Frequency and Severity of Neutropenia Associated with Food and Drug Administration Approved and Compounded Formulations of Lomustine in Dogs with Cancer.

BACKGROUND: Compounded lomustine is used commonly in veterinary patients. However, the potential variability in these formulations is unknown and concern exists that compounded formulations of drugs may differ in potency from Food and Drug Administration (FDA)-approved products. HYPOTHESIS/OBJECTIVES: The initial objective of this study was to evaluate the frequency and severity of neutropenia in dogs treated with compounded or FDA-approved formulations of lomustine. Subsequent analyses aimed to determine the potency of lomustine obtained from several compounding pharmacies. ANIMALS: Thirty-seven dogs treated with FDA-approved or compounded lomustine. METHODS: Dogs that received compounded or FDA-approved lomustine and had pretreatment and nadir CBCs performed were eligible for inclusion. Variables assessed included lomustine dose, neutrophil counts, and severity of neutropenia. Lomustine 5 mg capsules from 5 compounding sources were tested for potency using high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection. RESULTS: Twenty-one dogs received FDA-approved lomustine and 16 dogs were treated with lomustine prescribed from a single compounding pharmacy. All dogs treated with FDA-approved lomustine were neutropenic after treatment; 15 dogs (71%) developed grade 3 or higher neutropenia. Four dogs (25%) given compounded lomustine became neutropenic, with 2 dogs (12.5%) developing grade 3 neutropenia. The potency of lomustine from 5 compounding pharmacies ranged from 50 to 115% of the labeled concentration, with 1 sample within ±10% of the labeled concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: These data support broader investigation into the potency and consistency of compounded chemotherapy drugs and highlight the potential need for greater oversight of these products.

Carboplatin versus alternating carboplatin and doxorubicin for the adjuvant treatment of canine appendicular osteosarcoma: a randomized, phase III trial.

Despite numerous published studies describing adjuvant chemotherapy for canine appendicular osteosarcoma, there is no consensus as to the optimal chemotherapy protocol. The purpose of this study was to determine whether either of two protocols would be associated with longer disease-free interval (DFI) in dogs with appendicular osteosarcoma following amputation. Dogs with histologically confirmed appendicular osteosarcoma that were free of gross metastases and underwent amputation were eligible for enrollment. Dogs were randomized to receive either six doses of carboplatin or three doses each of carboplatin and doxorubicin on an alternating schedule. Fifty dogs were included. Dogs receiving carboplatin alone had a significantly longer DFI (425 versus 135 days) than dogs receiving alternating carboplatin and doxorubicin (P = 0.04). Toxicity was similar between groups. These results suggest that six doses of carboplatin may be associated superior DFI when compared to six total doses of carboplatin and doxorubicin.

Treatment of feline intermediate- to high-grade lymphoma with a modified university of Wisconsin-Madison protocol: 119 cases (2004-2012).

CHOP-based (cyclophosphamide, doxorubicin, vinca alkaloid, prednisolone) chemotherapy protocols are often recommended for treatment of feline lymphoma. While maintenance-free CHOP-based protocols have been published and readily used in dogs, there is limited literature regarding similar maintenance-free protocols in cats. The purpose of this study was to describe the outcome of cats with intermediate- to high-grade lymphoma that were prescribed a modified 25-week University of Wisconsin-Madison (UW-25) chemotherapy protocol. A secondary objective was examination of potential prognostic factors. One hundred and nineteen cats from five institutions treated with a UW-25-based protocol were included. The Kaplan-Meier median progression-free interval (PFI) and survival time (MST) were 56 and 97 (range 2-2019) days, respectively. Cats assessed as having a complete response (CR) to therapy had significantly longer PFI and MST than those with partial or no response (PFI 205 versus 54 versus 21 days, respectively, P < 0.0001 and MST 318 versus 85 versus 27 days, respectively, P < 0.0001).

Bacterial urinary tract infections associated with transitional cell carcinoma in dogs.

