RESUMO
Rabacfosadine (RAB), a novel double prodrug of the acyclic nucleotide phosphonate PMEG, preferentially targets neoplastic lymphocytes with reduced off target toxicity. Historical studies have suggested that every 21-day dosing is effective with acceptable toxicity. The purpose of this study was to evaluate RAB's safety and efficacy at 2 different doses every 21 days in dogs with relapsed B-cell lymphoma. Dogs that had failed 1 doxorubicin-based chemotherapy protocol were eligible for inclusion in this prospective trial. Once enrolled, dogs were randomized to receive RAB at either 0.82 mg/kg or 1.0 mg/kg as a 30-minute IV infusion every 21 days for up to 5 treatments. Response assessment and adverse event (AE) evaluation were performed every 21 days via VCOG criteria. Fifty dogs were enrolled, with 16 treated at 0.82 mg/kg and 34 treated at 1.0 mg/kg. The overall response rate was 74%, with 45% of dogs experiencing a complete response (CR). The median progression free intervals (PFIs) were 108 days, 172 days and 203 days for all dogs, all responders, and all CRs, respectively. Response rates and PFIs were similar in both treatment groups. The incidence of AEs, dose delays, dose reductions and withdrawals were not statistically different between the 2 groups. The AEs observed were similar to those previously reported and included hematologic, gastrointestinal, dermatologic and pulmonary AEs. One dog had grade 5 pulmonary fibrosis; otherwise, AEs resolved with supportive treatment. Rabacfosadine is a generally well tolerated, effective chemotherapy option for dogs with relapsed B-cell lymphoma.
Assuntos
Alanina/análogos & derivados , Antineoplásicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Linfoma de Células B/veterinária , Purinas/uso terapêutico , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cães , Relação Dose-Resposta a Droga , Linfoma de Células B/tratamento farmacológico , Purinas/administração & dosagem , Purinas/efeitos adversos , Recidiva , Resultado do TratamentoRESUMO
Glutathione S-transferase-theta (GSTT1) is a carcinogen detoxification enzyme, and low activity variants are associated with lymphoma in humans. We recently found a variant in the 3' untranslated region (UTR) of canine GSTT1, *101_102insT, which was predicted to change miRNA binding and was found in 5 of 17 golden retriever (GR) dogs with lymphoma but none of 14 healthy GRs. The aim of this study was to determine whether this variant led to decreased GSTT1 expression and was a discernible risk factor for lymphoma within the GR breed. On resequencing, *101_102insT appeared to be in complete linkage disequilibrium with 3 additional 3'UTR variants, leading to the inferred haplotype *3T>C; *101_102insT; *190C>A; *203T>C. In canine livers that were heterozygous for this variant haplotype, GSTT1 protein expression was significantly lower compared to the reference haplotype (densitometry .40 vs .64, P = .022), and GSTT1 transcript levels by qPCR were also significantly lower (fold difference .52, P = .012), without evidence of substantial allelic expression imbalance. The variant haplotype led to >50% decrease in expression in vitro (.31 ± .07 vs .64 ± .19; P = .019). We found no significant difference in minor allele frequencies between 71 GR dogs with lymphoma (MAF .162) and 33 healthy age-matched controls (MAF .136, P = .69). Our results indicate that the variant GSTT1 3'UTR haplotype containing *101_102insT reduces gene expression, which could lead to impaired carcinogen detoxification, but was not a detectable risk factor for lymphoma in GR dogs.
