sarcoma.

8. Immunohistochemistry for Diagnosis & Prognostication

To be reviewed at the lecture with special emphasis on importance to lymphoma, mast cell tumor and other malignancies.

9. Web-based oncology enhancements

An extremely new venture in veterinary oncology called Oncura Partners (www.oncurapartners.com) is now available to practitioners wanting access to the latest and greatest in veterinary medicine. Drs. Neal Mauldin and I are the medical directors of Oncura Partners, which is a new web-based service that partners veterinary oncologists, veterinarians and their clients to provide state-of-the-art veterinary oncology care. Through an extremely easy to use web-based interface, veterinarians are able to interact with veterinary oncologists on their cases. This allows the veterinary practitioner to obtain oncologist-driven case-specific treatment protocols and prognoses, unit-dose chemotherapy (dose and protocol driven by the oncologist but with you and your client's input) and associated administration/safety/disposal materials delivered to your door, as well as a wealth of information through FAQ's, MSDS's, etc. In addition, our system allows the practitioner to develop a printable pre-treatment itemized quote (with incorporation of estimates of costs for various services within your hospital such as blood counts, administration fees, etc.) for the client contemplating a certain treatment protocol. The goal of Oncura Partners is to provide quality comprehensive oncology care for those clients and their pets that are unable to see an oncologist.

10. Putting the cart before the horse

To be reviewed at the lecture with special emphasis on MAb 23112, Acemannan13, Bladder TCC tests, Gemzar and others.

References:

1. Garrett,L.D., Thamm,D.H., Chun,R., Dudley,R. & Vail,D.M. Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet. Intern. Med. 16, 704-709 (2002).
2. Langenbach,A., McManus,P.M., Hendrick,M.J., Shofer,F.S. & Sorenmo,K.U. Sensitivity and specificity of methods of assessing the regional lymph nodes for evidence of metastasis in dogs and cats with solid tumors. J Am Vet. Med. Assoc 218, 1424-1428 (2001).
3. Axlund,T.W., McGlasson,M.L. & Smith,A.N. Surgery alone or in combination with radiation therapy for treatment of intracranial meningiomas in dogs: 31 cases (1989-2002). J Am Vet. Med. Assoc 221, 1597-1600 (2002).
4. Josel,J.R. et al. The role of surgical debulkment in dogs with transitional cell carcinoma of the urinary bladder: A retrospective study of 122 dogs. Proc. Vet. Canc. Soc. 5 (2002).
5. McKnight,J.A., Mauldin,G.N., McEntee,M.C., Meleo,K.A. & Patnaik,A.K. Radiation treatment for incompletely resected soft-tissue sarcomas in dogs. J Am Vet. Med. Assoc 217, 205-210 (2000).
6. LaDue,T., Price,G.S., Dodge,R., Page,R.L. & Thrall,D.E. Radiation therapy for incompletely resected canine mast cell tumors. Vet. Radiol. Ultrasound 39, 57-62 (1998).
7. Rassnick,K.M. et al. MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases (1989-2000). J. Vet. Intern. Med. 16, 576-580 (2002).
8. Moore,A.S. et al. Lomustine (CCNU) for the treatment of resistant lymphoma in dogs. J. Vet. Intern. Med. 13, 395-398 (1999).
9. McCaw,D.L. et al. Response of canine mast cell tumors to treatment with oral prednisone. J Vet. Intern. Med. 8, 406-408 (1994).
10. Thamm,D.H., Mauldin,E.A. & Vail,D.M. Prednisone and vinblastine chemotherapy for canine mast cell tumor--41 cases (1992-1997). J Vet. Intern. Med. 13, 491-497 (1999).
11. Rassnick,K.M. et al. Treatment of canine mast cell tumors with CCNU (lomustine). J. Vet. Intern. Med. 13, 601-605 (1999).
12. Jeglum,K.A. Chemoimmunotherapy of canine lymphoma with adjuvant canine monoclonal antibody 231. Vet. Clin. North Am Small Anim Pract. 26, 73-85 (1996).
13. King,G.K. et al. The effect of Acemannan Immunostimulant in combination with surgery and radiation therapy on spontaneous canine and feline fibrosarcomas. J. Am. Anim. Hosp. Assoc. 31, 439-447 (1995).

