State of the Art Lecture

Stephen J. Withrow, DVM

Professor of Surgery and Chief of Clinical Oncology Service

Dr. Withrow is Professor of Surgery and Chief of the Clinical Oncology Service at the Colorado State University College of Veterinary Medicine and Biomedical Sciences. He is a Diplomate of the American College of Veterinary Surgeons and the American College of Veterinary Internal Medicine (oncology). Dr. Withrow graduated from the University of Minnesota in 1972 and completed an internship and surgical residency at the Animal Medical Center in New York City.

Dr. Withrow has been at Colorado State University in Fort Collins, Colorado since 1978. He has received numerous teaching, service, and research awards, and is the author of over 200 scientific articles and one textbook. His research interests include multimodality treatment of cancer in animals as a model for humans with cancer.

Dr. Withrow is the only veterinarian admitted as a member of the Musculoskeletal Tumor Society. He is also the past president of the Veterinary Cancer Society and is a member of numerous professional organizations.

Canine osteosarcoma (OSA) is a common malignancy of dogs with over 10,000 new dogs affected each year. It is by far the most common primary bone cancer. It generally occurs in large breed (> 20 kg), middle-aged dogs with a slight predilection for males over females. Seventy-five percent affect the limbs with 60% in the front leg and 40% in the back leg. Metaphyseal sites are most common with only rare involvement of the bones of the elbow. Histologic varieties occur (osteoblastic, chondroblastic, fibroblastic, and telangiectatic) but no proof exists that these variants have a different biologic behavior or response to therapy. Radiographic features are generally of a mixed pattern (lytic and blastic change). Many tumors can be “diagnosed” on signalment, history, and radiographs but a needle core biopsy (Jamshidi) is generally recom­mended. If limb sparing is contemplated, the biopsy technique and position should be carefully planned.

The pretreatment evaluation should generally include a CBC, urinalysis, biochemical profile (paying particular emphasis to the serum alkaline phosphatase, which has negative prognostic implications), thoracic radiographs, and bone survey or nuclear bone scan. As many as 10-15% of patients will have multiple lesions demonstrable at presentation and these patients carry a very poor prog­nosis. Metastasis is generally hematogenous to lung or other bones while lymph node metastasis is rare. Once a diagnosis is confirmed, numerous options exist for therapy. Two major areas of concern must be addressed: leg and life.

Leg

Without treatment, most dogs will be euthanized within one to two months for intrac­table pain. Minimal local treatment would include nonsteroidal anti-inflammatories and/or palliative radiation. Amputation is an easy, inexpensive, and effective method of permanent local disease control. Virtually any size dog can undergo an amputation with good quality of life postoperatively.

Limb sparing is designed to produce a pain-free and functional extremity without jeopard­izing survival. In a series of almost 400 limb sparings performed at CSU, the following conclu­sions can be drawn:

 Front leg sites (radius, ulna, and occasionally diaphyseal sites in any bone) are better salvage candidates than most metaphyseal sites.

 Preoperative treatment that produces significant local tumor death will facilitate the surgical resection and decrease local recurrences. The “best” preoperative treatment ap­pears to be cisplatin to act as a radiation sensitizer and a moderate dose of radiation (30 Gy in 10 frac­tions). The optimal dose, route of delivery, and timing of cisplatin relative to the radiation is still unclear. This adds significantly to the cost of treatment and is not in common usage.

 The tumor is excised and replaced with a cortical allograft. Plate fixation usually results in fusion of the radiocarpal or adjacent joint. Occasionally, osteoarticular or composite (bone and prosthesis) grafts are utilized. Partial ulnectomy does not require an allograft or internal fixation.

 Complications include infection (~30%), local recurrence (10–20%), and mechanical instability (< 5%). Most of these complications can be controlled or corrected (except local recurrence) with re-opera­tion or antibiotics (oral and/or local antibiotic beads). The “overall” success rate with limb sparing is approximately 80% for a pain free and functional leg.

 Graft instability and infection have been decreased by the use of antibiotic im­preg­nated cement in the marrow space of the allograft.

 A new biodegradable form of local chemotherapy using a polymer sponge and cisplatin has allowed immediate limb salvage and a less than 20% local recurrence rate.

 Limb salvage is difficult, costly, and not as predictable as amputation but offers an alter­native to amputation for selected patients.

