Adjuvant carboplatin and gemcitabine combination chemotherapy postamputation in canine appendicular osteosarcoma

Background: Appendicular osteosarcoma (OSA), the most common bone tumor in dogs, is typically treated by amputation and adjuvant chemotherapy. Despite numerous efforts, the median survival time (MST) for dogs receiving a platinum compound, doxorubicin, or a combination of these remains at 8–12 months. Evidence from studies in mice suggests that gemcitabine has activity against OSA in vivo. Our preliminary work demonstrated that the addition of low‐dosage (10 mM) gemcitabine to carboplatin resulted in synergistic inhibition of OSA cell viability in vitro. Objective: The purpose of the following study was to determine whether the addition of low‐dosage (2 mg/kg) gemcitabine to carboplatin chemotherapy in dogs with OSA after amputation would improve MST over carboplatin monotherapy. Animals: Fifty dogs with histologically confirmed appendicular OSA. Methods: Dogs were treated prospectively with amputation and up to 4 dosages of carboplatin and gemcitabine in combination every 3 weeks. Results: The chemotherapeutic regimen was well tolerated with only 5 episodes of grade 3 or 4 hematologic toxicity. The median disease‐free interval (DFI) was 203 days and the MST was 279 for all dogs in this study. The 1‐ and 2‐year survival rates were 29.5 and 11.3%, respectively. Dogs with proximal humeral OSA had a shorter median DFI (P= .04) compared with dogs with OSA in other locations. Conclusions and Clinical Importance: These results are comparable to those reported for carboplatin monotherapy indicating that the addition of gemcitabine to carboplatin in dogs with appendicular OSA does not appear to improve outcome.     

Carboplatin and doxorubicin combination chemotherapy for the treatment of appendicular osteosarcoma in the dog

Twenty-four client-owned dogs with histologically diagnosed appendicular osteosarcoma (OSA) and no evidence of gross metastatic disease were treated with amputation or limb salvage followed by combination chemotherapy consisting of carboplatin (175mg/ m2 IV, day 1) and doxorubicin (15 mg/m2 IV, day 2) given on a 21-day cycle for a maximum of 4 cycles. Hematologic and gastrointestinal adverse effects were graded according to National Cancer Institute guidelines. Thoracic radiographs were obtained before the 3rd chemotherapy cycle and then every 2 months. Median disease-free interval was 195 days (95% confidence interval 111-228 days) and median survival was 235 days (95% confidence interval 150-283 days). Two patients required dose reductions: 1 for grade 3 thrombocytopenia and 1 for grade 3 adverse gastrointestinal effects. Patients with a longer duration of clinical signs before definitive diagnosis and surgery (greater than 30 days) were more likely to develop progressive disease and to die or be euthanized because of progressive disease on any day; hazard ratios were 3.0 (P = .02) and 3.7 (P .02), respectively. In conclusion, although this combination chemotherapy protocol was well tolerated, it did not provide any improvement over historical single-agent protocols.     

Toxicity and efficacy of cisplatin and doxorubicin combination chemotherapy for the treatment of canine osteosarcoma

Thirty-five dogs with appendicular osteosarcoma underwent amputation and chemotherapy with cisplatin and doxorubicin every 21 days for up to four cycles. Sixteen dogs completed all four cycles. Two dogs had therapy discontinued because of metastases. The remaining 17 dogs experienced toxicities necessitating protocol alteration or discontinuation. The median survival time of 300 days was not improved over previously reported single-agent protocols, but the 10 dogs that survived to a year lived a median of 510 days.     

