New Treatments For Osteosarcoma Aim To Extend Life And Save Limbs

Angie Johnson, D.V.M., of Kodiak, Alaska, knew immediately when she felt a bulge on her 8-year-old fawn Great Dane's lower right foreleg last May that it could be bone cancer. As a veterinarian at the Kodiak Veterinary Clinic, Johnson was aware that the bump warranted having a radiograph taken.

Her Great Dane, CH MeadoWood's Humble Knight's Baxter, RN, CGC, TDI, was a blood donor at the veterinary clinic, a tracking dog for Alaska Search and Rescue Dogs, and an agility and obedience competitor in fun trials. "Baxter," who often joined Johnson on hikes and runs in the Alaskan bush, saved her last year from a near attack by a grizzly bear.

Baxter's radiograph showed a distinctive starburst lesion in the radius formed from needle-like fragments of bone, indicating a diagnosis of osteo­sarcoma. "The radius looked awful," Johnson says. "There were spicules around it that come from the cancer simultaneously eating and growing bone."

The fast-spreading, painful cancer affects about 9 percent of giant breeds like Great Danes. Comparatively, 1 percent of large breeds and 0.1 percent of toy breeds develop the cancer. There is no cure for bone cancer, so owners and veterinarians work together to provide the best treatment possible using surgery, chemotherapy, radiation therapy and medications for palliative care. Usually, amputation of the affected limb followed by chemotherapy is recommended to increase survival, but owners of Great Danes and other giant breeds often are reluctant to amputate, particularly a forelimb, because it can make walking difficult and may compromise quality of life.

Since osteosarcoma generally occurs in the leg bones, lameness and difficulty going up and down stairs are the most common signs that owners notice. Last July, two months after Baxter was diagnosed with the cancer, he began limping and having difficulty sleeping due to pain. His condition improved after Johnson gave him Rimadyl, a nonsteroidal anti-inflammatory drug (NSAID); tramadol, a drug that blocks receptors that transmit pain; and amantadine, a pain reliever com­monly given to dogs with osteosarcoma.

While the conventional therapies for treating osteosarcoma aim to increase survival, research veterinarians are investigating promising new treatments. These include a recombinant bacteria vaccine and a powerful limb-sparing stereotactic radiosurgery that kills tumor cells and spares healthy tissue.

The Most Common Cancer

Osteosarcoma mostly occurs in dogs over the age of 8, long after they have been bred, but dogs as young as 1 or 2 years old can develop the cancer. The most common cancer in Great Danes, osteosarcoma arises from mutated cells that stop bone-matrix remodeling and the production of bone cells.

"Normally, a dog's body makes new, healthy bone as old cells die," explains Brian Saunders, D.V.M., Ph.D., DACVS, assistant professor of orthopedic surgery at Texas A&M University College of Vet­erinary Medicine & Biomedical Sciences. "Osteosarcoma turns off the rebuilding function, and the bone matrix is de­stroyed without being properly remade."

A definitive diagnosis is made from a bone biopsy, but characteristic lesions on radiographs are a strong indicator of osteosarcoma. As in Baxter's case, tumors are depicted in radiography as a starburst pattern of needle-like fragments of bone. In 90 to 95 percent of dogs, osteosarcomas have micro­metastasized at the time of diagnosis. Micrometatasis is not clinically evident on radiographs but will eventually lead to large metastatic tumors usually in the lungs or other bones.

During a bone biopsy, a small core of bone tissue is extracted using a bone biopsy needle for analysis of cells and tissues that may indicate cancer. A biopsy can help rule out fungal disease, but the puncture from the aspiration also can fracture weakened bone.

Dogs diagnosed with osteosarcoma suffer from pain that is complicated by fractures in the weakened bone. Sensory receptors, called nociceptors, send nerve signals of severe pain to the brain, and destroyed bone cells cause inflammation. Reducing pain is of primary importance.

Amputation combined with chemo­therapy is considered the standard of care, but Great Dane owners often opt for limb-sparing surgery. Fifty percent of dogs that receive amputation and chemotherapy survive one year. Less than 30 percent survive two years, and less than 10 percent survive three years.

A variety of limb-sparing surgeries involving bone replacement techniques, mostly offered at university veterinary teaching hospitals or large specialty practices, are available that reduce pain and help to provide a functioning limb. Limb-sparing surgery followed by chemotherapy results in survival times that are similar to dogs receiving amputation and chemotherapy.

Palliative radiation provides pain relief for two to four months in 70 to 90 percent of dogs by reducing inflammation and promoting bone recalcification. Among the medications given to dogs with osteosarcoma are NSAIDS, which help reduce pain from inflammation; narcotics, which block the nociceptor sensory receptors; and bisphosphonates, which relieve pain by decreasing bone loss.

In dogs with osteosarcoma, osteolysis, or destruction of the mineral matrix of bone, causes pain and fractures. "Bisphosphonates inhibit osteolysis," explains Sarah Charney, D.V.M., DACVIM, DACVR, adjunct professor of radiation oncology at the University of Illinois College of Veterinary Medicine and staff radiation oncologist at Animal Specialty Center in Yonkers, N.Y. "As a result, bone pain and fractures are reduced."

Pamidronate disodium is a bisphos­phonate that provides pain control and extends life span about eight months for about 30 percent of dogs. A newer bisphosphonate, zoledronate, costs more but may attack cancer cells and protect bones. Both drugs can be used with radiation to help alleviate pain.

"I suggest that Great Dane owners work with their veterinarians and follow the studies of zoledronate combined with palliative radiation therapy," Charney says. "Early preliminary reports suggest a nine- to 10-month median survival time."