Eighty-five to ninety percent of dogs and cats with MCT's have solitary lesions. It is important to note that not all dogs or cats with multiple MCT's have metastatic or systemic mastocytosis. Studies suggest that well-differentiated MCT's are slow-growing, usually < 3-4 cm in diameter, without ulceration of overlying skin, variably alopecic and commonly present for more than 6 months. In contrast, poorly differentiated MCT's are rapidly growing, variably sized (but generally large), with ulceration of the underlying skin and inflammation/edema of surrounding tissues and lastly rarely present for more than 2-3 months before presentation to the practitioner. Since most MCT's are of moderate-differentiation, signs may be somewhere between these two extremes.

The history and clinical signs of dogs and cats with MCT's can be extremely variable. Most do not show any clinical signs referable to their MCT, however, some may have signs referable to the release of heparin, histamine and/or other vasoactive amines. Mechanical manipulation or extreme changes in temperature can lead to degranulation of MCT's and subsequent erythema/wheal formation (Darier's sign) and gastrointestinal ulceration (anorexia, vomiting, melena, etc.).

Fine needle aspiration and cytology is the mainstay for diagnosis of MCT prior to surgical removal. Mast cells of MCT's have a characteristic discrete cell cytological appearance with eccentrically placed nuclei and abundant red to purple (ie metachromatic) cytoplasmic granules. Occasional MCT's, predominately undifferentiated MCT's, do not have the classic metachromatic cytoplasmic granules and must be diagnosed via other means (histopathology, special stains, etc.). Once a diagnosis is obtained, staging (looking for disease elsewhere) is routinely recommended, however, the completeness of staging is presently extremely controversial. After an FNAC diagnosis of MCT has been made, this author recommends routine staging diagnostics (full physical examination, bloodwork/urinalysis, FNAC of any enlarged lymph nodes and abdominal ultrasound). Additional diagnostics such as thoracic radiography and bone marrow aspiration/cytology may be employed. The use of buffy coat cytology and liver/spleen FNAC is presently controversial in the routine staging of dogs and cats with MCT and this author does not routinely employ these diagnostics for staging of MCT's.

Once the diagnosis of MCT has been made with FNAC and/or incisional biopsy and staging has been completed showing no evidence of metastasis to other sites, surgical excision is the preferred choice of therapy. The standard recommendation for complete surgical removal of MCT's has been three centimeters lateral and deep to the MCT. The derivation of this recommendation is unknown and the routine use of smaller margins is presently under investigation. This author still recommends continuing use of 3 cm lateral margins and one fascial plane deep margins whenever possible, but we have a study in press at JAVMA that shows that 2cm lateral and one fascial plane deep margins are sufficient for most grade II MCT. Recent studies in cats with skin/SQ MCT suggest that the vast majority are minimally invasive tumors with low recurrence rates suggesting that as wide and deep surgical margins may not be as necessary.

Histopathologic examination of MCT's has been found to be an important prognostic indicator by multiple groups. The Patnaik grading scheme (well-differentiated = grade I, moderately-differentiated = grade II and poorly-differentiated = grade III) has shown that 83%, 44% and 6% of dogs with grade I, II and III tumors were alive approximately 4 years after surgery, respectively. This grading scheme has not been found to be of use for cats with MCT. Additional negative prognostic factors include advanced stage, caudal half of body location, high growth rates, aneuploidy and presence of systemic signs. Newly discovered molecularly-based negative prognostic factors include increased AgNOR (silver nucleolar organizing regions) scores, increased PCNA/Ki67 immunohistochemistry (IHC) expression (proliferation markers) and increased c-kit IHC expression. This author is presently investigating the use of PCNA, Ki67 and c-kit immunocytochemistry on FNA samples from dogs with MCT as a pre-surgical prognostic system. This author is also investigating the prognostic significance of panels of special stains for canine MCT (AgNOR, Ki-67, PCNA and c-kit by immunohistochemistry). The cost for this service is $200. If you are interested, please call Diane (Flaherty Comparative Oncology Lab technician @ 212-329-8675. Preliminary results suggest that these tests are of potential benefit in delineating "bad" from "good" grade II MCT.

