Results of a phase II clinical trial on the use of ifosfamide for treatment of cats with vaccine-associated sarcomas

OBJECTIVE: To determine clinical activity and toxic effects of ifosfamide when used to treat cats with vaccine-associated sarcoma (VAS). ANIMALS: 27 cats with a nonresectable, recurrent, or metastatic VAS. PROCEDURE: Each cat received ifosfamide (900 mg/m(2) of body surface area) as an IV infusion during a 30-minute period. Diuresis by infusion of saline (0.9% NaCl) solution and administration of mesna were used to prevent urothelial toxicosis. Treatments were administered every 3 weeks, and tumor response was assessed after the second treatment. All ifosfamide-associated toxic effects were graded in accordance with predetermined criteria. RESULTS: 61 treatments were administered to 27 cats (median, 2 treatments/cat; range, 1 to 4 treatments/cat). After ifosfamide treatment, 1 cat had a complete response and 10 had partial responses for an overall response rate of 11 of 27 (41%; 95% confidence interval [CI], 25% to 59%). Responses lasted from 21 to 133 days (median, 70 days; 95% CI, 60 to 113 days). The acute dose-limiting toxicosis was neutropenia, which was detected 5 to 28 days (median, 7 days) after treatment. Median nadir neutrophil count was 1,600 cells/muL (range, 200 to 5,382 cells/microL). Nine (33%) cats had adverse gastrointestinal effects (primarily salivation during the ifosfamide infusion and inappetence after treatment). Two cats were euthanatized because of severe nephrotoxicosis, and 1 cat developed pulmonary edema during diuresis. CONCLUSIONS AND CLINICAL RELEVANCE: Ifosfamide has antitumor activity against VAS in cats and is tolerated well by most cats. Ifosfamide should be evaluated as an adjuvant treatment for cats with VAS.     

Phase I clinical trial evaluating STI571 in tumor bearing cats

Introduction: STI571 (Gleevec, imatinib mesylate) is a receptor tyrosine kinase inhibitor with selectivity for Bcr‐Abl, platelet‐derived growth factor (PDGF), stem cell factor (SCF), and c‐Kit. Side effects with use in humans include vomiting, diarrhea, nausea, myalgia, edema, and cutaneous reactions. Renal and hepatic toxicity have also been reported. In dogs, there is significant hepatic toxicity at sub‐clinical doses. The purpose of this prospective study was to determine the toxicity level and potential treatment protocol in tumor bearing cats. Methods: A phase I clinical trial was performed in client owned cats using an escalating dose of STI571 in tumor bearing cats. Cats included in the study had a histologic diagnosis of fibrosarcoma or other tumors and were staged with CBC, biochemical profile, thoracic radiographs, and abdominal ultrasound. None of the cats received concurrent chemotherapy, but those previously treated with surgery, radiation therapy, or chemotherapy, were not excluded. The initial starting dose was 5 mg/cat PO SID and was gradually increased to 10 and 20 mg/cat PO SID at a 2–6 week interval depending on laboratory work and disease progression. A repeat physical examination, CBC, and biochemical profile, were performed every 2 weeks for 2 rechecks, then every 4 weeks. Results: Six cats were enrolled in the study. Four cats had oral squamous cell carcinoma, and two cats had cutaneous fibrosarcoma. One cat demonstrated leukocytosis, increased liver enzymes, and signs of acute renal failure two weeks after initiating therapy (5 mg PO SID). No dose escalation was made in this cat. Five cats endured dose escalations of 10 mg PO SID in two cats and 20 mg PO SID in three cats and were treated for 2–4 months. None of these cats experienced any signs of toxicity as measured by CBC and biochemical profile. Conclusions: Only one cat experienced toxicity that may have been associated with low dose administration of STI571. As most cats tolerated the drug without an adverse effect, further evaluation of STI571 in a phase II clinical trial is warranted.     

Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing cats

Intravenously administered docetaxel (DT) is problematic in cats because of the requirement for premedication to ameliorate acute vehicle-induced hypersensitivity reactions. Previously we have revealed that therapeutic plasma concentrations of DT can be achieved in normal and tumor-bearing dogs when DT is administered PO in combination with oral cyclosporin A (CSA). The purpose of this study was to identify the maximally tolerated dosage and characterize the pharmacokinetic disposition of oral DT combined with CSA in cats with tumors. Eighteen tumor-bearing cats were enrolled in this phase I dose escalation and pharmacokinetic study. DT was administered by gavage with CSA (5 mg/kg) twice over a 3-week period. The starting dose of DT was 1.0 mg/kg. Based on the clinical toxicity profile, with gastrointestinal adverse effects and hematologic toxicity the maximal tolerated dose of oral DT was 1.75 mg/kg in combination with 5 mg/kg CSA. Additional studies are necessary to determine the efficacy of DT/CSA in cats with epithelial tumors.     

Injection site sarcomas in cats

Feline injection-site sarcomas have mostly been associated with the administration of vaccines. Although the pathogenesis remains largely unknown, it is believed that the inflammatory reaction caused from the injection of the compound leads to uncontrolled proliferation of fibroblasts and myofibroblasts that in a subset of cats undergo malignant transformation. Pretreatment evaluation and proper planning of the therapy are essential. Because of the aggressive nature of these tumors, a multimodality treatment approach is being recommended. A combination of surgery and radiation therapy with or without chemotherapy appears to be providing the best prognosis.     

Phase I evaluation of CCNU (lomustine) in tumor-bearing cats

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.     

Do postvaccinal sarcomas occur in Australian cats ?

SUMMARY: A soft tissue sarcoma occurred in the interscapular area of a cat, 1 to 7 months after vaccination at that site. The vaccine contained inactivated feline panleucopaenia virus combined with modified live feline herpesvirus and calicrvirus. The tumour showed histological features of both fibrosarcoma and malignant fibrous histiocytoma. The tumour was observed to evolve from the site of a presumed postvaccinal granuloma. Local recurrence 6 weeks post excision necessitated more radical resection. Euthanasia was performed 2 years later when pleural effusion developed. The cause of effusion was not determined. There was no palpable evidence of local tumour regrowth at the time of euthanasia. A causal relationship between vaccination and sarcoma formation is considered based on the temporal association between the two events, the anatomical location of the tumour and histopathology consistent with postvaccinal sarcomas reported overseas. Six other vaccine site fibrosarcomas, potentially vaccine associated using the above criteria, are summarised.     

Interaction of clarithromycin with cyclosporine in cats: pharmacokinetic study and case report

Clarithromycin (CLM) has been known to increase the cyclosporine (CsA) trough levels in human transplant patients. However, the interaction of CLM with CsA has not been reported in cats. In this study, the effects of oral dosing of CLM on the pharmacokinetics and dosing of CsA in cats were investigated. Co-administration of CLM with CsA resulted in significant increases of oral bioavailability of CsA. In addition, CLM reduced the CsA dosage required to maintain the therapeutic CsA trough levels to almost 35% of the initial CsA therapy and the dose frequency was successfully replaced from a twice a day schedule to once a day in a feline kidney transplant patient. The addition of CLM to the regular CsA-based immunosuppression could be used as an effective alternative to classical ketoconazole treatment in feline kidney transplant patients and may result in substantial cost saving and convenience for the cat owners.     

Comparative vaccine-specific and other injectable-specific risks of injection-site sarcomas in cats

Objective-To compare associations between vaccine types and other injectable drugs with development of injection-site sarcomas in cats. Design-Case-control study. Animals-181 cats with soft tissue sarcomas (cases), 96 cats with tumors at non-vaccine regions (control group I), and 159 cats with basal cell tumors (control group II). Procedures-Subjects were prospectively obtained from a large pathology database. Demographic, sarcoma location, basal cell tumor, and vaccine and other injectable history data were documented by use of a questionnaire and used to define case, control, and exposure status. Three control groups were included: cats with sarcomas at non-vaccine sites, cats with basal cell tumors, and a combined group of cats with sarcomas at non-vaccine sites and cats with basal cell tumors. χ(2) tests, marginal homogeneity tests, and exact logistic regression were performed. Results-In the broad interscapular region, the frequency of administration of long-acting corticosteroid injections (dexamethasone, methylprednisolone, and triamcinolone) was significantly higher in cases than in controls. In the broad rear limb region, case cats were significantly less likely to have received recombinant vaccines than inactivated vaccines; ORs from logistic regression analyses equaled 0.1, with 95% confidence intervals ranging from 0 to 0.4 and 0 to 0.7, depending on control group and time period of exposure used. Conclusions and Clinical Relevance-This case-control study measuring temporal and spatial exposures efficiently detected associations between administrations of various types of vaccines (recombinant vs inactivated rabies) and other injectable products (ie, long-acting corticosteroids) with sarcoma development without the need to directly measure incidence. These findings nevertheless also indicated that no vaccines were risk free. The study is informative in allowing practitioners to weigh the relative merits and risks of commonly used pharmaceutical products.     

