Osteosarcoma: Causes, Diagnosis, and Treatment

Osteosarcoma (OSA) has been found in every vertebrate class and has even been identified in dinosaur fossils, but it appears to be more prevalent in dogs than in any other species. While there are different types of bone cancer, more than 85% of the bone malignancies diagnosed in dogs are OSA.

When compared to other types of cancers found in dogs, the incidence rate of primary OSA is low, with an estimated 10,000 dogs newly diagnosed each year. Its survival rate varies considerably depending on which treatments are used, but, unfortunately, none of the current treatments have high rates of success. Many promising new treatments are in the works, however.

The most common clinical signs associated with OSA are pain, swelling, and lameness in the affected leg. Lameness occurs due to pain, inflammation, microfractures, or pathologic fractures (fractures caused by normal movements due to bone deterioration caused by disease). If swelling is present, it is likely due to the spread of the tumor into the surrounding soft tissues.

Where OSA Is Found

OSA can develop in any bone, but the most common form – the appendicular (limb) form – occurs in the long bones of the legs and accounts for 75 to 85% of cases. Within this subtype, the rate of occurrence in the forelimbs is twice that of the hindlimbs, often located at the top of the humerus (shoulder) or the bottom of the radius (wrist). On the hindlimbs, knee and ankle areas are common locations. These locations are at the ends of bones, at or near the growth plates where cell turnover is high during growth.

While the majority of the remaining cases occur in the axial skeleton (the bones of the head and trunk), there have been cases of OSA documented in extraskeletal sites including the skin and subcutaneous tissues, as well as the lungs, liver, mammary glands, and other organs and glands.

Cancer Terminology

Sarcomas are a group of malignant tumors that form in the connective tissues of the body. They are usually further defined by the type of cell, tissue, or structure involved, such as with osteosarcoma. The prefix osteo derives from the Greek word osteon, meaning bone – hence bone cancer.

Osteosarcoma affects mostly middle-aged and older dogs; 80% of cases occur in dogs over 7 years of age, with 50% of cases occurring in dogs over 9 years old. Younger dogs are not immune; approximately 6 to 8% of OSA cases develop in dogs who are just 1 to 2 years of age. OSA of the rib bones also tends to occur in more often in younger dogs with a median age of 4.5 to 5.4 years.

Cause

As with most canine cancers, the cause is unknown. There has been no gender predisposition documented. There does appear to be a genetic component as OSA predominates in long-limbed breeds. Large and giant breeds have an increased risk of OSA because of their size and weight. Small dogs can develop OSA as well, but it is far less common.

Notably, the forelimbs support about 60% of total body weight of the dog and are the most common limbs to develop OSA. It is theorized that in addition to body size, the fast growth rate to create the longer bones in large breeds might contribute directly to OSA risk. Rapid bone growth results in increased bone remodeling and increased cell turnover; high cell division and turnover occurs naturally at and near the growth plates, which are also the most common sites for tumor development.

A dog’s risk also appears to increase if he has had surgery for a fracture repair or an orthopedic implant. These conditions spur the proliferation of bone-forming cells. OSA also has been associated with fractures in which no internal repair was performed. Other possible causes include chronic bone and bone marrow infections, microscopic injury in the weight-bearing bones of young growing dogs, ionizing radiation, phenotypical variations in interleukin-6 (a protein produced by various cells), abnormalities in the p53 tumor-suppressor gene, viral infections, and chemical carcinogens.

Hormonal risk factors are being actively explored in an effort to determine if there is an increased risk for OSA based on the age of spay or neuter (gonadectomy). In May 2019 Makielski et al. authored a comparative review of OSA risk factors and included this commentary on trending current hormonal studies (Veterinary Sciences Vet Sci 2019, 6, 48):

 

“Similarly, associations between reproductive status and development of osteosarcoma have been inconsistent. Although several reports suggest that spayed and/or neutered dogs have higher incidence of certain cancers, including osteosarcoma, the relationship between reproductive status and cancer risk may be confounded by other variables, such as the documented tendency toward increased adiposity and body condition in gonadectomized dogs. Increased load combined with delayed physeal (growth plate) closure, a result of gonadectomy prior to skeletal maturity, could theoretically contribute to increased osteosarcoma risk in dogs.”