 A palliative form of limb salvage is course fractions of radiation (800 rads) given two or three times to the local or metastatic site. Pain relief is often good but long-term control (> 6 months) is rare. Feldene (nonsteroidal anti-inflammatory agent) may allow transient pain relief.

 Newer techniques under investigation include intraoperative irradiation of the exposed bone (70 Gy) and reimplantation as well as full course fractionated radiation with cisplatin chemosensitization.

Life

With local disease control alone (amputation or limb sparing), the one-year survival is less than 10% and most patients die of pulmonary metastasis. The most intensely studied chemo­therapies for OSA are doxorubicin, cisplatin, and carboplatin. Most chemotherapy regimens (doxorubicin alone or doxorubicin and one of the platinum drugs) result in an approximate 50% one-year survival, 30% two-year survival, and 15% long-term systemic control rate. The optimal adjuvant chemotherapy protocol is unclear at this time.

Metastasis, especially to lung, is not hopeless; pulmonary metastasectomy in carefully selected patients can result in long-term remission or cure.

These treatments are expensive and for a M² dog (~ 30 kg), the cost of each drug treatment with cisplatin is approximately $400, carbo­platin is approximately $1,000, and doxorubicin is approximately $200. Limb salvage alone is approximately $4,000–$5,000 U.S.

Canine OSA offers a readily available and biologically predictable model for study to ben­efit both dogs and man. Studies on normal dogs as well as dogs with osteosarcoma have led to many innovations and advances in the use of allografts and the treatment of malignant bone tumors in humans.

Selected References

1.  Straw RC, Withrow SJ, Richter SL, et al. Amputation and cisplatin for treatment of canine os­teosar­coma. J Vet Int Med 5 (No 4), 1991.

2.  Carberry CA, Harvey HJ. Owner satisfaction with limb amputation in dogs and cats. J Am Anim Hosp Assoc 1987;23:227-232.

3.  Mauldin GN, Matus RE, Withrow SJ, Patnaik AK. Canine osteosarcoma: Treatment by am­puta­tion versus amputation and adjuvant chemotherapy using doxorubicin and cisplat­in. J Vet Int Med 1988;2:177-180.

4.  Powers BE, LaRue SM, Withrow SJ, et al. Jamshidi needle biopsy for diagnosis of bone lesions in small animals. J Am Vet Med Assoc 1988;193:205-210.

5.  Withrow SJ, Powers BE, Straw RC, et al. Comparative aspects of osteosarcoma. Clin Orthop Rel Res 1991;270:159-168.

6.  Straw RC, Powers BE, Withrow SJ, et al. The effect of intramedullary polymethyl­methacrylate on healing of intercalary cortical allografts in a canine model. J Orthop Res 1992;10:434-439.

7.  Withrow SJ, Thrall DE, Straw RC, et al. Intra-arterial cisplatin with or without radiation in limb sparing for canine osteosarcoma. Cancer 1993;71:2484-2490.

8.  O'Brien MG, Straw RC, Withrow SJ, et al. Resection of pulmonary metastases in canine osteosar­coma: 36 cases (1983-1992). Vet Surg 1993;22:105-109.

9.  Straw RC, Withrow SJ, Douple EB, et al. Effects of Cis-diamminedichloroplatinum II released from D,L-polylactic acid implanted adjacent to cortical allografts in dog. J Orthop Res 1994;12:871-877.

10. Bergman PJ, MacEwen EG, Kurzman ID, et al. Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1991 to 1993). J Vet Int Med 1996;10:76-81.

11. Withrow SJ, Straw RC, Brekke JH, et al. Slow release adjuvant cisplatin for treatment of metastatic canine osteosarcoma. Eur J Exp Musculoskel Res 1995;4:105-110.

12. Straw RC, Withrow SJ. Limb-sparing surgery versus amputation for dogs with bone tumors. Vet Clin North Am: Small Anim Pract 1996;26:135-143.

13. Withrow SJ. Surgery for skeletal sarcomas. Clin Tech Small Anim Pract 1998;13:53-58.

14. Ehrhart N, Dernell WS, Hoffmann WE, et al. Prognostic importance of alkaline phosphatase activity in serum from dogs with appendicular osteosarcoma: 75 cases (1990-1996). J Am Vet Med Assoc 1998;213:1002-1006.