TOP 10 Recent Advances in Veterinary Oncology 1. Six month chemo for lymphoma.1 2. FNA of non-palpable LN s.2

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1 TOP 10 Recent Advances in Veterinary Oncology Philip J. Bergman DVM, MS, PhD Diplomate ACVIM, Oncology Chief Medical Officer BrightHeart Veterinary Centers 80 Business Park Drive, Suite 110, Armonk, NY (office), (fax), This discussion will review what I feel to be the top 10 clinically relevant advances in veterinary oncology over the last ~ 10 years. Topic #10 will be a stinker topic and will briefly summarize advances that have really NOT been advances. I will post the abstracts from these publications and then summarize them in the lecture. It is important to point out that major advances in surgical oncology have occurred over the last 30 years (e.g. hemipelvectomy, limb-sparing, nasal planectomy, scapulectomy, etc.) but they will not be discussed here. 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 = ) 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.

2 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 nonsteroidal 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 Efficacy of RT for incompletely resected MCT & STS. A. OBJECTIVE: To evaluate efficacy of radiation for treatment of incompletely resected softtissue 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

3 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 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-perfraction, 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 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 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 Chemotherapy for canine MCT.

4 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. The efficacy and toxicity of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosourea) were evaluated in 23 dogs with measurable mast cell tumors (MCT). Twenty-two dogs had cutaneous MCT and 1 dog had an intranasal MCT Nineteen (83%) dogs had biopsy of their original mass performed and 4 (17%) had aspiration cytology of masses. Of the 19 tumors histologically graded, 1 (5%) neoplasm was classified as grade I, 10 (53%) were grade II, and the remaining 8 (42%) were grade III. Dogs were treated with CCNU at a dosage of 90 mg/m2 body surface area every 3 weeks. Response could be evaluated in 19 dogs. Eight of the 19 dogs (42%) had a measurable response to CCNU. One dog had a durable complete response for 440 days. Seven dogs (37%) had a partial response for a median and mean duration of 77 days and 109 days, respectively (range, days). Treatment with CCNU resulted in stable disease in 6 dogs (32%) for a median and mean duration of 78 days and 122 days, respectively (range, days). The acute dose-limiting toxicity was neutropenia 7 days after administration of CCNU. The median and mean neutrophil counts 7 days after CCNU were 1,452 cells/microl and 1,683 cells/microl, respectively (n = 17). Other toxicoses were uncommon. CCNU should be considered an active agent in the treatment of MCT in dogs 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. Zinecard for the attenuation of side effects from adriamycin/doxorubicin extravasation. To be reviewed at the lecture with special emphasis on practical use of this extremely new medication. 10. Putting the cart before the horse. To be reviewed at the lecture with special emphasis on MAb , Acemannan 13, Bladder TCC tests 14-16, Gemzar 17,18 and others.

5 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, (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, (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 ( ). J Am Vet. Med. Assoc 221, (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, (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, (1998). 7. Rassnick,K.M. et al. MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases ( ). J. Vet. Intern. Med. 16, (2002). 8. Moore,A.S. et al. Lomustine (CCNU) for the treatment of resistant lymphoma in dogs. J. Vet. Intern. Med. 13, (1999). 9. McCaw,D.L. et al. Response of canine mast cell tumors to treatment with oral prednisone. J Vet. Intern. Med. 8, (1994). 10. Thamm,D.H., Mauldin,E.A. & Vail,D.M. Prednisone and vinblastine chemotherapy for canine mast cell tumor--41 cases ( ). J Vet. Intern. Med. 13, (1999). 11. Rassnick,K.M. et al. Treatment of canine mast cell tumors with CCNU (lomustine). J. Vet. Intern. Med. 13, (1999). 12. Jeglum,K.A. Chemoimmunotherapy of canine lymphoma with adjuvant canine monoclonal antibody 231. Vet. Clin. North Am Small Anim Pract. 26, (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, (1995). 14. Henry,C.J. et al. Evaluation of a bladder tumor antigen test as a screening test for transitional cell carcinoma of the lower urinary tract in dogs. Am. J. Vet. Res. 64, (2003). 15. Borjesson,D.L., Christopher,M.M. & Ling,G.V. Detection of canine transitional cell carcinoma using a bladder tumor antigen urine dipstick test. Vet. Clin. Pathol. 28, (1999). 16. Billet,J.P., Moore,A.H. & Holt,P.E. Evaluation of a bladder tumor antigen test for the diagnosis of lower urinary tract malignancies in dogs. Am. J. Vet. Res. 63, (2002). 17. Kosarek,C.E., Kisseberth,W.C., Gallant,S.L. & Couto,C.G. Clinical evaluation of gemcitabine in dogs with spontaneously occurring malignancies. J. Vet. Intern. Med. 19, (2005). 18. LeBlanc,A.K., LaDue,T.A., Turrel,J.M. & Klein,M.K. Unexpected toxicity following use of gemcitabine as a radiosensitizer in head and neck carcinomas: a veterinary radiation therapy oncology group pilot study. Vet. Radiol. Ultrasound 45, (2004).