BACKGROUND: Urinary tract infections (UTI) are believed to be common in dogs with transitional cell carcinoma (TCC), but incidence and contributing factors have not been reported. OBJECTIVES: To determine the frequency and bacterial agents associated with UTI in dogs with TCC and define contributing factors. ANIMALS: Eighty-five dogs with a history of urogenital TCC undergoing treatment with chemotherapy that had at least 1 urine culture performed. METHODS: Medical records and culture results were retrospectively reviewed and ultrasound images were reviewed when available. Clinical factors were evaluated statistically for association with positive culture. RESULTS: Fifty-five percent (47/85) of dogs had at least 1 positive culture during the course of treatment. Female dogs (80%, 40/50) were more likely than male dogs (29%, 10/35) to have at least 1 positive culture. Ultrasound examination determined that female dogs were more likely to have urethral (74%, 31/42) or trigonal tumor involvement (71%, 30/42) compared to male dogs (32%, 9/28 and 43%, 12/28, respectively). The most commonly isolated organisms were Staphylococcus spp. (23.9%, 29/121) and Escherichia coli (19.8%, 24/121). Dogs with urethral involvement of TCC were significantly more likely to have at least 1 positive culture than dogs without urethral involvement (75%, 30/40 versus 30%, 9/30). CONCLUSIONS: Urinary tract infection is common in dogs with TCC highlighting the importance of regular monitoring for bacterial cystitis in dogs with TCC. In addition, clinical factors such as tumor location and sex may be predictive of positive culture and can help clinicians assess the risk of UTI.

Randomized phase III trial of piroxicam in combination with mitoxantrone or carboplatin for first-line treatment of urogenital tract transitional cell carcinoma in dogs.

BACKGROUND: Reported response rates of transitional cell carcinoma (TCC) in dogs to piroxicam in combination with either mitoxantrone or carboplatin are similar; however, it is unknown whether either drug might provide superior duration of response. HYPOTHESIS/OBJECTIVES: To determine if the progression-free interval (PFI) of dogs with TCC treated with mitoxantrone and piroxicam was different than that of dogs receiving carboplatin and piroxicam. The hypothesis was that the efficacy of mitoxantrone is no different from carboplatin. ANIMALS: Fifty dogs with TCC without azotemia. METHODS: Prospective open-label phase III randomized study. Either mitoxantrone or carboplatin was administered every 3 weeks concurrently with piroxicam with restaging at 6-week intervals. Twenty-four dogs received carboplatin and 26 received mitoxantrone. RESULTS: Response was not different between groups (P = .56). None of the dogs showed complete response. In the mitoxantrone group, there were 2 (8%) partial responses (PR) and 18 (69%) dogs with stable disease (SD). In the carboplatin group, there were 3 PR (13%) and 13 (54%) dogs with SD. The PFI was not significantly different between groups (mitoxantrone = 106 days; carboplatin = 73.5 days; P = .62; hazard ratio 0.86; 95% confidence interval 0.47-1.56). Dogs with prostatic involvement experienced a shorter survival (median, 109 days) compared to dogs with urethral, trigonal, or apically located tumors; this difference was significant (median 300, 190, and 645 days, respectively; P = .005). CONCLUSIONS AND CLINICAL IMPORTANCE: This study did not detect a different in outcome in dogs with TCC treated with either mitoxantrone or carboplatin in combination with piroxicam.

Biological behaviour of canine mandibular osteosarcoma. A retrospective study of 50 cases (1999-2007).

The purpose of this retrospective study was to describe the biological behaviour of canine mandibular osteosarcoma (OSA) and to examine factors for their impact on metastasis-free interval (MFI) and survival time (ST). Records from dogs treated with mandibulectomy for OSA (1999-2007) were reviewed. Archived tumour samples were evaluated for mitotic index (MI) and tumour grade. Fifty dogs were included, 21 received chemotherapy. Twenty-nine dogs (58%) developed metastatic disease. The median MFI was 627 days, and median ST was 525 days. In univariate analysis MI > 40 was prognostic for decreased MFI and ST. Grade also influenced MFI and ST, with 5/21 (24%) dogs with grade II/III tumours metastasis-free at one year versus 16/22 (72%) dogs with grade I tumours (P = 0.002); and 5/21 (24%) dogs with grade II/III tumours alive versus 17/22 (77%) dogs with grade I tumours (P = 0.001). In multivariate analysis, histological grade and adjuvant chemotherapy were prognostic for MFI and ST.

Paraneoplastic hypertrophic osteopathy in 30 dogs.