Assuntos
Glutationa Transferase/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Estudos de Casos e Controles , Doenças do Cão/genética , Cães/genética , Cães/metabolismo , Feminino , Predisposição Genética para Doença/genética , Glutationa Transferase/genética , Haplótipos , Fígado/enzimologia , Linfoma/genética , Linfoma/veterinária , Masculino , Fatores de RiscoRESUMO
Efficacious therapies for measurable metastatic canine osteosarcoma (OSA) are generally lacking. Preliminary retrospective studies suggested that approximately 50% of dogs with measurable metastatic OSA experienced clinical benefit (objective response or clinically meaningful disease stabilisation) following toceranib (TOC) treatment. The purpose of this clinical trial was to prospectively evaluate the clinical outcome following TOC treatment in dogs with measurable pulmonary metastatic OSA. A secondary goal was to identify potential biomarkers of clinical benefit by measuring changes in plasma vascular endothelial growth factor (VEGF) and circulating regulatory T-cell (Treg) percentage. Twenty-two dogs with pulmonary metastasis from appendicular OSA having undergone previous amputation were treated prospectively with TOC. Adverse events (AEs) were common but predominantly low grade. Nine patients were withdrawn from the study prior to the week 8 assessment of response either due to progressive disease (PD), decreased quality of life or owner perceived unacceptable AEs. Of the patients evaluable for disease progression at week 8 (or earlier), 3/17 (17.6 %) had stable disease with the remainder having PD. The median progression-free survival time for all patients was 57 days (range 7-176 days) with a median overall survival time of 89 days (range 7-574 days). Plasma VEGF concentrations were significantly elevated in patients after 4 weeks of TOC treatment, but no changes were observed in percentage of Treg in peripheral blood. Overall, the results of this clinical trial do not support the use of TOC as single agent therapy for canine metastatic OSA.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/veterinária , Doenças do Cão/tratamento farmacológico , Indóis/uso terapêutico , Osteossarcoma/veterinária , Pirróis/uso terapêutico , Animais , Biomarcadores/sangue , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Doenças do Cão/mortalidade , Cães , Ensaio de Imunoadsorção Enzimática/veterinária , Feminino , Masculino , Osteossarcoma/tratamento farmacológico , Osteossarcoma/mortalidade , Estudos Prospectivos , Análise de Sobrevida , Linfócitos T Reguladores/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: KIT inhibitors, such as toceranib (TOC), and vinblastine (VBL) have not been prospectively compared in the treatment of macroscopic mast cell tumors (MCTs). Also, it is unknown whether VBL or TOC is superior for treating MCT without c-kit mutations. HYPOTHESIS/OBJECTIVES: To determine the value of KIT genotyping and localization in treatment decisions for dogs with macroscopic MCT. We hypothesized that c-kit mutated MCT would have a better response to TOC than VBL. ANIMALS: Eighty-eight client-owned dogs with macroscopic MCT. METHODS: Prospective, randomized trial. Dogs were randomized to TOC (2.75 mg/kg EOD) or VBL (2.5 mg/m2 weekly × 4 then EOW) by KIT localization and c-kit mutation status using an adaptive randomization scheme. RESULTS: Sixty dogs were allocated to TOC and 28 to VBL. Of the dogs receiving TOC, 20% had c-kit mutations, compared to 30% receiving VBL (P = 0.74). Overall response rates were 46% (TOC) and 30% (VBL) (odds ratio = 1.56 [0.62-3.92]; P = 0.28). Median progression-free survival (PFS) for dogs receiving VBL was 78 days (7-1,521) and for TOC 95.5 (14-990); hazard ratio (HR) = 1.34 [0.72-2.50]; P = 0.36. Median overall survival (OS) was 241.5 days (10-1,521) for the VBL group and 159 (20-990) for the TOC group; HR = 0.80 ([0.45-1.41]; P = 0.44). CONCLUSIONS AND CLINICAL IMPORTANCE: Neither PFS nor OS was significantly different between treatment groups. As the proportion of dogs with c-kit mutations was not different between treatment groups in this population of dogs, c-kit mutation status did not predict treatment response.
