Top 10 recent advances in veterinary oncology (Proceedings)

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.

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.

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) Use of CT for delineation of metastases.

A. Imaging studies in people indicate that x-ray computed tomography (CT) is a more sensitive technique than thoracic radiography for the detection of pulmonary metastatic neoplasia. Systematic studies comparing CT and thoracic radiographic techniques in veterinary patients have not been performed. The present retrospective study was designed to directly compare the efficacy of these 2 techniques in detecting pulmonary nodules in dogs. Eighteen dogs with histologically confirmed pulmonary metastatic neoplasia had contemporaneous thoracic radiographs and pulmonary CT scans compared. Quantitative analyses included estimation of pulmonary nodule size, number, and lobar distribution on thoracic radiographs and CT images. Only 9% of CT-detected pulmonary nodules were identified on thoracic radiographs (P < .003). The lower size threshold was approximately 1 mm to detect pulmonary nodules on CT images and 7-9 mm to reliably detect nodules on radiographs (P < .0001). Additionally, pulmonary nodules were detected in a significantly greater number of lung lobes using CT as compared with thoracic radiographs (P < .0001). These data indicate that CT is significantly more sensitive than thoracic radiography for detecting soft-tissue nodules in dogs. As such, thoracic CT should be considered in any patient with neoplasia that has potential for pulmonary metastasis to more reliably stage the disease, particularly when accurate characterization of the extent and distribution of pulmonary metastatic disease affects therapeutic planning.

B. OBJECTIVE: To compare results of computed tomography (CT) and radiography with histopathologic findings in tracheobronchial lymph nodes (TBLNs) in dogs with primary lung tumors. DESIGN: Retrospective case series. ANIMALS: 14 client-owned dogs. PROCEDURES: Criteria for inclusion were diagnosis of primary lung tumor, use of thoracic radiography and CT, and histologic confirmation of TBLN status. Medical records were reviewed for signalment; history; and physical examination, clinicopathologic, radiographic, CT, surgical, and histopathologic findings. RESULTS: Tracheobronchial lymphadenopathy was not identified via radiography in any dogs. Tracheobronchial lymphadenopathy was diagnosed in 5 dogs via CT. Six dogs had histologic confirmation of metastasis to TBLNs. Radiographic diagnosis yielded 6 false-negative and no false-positive results for tracheobronchial lymphadenopathy. Computed tomography yielded 1 false-negative and no false-positive results. Sensitivity of CT for correctly assessing TBLN status was 83%, and specificity was 100%. Positive predictive value was 100%, and negative predictive value was 89%. Dogs with lymphadenopathy via CT, histologic confirmation of TBLN metastasis, or primary tumors with a histologic grade > 1 had significantly shorter survival times than their counterparts. CONCLUSIONS AND CLINICAL RELEVANCE: Results of CT evaluation of TBLN status were in agreement with histopathologic findings and more accurate than use of thoracic radiography for evaluating TBLNs in dogs with primary lung tumors. Computed tomography imaging should be considered as part of the staging process to more accurately assess the TBLNs in dogs with primary lung tumors.4

4) Cerenia.

A. Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of cisplatin therapy. Maropitant (Cerenia TM ), a novel neurokinin-1 receptor antagonist, was evaluated for prevention and treatment of cisplatin-induced emesis in tumour-bearing dogs. Dogs (n = 122) were randomly allocated to three treatment groups: T01, placebo before and after cisplatin; T02, placebo before and maropitant after cisplatin; or T03, maropitant before and placebo after cisplatin. Maropitant treatment (T02) following a cisplatin-induced-emetic event resulted in significantly fewer subsequent emetic events ( P = 0.0005) than in placebo-treated dogs (T01). In placebo-treated (T01) dogs, 56.4% were withdrawn from the study because of treatment failure compared with 5.3% in group T02. When maropitant was administered prior to cisplatin treatment (T03) in a prevention regime, 94.9% did not vomit compared with only 4.9% of placebo-treated dogs, and significantly fewer emetic events (P < 0.0001) were observed in those dogs that did vomit. In summary, maropitant was safe and highly effective in reducing or completely preventing cisplatin-induced emesis.5

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.6

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.7

6) Melanoma Vaccine.