Treatment of osteosarcoma is challenging partly because the cancer is likely to metastasize, or spread, especially to the lungs. Metastasis in the lungs usually is the ultimate cause of death for dogs with bone cancer.

It is not known definitely whether osteosarcoma is an inherited condition in dogs. Nicola Mason, B.Vet.Med., Ph.D., DACVIM, the Pamela Cole Chair in Companion Animal Medicine at the University of Pennsylvania School of Veterinary Medicine, says, "Large and giant breeds may be predisposed to osteosarcoma because of genetic influences, but other factors may also be involved. Rapidly proliferating cells tend to be more susceptible to cancer-forming events, therefore dogs whose bones grow rapidly, such as large and giant breeds, or dogs that experience bone trauma and damage that requires cellular proliferation for repair may be at higher risk for developing osteosarcoma.

"Chronic inflammation is known to be associated with the development of other cancers, although it is unknown whether persistent bone inflammation predisposes to bone cancer. Most likely the cause of osteosarcoma, like other tumors, is multifactorial, involving both genetic and as-yet unknown environmental factors that together can create the perfect situation for bone cancer to develop."

Alternative Treatment Approaches

Alternative approaches to treating osteosarcoma are being investigated. Charney is part of a team that has pioneered a limb-sparing CyberKnife® radiosurgery technique for dogs where amputation is not possible or desired. Combined with chemotherapy, this radiosurgery, also known as stereotactic surgery, has a survival time that is similar to the standard of care with amputation and chemotherapy for good candidates. Unfortunately, not all dogs are good candidates. The viability of radiosurgery is best assessed by a CT (computed tomography) scan. The benefit of radiosurgery is that it saves the limb.

"With this procedure, a radiation oncologist uses a high-tech, image-guided and computerized robotic control system to deliver radiation with submillimeter accuracy," Charney explains. "The CyberKnife radiation beams are sculpted to conform tightly to complex masses and deliver multiple radiation beams from many points outside the dog's body to the targeted tumor. The beams kill tumor cells yet spare healthy tissue. When the beams converge on the tumor mass, they deliver high-energy, pinpointed radiation with astounding power."

Compared to conventional radiation therapy, the precision of CyberKnife radiosurgery allows higher doses of radiation to be delivered to the tumor while minimizing damage to healthy tissue. One to three treatments are the same as 15 to 20 treatments of conventional radiation. The benefits include fewer hospital visits, fewer anesthetic episodes and reduced stress. Treatment is based on how much bone destruction has occurred as seen on on a CT scan.

Meanwhile, at the University of Pennsylvania, Mason is testing a recombinant Listeria monocytogenes tumor vaccine. "Our project focuses on finding and killing the cancer cells that amputation and chemotherapy overlook," she says. "This method uses the body's immune system to elicit anti-tumor immunity and prolong survival in dogs with cancer of their long bones."

Last July, a 12-year-old Bulldog named "Sasha" from North Carolina was the first of 18 canine patients that will receive the vaccination in a pilot study. To be eligible, dogs with osteosarcoma must have had a limb amputation and standard chemotherapy consisting of four doses of carboplatin.

Sasha's family made three eight-hour round trips to Philadelphia to the veterinary teaching hospital for three vaccine treatments. Veterinarians closer to home at the North Carolina State University Veterinary Health Complex performed Sasha's follow-up visit and will continue to examine Sasha every two months to determine whether tumors have formed in her lungs. So far, Mason considers Sasha's response "very positive."

"If Sasha and the other dogs live for more than eight months following vaccination, which is greater than one year post-diagnosis, then we will have increased median survival and will consider that the vaccine is having some effect," Mason says.

"We hope in the future to test whether this vaccine is effective in dogs that have not had amputations. This technology could be applied to other cancers, such as canine mammary cancer," she says. "It also may help people. Pediatric oncologists are watching our trial closely. This bacteria-based vaccine could possibly stimulate an immune response in children with osteosarcoma."

Saunders and Carl Gregory, Ph.D., assistant professor of molecular and cellular medicine at Texas A&M University's Institute for Regenerative Medicine, are collaborating on a study to determine whether adult stem cells isolated from canine bone marrow or fat can improve bone healing. Their long-term goal is to use enhanced stem cells in prefabricated tissue engineering constructs to improve bone healing after limb-sparing surgery.

"Unfortunately, the techniques that stimulate human adult stem cells to turn into bone are not very effective with dog stem cells," Saunders explains. "In addition, the ability of stem cells from different dogs to transform into bone varies widely. The challenge is that we don't know enough about dog stem cells to make rapid clinical advancements."

While the adult stem-cell research, Cyberknife radiosurgery and L. monocytogenes vaccine provide a glimpse of future treatment possibilities for osteosarcoma, Great Dane owners today continue to struggle to determine the best treatment that will extend longevity for their individual dog.

Johnson, whose Great Dane Baxter was diagnosed last May, knew that amputation was not an option. "Baxter's favorite thing in the world was hiking in the Alaskan woods," she says. "I could not, in good conscience, take his leg away. It would take away the things he loved best in this world."

Baxter lived four months after being diagnosed with osteosarcoma. "He had a wonderful, pain-free summer," Johnson says. "In September, high doses of anti-inflammatory and pain medi­cations were no longer working, and he couldn't go on hikes anymore. I made the decision that it was time. I was so blessed to have had the time I did with him."

Purina appreciates the support of the Great Dane Club of America and particularly J.P. Yousha, chair­ of the GDCA Health and Research Committee, in helping to identify topics for the Purina Pro Club Great Dane Update newsletter.