Assuntos
Doenças do Cão/tratamento farmacológico , Indóis/uso terapêutico , Mastocitose Cutânea/veterinária , Prednisona/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Pirróis/uso terapêutico , Vimblastina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Cães , Feminino , Masculino , Mastocitose Cutânea/tratamento farmacológico , Mastocitose Cutânea/genética , Mutação , Estudos ProspectivosRESUMO
BACKGROUND: Cutaneous plasmacytosis (CP) is a syndrome of multiple cutaneous plasma cell tumors, in the absence of multiple myeloma. Although rare in both humans and dogs, treatment recommendations are usually extrapolated from multiple myeloma protocols. To date, no case series of CP have been described in the veterinary literature. HYPOTHESIS/OBJECTIVES: To describe clinical presentation, determine treatment response rates and duration, and report overall survival of dogs with CP. ANIMALS: Twenty-one client-owned dogs with CP. METHODS: Medical records of 21 dogs with CP were reviewed. Diagnosis was based on histopathologic evaluation of at least 1 representative cutaneous or subcutaneous lesion in dogs with ≥3 lesions. Dogs with suspicion of multiple myeloma were excluded. RESULTS: The most commonly affected breeds were the golden (5/21) and Labrador retriever (3/21). Fourteen of 21 dogs had >10 lesions, with some having >100. Lesions commonly were described as round, raised, pink-to-red, and variably alopecic or ulcerated. The most commonly used drug protocol was combined melphalan and prednisone, with an overall response rate (ORR) of 73.7% (14/19 dogs). Single-agent lomustine was associated with a similar ORR of 71.4% (5/7 dogs). For all treatments combined, the median progression-free interval after the first treatment was 153 days. The median survival time from the first treatment was 542 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Alkylating agents were effective in inducing remission of CP; corticosteroids, melphalan, and lomustine were the most commonly used drugs. Survival times were similar to those reported in dogs with multiple myeloma treated with alkylating agents.
Assuntos
Doenças do Cão/patologia , Plasmocitoma/veterinária , Neoplasias Cutâneas/veterinária , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Doenças do Cão/diagnóstico , Doenças do Cão/tratamento farmacológico , Doenças do Cão/mortalidade , Cães , Quimioterapia Combinada/veterinária , Feminino , Lomustina/uso terapêutico , Masculino , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Plasmocitoma/diagnóstico , Plasmocitoma/tratamento farmacológico , Plasmocitoma/patologia , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Standard of care treatment for multicentric lymphoma in dogs remains doxorubicin (DOX)-based combination chemotherapy, but owners may hesitate to commit the time and financial resources to complete such a protocol, typically requiring 12-16 visits. Rabacfosadine (RAB), a double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine, has substantial single-agent activity in dogs with lymphoma, and a different mechanism of action than DOX. HYPOTHESIS/OBJECTIVES: Our objective was to evaluate the efficacy and adverse effect (AE) profile of alternating doses of RAB and DOX in dogs with naïve multicentric lymphoma. ANIMALS: Fifty-four dogs with previously untreated lymphoma. METHODS: Open-label, multicenter prospective clinical trial. Dogs received alternating RAB (1.0 mg/kg IV weeks 0, 6, 12) and DOX (30 mg/m2 IV weeks 3, 9, 15). Dogs that achieved complete response (CR) were followed by monthly evaluations. Complete clinicopathological evaluation and assessment of remission and AEs were performed every 21 days. RESULTS: The overall response rate was 84% (68%; CR; 16%; partial response [PR)]. The overall median progression-free interval (PFI) was 194 days (216 for CR and 63 for PR). Most AEs were mild and self-limiting: gastrointestinal and hematologic AEs were most common. Thirteen dogs experienced dermatologic AEs, and 2 dogs developed grade 5 pulmonary fibrosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Alternating RAB/DOX generally was well tolerated and resulted in PFIs comparable to standard DOX-based multi-agent protocols, with fewer treatment visits. Most adverse events were mild or moderate and self-limiting. Further studies are warranted to explore long-term outcome and other RAB chemotherapy combinations.
