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 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.     

Retrospective comparison of first‐line adjuvant anthracycline vs metronomic‐based chemotherapy protocols in the treatment of stage I and II canine splenic haemangiosarcoma

Splenectomy followed by adjuvant chemotherapy is commonly used to treat canine splenic haemangiosarcoma (HSA), although it is unclear if different treatment protocols may have a similar efficacy. The objective of this retrospective study was to assess outcome in dogs with stage I and II splenic HSA treated with either first‐line adjuvant anthracycline (AC) or metronomic (MC)‐based chemotherapy protocols, by comparing median time to progression (TTP) and median survival time (MST). Medical records of nine institutions were searched for dogs diagnosed with stage I and II splenic HSA that underwent adjuvant treatment with AC‐ or MC‐based protocols following splenectomy. Patients treated with MC following AC were included in an additional group (AMC). Ninety‐three dogs were included: 50 in the AC group, 23 in the AMC group and 20 in the MC group. The overall MST was 200 days (range 47‐3352) and the overall median TTP was 185 days (range 37‐1236). The median TTP of stage I dogs was significantly longer compared to stage II dogs (338 vs 151 days, respectively, P = .028). When adjusting for treatment type, the MST was 154 days for the AC group (range 47‐3352 days), 338 days for the AMC group (range 79‐1623 days) and 225 days for the MC group (range 57‐911 days). The difference in MST and median TTP was not found to be statistically significant between treatment groups. This study suggests that adjuvant MC in canine splenic HSA may result in a similar outcome when compared to other treatment protocols. Further studies are warranted to confirm these findings.     

Amputation and Carboplatin for Treatment of Dogs With Osteosarcoma: 48 Cases (1991 to 1993)

Forty-eight dogs with histologically confirmed appendicular osteosarcoma (OSA) entered a prospective clinical trial evaluating treatment with amputation and up to 4 doses of carboplatin given every 21 days. The median disease-free interval (DFI) was 257 days, with 31.2% of the dogs disease-free at 1 year. The median survival time was 321 days, with 35.4% of the dogs alive at 1 year. Dogs with proximal humeral OSA had shorter DFI (P = .016) and survival (P = .037) times than dogs with OSA at other locations. Dogs with lower body weights (40 kg) had longer DFI (P = .0056) and survival (P = .007) times than larger dogs. Survival times for dogs that received carboplatin were statistically longer than those previously reported for amputation alone (P < .001). DFI and survival times are similar to those previously reported for 2 to 4 doses of cisplatin. Carboplatin appears to be a well-tolerated chemotherapeutic drug that can be given safely every 21 days at a dose of 300 mg/m². Neutropenia was the dose-limiting toxicity in this study. J Vet Intern Med 1996_;10:76–81. Copyright © 1996 by the American College of Veterinary Internal Medicine .     

Association of macrophage and lymphocyte infiltration with outcome in canine osteosarcoma

Immunotherapeutic strategies have shown promise for the treatment of canine osteosarcoma (cOSA). Very little is known about the immune microenvironment within cOSA, however, limiting our ability to identify potential immune targets and biomarkers of therapeutic response. We therefore prospectively assessed the disease‐free interval (DFI) and overall survival time (ST) of 30 dogs with cOSA treated with amputation and six doses of adjuvant carboplatin. We then quantified lymphocytic (CD3+, FOXP3+) and macrophage (CD204+) infiltrates within the primary tumours of this cohort using immunohistochemistry, and evaluated their association with outcome. Overall, the median DFI and ST were 392 and 455 days, respectively. The median number of CD3+ and FOXP3+ infiltrates were 45.8 cells/mm² (4.6‐607.6 cells/mm²) and 8.5 mm² (0‐163.1 cells/mm²), respectively. The median area of CD204+ macrophages was 4.7% (1.3%‐23.3%), and dogs with tumours containing greater than 4.7% CD204+ macrophages experienced a significantly longer DFI (P = 0.016). Interestingly, a significantly lower percentage of CD204+ macrophages was detected in cOSA arising from the proximal humerus compared to other appendicular bone locations (P = 0.016). Lymphocytic infiltrates did not appear to correlate with outcome in cOSA. Overall, our findings suggest that macrophages may play a role in inhibiting cOSA progression, as has been suggested in human osteosarcoma.     