Toxicity and efficacy of a novel doxorubicin and carboplatin chemotherapy protocol for the treatment of canine appendicular osteosarcoma following limb amputation

Objective To evaluate the safety and efficacy of a novel doxorubicin and carboplatin chemotherapy protocol for the treatment of dogs with appendicular osteosarcoma following limb amputation. Design Retrospective study. Procedure Dogs diagnosed with appendicular osteosarcoma, with no evidence of metastatic disease, treated with amputation and adjuvant chemotherapy consisting of two doses of doxorubicin given 14 days apart, followed by four doses of carboplatin at 3‐weekly intervals between September 2003 and December 2009 were identified from the medical records of Perth Veterinary Oncology. Haematological and gastrointestinal toxicities were assessed based on information in the medical records and recorded complete blood count results. The efficacy of the protocol was assessed by determining the median disease‐free interval (DFI) and overall survival time (OST) using the Kaplan‐Meier product‐limit method. Results In total, 33 dogs met the inclusion criteria. The median DFI was 231.5 days and the median OST was 247 days. With regard to haematological toxicity, 56% of dogs had a grade 1–2 neutropenia recorded as their highest marrow toxicity and 9% of dogs experienced a grade 3–4 neutropenia, all subsequent to doxorubicin administration. The highest gastrointestinal toxicity was grade 1–2 in 15 dogs (47%) and 5 dogs (16%) experienced grade 3–4 gastrointestinal toxicity. Conclusion This chemotherapy protocol did not result in a longer time to disease recurrence or OST in this population of dogs. Dual‐agent protocols have failed to improve survival times and therefore we conclude that a single‐agent protocol using carboplatin may be equally effective with less toxicity.     

Masitinib for the treatment of canine atopic dermatitis: a pilot study

There is an on-going need to identify medications suitable for the long-term treatment of canine atopic dermatitis (CAD). Masitinib mesilate is a potent and selective tyrosine kinase inhibitor of the c-KIT receptor. A strong relationship exists between the SCF/c-KIT pathway and pathogenesis of CAD, suggesting that masitinib may potentially fulfil the above role. This study reports on an uncontrolled pilot study of masitinib in CAD. Masitinib was administered orally to 11 dogs at a mean dose of 11.0 ± 1.83 mg/kg/day (free base) for 28 days. Treatment response was assessed by evolution of clinical appearance according to a modified version of the Canine Atopic Dermatitis Extent and Severity Index (mCADESI), pruritus scale and surface area of lesions. Masitinib improved CAD with a mean reduction in mCADESI of 50.7 ± 29.8% (95% C.I. = 29.4–72.0; p = 0.0004) at day 28 relative to baseline, with 8/10, 8/10 and 4/10 dogs showing improvement of ≥33%, ≥40% and ≥50%, respectively. Improvement was further evidenced by a decrease in pruritus score and the surface area of lesions. No serious or severe adverse events occurred during this trial, although 6/11 dogs presented with mild to moderate treatment related adverse events. There is sufficient compelling evidence to warrant further investigation.     

Comparison of efficacy and toxicity of doxorubicin and mitoxantrone in combination chemotherapy for canine lymphoma

Forty-four dogs with multicentric lymphoma were treated using a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) induction protocol or treated using a cyclophosphamide, mitoxantrone, vincristine, and prednisolone (CMOP) induction protocol. There was no statistical difference in signalment and the presence of historical negative prognostic factors between the groups. The median progression-free survival (PFS) in the CHOP and CMOP groups were 222 d and 162 d, respectively (P = 0.75). The median survival time (MST) of dogs in CHOP and CMOP groups were 318 d and 242 d, respectively (P = 0.63). Anorexia and diarrhea episodes were significantly higher in the CHOP group than in the CMOP group (P = 0.02 and P = 0.01, respectively). These results suggest that the CMOP protocol provides similar PFS, MST and causes fewer side effects compared to the CHOP protocol. Therefore, the CMOP protocol may be another treatment choice for canine multicentric lymphoma.     

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.     

A combination chemotherapy protocol with MOPP and CCNU consolidation (Tufts VELCAP-SC) for the treatment of canine lymphoma

