Update on osteosarcoma (Proceedings)

Osteosarcoma (OSA) is the most common primary bone tumor in dogs accounting for up to 85% of bone tumors in the dog.  This disease has a biphasic age distribution affecting dogs under the age of 3 and over 7 years.  Osteosarcoma typically affects large to giant breed dogs with a slight male sex predilection with the exception of Saint Bernards, rottweilers and Great Danes. 

When smaller dogs get osteosarcomas, they tend to get them of the axial skeleton rather than the appendicular skeleton.   Intact dogs tend to have an increased risk of developing OSA with the exception of rottweilers, where animals spayed or neutered early actually had the increased risk of disease development.

Osteosarcomas tend to affect the appendicular skeleton most of the time (75% of the time).  These tumors are often distributed away from the elbow and towards the knee (proximal humerus, distal radius, distal femur and proximal tibia) though other sites have been seen.  Generally it is the metaphyseal portion of the bone that is affected.  The most common locations for OSA in the axial skeleton are the mandible and maxilla followed by the spine, cranium, ribs, nasal cavity and pelvis. 

Etiology

Due to the location of most of these tumors and the size of the patients affected, many people think that multiple minor traumas to the sensitive physeal cells are the reason for the development of these tumors.  Mitogenic signals may be sent during healing and repeated injury may prime these cells for malignant transformation.

Orthopedic implants may also lead to formation of an OSA at the previous site of trauma.  OSA may also occur at sites of chronic osteomyelitis and unrepaired fractures.  Chronic inflammation is a known cause of malignant transformation for many tumors.

Previous radiation therapy sites have a small chance (incidence 4-6%) of developing a second tumor.  This typically occurs in dogs receiving definitive radiation therapy for a mast cell tumor or a soft tissue sarcoma, where high total doses of radiation were achieved and the dog has a long term expected survival.  This often occurs years after the radiation therapy and typically results in an OSA of the underlying bone.

Behavior of OSA based on location

Appendicular OSAs have an aggressive behavior.  Up to 90% of them metastasize, often to the lungs within a year of diagnosis regardless of treatment.  These tumors may develop months after amputation.  At the time of diagnosis, only 10-15% of dogs will have gross evidence of metastasis present on chest radiographs, however 90% of metastases present on a microscopic level.  The growth of these metastatic lesions is suppressed by the primary tumor.  Once the primary tumor is removed and its suppression lifted, these lesions are free to grow.  With amputation alone dogs will often only live 3-4 months before metastases are seen grossly on chest films.

OSAs of mandibular and calvarium origin tend to have a less aggressive behavior and lower metastatic rate. Surgery may even be curative for these tumors (if surgery is possible). Chemotherapy may even be controversial for tumors in these locations.

OSAs of the rib have a very aggressive behavior and a high metastatic rate. These tumors spread faster than those of appendicular origin even if they are surgically removed.

It is hard to predict the metastatic behavior of OSAs of the spine and pelvis.  Often there are few therapeutic options and dogs are euthanized soon after diagnosis due to a poor quality of life. 

Diagnosis and staging

Though OSAs account for 85% of primary bone tumors, there are other primary bone tumors that must be ruled out before amputation is considered.  Differentials for a lytic and proliferative lesion of bone include:

·         Osteosarcoma

·         Bacterial and fungal osteomyelitis

·         Lymphoma

·         Multiple myeloma

·         Solitary osseous plasma cell tumor (SOP)

·         Hemangiosarcoma

·         Fibrosarcoma

·         Chondrosarcoma

·         Bone cyst

·         Secondary bone tumors

The round cell tumors may not require amputation and may be treated medically or with radiation therapy.  Bacterial and fungal osteomyelitis may be managed with medical therapy in many cases and bone cysts may require not treatment depending on size and location.

A diagnosis of osteosarcoma may be achieved 60% of the time using a fine needle aspirate.  Dogs should be heavily sedated and a large bore needle (20-16 guage) can be used.  Aim for the center of the lesion and walk along the bone until you fall into it.  Cover the hub of the needle to limit hemodilution of the sample.  Move the needle back and forth at varying angles and twist the needle to help loosen cells inside the needle.