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.     

Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs†

Sixty‐four dogs were treated with single‐agent doxorubicin (DOX) for presumptive cardiac hemangiosarcoma (cHSA). The objective response rate (CR + PR) was 41%, and the biologic response rate (CR + PR + SD), or clinical benefit, was 68%. The median progression‐free survival (PFS) for treated dogs was 66 days. The median survival time (MST) for this group was 116 days and was significantly improved compared to a MST of 12 days for untreated control dogs (P = 0.0001). Biologic response was significantly associated with improved PFS (P < 0.0001) and OS (P < 0.0001). Univariate analysis identified larger tumour size as a variable negatively associated with PFS. The high rate of clinical benefit and improved MST suggest that DOX has activity in canine cHSA.     

Evaluation of intracavitary mitoxantrone and carboplatin for treatment of carcinomatosis,sarcomatosis and mesothelioma,with or without malignant effusions: A retrospective analysis of 12 cases (1997–2002)*

Carcinomatosis, sarcomatosis and mesothelioma, with or without malignant effusions, are difficult to treat and generally carry a poor prognosis. The purpose of this study was two‐fold; first, to determine the prognosis for dogs with carcinomatosis, sarcomatosis, or mesothelioma, with or without malignant effusions; second, to evaluate the safety and efficacy of treatment with intracavitary (IC) carboplatin and mitoxantrone in dogs with these syndromes. Nineteen dogs were evaluated. Seven were untreated and 12 were treated with IC chemotherapy (mitoxantrone and/or carboplatin), and multiple factors were analysed for significance with respect to survival time. The median survival time (MST) for untreated dogs was 25 days, whereas the MST for treated dogs was 332 days (Log Rank, P < 0.0001). Treatment with IC chemotherapy was well tolerated. This study suggests that IC chemotherapy with mitoxantrone and/or carboplatin is an effective treatment for dogs with carcinomatosis, sarcomatosis or mesothelioma, with or without malignant effusion.     

Single-agent pamidronate for palliative therapy of canine appendicular osteosarcoma bone pain

BACKGROUND: Canine appendicular osteosarcoma (OSA) causes focal bone destruction, leading to chronic pain and reduced quality-of-life scores. Drugs that inhibit pathologic osteolysis might provide additional treatment options for managing cancer-induced bone pain. Aminobisphosphonates induce osteoclast apoptosis, thereby reducing pain associated with malignant osteolysis in human patients with cancer. HYPOTHESIS: Treatment of dogs with pamidronate administered intravenously will alleviate bone pain and reduce pathologic bone turnover associated with appendicular OSA in dogs. ANIMALS: Forty-three dogs with naturally occurring appendicular OSA administered pamidronate intravenously. METHODS: Prospective study. Therapeutic responses in dogs treated with pamidronate administered intravenously and nonsteroidal anti-inflammatory drugs (NSAID) were evaluated by using a numerical cumulative pain index score (CPIS), and by quantifying urine N-telopeptide (NTx) excretion and relative primary tumor bone mineral density (rBMD) assessed with dual energy x-ray absorptiometry. In addition, variables, including pamidronate dose, skeletal mass, baseline and change for CPIS, urine NTx and rBMD during treatment, and baseline tumor volume and radiographic pattern were compared between dogs clinically responsive and nonresponsive to pamidronate therapy. RESULTS: Twelve of 43 dogs (28%) had pain alleviation for >4 months, lasting a median of 231 days. Changes in CPIS and rBMD during treatment were statistically different between responders and nonresponders (P = .046 and .03, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Substantiated by reductions in CPIS and increases in rBMD, single-agent pamidronate administered intravenously with NSAID therapy relieves pain and diminishes pathologic bone turnover associated with appendicular OSA in a subset of dogs.     

