Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas

Background: Continuous administration of low doses of cyclophosphamide and standard doses of cyclooxygenase‐inhibiting drugs has been shown to suppress tumor angiogenesis, reverse immunosuppression, and deplete regulatory T cells in cancer models. Hypothesis: We hypothesized that continuous treatment with low‐dose cyclophosphamide and full‐dose piroxicam would delay tumor recurrence in dogs with soft tissue sarcomas (STS). Animals: Eighty‐five dogs with incompletely resected STS, 30 treated dogs, and 55 contemporary control dogs. Methods: Treatment outcomes in 85 dogs with incompletely resected STS were evaluated in a retrospective study. Dogs in the treatment group received continuously administered low‐dose cyclophosphamide (10 mg/m²) and standard dose piroxicam (0.3 mg/kg) therapy. Time to local tumor recurrence (disease‐free interval; DFI) was compared between the 30 treated dogs and 55 untreated control dogs matched for age and tumor site and grade. Results: DFI was significantly (P < .0001) prolonged for STS of all sites (trunk and extremity) in treated dogs compared with untreated control dogs. The DFI also was significantly longer in treated dogs when tumor site (trunk and extremity) was compared. Twelve treated dogs (40%) experienced mild toxicity (grade 1 and 2) at some point during treatment and 1 dog developed grade 4 cystitis. Every other day dosing was tolerated better than daily dosing. Conclusions: Metronomic therapy with cyclophosphamide and piroxicam was very effective in preventing tumor recurrence in dogs with incompletely resected STS. These findings suggest that further evaluation of this approach is warranted as adjuvant therapy in dogs with highly metastatic tumors such as osteosarcoma and melanoma.     

Efficacy of Vinblastine for Treatment of Canine Mast Cell Tumors

Background: The optimal dosage and clinical efficacy of vinblastine (VBL) for treatment of mast cell tumors (MCTs) in dogs has not been established. Hypothesis: Single‐agent VBL has antitumor activity against MCTs in dogs. Animals: Fifty‐one dogs with nonresectable grade II or III cutaneous MCTs. Methods: Prospective, open clinical trial. Dogs were systematically allocated (by hospital record number) to receive IV treatment with VBL at a dosage of 2.0 mg/m² (weekly for 4 treatments then biweekly for 4 treatments; VBL 2.0) or treatment with VBL at a dosage of 3.5 mg/m² (biweekly for 5 treatments; VBL 3.5). The primary outcome measure was reduction in tumor size. Results: Twenty‐five dogs were allocated to the VBL 2.0 group and 26 were allocated to the VBL 3.5 group. In the VBL 2.0 group, 3 (12%) had a partial response (PR) for a median of 77 days (range, 48–229 days). Overall response rate in the VBL 3.5 group was 27%. One dog (4%) had a complete response for 63 days and 6 dogs (23%) had a PR for a median of 28 days (range, 28–78 days). Toxicoses were uncommon in the VBL 2.0 group. Twelve (46%) dogs in the VBL 3.5 group had <500 neutrophils/μL 7 days after treatment; 2 dogs with neutropenia developed concurrent fevers. Conclusions and Clinical Importance: VBL, when used as a single‐agent, has activity against MCTs in dogs although the response rate is lower than those reported for VBL‐containing combination protocols. Further, findings suggest VBL at a dosage of 3.5 mg/m² should be considered for use in future phase II/III trials.     

Prognostic factors in dogs with urinary bladder carcinoma

Medical records and biopsy specimens were retrospectively reviewed from 25 dogs diagnosed with unresectable urinary bladder carcinoma and treated with chemotherapy. Our intention was to identify clinical, histologic, and immunohistochemical indicators of prognosis. Immunohistochemical stains for P-glycoprotein, glutathione-S-transferase pi, and factor VIII-related antigen were applied to archived tissue. There were more spayed female dogs than castrated male dogs (76% versus 24%). Transitional cell carcinoma was the most common tumor (88%, n = 22), followed by undifferentiated carcinoma (8%, n = 2) and squamous cell carcinoma (4%, n = 1). Overall median survival was 251 days. Histologic diagnosis and immunohistochemical characteristics did not correlate with prognosis. Spayed females survived significantly longer than castrated males (358 days versus 145 days, P = .042). Dogs that received either doxorubicin or mitoxantrone in addition to a platinum-based chemotherapeutic (either cisplatin or carboplatin) lived significantly longer than those that received only a platinum compound (358 days versus 132 days, P = .042).     

