David M. Lurie

Cisplatin: a review of toxicities and therapeutic applications.

Cisplatin is a platinum chemotherapeutic used in a variety of malignancies. The antineoplastic activity occurs from DNA cross-links and adducts, in addition to the generation of superoxide radicals. Nephrotoxicity is the most well-known and potentially most clinically significant toxicity. Unfortunately, the mechanism for cisplatin nephrotoxicity has not been completely elucidated; however, many theories have been developed. Other toxicities include gastrointestinal, myelosuppression, ototoxicity and neurotoxicity. Saline diuresis is currently the most accepted way to prevent cisplatin nephrotoxicity. Research has focused on pharmaceuticals and enzyme/molecular alterations as alternatives to long-term diuresis. No agents have currently been identified that can protect from all toxicities. Cisplatin has shown activity against osteosarcoma, transitional cell carcinoma, squamous cell carcinoma (SCC), melanoma, mesothelioma, carcinomatosis and germinal cell tumours in the dog. In the cat, cisplatin cannot be utilized because of fulminant pulmonary oedema that occurs at standard doses. Intralesional cisplatin has been utilized in horses for the treatment of SCC and sarcoids.

Radiation therapy for canine appendicular osteosarcoma.

Radiation therapy (RT) for the management of canine appendicular osteosarcoma (OSA) can be described as either palliative- or curative intent. Palliative RT uses coarsely fractionated external beam RT or radiopharmaceuticals to provide relief of pain and lameness associated with OSA while resulting in minimal, if any, radiation-induced acute adverse effects. Limb amputation and chemotherapy are considered (together) the standard of care for curative-intent treatment of canine appendicular OSA. When limb amputation is not possible, RT can be used for limb sparing and is supplemented with chemotherapy for presumed micrometastatic disease. Fractionated tumour irradiation with curative intent appears to be ineffective and local disease control can more likely be achieved when stereotactic radiosurgery or intra-operative extracorporeal irradiation is combined with strict case selection and adjunctive chemotherapy. The availability of limb-sparing RT is limited by experience and availability of specialised equipment. When planned and administered appropriately, radiation-associated adverse effects are often mild and self-limiting.

Immunophenotypic and cytomorphologic subclassification of T-cell lymphoma in the boxer breed.

The boxer breed is at high risk for developing lymphoma and, in contrast to the general canine population, is predisposed to the T-cell variant of the disease. The purpose of this study was to more accurately classify lymphoma in this breed. Clinical, cytomorphologic and immunophenotypic data were examined in 43 boxers with lymphoma. Twenty-five cases were collected prospectively and a further 18 cases were obtained retrospectively. Lymphomas were classified as multicentric (n=29), mediastinal (n=6) and intestinal (n=8). Of the 40 immunophenotyped samples, 34 (85%) were T-cell, 5 (12.5%) were B-cell and 1 was a non-B-cell non-T-cell lymphoma. Immunophenotypic subtyping was done on prospectively collected T-cell lymphoma samples (n=22) to differentiate CD4 (helper) from CD8 (cytotoxic) T-cell origin as well as to determine the T-cell receptor (TCR) expression (TCRalphabeta vs. TCRdeltagamma). Phenotypic expression was CD4+ (n=12), double negative (DN) (n=6), double positive (DP) (n=1) and CD8+ (n=1), respectively, while two samples had no interpretable result. 20/22 samples were TCRalphabeta+ with only 1 sample being TCRdeltagamma+ and 1 with no interpretable result. Cytomorphologic analysis was done on the same 22 samples using the World Health Organization (WHO) classification scheme. According to this scheme, 17/22 samples were classified as lymphoblastic, 2/22 as large cell peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS), 2/22 as large granular lymphoma (LGL) high-grade and 1/22 as small lymphocytic. The results of this study indicate that lymphoma in the boxer breed is a disease comprised predominantly of TCRalphabeta+, CD4+ (helper) T-cells with lymphoblastic (high-grade) morphology.