A chemotherapy protocol using a consolidation phase of alkylating agents was used for treating 94 dogs with lymphoma. Fifty‐seven percent of dogs were in stage V, 63% were ill and 38% had T‐cell lymphoma. The complete remission (CR) rate was 70% and is comparable to results achieved with previously published chemotherapy protocols. Anorexia predicted the remission; of the 40 dogs without anorexia, 35 (88%) achieved CR whereas of 52 dogs with anorexia, 30 (58%) achieved CR. Median first CR duration was 168 days and 1‐ and 2‐year CR rates were 17.4 and 15.5%, respectively. Platelet count affected length of first CR, with a 53.2% reduced chance of coming out of remission with each log increase in platelet count. Median survival time was 302 days. One and 2‐year survival rates were 44 and 13%, respectively. Anorexia and no dose reduction of any drug were independent negative variables. Of 93 dogs with toxicity data, 65 dogs (70%) required a dose reduction. Cyclophosphamide was most commonly reduced with reductions in 31 (38%) of 82 dogs. A dose reduction was significantly more likely in dogs with B‐cell lymphoma than in those with T‐cell lymphoma.     

Pasteurized tumoral autograft and adjuvant chemotherapy for the treatment of canine distal radial osteosarcoma: 13 cases

OBJECTIVE: To report outcome in 13 dogs with distal radial osteosarcoma, without evidence of metastasis, treated by a combination of adjuvant chemotherapy and a pasteurized autograft limb-sparing procedure. STUDY DESIGN: Prospective clinical study. ANIMALS: Thirteen dogs with distal radial osteosarcoma. METHODS: Limb-sparing procedure was performed using an autograft from the excised tumoral segment, pasteurized at 65 degrees C for 40 minutes. Adjuvant chemotherapy (cisplatin or cisplatin and doxorubicin) was administered in all dogs. RESULTS: Mean and median survival times were 531 and 324 days, respectively (range, 180 to 1,868 days). Overall survival was 100% at 6 months, 50% at 12 months, 44% at 18 months, and 22% at 24 months. Lung metastasis occurred in 5 (38%) dogs. Observed complications were local recurrence (2 dogs, 15%), allograft infection (4 dogs, 31%), and implant failure (3 dogs, 23%). Limb function was good in 12 dogs (92%) and fair in 1 dog. CONCLUSIONS: Pasteurized bone autograft derived from the tumoral bone segment was an effective alternative to cortical bone allograft for limb sparing in canine distal radial osteosarcoma, in terms of feasibility, pattern of healing, complications, and survival. CLINICAL RELEVANCE: Use of a pasteurized bone autograft eliminates the need for a canine bone allograft bank and has the added advantage of good fit to the recipient site.     

Mitoxantrone and cyclophosphamide combination chemotherapy for the treatment of various canine malignancies.

Thirteen dogs with histopathologically confirmed malignancies were treated with mitoxantrone and cyclophosphamide combination therapy. One to four doses were administered at 21-day intervals. Recombinant human granulocyte colony-stimulating factor was administered to ameliorate myelosuppression in dogs with neutrophil nadirs less than 1,000/microl. While the protocol appears to be safe for use in tumor-bearing dogs, an advantage over mitoxantrone single-agent protocols in terms of tumor response was not demonstrated in this initial pilot study.     

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.     

Neutropenia associated with vincristine and L-asparaginase induction chemotherapy for canine lymphoma

Vincristine (VCR) and L-asparaginase (L-ASP) are commonly used to treat canine lymphoma. As single agents, these drugs are not myelosuppressive. However, in combination, VCR and L-ASP cause severe neutropenia in some dogs. It has been recommended that L-ASP be administered 12-24 hours after VCR to minimize toxicity. The purpose of this retrospective study was to determine the prevalence of neutropenia after VCR/L-ASP induction therapy for canine lymphoma and to evaluate risk factors for myelosuppression, especially the interval between VCR and L-ASP administration. Medical records of 147 dogs were reviewed. L-ASP was given 0 (n = 50), 6 (n = 23), 18 (n = 20), or 24 (n = 54) hours after VCR. Forty percent of the dogs were neutropenic 7 days after VCR/L-ASP, and 18% had neutrophil counts of <1,000 cells/microL. The median neutrophil count was 3,712 cells/microL (range 0-30,968 cells/microL). No correlation was found between administration interval and day 7 neutrophil count (P = .84) or development of gastrointestinal signs, including vomiting (P = .80), diarrhea (P = .52), and decreased appetite (P = .30). No significant predictors of neutropenia were identified. Higher clinical stage and substage b were associated with decreased appetite after treatment (P = .04 and .01, respectively). Sixteen percent of the dogs were hospitalized. This study demonstrates that VCR/L-ASP induction for canine lymphoma may result in neutropenia but that separation of VCR and L-ASP administration may not be necessary to avoid toxicity.     

