Osteosarcoma

Osteosarcoma in Dogs
Robyn Elmslie, DVM DACVIM (Oncology)
Kim Statham-Ringen, DVM DACVIM (Oncology)
Veterinary Cancer Specialists
Veterinary Referral Center of Colorado

Quick facts at a glance:

• Primarily affects large and giant breed dogs
• Front limbs (radius and humerus) most commonly affected
• Microscopic metastasis to lungs present at time of diagnosis
• Early neutering increases risk of osteosarcoma in Rottweilers
• Treatment with chemotherapy significantly increases survival time
• Radiation therapy is very effective for pain control

Clinical presentation at time of diagnosis
Appendicular osteosarcoma is most common in giant and large breed dogs, with an average age of onset of 7 years. The most common site of development in long bones is in the distal radius, followed by the proximal humerus.  Less common sites include the proximal and distal femur and tibia.  Most animals with osteosarcoma present with a history of progressive lameness over several weeks, though some dogs may present with acute lameness due to pathologic fracture.  The diagnosis of osteosarcoma can sometimes be delayed when patients have concurrent arthritis, as the lameness due to the bone cancer is initially attributed to arthritis.  Bone swelling is a common finding when osteosarcoma affects the distal radius, distal femur or distal tibia.

Many large and giant breeds are at high risk for the development of osteosarcoma, but the prevalence is particularly high in Scottish Deerhounds, Greyhounds, Rottweilers and Great Danes.  For reasons that are currently not well understood, early neutering significantly increases the risk of osteosarcoma development in Rottweiler dogs.  Male Rottweiler dogs that were castrated and female Rottweilers that underwent overiohysterectomy before the age of 1 year were shown to have a 1 in 4 lifetime risk of developing osteosarcoma and were at significantly greater risk of developing osteosarcoma than intact Rottweilers.  Studies investigating the genetic basis of increased susceptibility to osteosarcoma in Rottweilers and other breeds are currently underway through funding by the Canine Health Foundation and the Morris Animal Foundation.

What tests are done to diagnose osteosarcoma?
The classical radiographic changes associated with bone cancer include cortical bone lysis, varying degrees of periosteal changes, loss of trabecular detail of the metaphysis, and tumor extension into soft tissue.  This latter process is known as Codman's triangle or a "sunburst" effect.  In animals with bone lesions suggestive of osteosarcoma, it is recommended that thoracic radiographs (2 lateral views and one ventrodorsal view) be taken prior to any surgery, although fewer than 10% of dogs have radiographically visible evidence of pulmonary metastasis at the time of presentation.  CT scan of the lungs is more sensitive than radiographs for the identification of small metastatic lesions.  Bone scintigraphy (bone scan or nuclear scan) can be a helpful diagnostic procedure to rule out metastatic disease to bone.  However, fewer than 3% of patients will have bone metastases at the time of presentation.

Bone biopsy is required for definitive diagnosis of osteosarcoma.  However, because the bone biopsy procedure does carry some risks, such as bone fracture and collection of a non-diagnostic sample due to extensive inflammation within the tumor.
A diagnostic bone biopsy is more likely obtained when impression cytology of the bone biopsy tissue is performed at the time of sample collection.

In many cases, definitive treatment of osteosarcoma can be undertaken in animals with characteristic clinical findings, even without a biopsy.  This is especially true in dogs with extensive bone lesions that are very painful.  In fact, the odds of a destructive bone tumor in a large breed dog not being osteosarcoma are very low.  For example, fewer than 1% of dogs with characteristic bone lesions will be found to have a tumor other than osteosarcoma, and an even smaller percentage (< 0.25%) will have fungal infection of the bone.  Therefore, in many cases surgery is performed without a bone biopsy as most dogs with osteosarcoma are very painful and have radiographic evidence of extensive bone destruction.

Several recent studies indicate that simple blood test results can be very informative with respect to prognosis for dogs with osteosarcoma.  For example, dogs with an abnormal increase in serum alkaline phosphatase have a significantly decreased survival time compared to dogs with normal alkaline phosphatase concentrations.  Similarly, dogs with elevated or high normal monocyte or lymphocyte counts also have much shorter survival times than dogs with low normal cell counts.