Make smears or squash preps on slides and examine for evidence of tumor cells. Large multinucleat giant cells represent osteoclasts and are part of the boney reaction to the disease process.  Osteosarcoma cells are derived from osteoblasts and may have a round to mesenchymal appearance.  They have a basophilic cytoplasm with an eccentrically located nucleus and may be producing matrix.  If matrix is present a small pink zone near the nucleus may appear.  Matrix may also be present between cells.

If a sample cannot be collected using a fine needle aspirate (more productive or sclerotic tumors), then a bone biopsy may be necessary.  A Jamshidi biopsy instrument can be used to go through one cortex of the bone lesion.  Again, aim for the center of the lesion to avoid getting reactive bone in your sample.  The sample is collected by stabilizing the biopsy instrument in the bone, removing the stylet and advancing the instrument through a single cortex by twisting back and forth. 

Once the instrument is through one cortex, move it around like a joy-stick gently and then remove.  Use the shepherd's hook in a retrograde fashion to remove your sample from the instrument.  Roll preps of the sample canbee made for a quick diagnosis, but the tissue should go into formalin immediately afterwards. 

Once a diagnosis of OSA has been made, several staging tests are necessary before initiating treatment.  Baseline blood work is necessary (CBC, Chem, UA) and three view chest films.  Additionally, a careful orthopedic exam should be done as 14% of these tumors will spread to other bones, usually flat bones, in the body. 

Prognostic factors

Location: As discussed above, certain locations carry a better prognosis (mandibular, cranium) and certain locations can be associated with a worse prognosis (ribs, scapula, extra-skeletal sites).  Rib OSA has a MST of only 3 months, while those of the scapula and extraskeletal sites are not much better at around 5 months.

Age: Age is not a disease and should not preclude and animal from receiving treatment.  However, older animals may have diseases that preclude them from receiving standard of care therapy.  Severe arthritis or other orthopedic disease may make amputation impossible.  Severe kidney or liver disease may preclude one from using chemotherapy.  Significant illness may also make a patient a poor anesthetic candidate.  Younger dogs may be good candidates for standard of care therapy, however, in a study of 162 dogs, those under 5 years of age at diagnosis did not live as long as those that were over 5 years of age when diagnosed.

Size of lesion: is prognostic in dogs with axial OSA due to the fact that a small lesion is more likely to be completely excised leading to a better prognosis.

Grade: High grade tumors have shorter median survival times.

Elevated Serum Alkaline Phosphatase: is a negative prognostic factor for dogs with appendicular OSA and is associated with the bone isoenzyme of Alk Phos.  

Treatment options

Local control is often achieved with surgical removal.  Amputation is the most common therapy for a dog with appendicular OSA.  Amputation is not for patients with severe orthopedic or neurological diseases. A complete forequarter amputation including the scapula is recommended in the forelimb and a coxofemoral disarticulation is recommended for hind limb OSA.

In some cases where amputation is not possible, then a limb sparing procedure can be performed. The most common form of limb sparing is an allograft implant.  There are several criteria that must be met for a dog to be a candidate for a limb sparing procedure.  The tumor must be in a location that is amendable to this procedure (distal radius, distal ulna or distal tibia).

The tumor with margins must not take up more than 50% of the long bone it is affecting.  No pathologic fractures, soft tissue component or significant breakdown of the cortex is permitted.  This would lead to an incomplete excision of the tumor as the soft tissues are left behind.  Dogs cannot have any evidence of distant metastasis at the time and they must have a very dedicated owner. 

Other forms of limb sparing include:

·Metal endoprosthesis- a metal prosthesis is implanted in place of the bone.

·Pasteurized tumoral autograft- the affected bone is removed, autoclaved for 40 min and reimplanted.

·Longitudinal bone transport osteogenesis (BTO) - using external fixators and distraction osteogenesis, new bone is regrown at the site where the tumor was removed.

·Ulna transposition limb sparing- A distal piece of the ulna is used to replace the section of distal radius removed. The interosseous vessel is preserved to provide blood supply to the transposed bone.

