Osteosarcoma and hemangiosarcoma: The ugly sarcomas (Proceedings)
Osteosarcoma (OSA) and hemangiosarcoma (HSA) are highly malignant tumors that have both a locally invasive and highly metastatic biologic behavior. Multimodality therapy must be employed to provide patients with these cancers the best chance for improved quality and quantity of life. Despite these therapies, however, dogs with OSA or HSA generally succumb to their disease within 6-12 months. This presentation will highlight new information regarding diagnostics and therapeutics for these aggressive tumors.
Appendicular OSA is the most common primary bone tumor in dogs, accounting for up to 85% of all primary bone tumors. There is a bimodal peak in age of occurrence, at 2 years of age and middle-aged to older dogs. Males are reported to be over-represented with a male:female ratio of 1.5:1. Large to giant breed dogs are at greater risk with Irish setters, St Bernards, Rottweilers, etc. likely to be affected. One study found a mutation in a proto-oncogene (MET) in 70% of Rottweilers; this mutation was found in < 5% of all other breeds examined. This breed-specific finding suggests a heritable mutation with the Rottweiler breed.Diagnostics
• Radiographs of the primary lesion will show a mix of bone proliferation and lysis; the degree of each finding can vary widely between tumors. The long bone locations for the tumors are at the metaphyseal region: away from the elbow, but towards or away from the knee (i.e. in the rear leg the tumor may arise at either end of the femur or tibia). Thoracic radiographs will show metastasis in only ~8% of dogs at diagnosis, but microscopic metastasis is present in another 80%. Finding visible metastatic lesions greatly changes the prognosis, as visible nodules do NOT respond to chemotherapy. Thus, a complete metastasis check with 3 radiographic views (right and left lateral and a DV) is critical. CT scan is a more sensitive way to detect nodules; the response to chemotherapy of CT visible yet non-radiographically visible nodules is unknown.
• Fine needle aspirates may be diagnostic in the majority of cases. OSA is easily exfoliative and reveals large, immature mesenchymal cells that may be producing osteoid (pink matrix). OSA may have a plasmacytoid appearance, with round-ish margins and deep blue cytoplasm. Alkaline phosphatase staining is a highly sensitive and specific way to determine if a malignant cell is of bone origin. If cellularity is poor, a biopsy may be needed. The least invasive technique is with a Jam Shidi bone core biopsy instrument; most dogs are not significantly more lame after this type of biopsy.
• Serum alkaline phosphatase is prognostic in that dogs with elevated levels have shorter survival times by 50% even when treated aggressively with surgery and chemotherapy.
Treatment and Prognosis
The treatment option associated with the longest disease control and overall survival times is surgical amputation followed by 4 to 6 doses of a platinum based chemotherapy drug (cisplatin or carboplatin). Doxorubicin may also be used; it may be slightly less effective. With amputation alone, median survival times range from 3-5 months; chemotherapy post-surgery will extend that to a median survival of 10-12 months. While combination chemotherapy would seem to offer benefits over single-agent treatments, no studies to date have shown strong support for the use of combination chemotherapy. Survival times with such combinations remain similar to single agent treatments, and toxicities are higher. As an alternative to amputation for local tumor control, limb salvage procedures, which remove the tumor but spare the limb, can be effective for tumors at the distal radius.
Palliative therapy provides median survival times from 3-6 months. One of the most affective palliative treatments is coarse (large) doses of radiation (RT) given weekly for 3-4 total doses. A recent paper showed good benefits in dogs receiving 2 doses of RT given daily on sequential days. Following RT, improved function can occur in up to 75% of patients. Interestingly, while dogs treated with amputation alone succumb to pulmonary metastasis at a median of 3-5 months, dogs treated only with palliative RT are typically free of pulmonary metastasis at the point at which they succumb to local pain, also at roughly 4 months. Studies have shown that the primary OSA tumor secretes anti-angiogenic factors that are likely involved with the suppression of growth of metastatic lesions. Thus, chemotherapy may not have a role in disease control in dogs treated palliatively with the tumor not removed.
Pain medications alone are generally not very effective at controlling bone pain. Combinations of a nonsteroidal antiinflammatory drug, tramadol, and gabapentin may provide increased comfort for some amount of time. These drugs are often used in conjunction with RT.
Bisphosphonates are widely used in humans with lytic bone disorders. These drugs inhibit osteoclast activity and thus may help decrease boney lysis at the tumor site. Other actions include induction of apoptosis of osteoclasts and potentially malignant osteoblasts; they may also alter the microenvironment within the bone. Interestingly, 3 groups of investigators have shown that bisphosphonates also have direct anti-cancer effects on OSA cell lines in tissue culture. The anticancer effect of bisphosphonates in OSA patients is under investigation. Pamidronate (1-2 mg/kg IV over 2 hrs in 250 mls 0.9% NaCl once every 4 weeks) alone increases comfort in about 1/4 of dogs with OSA. When pamidronate was given with palliative radiation and chemotherapy, an increase in pain control was not seen over radiation/chemotherapy alone. Zoledronate (0.1 mg/kg IV over 15 minutes in 60 mls 0.9% NaCl), a next generation bisphosphonate, showed a 50% response in dogs with OSA as a single agent. Preliminary findings of an ongoing study with zoledronate combined with palliative radiation are very encouraging. Oral bisphosphonates are very poorly absorbed in the dog and should not be used.
Immunotherapy using L-MTP-PE, a liposome-encapsulated immunostimulant derived from a bacterial cell wall, increased survival time to a median of 14.5 months when used after amputation and 4 doses of cisplatin. This drug, known as mifamurtide, has recently received approval in Europe and thus may be available for purchase for patients in the United States in the future.