Dogs and cats with incomplete surgical removal of their MCT should undergo re-resection whenever possible. When re-resection is not feasible, external beam radiation therapy has now been found to be an excellent post-operative therapeutic modality affording 80-85% control at 4-5 years in dogs with incompletely resected grade II MCT. Unfortunately, it is presently unknown what percentage of completely and incompletely resected MCT's will recur.

Surgery and radiation therapy should be considered the mainstays of therapy for MCT's. Chemotherapy is a distant third modality that may be useful for dogs and cats with systemic or metastatic mast cell tumor. Recent studies suggest that CCNU (lomustine), vinblastine and prednisone have limited activity against MCT.

References:

1. Thamm DH, Mauldin EA, Vail DM. Prednisone and vinblastine chemotherapy for canine mast cell tumor--41 cases (1992-1997). J Vet Intern Med. 1999 Sep-Oct;13(5):491-7.
2. LaDue T, Price GS, Dodge R, Page RL, Thrall DE. Radiation therapy for incompletely resected canine mast cell tumors. Vet Radiol Ultrasound. 1998 Jan-Feb;39(1):57-62.
3. Patnaik AK, Ehler WJ, MacEwen EG. Canine cutaneous mast cell tumor: morphologic grading and survival time in 83 dogs. Vet Pathol. 1984 Sep;21(5):469-74.
4. Rassnick KM, Moore AS, Williams LE, London CA, Kintzer PP, Engler SJ, Cotter SM. Treatment of canine mast cell tumors with CCNU (lomustine). J Vet Intern Med. 1999 Nov-Dec;13(6):601-5.
5. Chaffin K, Thrall DE. Results of radiation therapy in 19 dogs with cutaneous mast cell tumor and regional lymph node metastasis. Vet Radiol Ultrasound. 2002 Jul-Aug;43(4):392-5.
6. Turrel JM, Kitchell BE, Miller LM, Theon A. Prognostic factors for radiation treatment of mast cell tumor in 85 dogs. J Am Vet Med Assoc. 1988 Oct 15;193(8):936-40.
7. Frimberger AE, Moore AS, LaRue SM, Gliatto JM, Bengtson AE. Radiotherapy of incompletely resected, moderately differentiated mast cell tumors in the dog: 37 cases (1989-1993). J Am Anim Hosp Assoc. 1997 Jul-Aug;33(4):320-4.
8. Seguin B, Leibman NF, Bregazzi VS, Ogilvie GK, Powers BE, Dernell WS, Fettman MJ, Withrow SJ. Clinical outcome of dogs with grade-II mast cell tumors treated with surgery alone: 55 cases (1996-1999). J Am Vet Med Assoc. 2001 Apr 1;218(7):1120-3.
9. O'Keefe DA, Couto CG, Burke-Schwartz C, Jacobs RM. Systemic mastocytosis in 16 dogs. J Vet Intern Med. 1987 Apr-Jun;1(2):75-80.
10. Al-Sarraf R, Mauldin GN, Patnaik AK, Meleo KA. A prospective study of radiation therapy for the treatment of grade 2 mast cell tumors in 32 dogs. J Vet Intern Med. 1996 Nov-Dec;10(6):376-8.

The vaccines generally associated with this disease to date have been the adjuvanted rabies and feline leukemia virus vaccines, however, association with non-adjuvanted FVRC-P vaccines have been occasionally reported. The potential role of inflammation as a necessary antecedent to the development of this disease has been previously published and seems highly plausible based on the aforementioned association with adjuvanted vaccinations. Newer non-adjuvanted vaccines are likely a step in the right direction for the prevention of this disease, and we eagerly await longer-term results on the incidence of tumors with these vaccines.

Currently, VAFSTF (Vaccine-Associated fibrosarcoma Task Force) in concert with the AVMA and AAFP recommend that: 1) use of vaccines packaged in single-dose vials is strongly encouraged, 2) occurrences of VAS or other adverse reactions be reported to the vaccine manufacturer and the United States Pharmacopoeia (USP; 1-800-4-USP-PRN), 3) vaccination protocols be standardized within practices so that location, type, manufacturer and serial number is entered into the permanent medical record, 4) vaccines limited to panleukopenia, herpesvirus and calicivirus should be administered on the right shoulder, 5) rabies vaccines should be administered as distally as possible on the right rear limb, 6) feline leukemia virus vaccines should be administered as distally as possible on the left rear limb, and 7) injection sites of ALL other medications be recorded in the permanent medical record. This information can also be accessed at www.avma.org.