A. Canine malignant melanoma (CMM) is an aggressive neoplasm treated with surgery and/or fractionated RT; however, metastatic disease is common and chemoresistant. Preclinical and clinical studies by our laboratory and others have shown that xenogeneic DNA vaccination with tyrosinase family members can produce immune responses resulting in tumor rejection or protection and prolongation of survival. These studies provided the impetus for development of a xenogeneic DNA vaccine program in CMM. MATERIALS AND METHODS: Cohorts of three dogs each received increasing doses of xenogeneic plasmid DNA encoding either human tyrosinase (huTyr; 100/500/1500 mcg), murine GP75 (muGP75; 100/500/1500 mcg), murine tyrosinase (muTyr; 5 dogs each at 100/500 mcg), muTyr±HuGM-CSF (9 dogs at 50 mcg muTyr, 3 dogs each at 100/400/800 mcg HuGM-CSF, or 3 dogs each at 50 mcg muTyr with 100/400/800 mcg HuGM-CSF), or 50 mcg MuTyr intramuscularly biweekly for a total of four vaccinations. RESULTS: The Kaplan-Meier median survival time (KM MST) for all stage II-IV dogs treated with huTyr, muGP75 and muTyr are 389, 153 and 224 days, respectively. Preliminarily, the KM MST for stage II-IV dogs treated with 50 mcg MuTyr, 100/400/800 mcg HuGM-CSF or combination MuTyr/HuGM-CSF are 242, 148 and >402 (median not reached) days, respectively. Thirty-three stage II-III dogs with loco-regionally controlled CMM across the xenogeneic vaccine studies have a KM MST of 569 days. Minimal to mild pain was noted on vaccination and one dog experienced vitiligo. We have recently investigated antibody responses in dogs vaccinated with HuTyr and found 2- to 5-fold increases in circulating antibodies to human tyrosinase. CONCLUSIONS: The results of these trials demonstrate that xenogeneic DNA vaccination in CMM: (1) is safe, (2) leads to the development of anti-tyrosinase antibodies, (3) is potentially therapeutic, and (4) is an attractive candidate for further evaluation in an adjuvant, minimal residual disease Phase II setting for CMM.8

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) 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 231, Acemannan, Bladder TCC tests, Gemzar and others.

References

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).

.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).

Nemanic S, London CA, Wisner ER. Comparison of thoracic radiographs and single breath-hold helical CT for detection of pulmonary nodules in dogs with metastatic neoplasia. J Vet Intern Med. 2006 May-Jun;20(3):508-15.

Paoloni MC, Adams WM, Dubielzig RR, Kurzman I, Vail DM, Hardie RJ. Comparison of results of computed tomography and radiography with histopathologic findings in tracheobronchial lymph nodes in dogs with primary lung tumors: 14 cases (1999-2002). J Am Vet Med Assoc. 2006 Jun 1;228(11):1718-22.

Vail DM, Rodabaugh HS, Conder GA, Boucher JF, Mathur S. Effi cacy of injectable maropitant (Cerenia TM ) in a randomized clinical trial for prevention and treatment of cisplatin induced emesis in dogs presented as veterinary patients. Vet Comp Oncol, 5, 1, 38–46.

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).

Moore,A.S. et al. Lomustine (CCNU) for the treatment of resistant lymphoma in dogs. J. Vet. Intern. Med. 13, 395-398 (1999).

Bergman PJ, Camps-Palau MA, McKnight JA, Leibman NF, Craft DM, Leung C, Liao J, Riviere I, Sadelain M, Hohenhaus AE, Gregor P, Houghton AN, Perales MA, Wolchok JD. Development of a xenogeneic DNA vaccine program for canine malignant melanoma at the Animal Medical Center. Vaccine. 2006 May 22;24(21):4582-5.

Jeglum,K.A. Chemoimmunotherapy of canine lymphoma with adjuvant canine monoclonal antibody 231. Vet. Clin. North Am Small Anim Pract. 26, 73-85 (1996).

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).

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, 1017-1020 (2003).

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, 33-38 (1999).

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, 370-373 (2002).

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, 81-86 (2005).

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, 466-470 (2004).