Association of Blood Monocyte and Lymphocyte Count and Disease‐Free Interval in Dogs with Osteosarcoma

Background: Identification of biomarkers that predict outcomes in dogs with osteosarcoma (OSA) would be valuable to veterinarians and owners. Leukocyte numbers in peripheral blood are associated with outcomes in some types of cancer in humans. Hypothesis/Objectives: We hypothesized that increased numbers of monocytes would be associated with reduced disease‐free interval (DFI) in dogs with OSA. Animals: Medical data from 69 dogs with appendicular OSA treated with amputation and chemotherapy were selected for study. Methods: Retrospective study. Statistical associations were assessed by univariate and multivariate analysis. Information about DFI and leukogram values, tumor location, and serum alkaline phosphatase was abstracted from the medical record. Results: Higher numbers of circulating monocytes (>0.4 × 10³ cells/μL) and lymphocytes (>1.0 × 10³ cells/μL) before treatment were found to be significantly (P < .05) associated with shorter DFI in dogs with OSA. Other parameters associated with poor outcomes were increased alkaline phosphatase, primary tumor location, and age. Conclusion and Clinical Importance: These results indicated that pretreatment evaluation of monocyte and lymphocyte counts provided prognostic information for dogs with appendicular OSA. Notably, most animals in this study had monocyte counts within the normal reference range, indicating that variations within the reference range of leukocyte values might also have prognostic significance.     

Prolongation of survival of dogs with oral malignant melanoma treated by en bloc surgical resection and adjuvant CSPG4‐antigen electrovaccination

Reported post‐surgery 1‐year survival rate for oral canine malignant melanoma (cMM) is around 30%; novel treatments are needed as the role of adjuvant chemotherapy is unclear. This prospective study regards adjuvant electrovaccination with human chondroitin sulfate proteoglycan‐4 (hCSPG4)‐encoded plasmid in 23 dogs with resected II/III‐staged CSPG4‐positive oral cMM compared with 19 dogs with resected only II/III‐staged CSPG4‐positive oral cMM. Vaccination resulted in 6‐, 12‐, 18‐ and 24‐month survival rate of 95.6, 73.9, 47.8 and 30.4%, respectively [median survival time (MST) 684 days, range 78–1694, 8 of 23 dogs alive] and 6‐, 12‐, 18‐ and 24‐month disease‐free interval (DFI) rate of 82.6, 47.8, 26.1 and 17.4%, respectively (DFI 477 days, range 50–1694). Non‐vaccinated dogs showed 6‐, 12‐, 18‐ and 24‐month survival rate of 63.2, 26.3, 15.8 and 5.3%, respectively (MST 200 days, range 75–1507, 1 of 19 dogs alive) and 6‐, 12‐, 18‐ and 24‐month DFI rate of 52.6, 26.3, 10.5 and 5.3%, respectively (DFI 180 days, range 38–1250). Overall survival and DFI of vaccinated dogs was longer in those <20 kg. In vaccinated and non‐vaccinated dogs local recurrence rate was 34.8 and 42%, respectively while lung metastatic rate was 39 and 79%, respectively.     

Radiation therapy for canine appendicular osteosarcoma

Radiation therapy (RT) for the management of canine appendicular osteosarcoma (OSA) can be described as either palliative‐ or curative intent. Palliative RT uses coarsely fractionated external beam RT or radiopharmaceuticals to provide relief of pain and lameness associated with OSA while resulting in minimal, if any, radiation‐induced acute adverse effects. Limb amputation and chemotherapy are considered (together) the standard of care for curative‐intent treatment of canine appendicular OSA. When limb amputation is not possible, RT can be used for limb sparing and is supplemented with chemotherapy for presumed micrometastatic disease. Fractionated tumour irradiation with curative intent appears to be ineffective and local disease control can more likely be achieved when stereotactic radiosurgery or intra‐operative extracorporeal irradiation is combined with strict case selection and adjunctive chemotherapy. The availability of limb‐sparing RT is limited by experience and availability of specialised equipment. When planned and administered appropriately, radiation‐associated adverse effects are often mild and self‐limiting.     