If you suspect you are dealing with a VAS in a cat, the appropriate staging diagnostics should include full physical examination, bloodwork/urinalysis, retroviral testing and 3-view chest radiographs. Retroviral testing is recommended to ensure that FeLV is not acting as a helper virus for the production of a feline sarcoma virus-associated sarcoma. Radiography for the evaluation of metastasis is performed since it appears that approximately 5% of cats with VAS have metastasis at presentation, whereas approximately 20-25% have metastasis at necropsy. Confirmation of the suspected diagnosis should be performed by obtaining an incisional biopsy with a Tru-Cut biopsy instrument (or similar incisional biopsy instrument), or small wedge biopsy. The tumor should NOT be removed until a complete diagnosis is made and a consultation with an oncologist or surgeon has been performed.

Recent studies document that RADICAL first excision of VAS is essential for an extended period of time without recurrence. In addition, recent studies also document that the practice of vaccination of the distal portions of the limbs for rabies and/or FeLV vaccinations appears appropriate since patients with VAS of the distal limbs can undergo radical surgical extirpation via amputation. Unfortunately, even with aggressive surgery alone, relatively few cats with VAS are cured. Due to poor cure rates with surgery alone, the additional use of adjuvant radiation therapy and/or chemotherapy has been under investigation at multiple veterinary cancer centers for the last few years. It is presently unknown whether it is better to perform radiation therapy prior to radical surgery, or perform radical surgery and then post-operative radiation therapy. However, the combination of radical surgery and radiation therapy in recent studies appears to have a median survival time of 600-800 days, suggesting that additional therapies is worthwhile in the treatment of this disease. Similarly, the use of chemotherapy has been reported by multiple investigators to have efficacy against feline VAS. When given to cats with grossly palpable VAS, carboplatin or a combination of doxorubicin and cyclophosphamide resulted in a 50-60% response rate. Feline non-VAS would be expected to have a 10-15% response rate to these forms of chemotherapy, thereby suggesting that feline VAS is a remarkably different beast than non-VAS. The use of radical surgery, radiation therapy and chemotherapy as tri-modality therapy in feline VAS is likely the best form of therapy for cats with VAS based on recent abstracts from the Veterinary Cancer Society. Unfortunately, these data are extremely immature, but preliminary indications suggest tri-modality therapy will very likely be the preferred therapy for this extremely malignant tumor.

Through the support of VAFSTF, there are currently a number of research studies ongoing throughout the country to elucidate the etiopathogenesis, epidemiology, treatment and prevention of this disease (reader is referred to www.avma.org and the VAFSTF link). It is easy to see that even with aggressive therapies, we many times lose the battle against this remarkable tumor. The key to this disease is a better understanding of what causes this tumor, so that we may determine ways to vaccinate our feline friends without inducing extremely malignant tumors. We eagerly await the results of currently funded VAFSTF-sponsored studies as well as ongoing research studies by the vaccine manufacturers to rid this disease from our profession.

References:

1. Hershey AE, Sorenmo KU, Hendrick MJ et al. Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases (1986-1996). J Am Vet Med Asoc 2000;216:58-61.
2. Vaccine-Associated Feline Sarcoma Task Force guidelines. Diagnosis and treatment of suspected sarcomas. J Am Vet Med Assoc 1999;214:1745.
3. Couto CG, Macy DW. Review of treatment options for vaccine-associated feline sarcoma. J Am Vet Med Assoc 1998;213:1426-1427.
4. Bergman PJ. Etiology of feline vaccine-associated sarcomas: history and update. J Am Vet Med Assoc 1998;213:1424-1425.
5. Kobayashi T, Hauck ML, Dodge R, Page RL, Price GS, Williams LE, Hardie EM, Mathews KG, Thrall DE. Preoperative radiotherapy for vaccine associated sarcoma in 92 cats. Vet Radiol Ultrasound. 2002 Sep-Oct;43(5):473-9.
6. Gobar GM, Kass PH. World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sarcomas in cats. J Am Vet Med Assoc. 2002 May 15;220(10):1477-82.
7. Cohen M, Wright JC, Brawner WR, Smith AN, Henderson R, Behrend EN. Use of surgery and electron beam irradiation, with or without chemotherapy, for treatment of vaccine-associated sarcomas in cats: 78 cases (1996-2000). J Am Vet Med Assoc. 2001 Dec 1;219(11):1582-9.
8. McEntee MC, Page RL. Feline vaccine-associated sarcomas. J Vet Intern Med. 2001 May-Jun;15(3):176-82.
9. Bregazzi VS, LaRue SM, McNiel E, Macy DW, Dernell WS, Powers BE, Withrow SJ. Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995-2000). J Am Vet Med Assoc. 2001 Feb 15;218(4):547-50.
10. Barber LG, Sorenmo KU, Cronin KL, Shofer FS. Combined doxorubicin and cyclophosphamide chemotherapy for nonresectable feline fibrosarcoma. J Am Anim Hosp Assoc. 2000 Sep-Oct;36(5):416-21.
11. Macy DW, Hendrick MJ. The potential role of inflammation in the development of postvaccinal sarcomas in cats. Vet Clin North Am Small Anim Pract. 1996 Jan;26(1):103-9.