Assuntos
Alanina/análogos & derivados , Antineoplásicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Doxorrubicina/uso terapêutico , Linfoma/veterinária , Pró-Fármacos/uso terapêutico , Purinas/uso terapêutico , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cães , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação/veterinária , Feminino , Linfoma/tratamento farmacológico , Masculino , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Purinas/administração & dosagem , Purinas/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: In humans geographical differences in the incidence and presentation of various cancers have been reported. However, much of this information has not been collected in veterinary oncology. AIM: The purpose of this study was to determine if a geographic difference in progression free survival exists for dogs with lymphoma treated within the US. MATERIALS AND METHODS: Medical records of 775 cases of canine lymphoma from 3 US regions (west, south and north), treated with CHOP chemotherapy, were retrospectively evaluated. Cases were collected from referral institutions and were required to have received at least one doxorubicin treatment and have follow up information regarding time to progression. RESULTS: Significant differences in sex (p = 0.05), weight (p = 0.049), stage (p < 0.001), immunophenotype (p = <0.001), and number of doxorubicin doses (p = 0.001) were seen between regions. Upon univariate analysis, progression free survival (PFS) differed by region (p = 0.006), stage (p = 0.009), sub-stage (p = 0.0005), and immunophenotype (p = 0.001). A multivariable Cox regression model showed that dogs in the western region had a significantly shorter PFS when compared to the south and east. CONCLUSION: PFS was significantly affected by stage, sub-stage and phenotype.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Cão/tratamento farmacológico , Linfoma não Hodgkin/veterinária , Animais , Ciclofosfamida/uso terapêutico , Doenças do Cão/mortalidade , Cães , Doxorrubicina/uso terapêutico , Feminino , Geografia Médica , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/mortalidade , Masculino , Prednisona/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Estados Unidos/epidemiologia , Vincristina/uso terapêuticoRESUMO
Canine transitional cell carcinoma (TCC) of the bladder has historically been treated with a combination of chemotherapy, cyclooxygenase inhibitors and radiation therapy. While surgery has been used to treat TCC of the bladder, its efficacy has yet to be established. Thirty-seven client owned dogs that underwent partial cystectomy +/- various nonsurgical treatments for TCC were retrospectively evaluated. The overall median progression-free interval (PFI) was 235 days and the median survival time (ST) was 348 days. Prognostic factors identified on univariate analysis significant for ST were age, tumor location, full thickness excision and frequency of piroxicam administration. Prognostic factors significant for PFI were full thickness excision and frequency of piroxicam administration. The median ST with partial cystectomy and daily piroxicam therapy, with or without chemotherapy, was 772 days. Dogs with non-trigonal bladder TCC treated with full thickness partial cystectomy and daily piroxicam (+/- chemotherapy) may have improved outcome compared to dogs treated with medical therapy.
Assuntos
Carcinoma de Células de Transição/veterinária , Cistectomia/veterinária , Doenças do Cão/cirurgia , Neoplasias da Bexiga Urinária/veterinária , Animais , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/cirurgia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Doenças do Cão/tratamento farmacológico , Doenças do Cão/mortalidade , Cães , Feminino , Masculino , Piroxicam/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
Canine cutaneous mast cell tumor (MCT) is the most common canine skin tumor and exhibits variable biologic behavior. Signaling through the KIT receptor tyrosine kinase promotes cellular proliferation and survival and has been shown to play a role in MCT progression. Despite investigations into numerous biomarkers and the proposal of several grading schemas, no single marker or grading system can accurately predict outcome in canine MCT. The first aim of this study was to develop an immunohistochemical assay to measure phosphorylated KIT (pKIT) to investigate its association with 2 commonly used grading systems and other established prognostic markers for canine MCT. Thirty-four archived MCTs were evaluated for expression of pKIT and Ki-67, KIT localization, mitotic count, mutations in exons 8 and 11 in c-kit, and grading by the Patnaik and 2-tier systems. Expression of pKIT was significantly ( P < .05) correlated with the 2-tier grading scheme and c-kit mutation. Correlation approached significance ( P = .06) with Mitotic Index (MI) and Ki-67. An additional aim was to determine whether pKIT labeling provides a pharmacodynamic marker for predicting response to the receptor tyrosine kinase inhibitor toceranib (TOC). MCTs from 4 of 7 patients demonstrated a partial response to TOC. pKIT expression was assessed by immunohistochemistry in biopsies obtained before and 6 hours after the patients were treated with TOC. Reduced pKIT expression after TOC treatment was demonstrated in 3 of the 4 patients with a partial response compared to 1 of the 3 nonresponders. Collectively, these results demonstrate that immunohistochemical detection of pKIT may be a clinically relevant assay to evaluate the activation status of the major oncogenic pathway in canine MCT.