Treatment of vascular and soft-tissue sarcomas in dogs using an alternating protocol of ifosfamide and doxorubicin

A retrospective analysis was done to assess the toxicity and efficacy associated with an alternating chemotherapy protocol of ifosfamide (375 mg m^?2) and doxorubicin (30 mg m^?2) for adjuvant treatment of 39 dogs with sarcomas. Twelve dogs had various soft‐tissue sarcomas and 27 dogs had hemangiosarcoma (HSA). Complete blood counts were evaluated 7 days after the first dose of ifosfamide and doxorubicin. One dog had grade 4 neutropenia (<500 µL^?1) after treatment with ifosfamide and one dog had grade 3 neutropenia (500–1000 µL^?1) after treatment with doxorubicin. One dog treated with doxorubicin was hospitalized for 24 h due to vomiting. The median survival time (ST) for the 27 dogs with HSA treated by surgery and with doxorubicin/ifosfamide was 149 days (mean 366 days). Although the protocol of alternating ifosfamide and doxorubicin was well tolerated, it failed to result in a statistically significant improvement in the ST when compared to a historical population of dogs with stage 2 splenic HSA treated by surgery alone.     

Oral pharmacokinetic and pharmacodynamic effects of FTY720 in cats

The aim of the study was to determine pharmacokinetic and pharmacodynamic profiles of FTY720 in cats and identify any toxic side effects. Six adult cats were used for the experimental study. Single oral dosages were tested at 0.05, 0.3 and 1.0 mg/kg. Whole blood drug concentration, total white blood cell and differential counts were monitored. Flow cytometry evaluated the effects on lymphocyte subsets. A toxicity study consisted of cats receiving a dose of 0.15 mg/kg daily for 30 days. Daily observation, physical examination and bloodwork were evaluated to assess for toxicity. All single doses resulted in > or =80% reduction in circulating lymphocytes within 12 h after administration, with the duration of lymphopenia being dose dependent. CD4+ and CD5+ T cells were specifically depleted. Peripheral neutrophils declined by approximately 70% at all dosages tested. No other toxic side effects were observed. Results of this study suggest that FTY720 is effective at inducing a peripheral lymphopenia in cats without any toxic side effects. Currently, cats appear to be the only species in which FTY720 induces a neutropenia. This study provides the foundation for future clinical transplantation trials using FTY720 in cats. By using combination therapy of FTY720 and low dose cyclosporine, the incidence of serious side effects may be reduced while still preventing allograft rejection.     

Multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats

OBJECTIVE: To determine whether particular vaccine brands, other injectable medications, customary vaccination practices, or various host factors were associated with the formation of vaccine-associated sarcomas in cats. DESIGN: Prospective multicenter case-control study. ANIMALS: Cats in the United States and Canada with soft tissue sarcomas or basal cell tumors. PROCEDURE: Veterinarians submitting biopsy specimens from cats with a confirmed diagnosis of soft tissue sarcoma or basal cell tumor were contacted for patient medical history. Time window statistical analyses were used in conjunction with various assumptions about case definitions. RESULTS: No single vaccine brand or manufacturer within antigen class was found to be associated with sarcoma formation. Factors related to vaccine administration were also not associated with sarcoma development, with the possible exception of vaccine temperature prior to injection. Two injectable medications (long-acting penicillin and methyl prednisolone acetate) were administered to case cats more frequently than to control cats. CONCLUSIONS AND CLINICAL RELEVANCE: Findings do not support the hypotheses that specific brands or types of vaccine within antigen class, vaccine practices such as reuse of syringes, concomitant viral infection, history of trauma, or residence either increase or decrease the risk of vaccine-associated sarcoma formation in cats. There was evidence to suggest that certain long-acting injectable medications may also be associated with sarcoma formation.     

Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing dogs

OBJECTIVE: To determine the maximum tolerated dose and characterize the pharmacokinetic disposition of an orally administered combination of docetaxel and cyclosporin A (CSA) in dogs with tumors. ANIMALS: 16 client-owned dogs with metastatic or advanced-stage refractory tumors. PROCEDURES: An open-label, dose-escalation, single-dose, phase I study of docetaxel administered in combination with a fixed dose of CSA was conducted. Docetaxel (at doses of 1.5, 1.625, or 1.75 mg/kg) and CSA (5 mg/kg) were administered concurrently via gavage twice during a 3-week period. Plasma docetaxel concentrations were quantified by use of high-performance liquid chromatography, and pharmacokinetic disposition was characterized by use of noncompartmental analysis. Dogs' clinical signs and results of hematologic and biochemical analyses were monitored for evidence of toxicosis. RESULTS: No acute hypersensitivity reactions were observed after oral administration of docetaxel. Disposition of docetaxel was dose independent over the range evaluated, and pharmacokinetic variables were similar to those reported in previous studies involving healthy dogs, with the exception that values for clearance were significantly higher in the dogs reported here. The maximum tolerated dose of docetaxel was 1.625 mg/kg. Gastrointestinal signs of toxicosis were dose limiting. CONCLUSIONS AND CLINICAL RELEVANCE: The absence of myelosuppression suggested that the docetaxel-CSA combination may be administered more frequently than the schedule used. Further studies are warranted to evaluate combination treatment administered on a biweekly schedule in dogs with epithelial tumors.     

A phase I clinical trial evaluating imatinib mesylate (Gleevec) in tumor-bearing cats

A phase I clinical trial evaluating the toxicity of orally-administered imatinib mesylate was performed in 9 tumor-bearing cats. Imatinib is a small molecule, tyrosine kinase inhibitor, which selectively blocks the function of overexpressed proteins associated with various malignancies. Cats included in the study had diagnoses of fibrosarcoma, squamous cell carcinoma, and mast cell tumor, and each cat was staged using CBC and serum biochemistry; urinalysis, thoracic radiographs, and abdominal ultrasonography were performed in some cats. Most cats were treated previously by surgery, radiation therapy, chemotherapy, or some combination of these treatments. None of the cats received any concurrent chemotherapy. Six cats were treated with imatinib mesylate at 1-2 mg/kg PO q24h. Dose escalations were made to 2, 4, and 10 mg/kg PO q24h in 5 cats. Two cats started therapy at 10 mg/kg PO q24h, and 1 cat started therapy at 15 mg/kg PO q24h; all 3 cats remained at these dosages. No signs of toxicity, as evaluated by CBC and serum biochemistry, were noted in 8 of the 9 cats, and minimal gastrointestinal toxicity was observed. Due to the low frequency of adverse effects, further evaluation of imatinib is ongoing at a dosage of 10 mg/kg PO q24h.     

Cardiac troponin I in cats with hypertrophic cardiomyopathy

The molecular structure of cardiac troponin I (cTnI) is highly conserved across mammalian species and assays developed for its measurement in human patients have been validated in a number of veterinary species. A raised concentration of circulating cTnI is a sensitive and specific marker of cardiac myocyte injury. Raised levels have been documented in a variety of cardiac diseases in both human and veterinary patients. This study compared serum cTnI concentrations between 16 cats diagnosed with hypertrophic cardiomyopathy (HCM) using echocardiography and 18 control cats. The results show that cats with HCM have significantly higher concentration of serum cTnI (median 0.95 ng/ml, range 0.2-4.1 ng/ml) than control cats (median <0.2 ng/ml, range <0.2-0.25 ng/ml) [P<0.0001]. Furthermore in cats with cardiomyopathy a weak correlation was found between the thickness of the left ventricular freewall in diastole measured by ultrasound and serum cTnI concentration (r(2)=0.28;P=0.036). These results suggest that measurement of serum cTnI concentration may enable cats with cardiomyopathy to be distinguished from normal cats using the assay described here.