Paraneoplastic hypertrophic osteopathy (pHO) is known to occur in both canine and human cancer patients. While the pathology of pHO is well-described in the dog, very little information exists regarding the true clinical presentation of dogs affected with pHO. The primary objective of this study was to provide a more comprehensive clinical picture of pHO. To this end, we retrospectively identified 30 dogs and recorded data regarding presenting complaints and physical examination (PE) findings on the date of pHO diagnosis. As a secondary objective, any blood test results were also collected from the computerized records. The most common clinical signs included leg swelling, ocular discharge and/or episcleral injection, lameness, and lethargy. The most common haematological and serum biochemical abnormalities included anaemia, neutrophilia and elevated alkaline phosphatase. In addition to presenting a more detailed clinical description of pHO in the dog, these data support the previously described haematological, serum biochemical and PE abnormalities published in individual case reports.

Aggressive local therapy combined with systemic chemotherapy provides long-term control in grade II stage 2 canine mast cell tumour: 21 cases (1999-2012).

This retrospective case series evaluates the outcome of 21 dogs with grade II stage 2 mast cell tumour (MCT) treated with adequate local therapy and adjuvant systemic chemotherapy (prednisone, vinblastine and CCNU). The median survival for all dogs was 1359 days (range, 188-2340). Median disease-free interval was 2120 days (149-2325 days). Dogs treated with surgery and chemotherapy had shorter survival (median, 1103 days; 188-2010 days) than those that underwent surgery, radiation therapy and chemotherapy as part of their treatment (median, 2056 days; 300-2340 days). Two patients had local recurrence in the radiation field and four patients had de novo MCT. Distant metastasis was not observed in any dogs. The results of this study suggest that, in the presence of loco-regional lymph node metastasis in grade II MCT, the use of prednisone, vinblastine and CCNU after adequate local-regional therapy can provide a median survival in excess of 40 months.

Phase I clinical trial of oral rosiglitazone in combination with intravenous carboplatin in cancer-bearing dogs.

Rosiglitazone is an FDA-approved peroxisome proliferator-activated receptor gamma (PPARγ) agonist and antidiabetic agent in humans that has been investigated for its ability to reduce tumor cell growth. The purpose of this study was to determine the maximally tolerated dose, peak plasma concentrations and side effect profile of oral rosiglitazone when combined with carboplatin in dogs with cancer. Rosiglitazone was administered at 6 and 8 mg/m(2) to seven dogs. Carboplatin was administered at 240-300 mg/m(2) in combination with rosiglitazone. For toxicity evaluation, the toxicity data for the seven dogs in this study were combined with the toxicity data from three dogs previously reported in a methodology study. Peak plasma rosiglitazone concentrations varied with dose. The dose-limiting toxicity was hepatic at a dose of 8 mg/m(2). Three dogs had mild to moderate alanine aminotransferase elevations but no changes in total bilirubin, alkaline phosphatase, blood glucose or γ-glutamyltranspeptidase values were noted.

Clinical characteristics and outcome in dogs with splenic marginal zone lymphoma.

BACKGROUND: Splenic marginal zone lymphoma (MZL) is a form of indolent B-cell lymphoma that is not well characterized in dogs. HYPOTHESIS/OBJECTIVES: The purpose of this study was to describe clinical characteristics and outcome in dogs with splenic MZL confirmed by histopathology, immunophenotyping, and molecular clonality assessment. We hypothesized that affected dogs would have prolonged survival time with splenectomy alone. ANIMALS: Thirty-four dogs were included. Twenty-nine dogs were diagnosed after splenectomy, and 5 dogs were diagnosed at necropsy. METHODS: Pathology records were searched for dogs with histologically confirmed splenic MZL. Clinical and outcome data were retrospectively collected by medical record review, and prognostic factors were evaluated. Histopathology was reviewed by a board-certified pathologist, and tissue sections were subjected to immunophenotyping and molecular clonality assessment by PCR. RESULTS: Immunohistochemistry confirmed a B-cell phenotype for all dogs. Molecular clonality assessment was performed in 33 of 34 dogs, of which 24 had clonal rearrangement of immunoglobulin (Ig) loci, 3 had pseudoclonal rearrangement, and 6 had polyclonal rearrangement. The overall median survival time (MST) for the 29 dogs that underwent splenectomy was 383 days. The MST for 14 of 29 asymptomatic dogs that underwent splenectomy for MZL was 1,153 days as compared to 309 days for 15/29 dogs with clinical signs referable to splenic MZL (P = .018). Lymph node involvement, hemoabdomen, anemia, chemotherapy, and concurrent malignancy did not affect survival outcome. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs diagnosed with splenic MZL can have prolonged survival with splenectomy alone, without the use of adjuvant chemotherapy. Asymptomatic dogs may have a better survival outcome.