Diagnosis and Staging

Clinical presentation of canine OSA typically appears as lameness of the affected limb, with or without visible swelling or mass at the affected area.

Breed Predisposition

OSA is overrepresented in large and giant breeds. The most commonly afflicted include the Rottweiler, German Shepherd, Boxer, Doberman Pinscher, Irish Setter, Saint Bernard, Great Dane, Golden Retriever, Labrador Retriever, Greyhound, Wolfhound, Deerhound, Borzoi, and Leonberger.

Small dog breeds (less than 33 pounds) with susceptibility are the Miniature Schnauzer, Cocker Spaniel, and Cairn Terrier. Overall size (height and weight), however, is more important than breed for developing OSA. Dogs weighing 55 to 99 pounds are more likely to develop OSA than those that weigh less than 55 pounds; there is an even greater susceptibility in dogs weighing more than 99 pounds.

Diagnostic exams usually include a physical exam, an orthopedic and neurological examination (to eliminate other causes of lameness), and radiographs (x-rays). Radiographs may allow for a presumptive diagnosis as OSA frequently has a characteristic appearance in the bones: patterns of bone destruction, abnormal bone growth, and sometimes fractures.

If a tentative diagnosis of OSA has been made, additional screening tests are recommended to ensure your dog is otherwise healthy; these may include a blood panel, thoracic radiographs, and CT scan. Ultrasounds are often performed but early metastasis to the abdomen is very rare. A bone aspirate for cytology with alkaline phosphate stain is common and recommended. This may occur as part of the screening process or obtained during surgery.

OSA is extremely aggressive and typically metastatic. While only 10 to 15% of dogs will have measurable metastasis, it is believed that up to 95% of dogs have undetectable metastasis at the time of diagnosis. Because of this high metastatic risk, additional assessment is recommended. Most metastatic spread appears in the lungs so thoracic radiographs are warranted.  Survey radiographs also may be recommended due to an 8% risk of metastasis to other bones. Metastasis may also be seen in lymph nodes (5%) and internal organs.

If available, PET scans or nuclear scintigraphy (sometimes referred to as a “bone scan” or “Gamma scan”) are even more sensitive diagnostic tools that can identify diseases not visible with other imaging methods. It can be useful for the detection of metastasis in dogs as it can distinguish any region of osteoblastic activity, including osteoarthritis and infection.

While there are several published histologic grading systems for OSA, there is no universally accepted system, making the predictive value of routine grading of OSA questionable.

Staging of OSA utilizes the TNM (Tumor-Node-Metastasis) System, the standard system used for most tumor staging in veterinary medicine. Three stages of OSA can be differentiated:

Stage I indicates a low-grade tumor (G1) with no evidence of metastasis (M0)

Stage II indicates a high-grade tumor (G2) without metastasis.

Stages I and II are further divided into two subgroups: Group A indicates that the tumor has stayed within the bone (T1). Group B indicates that the tumor has spread beyond the bone into other nearby structures (T2). Most dogs are diagnosed with Stage IIB OSA.

Stage III is a tumor with metastatic disease (M1).

Treatment

The primary considerations for treatment of OSA should include an understanding of how far the disease has metastasized, how to treat the bone tumor itself, and how to curb, delay, or prevent recurrence or spread of the disease. The disease develops deep in the bone and destroys it from the inside; as a result, it can be extremely painful and treating that pain can be a challenge. Above all, any approach should ensure that the dog maintains excellent quality of life.

  • Surgical

Wide-margin surgery, by either limb amputation or limb-sparing surgery, is indicated as the standard initial treatment of canine appendicular OSA. While biopsies are typically recommended prior to surgery for most types of cancer, it is not a necessity with OSA when there are other diagnostic indicators.