What are the surgical options for treatment of osteosarcoma?
Amputation remains the treatment of choice to alleviate pain, improve quality of life and control the primary tumor.  In our experience, greater than 90% of pet owners report good to excellent quality of life following limb amputation.  Severe, pre-existing arthritis is the primary limiting factor in deciding whether to proceed with amputation.   However, in dogs without arthritis that undergo amputation, they typically ambulate better after amputation than they did prior to amputation of the affected, painful limb.

When amputation is not a good option for the patient and the bone tumor is small and affecting only the distal radius, limb-sparing surgery can be considered.  While complications such as infection are a risk with this surgery, the majority of owners report good limb function after healing.

However, it is also important to realize that while surgery (amputation or limb-sparing surgery) immediately relieves the pain associated with the bone cancer, surgery alone only modestly improves survival times.  For example, the median survival time following surgery alone is 4.5 months, with nearly all dogs dying due to development of progressive pulmonary metastases.  Survival time is 2 months on average when treatment is not pursued.

What about chemotherapy for osteosarcoma?
The primary reason for administration of chemotherapy is to prolong patient survival time by slowing the development of tumor metastasis following surgery or radiation therapy.  Several chemotherapy drugs and protocols have been used for the treatment of osteosarcoma in dogs.  Currently, the most commonly used treatment protocols consist of treatment with carboplatin as a single agent treatment, or carboplatin given in alternating doses with doxorubicin.  Single agent carboplatin, administered at 3 week intervals for a total of 4 treatments, is very well tolerated and offers a median survival time of 307 days when initiated within 2 weeks following amputation.  Carboplatin and doxorubicin, administered 3 weeks apart in an alternating schedule for a total of three doses of each drug, results in a median survival time of 258 days, when initiated 2 weeks following amputation.  In a recent study performed at the University of California, carboplatin as a single agent given 3 weeks apart for 6 treatments was compared to an alternating protocol of carboplatin and doxorubicin.  All patients were treated within 2-3 weeks of amputation.  The median survival time was significantly longer  (p=0.007) in the patients treated with 6 cycles of carboplatin, 535 days as compared to 227 days for the patients treated with the carboplatin/ doxorubicin combination protocol.

Additional chemotherapy protocols are currently being investigated.  One of these protocols involves the use of metronomic chemotherapy following standard high-dose chemotherapy.  The metronomic chemotherapy protocol was recently shown by our group to be highly effective in preventing the local recurrence of soft tissue sarcoma in dogs.

How can we palliate or control pain in dogs with osteosarcoma?
When amputation or limb sparing surgery is not a good option for the patient due to size of the patient, the location of the tumor, or the presence of pre-existing osteoarthritis, several treatment options are available for pain management.  While long-term survival may not be achieved with these protocols, quality of life can be preserved for many months in most cases.  Thus, treatment with oral medications such as NSAIDs, tramadol (Ultram) and/ or gabapentin (Neurontin) often results in significant though short-term pain relief.  The median survival time for patients with osteosarcoma treated with oral pain medications alone is 2 months, with euthanasia usually occurring due to progressive unacceptable pain levels and poor quality of life.

Course fractionated radiation therapy is the single most effective treatment for rapidly alleviating bone pain in dogs with osteosarcoma.  A similar treatment approach is commonly used in humans for control of bone pain due to advanced breast or prostate cancer.  Our approach at Veterinary Cancer Specialists is to administer a total of 3 high doses of radiation therapy to the tumor and surrounding tissue.  The first and second treatments are spaced by one week and the second and third treatments are given 2 weeks apart.  The spacing of these high dose radiation fractions allows normal tissues to undergo repair, thereby avoiding many of the side effects commonly observed with full course radiation therapy.  General anesthesia is needed for each radiation therapy treatment but usually only lasts less than 15 minutes.