Masitinib is safe and effective for the treatment of canine mast cell tumors

Background: Activation of the KIT receptor tyrosine kinase is associated with the development of canine mast cell tumors (MCT). Hypothesis/Objective: To evaluate the efficacy of masitinib, a potent and selective inhibitor of KIT, in the treatment of canine MCT. Animals: Two hundred and two client‐owned dogs with nonmetastatic recurrent or nonresectable grade II or III MCT. Methods: Double‐blind, randomized, placebo‐controlled phase III clinical trial. Dogs were administered masitinib (12.5 mg/kg/d PO) or a placebo. Time‐to‐tumor progression (TTP), overall survival, objective response at 6 months, and toxicity were assessed. Resulsts: Masitinib increased overall TTP compared with placebo from 75 to 118 days (P= .038). This effect was more pronounced when masitinib was used as first‐line therapy, with an increase in the median TTP from 75 to 253 days (P= .001) and regardless of whether the tumors expressed mutant (83 versus not reached [P= .009]) or wild‐type KIT (66 versus 253 [P= .008]). Masitinib was generally well tolerated, with mild (grade I) or moderate (grade II) diarrhea or vomiting as the most common adverse events. Conclusions and Clinical Importance: Masitinib is safe and effective at delaying tumor progression in dogs presenting with recurrent or nonresectable grade II or III nonmetastatic MCT.     

CCNU in the treatment of canine epitheliotropic lymphoma

This retrospective study examined the use of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosurea) in 36 dogs with epitheliotropic lymphoma. Thirty-one (86%) dogs had the cutaneous form of disease, and 5 (14%) dogs had the oral form of disease. Nineteen (51%) dogs were treated with other chemotherapeutic agents before receiving CCNU. All dogs had detectable disease at the time CCNU therapy was initiated. Dogs received a median starting CCNU dosage of 70 mg/m2 (range, 50-100 mg/m2). The median number of treatments administered was 3 (range, 1-12 treatments). After the initial treatment, the CCNU dosage was adjusted in 9 of 26 (35%) dogs in which CCNU was continued: 7 had dosage reductions, and 2 had dosage escalations. Twenty-eight of 36 (78%) dogs had a measurable response to CCNU for a median duration of 106 days (95% confidence interval [CI], 75-182). Six dogs (17%) had a complete response, including 5 dogs with the cutaneous form and 1 dog with the oral form. Twenty-two dogs (61%) had a partial response, including 20 dogs with the cutaneous form and 2 dogs with the oral form, for a median duration of 88 days (95% CI, 62-170). Toxicoses after CCNU chemotherapy included myelosuppression in up to 29% of the dogs, gastrointestinal signs in up to 22% of the dogs, and liver enzyme activity increases in up to 86% of the dogs. This study demonstrates that CCNU chemotherapy can be considered a reasonable option for the treatment of canine epitheliotropic lymphoma in dogs.     