Surgical treatment of mammary carcinomas in dogs with or without postoperative chemotherapy

This retrospective study identified prognostic factors associated with survival; and compared survival data in 94 canine mammary carcinoma (MCA) dogs treated with surgery (n = 58), or surgery and adjunct chemotherapy (n = 36), and a subset of dogs with poor prognostic factors. On multivariate analysis independent predictors of median survival time (MST) were clinical stage, lymphatic invasion (LI; present 179 days; none 1098 days), ulceration (present 118 days; none 443 days) and surgical margins (incomplete 70 days; complete 872 days). Complete surgical margins were associated with MST in dogs with stages 1–3 MCA (incomplete 68 days; complete 1098 days) and dogs with LI (incomplete 70 days; complete 347 days). There was no statistically significant improvement in MST in dogs with advanced disease (stage 4 or LI) treated with adjunctive chemotherapy (chemotherapy 228 days; none 194 days); although five dogs with complete surgical margins that received mitoxantrone and carboplatin had a mean survival of 1139 days.     

A retrospective review of treatment and response of high‐risk mast cell tumours in dogs

This retrospective case series evaluates survival outcome of 94 dogs with high metastatic risk mast cell tumours (MCT). Patients were treated with a cytotoxic chemotherapy protocol or the tyrosine kinase inhibitor masitinib, in the presence of gross disease or as an adjunct to surgical resection of the primary tumour. In patients presenting with metastatic disease, surgical resection of the primary tumour with adjunctive therapy with any chemotherapy incurred a significant survival advantage [median survival time (MST): 278 days] compared to patients receiving chemotherapy without surgical excision of the primary tumour (MST: 91 days, P < 0.0001). Patients with a surgically excised Patnaik grade II tumour and high Ki‐67 in the absence of metastatic disease treated with vinblastine and prednisolone showed a significantly longer survival (MST: 1946 days) than those treated with masitinib (MST: 369 days, P = 0.0037). Further prospective case‐controlled clinical trials of high‐risk MCTs are required to make precise evidence‐based treatment decisions for individual patients.     

Biology, diagnosis and treatment of canine appendicular osteosarcoma: similarities and differences with human osteosarcoma

Osteosarcoma (OSA) is the most common primary bone tumour in dogs. The appendicular locations are most frequently involved and large to giant breed dogs are commonly affected, with a median age of 7–8 years. OSA is a locally invasive neoplasm with a high rate of metastasis, mostly to the lungs. Due to similarities in biology and treatment of OSA in dogs and humans, canine OSA represents a valid and important tumour model. Differences between canine and human OSAs include the age of occurrence (OSA is most commonly an adolescent disease in humans), localisation (the stifle is the most common site of localisation in humans) and limited use of neoadjuvant chemotherapy in canine OSA.     

Outcome after repair of a sarcoma-related pathologic fracture in dogs: a Veterinary Society of Surgical Oncology Retrospective Study

Objective: To report outcome in dogs after internal fixation of a sarcoma‐related pathologic fracture of the appendicular skeleton. Study Design: Multi‐institutional case series. Animals: Dogs (n=16). Methods: Medical records of participating VSSO members were reviewed for dogs with pathologic fracture associated with a confirmed bone sarcoma of the appendicular skeleton repaired by external or internal fixation. Dogs were included if they had a histological diagnosis of osteosarcoma or sarcoma and excluded if they had radiation before fracture. Data collected were analyzed for signalment, fracture location, staging performed, method of fracture fixation, histopathology, adjunctive treatment and outcome. Results: Signalment and fracture location of 16 dogs that met the inclusion criteria was similar to dogs with appendicular OSA without fracture. One of 14 dogs had pulmonary metastasis and 3 of 5 dogs had bone metastasis. Bone plate or interlocking nail were used for repair in 12 dogs. Limb use immediately after surgery in 13 dogs was good (4), weight‐bearing but lame (7) and non‐weight bearing (2). Adjunctive therapy was administered in 5 dogs (chemotherapy, 3; radiation, 4; pamidronate, 3). Survival time ranged from 18 to 897 days; median survival was 166 days. Conclusions: Repair of pathologic fracture can result in palliation and prolonged survival.     