Much of this sea-change in age of onset and location for cats with LSA can be attributed to changes in feline leukemia virus (FeLV). FeLV was the most common cause of hematopoietic tumors in cats, and these cats generally had T-cell mediastinal LSA. B cell alimentary LSA in cats is usually seen in older FeLV negative cats, and this is by far the most common presentation for cats presently. Some oncologists believe that all cats with LSA are FeLV positive. This author disagrees with this statement, as specific viruses have never been found to be responsible for all types of LSA in other species, and evidence for strong associations with certain herbicides (e.g. 2,4-D) continues to accumulate in people. Some oncologists believe that the rise in alimentary LSA seen recently is due to a decreased incidence of FeLV with a concomitant increase in food-related carcinogens, though no scientific evidence for the latter is available.

Dogs & cats with LSA are generally categorized based on anatomic and histologic classifications. The five major anatomical sites are alimentary, mediastinal, multicentric, leukemia and extra-nodal (CNS, cutaneous, other). Though there are a number of histologic classification systems available, the NIH Working Formulation has been the system most widely adopted by histopathologists. This system generally suggests that approximately 10%, 30% and 60% of dogs and cats with LSA have low, intermediate and high-grade tumors, respectively.

The history and clinical signs of dogs & cats with LSA are extremely variable and dependent on the extent of disease and anatomic location. For example, cats with alimentary LSA usually present for anorexia/weight loss, vomiting, diarrhea and an abdominal mass, whereas cats with mediastinal LSA usually present for tachypnea, dyspnea and vomiting/regurgitation. Many dogs with multicentric LSA present for abnormal lumps being found by the owner or groomer, or on routine physical examination by a veterinarian

The diagnostic evaluation of dogs cats with a suspicious diagnosis of LSA should include a full physical examination, bloodwork (CBC/platelet/biochemistry profile), retroviral testing in cats (FeLV/FIV) and urinalysis. Additional staging diagnostics may include abdominal radiography and/or ultrasonography, chest radiography and bone marrow aspiration/cytology. Additional tests may be necessary depending on the anatomic location of the LSA (e.g. mediastinal aspirate for mediastinal mass). Caution is noted for NOT making the diagnosis of multicentric LSA off of fine needle aspiration and cytology specifically in cats due to the common syndrome of non-neoplastic retroviral-associated lymphadenopathy. Similarly, the diagnosis of LSA should not be made cytologically with fine needle aspirates of the mandibular lymph nodes in dogs as these lymph nodes are responsible for drainage of the oral cavity, and may have focal areas of hyperplasia that could cytologically mimic LSA.

The last 20 years have shown significant advancements in the treatment of canine LSA, however, such advances have not been made in the treatment of feline LSA. The chemotherapeutic agents and protocols used in dogs are the same ones used in cats. These agents include cyclophosphamide, vincristine, prednisone, doxorubicin, methotrexate and L-asparaginase. The same approximate dosages for the above drugs can be used in dogs as well as cats except for doxorubicin. When cats are given doxorubicin at the originally described 30 mg/m2 dose, they may experience significant toxicity including myelosuppression, vomiting, diarrhea, and hepato-/nephrotoxicity. When cats are given doxorubicin at 1 mg/kg, the toxicity is quite manageable and typically self-limiting. In addition, the induction of adriamycin-associated cardiomyopathy that can be seen in dogs and humans is rarely if ever seen in cats.