Assuntos
Doenças do Cão/patologia , Mastocitose Cutânea/veterinária , Proteínas Proto-Oncogênicas c-kit/metabolismo , Animais , Biomarcadores , Doenças do Cão/diagnóstico , Cães , Mastocitose Cutânea/diagnóstico , Mastocitose Cutânea/patologia , Fosforilação , Prognóstico , Estudos RetrospectivosRESUMO
Mammalian cell tissue culture has been a critical tool leading to our current understanding of cancer including many aspects of cellular transformation, growth and response to therapies. The current use of large panels of cell lines with associated phenotypic and genotypic information now allows for informatics approaches and in silico screens to rapidly test hypotheses based on simple as well as complex relationships. Current cell line panels with large amounts of associated drug sensitivity and genomics data are comprised of human cancer cell lines (i.e. NCI60 and GDSC). There is increased recognition of the contribution of canine cancer to comparative cancer research as a spontaneous large animal model with application in basic and translational studies. We have assembled a panel of canine cancer cell lines to facilitate studies in canine cancer and report here phenotypic and genotypic data associated with these cells.
Assuntos
Linhagem Celular Tumoral , Descoberta de Drogas , Neoplasias/veterinária , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/patologia , Sobrevivência Celular , Descoberta de Drogas/métodos , Descoberta de Drogas/organização & administração , Humanos , MicroRNAs/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Pesquisa Translacional Biomédica , Medicina Veterinária/organização & administraçãoRESUMO
Epithelial cell adhesion molecule (EpCAM) is expressed in most human normal and neoplastic tissues of epithelial derivation and may have an association with tumour cell aggressiveness, a stem cell-like phenotype and clinical outcome. Antibody-based strategies for the targeting and capture of EpCAM-expressing tumour cells are showing promise, both as diagnostic tools and potential therapies. The aim of this study was to assess EpCAM expression in canine tumours. EpCAM expression was assessed in tumour cell lines via gene expression profiling and in formalin-fixed and paraffin wax-embedded tissues from canine carcinomas representing various anatomical sites by immunohistochemistry. EpCAM mRNA expression was higher in cell lines from carcinomas than those derived from sarcomas or haemopoietic tumours. EpCAM was expressed by >2/3 of tumour cells in 71% of canine carcinomas evaluated, irrespective of histotype, with the exception of carcinomas of the adrenal gland. Canine sarcomas and haemopoietic tumours were uniformly negative. Most canine carcinomas express EpCAM and so could be suitable for the study of EpCAM-directed diagnostics and therapeutics.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma/veterinária , Doenças do Cão/patologia , Molécula de Adesão da Célula Epitelial/biossíntese , Animais , Western Blotting , Cães , Molécula de Adesão da Célula Epitelial/análise , Imuno-Histoquímica , Análise Serial de TecidosRESUMO
Canine lymphoma (LSA) and osteosarcoma (OS) have high mortality rates and remain in need of more effective therapeutic approaches. Survivin, an inhibitor of apoptosis (IAP) family member protein that inhibits apoptosis and drives cell proliferation, is commonly elevated in human and canine cancer. Survivin expression is a negative prognostic factor in dogs with LSA and OS, and canine LSA and OS cell lines express high levels of survivin. In this study, we demonstrate that survivin downregulation in canine LSA and OS cells using a clinically applicable locked nucleic acid antisense oligonucleotide (EZN-3042, Enzon Pharmaceuticals, Piscataway Township, NJ, USA) inhibits growth, induces apoptosis and enhances chemosensitivity in vitro, and inhibits survivin transcription and protein production in orthotopic canine OS xenografts. Our findings strongly suggest that survivin-directed therapies might be effective in treatment of canine LSA and OS and support evaluation of EZN-3042 in dogs with cancer.
