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.     

Bone allografts and adjuvant cisplatin for the treatment of canine appendicular osteosarcoma in 18 dogs

The results achieved in 18 dogs following the use of frozen bone cortical allografts for limb-sparing resection of non-metastatic canine appendicular osteosarcoma are presented. Three to five cisplatin doses (70 mg/m2) were administered, starting the day after surgery. The mean and median survival times were 478 and 266 days (range 80 to 2,611 days), respectively. The survival rate was 94 per cent at three months, 78 per cent at six months, 35 per cent at 12 months, 23 per cent at 18 months and 19 per cent at 24 months; the disease-free interval was 80 to 1,246 days (mean 365 days, median 266 days). Lung metastasis developed in 55 per cent of the dogs within one year. Complications were observed in 14/18 dogs (78 per cent), comprising local recurrence (28 per cent), allograft infection (39 per cent) and implant failure (11 per cent). Despite complications, limb sparing is a useful alternative to amputation in selected cases of appendicular osteosarcoma.     

Use of cisplatin for treatment of appendicular osteosarcoma in dogs

Nineteen dogs were treated for osteosarcoma of the appendicular skeleton. Eleven dogs treated by amputation and adjunctive cisplatin chemotherapy had a significantly longer (P less than 0.003) median survival time of 43 weeks (range, 20 to 108 weeks) than did 8 dogs whose median survival time was 14.5 weeks (range, 8 to 46 weeks) after amputation alone. All 11 dogs given cisplatin were evaluated for signs of drug toxicosis. Transient episodes of vomiting were recorded in 9 of 11 dogs. Additional toxic effects included gradual decreases in endogenous creatinine clearance in 3 dogs and thrombocytopenia in 1 dog. On the basis of prolonged survival times and minimal adverse effects, we concluded that cisplatin has promise as an effective and relatively nontoxic agent, when combined with amputation, for treatment of dogs with osteosarcoma of the appendicular skeleton.     

Adjuvant therapy with carboplatin and pamidronate for canine appendicular osteosarcoma

Amputation and chemotherapy are the mainstay of treatment for canine appendicular osteosarcoma (OSA). In vitro studies have demonstrated anti‐tumour activity of pamidronate against canine OSA. The purpose of this study was to assess the safety of adding pamidronate to standard post‐operative carboplatin chemotherapy in 17 dogs with appendicular OSA treated with limb amputation. Median disease‐free interval (DFI) and median survival time (MST) were evaluated as secondary endpoints. Incidence of side effects and treatment outcomes were compared to 14 contemporary control patients treated with carboplatin alone. There were no identified side effects to the pamidronate treatment. The median DFI for the study group was 185 days compared to 172 days for the control group (P = 0.90). The MST of the study group was 311 days compared to 294 days for the control group (P = 0.89). Addition of pamidronate to carboplatin chemotherapy for the treatment of canine appendicular OSA is safe and does not impair efficacy of standard carboplatin treatment.     

Treatment of appendicular osteosarcoma in a horse

A 14‐year‐old Arabian gelding was examined for a mass on the lateral aspect of the left tarsus and proximal lateral metatarsus. Radiography revealed a predominately osteolytic lesion involving the fourth tarsal bone and the proximal third and fourth metatarsal bone. Results of histopathological examination of the mass prior to surgery were consistent with an undifferentiated sarcoma. The mass was surgically excised and the remaining bone defect treated with absorbable beads containing cisplatin. Histology and immunohistochemistry of the mass removed at surgery revealed a telangiectatic osteosarcoma. The surgical site healed uneventfully and the horse was performing as a low level jumper 8.5 years after surgery.     

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.     

Prognostic significance of serum alkaline phosphatase activity in canine appendicular osteosarcoma

Sixty-one dogs with appendicular osteosarcoma were treated with amputation and chemotherapy of cisplatin and doxorubicin. Serum samples were obtained before and after treatment for determination of total alkaline phosphatase (TALP) activity as well as the activities of the constituent bone (BALP), liver (LALP), and corticosteroid-induced (CALP) isoenzymes. The relationship between alkaline phosphatase activities and survival was examined by Cox proportional hazards regression analysis and Kaplan-Meier log rank analysis. Mean activity of TALP, BALP, and LALP decreased significantly after treatment (P < .001). TALP and LALP activities before treatment were significantly correlated with survival (P = .006 and .001, respectively). The correlation between BALP activity before treatment and survival approached significance (P = .054). CALP activity and TALP, BALP, and LALP activities after treatment were not significantly correlated with survival. Dogs with normal pretreatment TALP and BALP activities survived significantly longer than dogs with increased pretreatment activities (P = .001 and .003, respectively). Median survival times for dogs with normal or increased TALP activities before treatment were 12.5 and 5.5 months, respectively; and median survival times for dogs with normal or increased BALP activities before treatment were 16.6 and 9.5 months, respectively. In the design of future clinical trials involving dogs with osteosarcoma, consideration should be given to stratifying the randomization according to alkaline phosphatase activity. In addition, alkaline phosphatase activity should be a factor considered by clinicians attempting to tailor the aggressiveness of adjuvant chemotherapy to the needs of individual patients or owners.     