Frameless stereotactic radiosurgery for the treatment of primary intracranial tumours in dogs

Stereotactic radiosurgery (SRS) is a procedure that delivers a single large radiation dose to a well-defined target. Here, we describe a frameless SRS technique suitable for intracranial targets in canines. Medical records of dogs diagnosed with a primary intracranial tumour by imaging or histopathology that underwent SRS were retrospectively reviewed. Frameless SRS was used successfully to treat tumours in 51 dogs with a variety of head sizes and shapes. Tumours diagnosed included 38 meningiomas, 4 pituitary tumours, 4 trigeminal nerve tumours, 3 gliomas, 1 histiocytic sarcoma and 1 choroid plexus tumour. Median survival time was 399 days for all tumours and for dogs with meningiomas; cause-specific survival was 493 days for both cohorts. Acute grade III central nervous system toxicity (altered mentation) occurred in two dogs. Frameless SRS resulted in survival times comparable to conventional radiation therapy, but with fewer acute adverse effects and only a single anaesthetic episode required for therapy.

Sequential low-dose rate half-body irradiation and chemotherapy for the treatment of canine multicentric lymphoma.

BACKGROUND Sequential half-body irradiation (HBI) combined with chemotherapy is feasible in treating canine lymphoma, but prolonged interradiation intervals may affect efficacy. A 2-week interradiation interval is possible in most dogs receiving low-dose rate irradiation (LDRI) protocols at 6 Gy dose levels. HYPOTHESIS LDRI incorporated into a cyclophosphamide, doxorubicin, vincritine, and prednisone (CHOP)-based chemotherapy protocol is effective for the treatment of lymphoma in dogs. ANIMALS Thirty-eight client-owned animals diagnosed with multicentric lymphoma. METHODS Retrospective study evaluating the efficacy and prognostic factors for the treatment of canine lymphoma with sequential HBI and chemotherapy. RESULTS The median 1st remission was 410 days (95% confidence interval [CI] 241-803 days). The 1-, 2-, and 3-year 1st remission rates were 54, 42, and 31%. The median overall survival was 684 days (95% CI 334-1,223 days). The 1-, 2-, and 3-year survival rates were 66, 47, and 44%. CONCLUSIONS AND CLINICAL RELEVANCE Results of this study suggest that treatment intensification by a 2-week interradiation treatment interval coupled with interradiation chemotherapy is an effective treatment for dogs with lymphoma.

Evaluation of the University of Florida lomustine, vincristine, procarbazine, and prednisone chemotherapy protocol for the treatment of relapsed lymphoma in dogs: 33 cases (2003–2009)

OBJECTIVE To evaluate the toxicity and efficacy of a modification of a previously evaluated combination of lomustine, vincristine, procarbazine, and prednisone (LOPP) as a rescue protocol for refractory lymphoma in dogs. DESIGN Retrospective case series. Animals-33 dogs with a cytologic or histologic diagnosis of lymphoma that developed resistance to their induction chemotherapy protocol. PROCEDURES Lomustine was administered on day 0 of the protocol. Vincristine was administered on day 0 and again 1 time on day 14. Procarbazine and prednisone were administered on days 0 through 13 of the protocol. This cycle was repeated every 28 days. RESULTS Median time from initiation to discontinuation of the University of Florida LOPP protocol was 84 days (range, 10 to 308 days). Overall median survival time was 290 days (range, 51 to 762 days). Overall response rate with this protocol was 61% (20/33), with 36% (12) having a complete response and 24% (8) having a partial response. Toxicosis rates were lower than for the previously published LOPP protocol. CONCLUSIONS AND CLINICAL RELEVANCE The University of Florida LOPP protocol may be an acceptable alternative to the mechlorethamine, vincristine, procarbazine, and prednisone protocol as a rescue protocol for dogs with lymphoma.

OUTCOMES AND PROGNOSTIC FACTORS ASSOCIATED WITH CANINE SINONASAL TUMORS TREATED WITH CURATIVE INTENT CONE-BASED STEREOTACTIC RADIOSURGERY (1999-2013).

