Fig. 1 Lateral radiograph of the proximal femur of a dog with traditional high grade, stage IIB osteosarcoma (A), and sagital sectioned specimen of same dog (B). Note medullary origin, cortical lysis, and soft-tissue extent of classic osteosarcoma.
Courtesy of: Stephen J. Withrow, DVM

AAOS Now

Published 9/1/2009
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Annie Hayashi

Going to the dogs for novel tumor treatments

Canine model provides surrogate for osteosarcoma research

Osteosarcoma in children and adolescents is relatively rare, with between 500 to 600 new cases diagnosed every year in the United States. The incidence of osteosarcoma (OSA) in pet dogs, however, is 20 times higher, with about 10,000 to 15,000 new cases occurring annually.

“Canine OSAs share numerous clinical, biologic, molecular, and genetic signatures with the human disease—making them relevant models for translational research,” said Stephen J. Withrow, DVM, professor of surgical oncology and director of the Animal Cancer Center at Colorado State University–College of Veterinary Medicine and Biomedical Sciences, Fort Collins, Colo. Dr. Withrow, the only veterinarian member of the Musculoskeletal Tumor Society, presented the results of some of that research at the 2008 AAOS/Ortho­paedic Research Society research symposium on Molecular Biology and Therapeutics in Musculoskeletal Oncology.

“Canine research can help the orthopaedic community by advancing limb sparing, allograft, device, and implant technology. It also contributes to our understanding of the biology of cancer metastasis and control,” he said.

Characteristics of canine OSA
As the most common malignancy of bone found in dogs, OSA affects the extremities 4 times more often than the axial skeleton or the skull. It most commonly occurs in the metaphysis of the long bones of middle- to older-aged dogs and large breeds (> 20kg).

At diagnosis, most canine tumors are stage IIB (Fig. 1), and 15 percent have clinically detectable metastasis to lung or bone.

“We often achieve local control with amputation, although limb-sparing procedures can be applied in selected cases and centers,” explained Dr. Withrow. “We continue to study the use of stereotactic radiosurgery and bone-seeking radionuclides to improve local control.”

If amputation is the sole treatment, the 1-year survival rate is less than 10 percent, with most dogs dying of pulmonary metastasis. Adjuvant chemotherapy with cisplatin, carboplatin, and doxorubicin, however, increases survival rates significantly—to 50 percent at 1 year and 30 percent at 2 years.

Dogs take the lead
Because the incidence of OSA is so common in canines, multiple clinical trials can be conducted at one time.

“Owners are very willing and enthusiastic about participating in clinical trials with their pet animals. We are treating a disease that will rapidly kill their dog, so they are eager to help find a solution.

“We can conduct several, concurrent clinical trials, with 60 to 80 dogs per trial, and complete the studies with meaningful end points of survival and local disease control in a relatively short time,” said Dr. Withrow.

According to Dr. Withrow, the disease progresses more quickly in dogs so the end point of survival can be shown in 1 year as compared to 5 years in a child. “If a treatment provides a 25 percent or 50 percent advantage in survival, we will have that information in a year,” he said.

Many of these clinical trials are powered by the Comparative Oncology Trials Consortium (COTC)—a network of 18 veterinary university oncology centers coordinated by the National Institutes of Health/National Cancer Institute (NIH/NCI).

The COTC only supports translational clinical trials in dogs that assess novel cancer therapies for future use in human patients.

Dr. Withrow’s institution seeks advice and treatment strategies from the Children’s Oncology Group (COG)—a global clinical trial cooperative supported by the NIH/NCI.

“In cooperation with the COG, we currently are evaluating the antimetastatic potential of an old antibiotic and immunosuppressant agent known as rapamycin in canine osteosarcoma against the proposed target ezrin,” he explained.

Ezrin, a protein found in 40 percent of humans and canines, is a predictor of poor outcomes in osteosarcoma and other types of cancer. Rapamycin is known to block certain proteins including ezrin. Phase I of this clinical trial has been completed, and Phase II trials have recently begun.

In the 1980s, Dr. Withrow and his investigators participated in another NCI-sponsored program to determine whether chemotherapy could be used to reduce the size of inoperable osteosarcomas in pediatric patients so that limb sparing surgery could be performed. They evaluated the safety and efficacy of cisplatin delivered intra-arterially in a canine model. “We helped demonstrate that we could kill the tumor before surgery—making the surgical procedure much more feasible,” he noted.

A recent study by Ross M. Wilkins, MD, Dr. Withrow’s co-investigator, supports preoperative intra-arterial and intravenous use of chemotherapy to treat high-grade osteosarcoma and malignant fibrous histiocytoma of the bone in young people. Cisplatin (also known as cisplatinum) was one of two recommended agents.

“Recent advances with the immunomodulator muramyl tripeptide phosphatidyl-ethanolamine (MTP-PE) in pediatric osteosarcoma also had roots in canine osteosarcoma trials conducted 15 years ago,” Dr. Withrow explained.

According to a recently published study from the COG, the addition of MTP-PE to the same, cumulative doses of cisplatin, doxorubicin, and methotrexate improved 6-year overall survival from 70 percent to 78 percent (p = 0.03).

Canine model offers advantages
“The relevancy of the canine model to human disease is at the heart of what we do,” said Dr. Withrow. “It’s one reason that organizations such as the NIH/NCI and the American Cancer Society have been willing to provide funding for research in this area for the past 30 years.”

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org

References:

  1. Messerschmitt PJ, Garcia RM, Abdul-Karim FW, Greenfield EM, Getty PJ: Osteosarcoma. J Am Acad Orthop Surg 2009;17;515-527.
  2. Hugate RR, Wilkins RM, Kelly CM, Madsen W, Hinshaw I, Camozzi AB: Intraarterial chemotherapy for extremity osteosarcoma and MFH in adults. Clin Orthop Relat Res 2008;466:1292-1301.
  3. Kurzman ID, MacEwen EG, Rosenthal RC, et al: Adjuvant therapy for osteosarcoma in dogs: Results of randomized clinical trials using combined liposome-encapsulated Muramyl Tripeptide and Cisplatin. Clin Cancer Res 1995;1:1595-1601.
  4. Meyers PA, Schwartz CL, Kralilo MD, et al: Osteosarcoma: The addition of Muramyl Tripeptide to chemotherapy improves overall survival: A report from the Children’s Oncology Group. J Clin Oncol 2008;26;4:633-638.
  5. 2008 AAOS/ORS Symposium on Molecular Biology and Therapeutics in Musculoskeletal Oncology: www.aaos.org/research.asp