Assuntos
Apoptose/efeitos dos fármacos , Doenças do Cão/metabolismo , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Linfoma/veterinária , Oligonucleotídeos/farmacologia , Osteossarcoma/veterinária , Animais , Linhagem Celular Tumoral , Doenças do Cão/tratamento farmacológico , Cães , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/metabolismo , Linfoma/tratamento farmacológico , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
25-hydroxyvitamin D (25(OH)D) is important in bone health as well as many diseases including cancer. Supplementation may increase responsiveness of cancer cells to chemotherapy. Serum 25(OH)D, intact parathyroid hormone (iPTH) and canine C-reactive protein (c-CRP) were measured in healthy dogs and dogs with haemoabdomen. Regression analysis determined optimal 25(OH)D concentrations. In healthy dogs (n = 282), mean iPTH concentrations correlated inversely (r(2) = 0.88, P < 0.001) to 25(OH)D concentrations. Variation in both iPTH and c-CRP plateaued at 25(OH)D concentrations of 100-120 ng mL(-1) . Haemoabdomen dogs (n = 63, 43 malignant and 20 benign) had 25(OH)D concentrations ranging from 19.4 to >150 ng mL(-1) . Relative risk of cancer increased with decreasing 25(OH)D concentrations [RR = 3.9 for 25(OH)D below 40 ng mL(-1) (P = 0.0001)]. Serum 25(OH)D concentrations in dogs vary widely, and are influenced by dietary VitD content. Serum vitD measurement can identify dogs for which supplementation may improve health and response to cancer therapy.
Assuntos
Doenças do Cão/etiologia , Hemoperitônio/veterinária , Neoplasias/veterinária , Vitamina D/análogos & derivados , Animais , Proteína C-Reativa/metabolismo , Cálcio/sangue , Estudos de Casos e Controles , Doenças do Cão/sangue , Cães , Feminino , Hemoperitônio/sangue , Masculino , Neoplasias/sangue , Hormônio Paratireóideo/sangue , Fósforo/sangue , Fatores de Risco , Vitamina D/sangueRESUMO
Standard of care treatment of dogs with multicentric lymphoma includes combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP); however, owners may be hesitant to commit the resources necessary to complete a lengthy, multi-drug protocol. One hundred thirty-four client-owned dogs with multicentric lymphoma were treated with a 15-week CHOP chemotherapy protocol. The overall response rate was 98% with 104 dogs experiencing a complete response (CR). The median progression-free survival (PFS) time for all dogs was 176 days, and the median disease-specific overall survival time was 311 days. Prognostic factors identified on multivariate analysis as significant for PFS included substage, immunophenotype, hospitalization for adverse events, need for dose reduction, presence of neutrophilia at diagnosis, presence of anemia and experiencing a CR as best response to therapy. In conclusion, this protocol may be a viable alternative to CHOP protocols using a larger number of treatments.
Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Doenças do Cão/tratamento farmacológico , Linfoma não Hodgkin/veterinária , Animais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Colorado , Ciclofosfamida/farmacologia , Intervalo Livre de Doença , Doenças do Cão/sangue , Cães , Doxorrubicina/farmacologia , Feminino , Imunofenotipagem , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Análise Multivariada , Prednisolona , Prednisona , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Vincristina/farmacologiaRESUMO
BACKGROUND: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. HYPOTHESIS/OBJECTIVES: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. ANIMALS: Forty-seven client-owned dogs with measurable MCT. METHODS: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. RESULTS: The MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. CONCLUSIONS AND CLINICAL IMPORTANCE: Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Doenças do Cão/tratamento farmacológico , Indóis/uso terapêutico , Lomustina/uso terapêutico , Mastocitose/veterinária , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/uso terapêutico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Doenças do Cão/genética , Cães , Esquema de Medicação/veterinária , Quimioterapia Combinada , Feminino , Indóis/administração & dosagem , Lomustina/administração & dosagem , Masculino , Mastocitose/tratamento farmacológico , Mastocitose/genética , Reação em Cadeia da Polimerase/veterinária , Proteínas Proto-Oncogênicas c-kit/genética , Pirróis/administração & dosagemRESUMO
The goal of this study was to evaluate the anti-tumour activity and toxicoses of vinorelbine as a palliative rescue therapy for dogs with primary urinary bladder carcinoma. Thirteen dogs refractory to prior chemotherapeutics and one dog naïve to chemotherapeutic treatment were enrolled. Vinorelbine (15 mg m(-2) IV) was administered intravenously along with concurrent oral anti-inflammatory drugs, if tolerated. A median of six doses of vinorelbine (range: 1-16) was administered. Two dogs (14%) had partial responses, and eight (57%) experienced stable disease. Subjective improvement in clinical signs was noted in 11 dogs (78%). Adverse events were mild and primarily haematological in nature. Median time to progression was 93 days (range: 20-239 days). Median survival time for all dogs was 187 days; median survival for 13 pre-treated dogs was 207 days. Vinorelbine may have utility in the management of canine primary urinary bladder carcinoma and should be evaluated in a prospective study.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Neoplasias da Bexiga Urinária/veterinária , Vimblastina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Doenças do Cão/mortalidade , Cães , Esquema de Medicação/veterinária , Reposicionamento de Medicamentos/veterinária , Feminino , Masculino , Análise de Sobrevida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , VinorelbinaRESUMO
In veterinary medical oncology, there is currently no standardized protocol for assessing response to therapy in solid tumours. The lack of such a formalized guideline makes it challenging to critically compare outcome measures across various treatment protocols. The Veterinary Cooperative Oncology Group (VCOG) membership consensus document presented here is based on the recommendations of a subcommittee of American College of Veterinary Internal Medicine (ACVIM) board-certified veterinary oncologists. This consensus paper has used the human response evaluation criteria in solid tumours (RECIST v1.1) as a framework to establish standard procedures for response assessment in canine solid tumours that is meant to be easy to use, repeatable and applicable across a variety of clinical trial structures in veterinary oncology. It is hoped that this new canine RECIST (cRECIST v1.0) will be adopted within the veterinary oncology community and thereby facilitate the comparison of current and future treatment protocols used for companion animals with cancer.