·Intraoperative extracorporal radiation- the bone with the lesion present is isolated from the soft tissues, an osteotomy is performed to flip the tumor out and 70 gray of radiation are delivered to the tumor.  The bone is then put back into place.

Other sites of OSA may or may not be amendable to surgery depending on their location.  Mandibulectomy may be possible as long as the mass does not extend across midline.  Other areas may be resectable depending on location and size of the tumor.

Additionally, for those tumors that are incompletely excised (calvarium, mandible, maxilla), adjuvant radiation therapy may be helpful.  Though these tumors are radiation resistant in a bulky disease setting, with high total dose therapy microscopic disease can be treated resulting in durable remissions. Mandibular tumors have a MST of >18 months when completely excised, however, other locations tend to have survival times of less than 6 months due to local invasiveness and the inability to completely remove them.

Regardless of the type of surgery, adjuvant chemotherapy must be used.  The platinums (carboplatin and cisplatin) are used most often.  In most cases these drugs are given systemically, however, cisplatin bead implants have been put into the surgery site of dogs receiving a limb spare.  Without chemotherapy surgery is really only palliative because dogs die so quickly of metastatic disease. The average survival time for a dog treated with surgery alone is 3-6 months, whereas, those treated with a platinum generally live 10-12 months.  Doxorubicin can achieve MSTs of approximately 6-9 months when used alone.

Palliative therapy

Palliative therapy is reserved for those cases in which surgery is not possible either because of other disease processes or the location of the tumor.  Additionally, some owners will allow amputation in their dogs.  Palliative therapy is aimed at controlling pain and increasing quality of life without increasing the quantity of life.

Radiation therapy can be used to help control pain at the site.  In a gross disease setting, radiation therapy will not treat the primary tumors.  These tumors are very radiation resistant. Radiation will help to kill nerve endings and decrease pain.  This therapy lasts approximately 4-7 months and dogs may be treated repeatedly depending on the original dose and schedule administered.

Bisphosphonates are a class of drugs that can be used in conjunction with other palliative therapies to help decrease bone lysis and strengthen the bone.  These drugs decrease osteoclastic activity and help to sclerose the bone by adding calcium back in. They are nephrotoxic and must be used with a 2 hour diuresis of saline to prevent kidney damage.  These drugs should not be used in patients with underlying kidney disease.  The effects of this drug as a single agent are underwhelming.  It is controversial whether they help at all, but if used, they should be used in conjunction with other palliative therapies.

Pain meications are necessary in every case. Whether or not they act painful, dogs with lytic bone lesions are painful.  NSAIDs and synthetic opiods, like tramadol, are a good place to start. When these drugs cease to effectively control pain other medications such as Amantadine and gabapentin can also be used.

Amantadine is the most commonly used oral NMDA receptor antagonist. It was originally developed as an antiviral compound, and has also been used to treat extrapyramidal drug reactions and Parkinson's disease in humans. Elimination is almost exclusively via the kidneys, so dose reductions should be considered in cases of severe renal failure. Side effects are rare, but can include agitation or diarrhea.

Gabapentin was initially synthesized to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid (GABA), but is not believed to act on the same brain receptors. Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is thought to involve voltage-gatedN-type calciumion channels.  This drug is best for neurologic pain and its ability to control bone pain is likely very limited.

Opiods may also be used; however, when controlled drugs such as these are necessary, then the euthanasia should be soon to follow.  Fentanyl patches can be used for a couple of days to give the family a chance to say their goodbyes, but long term use of these drugs for OSA pain is discouraged.

New therapies on the horizon

Several new approaches for treating OSA are in the works.  Aerosolized chemotherapy for OSA has undergone several clinical trials and we will likely continue that work here at TAMU in the future.  Immunotherapy using T cells directed at Her2/neu is also underway and will likely be in clinical trials soon.  Molecular targets such as insuline-like growth factor and growth hormone may be used for future small molecule therapies in dogs as well.  Please keep and eye on our clinical trials website for new trials that may be starting in the next year.