Evaluation of a discontinuous treatment protocol (VELCAP-S) for canine lymphoma

Eighty-two dogs with lymphoma received a single 15-week course of chemotherapy, after which treatment was ceased until relapse. Fifty-six dogs (68%) achieved complete remission for a median 1st remission duration of 20 weeks. Forty-eight dogs relapsed, of which 30 repeated the induction cycle. In 22 of these dogs, 1st remission had been short, and they received maintenance chemotherapy; the other 8 dogs received 2 or 3 cycles of induction chemotherapy. Second remission rate for these 30 dogs was 87% (26 dogs). Overall disease control for the 38 dogs that remained on protocol was 44 weeks, which was not markedly shorter than for dogs treated with a previously reported protocol in which maintenance chemotherapy was instituted in all dogs after an identical 1st induction (VELCAP-L). Dogs that were febrile and dogs that were dyspneic were less likely to achieve a complete remission to induction chemotherapy. Of dogs that achieved a complete remission, those that were thrombocytopenic at entry had a shorter 1st remission, and dogs that were anorexic at entry had shorter overall disease control. There was a correlation between 1st remission duration and length of any subsequent remission obtained. The incidence of toxicity was high, particularly after the combination of doxorubicin and vincristine. Dose reductions because of toxicity did not markedly reduce remission duration. We conclude that discontinuous chemotherapy may reduce patient visits in a small number of patients because of long-term disease control. Delaying maintenance chemotherapy until after 2nd remission is achieved does not markedly affect overall disease control.     

Intestinal parasite infections in dogs affected by multicentric lymphoma and undergoing chemotherapy

Prevalence and species composition of intestinal parasites were evaluated in dogs affected by high-grade multicentric lymphoma and undergoing chemotherapy and in control healthy dogs. Obtained data were statistically analyzed. The overall prevalence of intestinal parasite infections was 33.3%. In lymphoma dogs, the prevalence of protozoa infections (46.7%) was significantly higher (p < 0.05) than that of helminth infections (6.7%) and Giardia duodenalis, Cryptosporidium spp., Neospora caninum, Cystoisospora ohioensis-complex, Entamoeba sp. and Spirocerca lupi were identified. In the control group, only 3/15 dogs (20%) were found positive and no statistically significant differences emerged regarding helminth (hookworms and Toxocara canis) and protozoa (G. duodenalis) infections. Results from this study may suggest a potential higher prevalence of opportunistic intestinal protozoa, including some potentially zoonotic species, in dogs affected by high-grade multicentric lymphoma, emphasizing the need to monitor lymphoma-affected dogs for these protozoa, especially those undergoing chemotherapy.     

A phase II clinical trial of vinorelbine in dogs with cutaneous mast cell tumors

Background: Few effective drugs are available to treat dogs with locally aggressive or metastatic mast cell disease.
Hypothesis: Vinorelbine, a semisynthetic derivative of vinblastine, is an effective drug for the treatment of canine mast cell tumors (MCT).
Animals: Twenty-four dogs with cutaneous MCT.
Methods: Dogs with at least 1 measurable, cytologically confirmed, and previously untreated cutaneous MCT received a single treatment with vinorelbine at the previously established dosage of 15 mg/m² IV. Tumor measurements and CBC were evaluated before and 7 days after treatment. Adverse events were graded according to Veterinary Cooperative Oncology Group (VCOG) guidelines.
Statistics: Data were accrued in accordance with a Simon's 2-stage design with a noninteresting response rate of .05, a target response of .25, and α and β values of .10.
Results: Three of 24 dogs (13%) had a response to treatment, including 1 measurable complete response and 1 measurable partial response. The 3rd dog had microscopic complete response to treatment with stable measurable disease. Twenty other dogs (83%) had stable disease and 1 dog (4%) had progressive disease. Neutropenia occurred in 13 dogs (54%) (grade 1, n = 4; grade 3, n = 6; grade 4, n = 3). Gastrointestinal toxicity occurred in 11 dogs (46%) (anorexia: grade 1, n = 3; grade 2, n = 1; grade 3, n = 1; diarrhea: grade 1, n = 2; grade 3, n = 1; vomiting: grade 1, n = 5; grade 3, n = 1).
Conclusions and Clinical Importance: Vinorelbine was associated with an overall response rate of 13% and a high prevalence of neutropenia. Additional studies are indicated to determine if repeated dosing of vinorelbine or combination of vinorelbine with other drugs increases the observed biologic activity against canine MCT.