Immunohistochemical characterization of feline mast cell tumors.

Expression of histamine, serotonin, and KIT was evaluated in 61 archived feline mast cell tumors (MCTs) from the skin (n = 29), spleen (n = 17), and gastrointestinal (GI) tract (n = 15) using immunohistochemistry. Twenty-eight percent of cutaneous MCTs, 18% of splenic MCTs, and 53% of GI MCTs displayed histamine immunoreactivity. Serotonin immunoreactivity was detected in 3 GI and 1 cutaneous MCT. Sixty-nine percent of cutaneous MCTs, 35% of splenic MCTs, and 33% of GI MCTs were positive for KIT. Expression of these biogenic amines and KIT was less common than expected. Results of this study suggest heterogeneity in feline MCTs based on anatomic location. Further studies are needed to explain the significance of these differences.

Outcome in dogs with surgically resected oral fibrosarcoma (1997-2008).

Oral fibrosarcoma (FSA) is a common oral tumour in dogs, and historically reported survival times after surgical excision range from 7.0 to 12.2 months with local recurrence rates of 32-57%. The purpose of this retrospective study was to report outcome in a cohort of dogs with oral FSA treated with surgical excision with or without adjuvant radiation therapy. Twenty-nine dogs with a histological diagnosis of FSA arising from the oral cavity that underwent surgical resection of their oral FSA were included in this study. Twenty-one dogs were treated with surgical excision alone and eight dogs with both surgery and radiation therapy. The median progression-free interval was >653 days. The median survival time was 743 days. The 1- and 2-year survival rates were 87.7 and 57.8%, respectively. Seven (24.1%) dogs developed local recurrence. Seven dogs (24.1%) developed metastasis.

Clinical outcome in 94 cases of dermal haemangiosarcoma in dogs treated with surgical excision: 1993-2007*.

Canine dermal haemangiosarcoma (HSA) is believed to have a better prognosis compared to HSA in other organs, but outcome has only been reported in a small number of dogs. The purpose of this study was to assess outcome and prognostic factors in a larger cohort of dogs with dermal HSA. Clinical data was collected retrospectively for 94 dogs and histopathology was reviewed in 53 dogs. Median overall survival time was 987 days. Dogs of predisposed breed with ventral location and histologic solar changes had longer survivals. Loco-regional recurrence occurred in 72/94 (77%) dogs. Predisposed breeds with ventral location and multiple masses were more likely to develop recurrence. Non-predisposed breeds with invasive tumours were more likely to develop metastasis. Results suggest that dogs with solar-induced dermal HSA may have high recurrence rates, but prolonged survivals. Dogs with non-solar tumours may be at increased risk for metastasis and shorter survival.

Phase I/II clinical trial of 2-difluoromethyl-ornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma.

Polyamines are essential for cell proliferation. Their production is dysregulated in many cancers and polyamine depletion leads to tumour regression in mouse models of squamous cell carcinoma (SCC). The purpose of this study was to determine the maximally tolerated dose of the polyamine transport inhibitor, MQT 1426, when combined with the ornithine decarboxylase (ODC) inhibitor, DFMO, and to determine whether this therapy results in reduction in tumour polyamine levels. Thirteen cats with oral SCC received both drugs orally and serial tumour biopsies were obtained for polyamine measurement. Cats were monitored for response to therapy and toxicity. A maximum tolerated dose (MTD) of MQT 1426 when combined with DFMO was determined. Dose-limiting toxicity was vestibular in nature, but was fully reversible. Spermidine and total polyamine levels decreased significantly in tissues, two cats experienced objective tumour regression and six cats had stable disease. These results suggest that further study of polyamine depletion therapies is warranted.

Prospective randomized clinical trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepatopathy in tumor-bearing dogs.