Combination chemotherapy protocols generally induce a complete remission in 70-85% of dogs and 50-60% of cats with LSA. Similarly, the median remission time for dogs is generally 6-11 months, whereas in cats it is 4-5 months. The median survival time of dogs on multi-agent chemotherapy protocols is 12-26 months, whereas in cats it is only 5-7 months. That said, the range of remission times and survival times in cats can be extremely wide, ranging from weeks to years. It is also important to note that it is extremely difficult to recommend precise treatments for the wide variety of clinical types of LSA seen in dogs and cats. Though studies have not specifically addressed this, this author believes that cats generally tolerate chemotherapy much better than dogs do. Other treatment modalities such as radiation therapy can be utilized in dogs and cats with mediastinal, nasal and CNS LSA, whereas surgery may be useful for dogs and cats with truly extra-nodal non-metastatic LSA (e.g. single small mycosis fungoides or epitheliotropic LSA lesion).

The prognosis for dogs and cats with LSA is extremely variable. A large number of prognostic factors have been identified in the dog and these will be presented and ranked as much as possible at the oral discussion. The duration and response to therapy will depend on stage, location and FeLV status. Recent studies suggest that the most important negative prognostic factors are lack of response to therapy, FeLV +, whether the cat is sick or not, advanced stage and lack of doxorubicin in the chemotherapy protocol. This author and others have noted extremely variable remission and survival times for cats with alimentary LSA treated with a wide variety of chemotherapy protocols, ranging from leukeran and prednisone (a la Fondacaro) to typical aggressive multi-agent chemotherapy protocols.. This author is presently investigating: 1) the potential for multiple sub-classifications of alimentary LSA in cats with hopeful prognostic and therapeutic significance, and 2) the use of immunohistochemical-based prognostic panels utilizing known prognostic factors (AgNOR, immunophenotype, proliferation markers, drug resistance proteins, etc.). If you have a case you would like to submit for the LSA prognostication panel, please call 212-329-8675 for more information.

Canine LSA Prognostic Factors:

1. Cotter SM. Treatment of lymphoma and leukemia with COP. II. Treatment of cats. J Am Anim Hosp Assoc 1983;19:166-72.
2. Jeglum KA, Whereat A, Young K. Chemotherapy of lymphoma in 75 cats. J Am Vet Med Assoc 1987;190:174-8.
3. Elmslie RE, Ogilvie GK, Gillette EL, et al. Radiotherapy with and without chemotherapy for localized lymphoma in 10 cats. Vet Radiol 1991;32:277-80.
4. Vail DM, Moore AS, Ogilvie GK, Volk LM. Feline Lymphoma (145 Cases): Proliferation Indices, Cluster of Differentiation 3 Immunoreactivity, and Their Association with Prognosis in 90 Cats. J Vet Intern Med 1998;12:349-54.
5. Zwahlen CH, Lucroy MD, Kraegel SA, Madewell BR. Results of Chemotherapy for Cats with Alimentary Malignant Lymphoma: 21 Cases (1993-1997). J Am Vet Med Assoc 1998;213:1144-49.
6. Chun R, Garrett LD, Vail DM. Evaluation of a high-dose chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med 2000;14:120-124.
7. Moore AS, Cotter SM, Rand WM, Wood CA et al. Evaluation of a discontinuous treatment protocol (VELCAP-S) for canine lymphoma. J Vet Intern Med 2001;15:348-354.
8. Kiupel M, Teske E, Bostock D. Prognostic factors for treated canine malignant lymphoma. Vet Pathol 1999;36:292-300.
9. Dobson JM, Blackwood LB, McInnes EF, et al. Prognostic variables in canine lulticentric lymphosarcoma. J Small Anim Pract 2001;42:377-384.
10. MacEwen EG, Brown NO, Patnaik AK, et al. Cyclic combination chemotherapy of canine lymphosarcoma. J Am Vet Med Assoc 1981;178:1178-1181.
11. MacEwen EG, Hayes AA, Matus RE, et al. Evaluation of prognostic factors for advanced multicentric lymphosarcoma in the dog: 147 cases. J Am Vet Med Assoc 1987;190:564-568.