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.     

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.     

Accuracy of computed tomography in determining lesion size in canine appendicular osteosarcoma

Multidetector contrast enhanced computed tomography with acquisition of 0.625-mm thick transverse images was used to measure the extent of appendicular osteosarcoma in 10 dogs. The measured length of tumor based on CT was compared to the true length of tumor using histopathology. There was a statistically significant association with good correlation between the true length of osteosarcoma compared to the length of intramedullary/endosteal abnormalities on CT with a mean overestimation of 1.8% (SD = 15%). There was not a statistically significant association between the true tumor length and the length of periosteal proliferation on CT with a mean overestimation of 9.7% (SD = 30.3%). There was a statistically significant association, but with poor correlation, between the true tumor length compared to the length of abnormal contrast enhancement with a mean overestimation of 9.6% (SD = 34.8%). The extent of intramedullary/endosteal CT abnormalities assessed from submillimeter transverse images may be of value in assessing patient candidacy and surgical margins for limb-sparing surgery.     

Palliative radiation therapy in the treatment of canine appendicular synovial sarcoma

Synovial sarcoma is a rare tumor in dogs, occurring in approximately 27% of neoplasms involving joints, with the elbow representing a common site of occurrence. The recommended treatment of canine synovial sarcoma is amputation. The authors describe the use of palliative radiation therapy for the treatment of synovial sarcoma involving the elbow of a dog and conclude that this treatment modality may have use in some patients affected with synovial sarcoma.     

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.     

Cutaneous metastasis of primary appendicular osteosarcoma in a dog

A 6-year-old, neutered male Rottweiler was presented to the University of Illinois Veterinary Teaching Hospital because of a lytic bone lesion involving the distal portion of the right radius and possible pulmonary metastases on thoracic radiographs. Results of serum biochemical analysis were unremarkable. Aspiration and cytologic examination of the bone lesion indicated likely sarcoma with reactive bone. Cutaneous masses were found on the left thigh, interscapular region, and dorsal lumbar region, 4 weeks after initial presentation. Neoplastic spindle cells were found in aspirates from 2 of the masses. The neoplastic cells stained positive for alkaline phosphatase activity using cytochemistry. Re-evaluation of serum biochemical values at this time revealed a marked increase in alkaline phosphatase activity (413 U/L, reference interval 12-110 U/L) compared with the initial value (26 U/L). Due to progressive disease, the dog was euthanized and a necropsy was performed. Histologic findings included primary osteosarcoma of the distal portion of the right radius, with metastases in the lungs, spleen, left fourth and fifth ribs, soft tissue of the right medial thigh, and T1-T3/interscapular region. Cutaneous metastasis of primary appendicular osteosarcoma has been reported rarely in animals and humans. Increased serum alkaline phosphatase activity may be a potential indicator of poor prognosis for this neoplasm.     

Blood vessel density in canine osteosarcoma.

Canine osteosarcoma is a prevalent bone neoplasm which has similarities to the human disease. We used a retrospective study to investigate the possibility that tumor vascularity may provide useful prognostic information, indicative of the role of this parameter in progression of this cancer. We quantified microvessel density in 52 histological specimens of primary tumor, immunostained for von Willebrand's Factor to identify vascular endothelium. For the 20 cases not euthanized at presentation or lost to follow-up, we found significantly higher tumor microvascular densities in animals presenting with detectable pulmonary metastases (5 of 20), and significantly lower densities in animals without metastatic disease at presentation, but later surviving to develop pulmonary metastases (7 of 20; P < 0.05). Animals with no evidence of pulmonary metastases at time of death (8 of 20) had intermediate vascular densities in their tumors. The results of this preliminary study suggest that vascularity of the primary tumor may be an indication of tumor progression. Future studies with a larger number of cases should establish whether vascular density can be a useful prognostic parameter for canine osteosarcoma.