Stereotactic radiosurgery (SRS) is a relatively new therapeutic option in veterinary oncology. The role of this modality has not been extensively evaluated for the use in canine nasal tumors. The objective of this retrospective, observational study was to describe the clinical outcome and prognostic factors associated with survival times in a sample of canine patients treated with SRS for sinonasal tumors. Fifty-seven dogs with sinonasal tumors met inclusion criteria. Histologic diagnoses included sarcoma (SA) (n = 9), carcinoma (CA) (n = 40), osteosarcoma (OSA) (n = 7), and round cell (n = 1). Four of 57 cases were treated twice with SRS. For these, the median and mean doses delivered were 30Gy and 33Gy, respectively (range 18.75Gy-56Gy). Late effects occurred in 23 cases and ranged from grades I-III. The median overall survival time was 8.5 months. The median overall survival times in dogs with tumor type of CA, SA, and OSA were 10.4, 10.7, and 3.1 months, respectively. Dogs with the tumor type of OSA had shorter overall survival time than that in dogs with tumor type of CA and SA. Findings from this retrospective study indicated that SRS may be beneficial for canine patients with sinonasal tumors, however a controlled clinical trial would be needed to confirm this. Prospective studies are also needed to better define the role of SRS as palliative or curative, and to further investigate the risk of clinically significant toxicity.

Radiosensitivity and capacity for radiation-induced sublethal damage repair of canine transitional cell carcinoma (TCC) cell lines

Understanding the inherent radiosensitivity and repair capacity of canine transitional cell carcinoma (TCC) can aid in optimizing radiation protocols to treat this disease. The objective of this study was to evaluate the parameters surviving fraction at 2 Gy (SF(2) ), α/β ratio and capacity for sublethal damage repair (SLDR) in response to radiation. Dose-response and split-dose studies were performed using the clonogenic assay. The mean SF(2) for three established TCC cell lines was high at 0.61. All the three cell lines exhibited a low to moderate α/β ratio, with the mean being 3.27. Two cell lines exhibited statistically increased survival at 4 and 24 h in the dose-response assay. Overall, our results indicate that the cell lines are moderately radioresistant, have a high repair capacity and behave similarly to a late-responding normal tissue. These findings indicate that the radiation protocols utilizing higher doses with less fractionation may be more effective for treating TCC.

Canine acute radiation dermatitis, a survey of current management practices in North America.

Acute radiation-induced dermatitis (ARID) is a common sequela of radiation therapy in dogs. There is no consensus regarding ARID management in human medicine and the standard of care in veterinary medicine has not been reported. The objective was to report the practice standards for ARID management in dogs in North America. The design used was a questionnaire survey. Fifty-eight private and university teaching veterinary hospitals were contacted, 54 participated. The topical and oral medications used to treat ARID, prevent or treat bacterial infection, control pain and the indications for and timing of treatment initiation were the outcome measures. A minority of facilities (4/54, 7.5%) use exactly the same protocol regarding all parameters. There was agreement (>75% of facilities) with respect to the general use of oral antibiotics (77.8%), the need for pain control (92.6%) and the use of tramadol for pain control (76%), although the details of their use varied widely. There is a divergence of opinions regarding all details of ARID management in dogs except the general use of oral antibiotics and pain control medications.

Outcome of definitive fractionated radiation followed by exenteration of the nasal cavity in dogs with sinonasal neoplasia: 16 cases.

Local control is a major challenge in treating canine nasal tumours. Surgical cytoreduction prior to radiation therapy has not been shown to offer a survival advantage. Only one study has previously evaluated the outcome when surgery is performed after radiation, which demonstrated an improved survival time compared with radiation alone. The purpose of this study was to investigate the outcome of surgery after definitive radiation on survival times in dogs with sinonasal tumours. Medical records were retrospectively reviewed for dogs with nasal tumours that received definitive radiation followed by surgery. Information obtained from medical record review included signalment, diagnosis, treatment and outcome. The median survival time was 457 days. No long-term side effects were observed. These findings suggest that exenteration of the nasal cavity following definitive radiation for treatment of dogs with nasal tumours is well-tolerated and provides a similar survival duration to previous reports of radiation alone.