Administration of aminobisphosphonates (eg, pamidronate or zolendronate), a group of drugs most commonly used for the treatment of bone pain associated with cancer in humans, can be administered alone or optimally in combination with radiation therapy in dogs with osteosarcoma to maximize bone pain relief.  Treatment with aminobisphosphonates can be given on the same day as radiation treatment.

Intravenous chemotherapy can reduce bone pain and improve and extend quality of life in some patients that do not undergo amputation for osteosarcoma and is therefore also used in combination with radiation therapy and aminobisphosphonates.

• Summary of survival statistics for dogs with osteosarcoma
• Oral pain relief only:  median survival time of 2 months
• No amputation; pain relief with oral medications and radiation therapy and/or aminobisphosphonates and/or chemotherapy:  4-10 months
• Amputation only: median survival time of 4.5 months
• Amputation with 4 treatments of carboplatin:  median survival time 10 months
• Amputation with 6 treatments of carboplatin: median survival time of 17.5 months

What can be done to control metastases once they develop?
Approximately 10% of dogs with osteosarcoma will have radiographic evidence of pulmonary metastasis at the time of diagnosis.  These patients have a very short survival time with a median of 2 months.  For these dogs, treatment with a combination of course fractionated radiation therapy and chemotherapy can extend their median survival time to 4.5 months.

Surgical excision of pulmonary metastases may be considered in patients that develop no more than 2 pulmonary nodules over a 1 year period following the initial diagnosis.  For these patients, the median survival time after surgery to remove the metastases is 4.5 months.  Chemotherapy may be helpful following surgery in these dogs to reduce the development of new metastases and prolong survival times further.

Current clinical studies for osteosarcoma patients at Veterinary Cancer Specialists: (Please contact us at 303-874-2054 for information regarding funded clinical trials)

References and reading:

1. Phase I study of liposome-DNA complexes encoding the interleukin-2 gene in dogs with osteosarcoma lung metastases.  Dow S, Elmslie R, et al.  Hum Gene Ther. 2005 Aug;16(8):937-46.
2. Increased Numbers of Circulating Monocytes and Lymphocytes are Associated with a Decreased Disease-Free Survival Interval In Dogs with Osteosarcoma. Sottnik,J et al. 29th Annual VCS Proceedings, Austin, Texas 2009.
3. Use of single-agent carboplatin as adjuvant or neoadjuvant therapy in conjunction with amputation for appendicular osteosarcoma in dogs. Phillips B, Powers BE, Dernell WS, Straw RC, Khanna C, Hogge GS, Vail DM.  J Am Anim Hosp Assoc. 2009 Jan-Feb;45(1):33-8.
4. Use of alternating administration of carboplatin and doxorubicin in dogs with microscopic metastases after amputation for appendicular osteosarcoma: 50 cases (1999-2006).  Bacon NJ, Ehrhart NP, Dernell WS, Lafferty M, Withrow SJ.  J Am Vet Med Assoc. 2008 May 15;232(10):1504-10.
5. Prevalence of and intrinsic risk factors for appendicular osteosarcoma in dogs: 179 cases (1996-2005).  Rosenberger JA, Pablo NV, Crawford PC.   J Am Vet Med Assoc. 2007 Oct 1;231(7):1076-80.
6. Evaluation of survival time in dogs with stage III osteosarcoma that undergo treatment: 90 cases (1985-2004).  Boston SE, Ehrhart NP, Dernell WS, Lafferty M, Withrow SJ.  J Am Vet Med Assoc. 2006 Jun 15;228(12):1905-8.
7. Endogenous gonadal hormone exposure and bone sarcoma risk.  Cooley DM, Beranek BC, Schlittler DL, Glickman NW, Glickman LT, Waters DJ. Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1434-40.
8. Heritability and segregation analysis of osteosarcoma in the Scottish deerhound. Genomics. 2007 Sep;90(3):354-63. Epub 2007 Jul 12.  Phillips JC, Stephenson B, Hauck M, Dillberger J.
9. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. Elmslie RE, et al.   J Vet Intern Med. 2008 Nov-Dec;22(6):1373-9. Epub 2008 Oct 3
10. http://tripawds.com/