  • Amputation
Two “tripod dogs” meet at the dog park: What are the odds? Amputation of a limb affected by OSA is the quickest way to relieve the dog’s pain and most of the destructive processes of the disease.

Removal of the limb extracts the local cancer immediately and is the quickest and most effective way of alleviating pain and most of the destructive processes of OSA. It also removes the risk of a painful pathological fracture, which often occurs as the disease progresses.

Because pain inhibits quality of life, amputation is considered a quality of life choice. The majority of dogs recover quickly and resume a normal life on three legs. Amputation completely removes the primary tumor, is not a complicated surgery and requires less anesthesia time, offers a decreased risk of postoperative complications, and is a less expensive procedure than limb-sparing surgery (discussed next).

  • Limb-Sparing Surgery

Limb sparing can be preferable to amputation for dogs who suffer from existing severe orthopedic or neurological diseases; candidates for limb-sparing surgery should be in otherwise good health with a primary tumor confined to the bone. This surgical procedure replaces the diseased bone with a metal implant or bone graft or combination of the two to reconstruct a functional limb.

On the Horizon: OSA Treatments in Development

Numerous drugs, nanoparticles, and antibody-drug conjugates (ADCs) have shown significant promise in targeting and treating OSA. Early results of studies using nanoparticles suggest that they may offer potent new therapeutic agents to treat primary tumors as well as to minimize or prevent the recurrence of OSA. There is emerging evidence that bone-targeted therapeutics using bisphosphonates have the potential to significantly improve treatments. ADCs are biopharmaceuticals designed to target and destroy tumor cells while sparing healthy cells. As of 2019, more than 50 pharmaceutical companies are researching the possibilities of ADCs.

  • PetCure Oncology, in collaboration with Varian Medical Systems, is currently accepting patients into a clinical trial to evaluate dogs that receive SRS/SRT to treat OSA of the appendicular skeleton. Early data suggests that SRS/SRT can lead to longer median survival time; the study will analyze whether SRS/SRT increases the circulation of immune cells that are responsible for attacking cancer.
  • The Blue Buffalo Veterinary Clinical Trials Office at The Ohio State University Veterinary Medical Center is researching a novel anti-cancer drug for dogs with OSA that has metastasized to the lungs. The drug is a chemically synthesized compound (PAC-1) that selectively induces cell death in cancerous cells. The study will evaluate the ability of the drug to decrease the size and growth of lung metastases in dogs when administered in combination with doxorubicin.
  • Because the presence of tumor-associated macrophages (TAMs) in bone tumors has been shown to be potentially associated with survival time, the Flint Animal Cancer Center at Colorado State University is conducting a study to develop a noninvasive way to determine how many TAMs are present in bone tumors through the use of an Ultra-Small Paramagnetic Iron Oxide Particle MRI for Imaging.
  • Auburn University in Alabama is evaluating zoledronate for treatment of pulmonary nodules associated with OSA metastasis. Bisphosphonates have documented efficacy for control of cancer-associated bone pain and recently have been investigated for its ability to induce cancer cell death as well interfere with metastasis.
  • Colorado State University Animal Cancer Center is conducting a study to predict which of the standard chemotherapy protocols will be most effective against an individual dog’s tumor and determine if this will provide for longer survival rates.
  • A ganglioside-targeted cancer vaccine for OSA is being studied in a Phase 1 trial at the University of Florida College of Veterinary College. A previous study of ganglioside (GD3) showed the vaccine caused a measurable immune response and prolonged survival in dogs with melanoma. (Gangliosides are glycosphingolipids that contribute a substantial presence to the outer leaflet of the cell plasma membrane.)
  • The University of Minnesota’s College of Veterinary Medicine is researching the genetically modified Vesicular Stomatitis Virus (VSV-IFNß-NIS, called VSV for short) for development of a novel oncolytic immunotherapy for OSA. A pilot study of eight dogs with cancer demonstrated VSV to be safe. Two additional separate studies (12 additional dogs with cancer) found similar results.
  • Veterinary Oncology Services in Middletown, NY, is conducting clinical trials to evaluate the benefit of treating OSA (as well as mammary cancer and transitional cell carcinoma) with a genetic DNA telomerase cancer vaccine along with a genetic HER2 cancer vaccine. The goal is to combine these two treatments as a synergistic attack against two different paths of cancer development. Because telomerase is not expressed in most differentiated cells, it is an ideal target for cancer therapeutics.
  • Veterinary Oncology Services is also testing whether an adenovirus-based vaccine followed by a DNA plasmid administered via electrogene transfer can elicit anti-tumor immunity and increase survival times for dogs with OSA. The vaccine targets the Her2/neu pathway of tumorigenesis allowing the body’s immune system to battle the cancer.
  • Aratana Therapeutics has developed an immunotherapy vaccine that uses a lyophilized formulation of a modified-live, attenuated, recombinant HER2/neu-expressing strain of Listeria (AT-014) that activates cytotoxic T cells. It received its conditional license from the USDA in December 2017 for the treatment of dogs 1 year or older diagnosed with appendicular OSA.