Monitoring response to aminobisphosphonate therapy in canine osteosarcoma using dual energy x‐ray absorptiometry (dexa)

Introduction: Palliative therapy is essential to improve the quality of life of dogs with osteosarcoma (OSA), when definitive therapy is not considered a valid option. Bisphosphonates, a novel class of antiosteoclastic drugs, are widely used in humans for several painful osteolytic conditions. Dual energy x‐ray absorptiometry (DEXA) is recognized as a reliable tool to measure bone mineral density (BMD), and to monitor treatment response to bisphosphonates in humans. A prospective evaluation of pamidronate, an injectable aminobisphosphonate, is ongoing in dogs with appendicular OSA. The potential value of DEXA for objective evaluation of BMD variations with palliative therapies is concurrently being assessed. Materials and Methods: Dogs with naturally occurring appendicular OSA treated with pamidronate constitute the patient population. A DEXA scan (QDR‐4500 W, Hologic, Bedford, MA) is performed on day 0 (baseline) and on every treatment day with pamidronate thereafter (every 28 days). For each dog, a whole body scan is performed, followed by a scan of the tumor, and contralateral normal bone. Three regions of interest are subsequently analyzed for BMD changes in tumor and normal bone. Statistical analysis was performed using Student t‐test and paired t‐tests, with significance being set at p < 0.05. Results: Nineteen dogs have been enrolled to date. Seven responders and 6 non‐responders have suitable data for analysis. A significant difference is observed (p = 0.04) between tumor BMD variations of responders and non‐responders at day 28 (mean variations +18.0% and ?4.6% respectively). The changes at day 28 are significant only in the responders (p = 0.038 vs p = 0.05 in non‐responders). When BMD of tumor and normal bone at day 84 is compared to day 0 in six responders, only tumor had a significant increase (p = 0.017 vs p = 0.279, respectively). Conclusions: Objective measurements of response to therapy are essential in pain palliation studies. Increased tumor bone BMD, as obtained by DEXA analysis, may correlate with subjective clinical improvement in pamidronate‐treated dogs with appendicular OSA.     

Use of alternating administration of carboplatin and doxorubicin in dogs with microscopic metastases after amputation for appendicular osteosarcoma: 50 cases (1999-2006)

OBJECTIVE:To evaluate the efficacy and toxicity of an alternating carboplatin and doxorubicin chemotherapy protocol in dogs with putative microscopic metastases after amputation for appendicular osteosarcoma and assess patient-, tumor-, and treatment-related factors for associations with prognosis. DESIGN: Retrospective case series. ANIMALS: 50 client-owned dogs. PROCEDURES: Records of dogs that underwent amputation for appendicular osteosarcoma and received an alternating carboplatin and doxorubicin chemotherapy protocol were reviewed. Dogs had full staging and were free of detectable metastases prior to chemotherapy. Data on disease-free interval (DFI), survival time, and toxicoses were retrieved from medical records and owner or referring veterinarian communications. RESULTS: Median DFI was 202 days. Median survival time was 258 days. Twenty-nine (58%) dogs completed the protocol as planned, and the rest were withdrawn typically because of metastases or toxicoses. Grade 3 or 4 myelosuppression was reported in 9 of 50 (18%) dogs and grade 3 or 4 gastrointestinal toxicosis in 6 of 50 (12%) dogs. There were no chemotherapy-related fatalities. Univariate factors associated with significant improvement in DFI included tumor location (radius), receiving doxorubicin as the first drug, starting chemotherapy more than 14 days after amputation, and no rib lesions on preamputation bone scans. Multivariate factors associated with a significant improvement in survival time were tumor location (radius) and completing chemotherapy. CONCLUSIONS AND CLINICAL RELEVANCE: Alternating administration of carboplatin and doxorubicin resulted in DFI and survival time similar to those reported for single-agent protocols. Clients should be counseled regarding the likelihood of toxicoses. Relevance of sequence and timing of starting chemotherapy should be further evaluated.