Assuntos
Doenças do Cão/diagnóstico , Doenças do Cão/terapia , Neoplasias/veterinária , Medicina Veterinária/normas , Animais , Consenso , Intervalo Livre de Doença , Cães , Humanos , Oncologia , Neoplasias/diagnóstico , Neoplasias/terapia , Médicos VeterináriosRESUMO
GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG) has significant activity as monotherapy in dogs with non-Hodgkin's lymphoma. Phase I trials have been initiated in humans based on the encouraging activity observed in canine lymphoma. Two new analogues of GS-9219 (GS-343074 and GS-424044) were recently produced for evaluation as potential novel antineoplastic agents against solid tumours. As a preclinical step, effect of GS-343074 and GS-424044 were evaluated against ten canine cancer cell lines for antiproliferative effect. Both analogues displayed antiproliferative activity against multiple canine cancer cell lines, although GS-343074 was more potent and of broader spectrum compared to GS-424044. Flow cytometric analysis of cells that experienced growth inhibition support apoptotic death as a mechanism of action for both analogues. On the basis of in vitro results described here, GS-343074 and GS-424044 show promise as novel anticancer agents in canine cancer.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doenças do Cão/tratamento farmacológico , Neoplasias/veterinária , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doenças do Cão/patologia , Cães , Relação Dose-Resposta a Droga , Citometria de Fluxo/veterinária , Guanina/análogos & derivados , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Concentração Inibidora 50 , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêuticoRESUMO
BACKGROUND: Canine cutaneous T-cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies are lacking. The novel anticancer nucleotide prodrug VDC-1101 (formerly known as GS-9219) has shown efficacy in dogs with multicentric lymphoma. One of the observed adverse effects with this drug was a skin change characterized by hair loss, erythema, and pruritus, implying delivery of VDC-1101 to the skin. HYPOTHESIS/OBJECTIVES: The primary study objective was to identify the objective response rate (ORR) to VDC-1101 in canine CTCL; secondary objectives included characterization of progression-free survival (PFS) and adverse events (AEs). ANIMALS: Twelve dogs with chemotherapy-naïve or relapsed, histologically and immunohistochemically confirmed CTCL. METHODS: Dogs received VDC-1101 as a 30-minute IV infusion once every 21 days. Prednisone (1 mg/kg PO q48h) was administered concurrently. RESULTS: In 11 evaluable patients, responses included 1 complete response (CR), 4 partial responses (PR), 2 stable disease (SD), and 4 progressive disease for an ORR of 45% and biologic response rate (CR/PR/SD) of 64%. The median PFS was 37.5 days (26 to >399 days), which includes 1 durable and ongoing CR (>1 year). Gastrointestinal and hematologic AEs were mild; no dogs developed grade 3 or 4 AEs. Three dogs developed dermatopathies and 1 of these dogs was removed from the study as a result of this AE. CONCLUSIONS AND CLINICAL IMPORTANCE: VDC-1101 has activity against canine CTCL and could provide another treatment option in a disease process with a poor prognosis.
Assuntos
Alanina/análogos & derivados , Antineoplásicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Linfoma Cutâneo de Células T/veterinária , Purinas/uso terapêutico , Neoplasias Cutâneas/veterinária , Alanina/efeitos adversos , Alanina/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Cães , Feminino , Linfoma Cutâneo de Células T/tratamento farmacológico , Masculino , Purinas/efeitos adversos , Dermatopatias/induzido quimicamente , Dermatopatias/veterinária , Neoplasias Cutâneas/tratamento farmacológico , Resultado do TratamentoRESUMO
Lymph node metastasis in dogs with mast cell tumour has been reported as a negative prognostic indicator; however, no standardized histological criteria exist to define metastatic disease. The primary aim of this study was to determine whether different histological patterns of node-associated mast cells correlate with clinical outcome in dogs with mast cell tumour. A secondary goal was to propose a criteria-defined classification system for histological evaluation of lymph node metastasis. The Colorado State University Diagnostic Medicine Center database was searched for cases of canine mast cell tumours with reported lymph node metastasis or evidence of node-associated mast cells. Additional cases were obtained from a clinical trial involving sentinel lymph node mapping and node extirpation in dogs with mast cell neoplasia. Forty-one cases were identified for inclusion in the study. Demographic data, treatment and clinical outcome were collected for each case. Lymph nodes were classified according to a novel classification system (HN0-HN3) based on the number of, distribution of, and architectural disruption by, nodal mast cells. The findings of this study indicate that characterization of nodal mast cells as proposed by this novel classification system correlates with, and is prognostic for, clinical outcome in dogs with mast cell tumours.