The vaccine is administered in a series of three doses given three weeks apart, with boosters every six months. The nonlyophilized (liquid) form of this therapeutic was administered to dogs with appendicular osteosarcoma following amputation or limb salvage surgery and chemotherapy consisting of four doses of carboplatin. The median disease-free interval was 615 days and median survival time was 956 days for the 18 dogs in the study (who had no evidence of metastatic disease at enrollment). Adverse events were mild to moderate and primarily consisted of fever, lethargy, and nausea/vomiting.

Aratana is progressing toward full licensure by conducting an extended clinical field study as required by the USDA. About 24 veterinary oncology practices throughout the U.S. are participating in the extended field study and have the vaccine available.

ADXS31-164, the nonlyophilized, frozen form of the USDA conditionally licensed therapeutic AT-014, has not been licensed by the USDA and is available only through clinical trial. This form of the vaccine is being employed in a separate clinical trial at 11 participating sites to evaluate the safety and efficacy in dogs with OSA (target enrollment is 100). This study is funded by Morris Animal Foundation and coordinated by the Comparative Oncology Trials Consortium (part of the National Institutes of Health).

Limb sparing surgery temporarily improves the overall condition of the leg, but eventually the cancer will progress and the bone will deteriorate. Limb function is preserved in more than 80% of dogs. However, complications are fairly common with this procedure. Infections occur in 30 to 50% of cases, implant failure in 20 to 40%, and 15 to 25% of dogs will experience tumor recurrence. Subsequent chemotherapy and radiation treatments also may be recommended.

  • Stereotactic Radiosurgery (aka SRS, Stereotactic Radiotherapy/SRT, Cyberknife)

Stereotactic radiosurgery is an alternative to amputation or limb-sparing surgery; it also may be used as an adjunct therapy following amputation. It is a nonsurgical procedure (but does require anesthesia) that delivers radiation directly to the tumor site. Radiation acts by making cancer cells unable to reproduce.

SRS precisely transmits several beams of radiation aimed from various angles to deliver a high dose of radiation to a designated tumor target. The delivery system is effective and efficient and therefore reduces the chance of damage to surrounding normal structures and tissues. Potential downsides to SRS include fracture from radiation-induced bone degradation and possible tumor regrowth. Early reports suggest that the outcomes of SRS followed by chemotherapy may be comparable to those achieved with amputation and chemotherapy.

  • Chemotherapy

The best outcomes for dogs with OSA to date have been for those undergoing amputation followed by chemotherapy. Since tumor removal does not address metastasis, systemic treatment via chemotherapy can be vital to a treatment plan. Several studies have reported prolonged survival rates using cytostatic drug protocols, with carboplatin, cisplatin, and doxorubicin the most commonly used.

Side effects from chemotherapy tend to occur infrequently; when they do, they are usually predictable, minor, and manageable. A dog undergoing chemotherapy can expect to have excellent quality of life.