Evaluation of ifosfamide for treatment of various canine neoplasms

lfosfamide (3-[2-chloroethyl]-2[(2 chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide) is an alkylating agent with a broad spectrum of antitumor activity. The efficacy and toxicity of ifosfamide were evaluated in 72 dogs with spontaneously occurring tumors. Forty dogs (56%) had lymphoma, 31 (43%) had sarcomas, and 1 had a metastatic carcinoma. Five dogs received ifosfamide at dosages <350 mg/m2 IV. Neither toxicity nor response were observed, and the remaining dogs received ifosfamide at 350 mg/m2 (n = 18) and 375 mg/m2 body surface area IV (n = 49). Saline diuresis and the thiol compound mesna were used to prevent urothelial toxicity. Fifty-two dogs had measurable tumors and could be evaluated for response. Complete responses were seen in 1 dog with metastatic leiomyosarcoma of the urinary bladder and in 1 dog with metastatic cutaneous hemangiosarcoma. One dog with lymphoma had a partial response for 112 days. Six dogs with splenic hemangiosarcoma received ifosfamide postsplenectomy and their median survival time was 147 days. The acute dose limiting toxicity was neutropenia 7 days after administration of ifosfamide. The median and mean neutrophil counts 7 days after ifosfamide at 350 mg/m2 were 2,035 cells/microL and 4,773 cells/microL, respectively (n = 12). The median and mean neutrophil counts 7 days after ifosfamide at 375 mg/m2 were 2,500 cells/microL and 3,594 cells/microL, respectively (n = 37). No dog developed clinical or microscopic evidence of hemorrhagic cystitis. Ifosfamide appears safe to use in tumor-bearing dogs, and the evaluation of combination chemotherapy protocols that include ifosfamide should be considered.     

Pilot clinical study of carmustine associated with a lipid nanoemulsion in combination with vincristine and prednisone for the treatment of canine lymphoma

A lipid nanoemulsion (LDE) resembling low‐density lipoprotein can target malignant tumours. In in vivo and clinical studies, association of chemotherapeutic agents to LDE decreased their toxicity and increased pharmacological action. Here, safety of LDE as carmustine carrier (50 mg m^?2, intravenous) combined with vincristine and prednisone for the treatment of dogs with lymphoma was tested and compared with commercial carmustine with vincristine and prednisone. In five dogs from LDE‐carmustine and six from commercial carmustine, complete remission was achieved (P > 0.05). Partial remission occurred in two dogs from each group. In both groups, the median progression‐free intervals (119 and 199 days) and overall survival times (207 and 247 days) were equal. Neutropenia was observed in both groups, but no other major toxicities occurred. Therefore, no difference was observed between the treatments. LDE‐carmustine was shown to be safe and effective in a drug combination protocol, which encourages larger studies to investigate the use of this novel formulation to treat canine lymphomas.     

A pilot study examining a proprietary herbal blend for the treatment of canine osteoarthritis pain

Osteoarthritis is the most common joint disease in dogs. Despite the use of nonsteroidal anti-inflammatory drugs (NSAIDs), many owners seek natural therapies; either to augment the response to NSAIDs, or as a replacement. Substantial research has been directed to investigation of novel therapies. A randomized, double-blinded, controlled study was conducted to assess the efficacy of a herbal remedy for treatment of canine osteoarthritis pain. Client-owned dogs (N = 24) with osteoarthritis were enrolled between 2 veterinary hospitals. Each dog underwent veterinary and owner assessment at 0, 4, and 8 weeks, using the Canine Brief Pain Inventory and Hudson activity scale. Blood was collected for a complete blood (cell) count (CBC) and serum chemistry analysis. The product was deemed to be safe and well-tolerated at the manufacturer recommended dosage, with no significant changes seen in the CBC or serum biochemical analyses. Aside from1 dog that developed gastrointestinal upset, all other dogs tolerated the supplement without complication. The supplement did not statistically improve clinical signs in dogs based on veterinary or owner assessments of lameness. There was a treatment/time effect when assessing veterinary pain scores; however, post-hoc analysis suggests no observable benefit of treatment compared with the placebo group at any time point.     

Influence of chemotherapy for lymphoma in canine parvovirus DNA distribution and specific humoral immunity

In man, the combination of cancer and its treatment increases patients’ susceptibility to opportunistic infections, due to immune system impairment. In veterinary medicine little information is available concerning this issue. In order to evaluate if a similar dysfunction is induced in small animals undergoing chemotherapy, we assessed the complete blood count, leukocytic, plasma and fecal canine parvovirus (CPV) viral load, and anti-CPV protective antibody titers, in dogs with lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) protocol, before and during chemotherapy.There was no evidence of decreased immune response, either at admission or after two chemotherapy cycles, indicating that the previously established immunity against CPV was not significantly impaired, supporting the idea that immunosuppression as a result of hematopoietic neoplasms and their treatment in dogs requires further investigation and conclusions cannot be extrapolated from human literature.