BACKGROUND: Increases in liver enzymes occur in up to 86% of dogs receiving CCNU and can result in treatment delay or early discontinuation of treatment. Denamarin contains S-adenosylmethionine and silybin, both of which have been investigated as treatments for various liver diseases. HYPOTHESIS: Dogs on CCNU receiving Denamarin have lower alanine aminotransferase (ALT) activity than dogs not receiving Denamarin. Dogs on Denamarin are less likely to require treatment delay because of hepatopathy and are more likely to complete their prescribed course of CCNU. ANIMALS: Dogs with lymphoma, mast cell tumor, or histiocytic sarcoma that were prescribed CCNU with or without corticosteroids and with normal ALT activity were eligible for enrollment. METHODS: Dogs were prospectively randomized to receive either concurrent Denamarin during CCNU chemotherapy or to receive CCNU alone. Liver-specific laboratory tests were run before each dose of CCNU. RESULTS: Increased liver enzyme activity occurred in 84% of dogs receiving CCNU alone and in 68% of dogs on concurrent Denamarin. Dogs receiving CCNU alone had significantly greater increases in ALT, aspartate aminotransferase, alkaline phosphatase, and bilirubin and a significantly greater decrease in serum cholesterol concentrations than dogs receiving concurrent Denamarin. Dogs receiving CCNU alone were significantly more likely to have treatment delayed or discontinued because of increased ALT activity. CONCLUSIONS: Increased liver enzyme activity occurs commonly in dogs receiving CCNU chemotherapy. These results support the use of concurrent Denamarin to minimize increased liver enzyme activity in dogs receiving CCNU chemotherapy. Denamarin treatment also increases the likelihood of dogs completing a prescribed CCNU course.

CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma.

Dogs with multicentric T-cell lymphoma are commonly treated with CHOP chemotherapy protocols that include cyclophosphamide, doxorubicin, vincristine and prednisone. The purpose of this study was to evaluate the use of CHOP chemotherapy for dogs with multicentric T-cell lymphoma. Identification of prognostic factors in this specific subset of dogs was of secondary interest. Twenty-three out of 24 dogs responded to CHOP chemotherapy and these dogs remained on the protocol for a median of 146 days. No variable was associated with progression free survival (PFS) including stage, substage, hypercalcemia or radiographic evidence of a cranial mediastinal mass. The median overall survival time (OST) for all dogs was 235 days. Dogs that were thrombocytopenic at presentation experienced a significantly longer OST (323 versus 212 days, P=0.01).

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.

Long-term survival in dogs with localized histiocytic sarcoma treated with CCNU as an adjuvant to local therapy.

Histiocytic sarcoma (HS) is associated with a poor prognosis owing to the presence of metastasis at the time of diagnosis in most dogs. Improved outcome has been reported in several dogs with localized HS following local therapy, however, distant metastasis occurs in 70-91% of dogs suggesting that adjuvant systemic therapy is necessary. The purpose of this retrospective study was to describe clinical characteristics and outcome in dogs with localized HS treated with aggressive local therapy plus adjuvant CCNU chemotherapy. Data from 16 dogs were evaluated. The median disease-free interval was 243 days. Two dogs had local recurrence and eight dogs developed metastatic disease with a median time to relapse of 201 days in these 10 dogs. The median survival time for all 16 dogs was 568 days. These results support the recommendation for aggressive local therapy combined with adjuvant CCNU chemotherapy in dogs with localized HS.

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 alpha and beta 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.

Identification of survivin, an inhibitor of apoptosis, in canine urinary bladder transitional cell carcinoma.

Survivin, an inhibitor of apoptosis, is overexpressed in human invasive transitional cell carcinoma (TCC) of the urinary bladder. Survivin expression in canine TCC has not been defined. This study was designed to compare survivin expression between canine TCC and normal urinary bladder tissue. Reverse-transcriptase polymerase chain reaction (PCR) and immunohistochemistry (IHC) were performed on fresh-frozen and formalin-fixed tissues, respectively. All TCC tissues (n = 6) and 11/22 normal tissues assessed by PCR were positive for survivin. This difference was not significant (P = 0.06). With regard to IHC, 28/41 TCC samples were positive for nuclear survivin, whereas 0/46 normal tissues had nuclear immunoreactivity (P < 0.001). Cytoplasmic immunoreactivity did not significantly differ between TCC (7/41) and normal tissues (17/46) (P = 0.07). We conclude that nuclear survivin is present in canine TCC, but not in normal bladder urothelium. Future studies will evaluate the role of nuclear survivin in TCC development and as a potential therapeutic target.