  • Immunotherapy

For the latest in immunotherapy treatment for OSA, see WDJ March 2019 “A New Bone Cancer Vaccine for Dogs.”

Other Treatments

  • Palliative Radiation

The primary goal of palliative radiation is to maintain good quality of life for cancer patients, whether human or canine. It is used to control clinical signs and pain associated with tumors that either cannot be treated by other techniques or where more aggressive treatments have been declined.

As an added benefit, palliative radiation may slow the rate of progression and reduce the size of the tumor, thereby further contributing to the well-being of the patient. Dogs with OSA initially undergo two to five treatment sessions (requiring anesthetic) and are typically administered in lower dosages than that used for stereotactic radiosurgery.

Most dogs will achieve some degree of pain relief within the first one to two weeks following treatment, with the potential for it to be effective for a couple of months. When pain returns, radiation can be re-administered for if deemed appropriate.

  • Bisphosonate Drugs

Bisphosphonates, such as pamidronate and zoledronate, are easily administered through intravenous (IV) infusions and are aimed at preventing or slowing bone destruction and reducing pain and risk of fracture, therefore prolonging the dog’s life. This treatment is relatively inexpensive, has a wide safety margin, and can even be used on dogs with renal or liver insufficiency.

These drugs are usually used in combination with chemotherapy and/or radiation therapy but may be used alone. Additionally, bisphononates appear to have potential cancer-suppression effects by impeding proliferation and inducing apoptosis (programmed cell death); as a result, they have become a targeted area for new research.

  • Pain Management

Again, because OSA can be extremely painful, recognition and alleviation of pain is essential for maintaining quality of life. Dogs with OSA may experience pain due to a number of causes: the cancer itself, a treatment modality, or a concurrent disease such as osteoarthritis. To preemptively and adequately control pain, more than one medication is often required.

Nonsteroidal anti-inflammatory drugs (NSAIDS) are typically a mainstay for controlling pain – but aren’t the best choice for the type of pain associated with OSA. However, they may be used to address other forms of pain being experienced concurrently. Gabapentin, amitriptyline, duloxetine, and amantadine are better suited to alleviating OSA-related pain.

Weight control can help by relieving the extra pressure on joints; supplements also may be recommended to help support the unaffected joints. Physical therapy and massage can be beneficial, especially for the compensating joints and muscles. Acupuncture, having been shown to increase endorphins (which inhibit pain perception), also can provide an avenue for pain management.

Palliative Care

Palliative care is an approach that prioritizes measures to relieve symptoms (without curative intent) and improve comfort. It is a valid and respected choice for care; only owners can decide what is best their dogs. Palliative care also can be provided to dogs who are at the end stage of their disease.

Prognosis

The heartbreaking reality is that the vast majority of dogs affected by OSA will succumb to the disease or be released through euthanasia due to disease progression. Dogs who do not receive any form of cancer-specific treatment are usually euthanized within one to two months of diagnosis due to uncontrolled pain.

Those treated with surgery alone (amputation) have an average survival period of about four to five months; almost all die within a year and only 2% live past two years.

Dogs receiving surgery and chemotherapy have average survival times of approximately 10 months, with up to 28% alive after two years.

The median survival time for dogs receiving radiation therapy and chemotherapy is about seven months.

In general, dogs between 7 and 10 years old tend to have longer survival times than younger and older dogs.

The prognosis is very poor for dogs with Stage III OSA; the average survival time is 2.5 months. Dogs less than 7 years old with a large tumor located at the top of the humerus also have a very poor prognosis. Dogs with axial OSA have an average survival time of four to five months as complete surgery is usually prohibitive due to tumor location and likely recurrence. If regional lymph node metastasis has been found, survival time is only about 1.5 months.

This Is A Tough One

With the increasing amount of research being conducted on OSA, there is hope for new therapies, increased survival times, and improved outcomes. But for many, it won’t be soon enough. Bear, my friend Keri’s dog, succumbed to OSA while I was writing this. He lived 16 months after diagnosis with palliative care and lots of love. He is very much missed.

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