OVERVIEW: What every practitioner needs to know

Are you sure your patient has osteosarcoma? What are the typical findings for this disease?

Osteosarcoma is the most common malignant bone tumor in children and adolescents. In the pre-chemotherapy era, surgery alone cured ~15% of those with localized disease; the addition of chemotherapy to the armamentarium in the 1980’s brought the 5 year event free survival (EFS) to 65-70%. Unfortunately, there have been relatively few advances in the last two decades that have further improved the overall survival for osteosarcoma despite multiple investigative studies with novel agents.

Patients present with pain or localized swelling at the primary tumor site, most commonly the femur – followed by the tibia and humerus. A biopsy must be performed by a trained oncologic orthopedic surgeon to prevent seeding of the area with malignant cells.

Treatment is multimodal and includes surgical resection and intensive chemotherapy. After diagnosis, patients receive neoadjuvant (preoperative) chemotherapy prior to surgical resection of the primary tumor and metastatic sites. Techniques that achieve full tumor resection with negative margins but allow for continued function of the involved limb are known as limb sparing procedures. The use of amputation has decreased in recent decades, but surgical control is essential for cure. Patients who do not achieve a full resection of tumor have a much worse prognosis.

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The degree of necrosis of the tumor at surgical resection, known as the “definitive” surgery, has been conclusively found to be prognostic of long term outcome, with EFS of ~80% for those with >90% necrosis. Patients are subsequently treated with several cycles of intensive chemotherapy after the resection. Recent trials have tried to improve outcome by augmentation of chemotherapeutic intensity for patients who achieve only poor necrosis (<90%). Intensification of chemotherapy for patients who only achieve poor necrosis has not been found to improve outcomes, however.

Between 10-20% of patients will have metastatic disease at presentation, most commonly lung followed by bone. Skip metastases refer to metastatic lesions within the primary bone site. The presence of metastatic disease at presentation drastically affects prognosis with overall survival reduced from approximately 70% to below 20%.

Key symptoms and signs of the disease:

  • Pain at the primary site

  • Pain that presents at night or rest

  • Localized swelling

  • Pathologic fracture in some cases

  • Cough or chest pain if pulmonary metastatic disease is present in some cases

Patients with osteosarcoma most commonly present with pain at the involved primary tumor sight which in some cases may be present for three or more months prior to a diagnosis being made. Localized swelling in the involved area can develop and can lead patients to seek medical attention. The pain is often described as worse with activity and, in some cases, is precipitated by antecedent minor trauma. A relationship between trauma and the development of osteosarcoma has not been proven. Pathologic fracture is an infrequent presenting sign. Pain is commonly reproducible to palpation.

Pulmonary metastases are found in approximately 10-20% of cases at diagnosis. Pulmonary symptoms are a very rare presenting sign of newly diagnosed osteosarcoma. Symptoms of pulmonary metastases include cough, chest pain, and/or hemoptysis in patients with widespread pulmonary disease (usually only seen in patients with endstage disease).

The most common primary tumor sight of origin is by far the femur which accounts for approximately 50% of all cases of osteosarcoma. The tibia and humerus are the next most common presenting sights and account for approximately 25% and 10% of all cases, respectively. These are followed by the fibula, pelvis, scapula, and jaw. Other skeletal sights are possible, albeit extremely rare.

What other disease/condition shares some of these symptoms?

Diseases/conditions that can mimic osteosarcoma:

Osteomyelitis

Trauma

Other Malignant Bone Tumors

Ewing’s Sarcoma

Chondrosarcoma

Fibrosarcoma

Benign Bone Tumors

Osteoma

Osteoid Osteoma

Osteochondroma

Osteoblastoma

Giant Cell Tumor of Bone

Aneurysmal Bone Cyst

Fibrous Dysplasia

Bone Infarct

Soft Tissue Sarcomas

Rhabdomyosarcoma

Synovial Sarcoma

Alveolar Soft Parts Sarcoma

Pleomorphic Undifferentiated Sarcoma

Other Soft Tissue Sarcomas

What caused this disease to develop at this time?

  • Spontaneous Development (no known risk factor) is by far the most common clinical scenario

  • Median age is related to age of the growth spurt (1 year earlier in females)

  • Osteosarcoma is more frequent in taller individuals

  • History of ionizing radiation exposure

  • Li Fraumeni Syndrome

  • Hereditary Retinoblastoma (Osteosarcoma is the second most common malignancy in patients with a germline Rb mutation after retinoblastoma)

  • Rothmund-Thomson syndrome

  • Bloom Syndrome

  • Associations with Osteochondroma, exostoses, fibrous dysplasia, metallic implanted devices, bone infarcts, and chronic osteomyelitis have been reported

  • Paget’s Disease (in adults)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Biopsy by trained oncologic orthopedic surgeon – critically important

  • LDH and serum alkaline phosphatase can be elevated and may be associated with prognosis although this is controversial and has not been statistically proven

  • Fine Needle Aspiration not indicated

The diagnosis is made by biopsy. It is essential that the biopsy be performed at a tertiary care center by an oncologically trained and experienced orthopedic surgeon who will ensure that the biopsy track can be resected at definitive surgery. This may prevent microscopic, metastatic spread which can drastically affect prognosis. Pathology will classically show anaplastic stromal tumor cells with the production of osteoid.

Imaging studies are necessary to rule out metastatic disease and document the extent of the primary lesion. These are listed in the next section.

Would imaging studies be helpful? If so, which ones?

  • Plain film of the affected area

  • Computed tomography (CT) Scan of the Chest to evaluate for pulmonary metastases

  • Magnetic resonance imaging (MRI) of the primary lesion

  • Bone Scintigraphy to evaluate for skeletal metastases

  • PET Scan is being more commonly used as a tool to identify metastatic disease especially in patients with recurrent disease although is not yet standard of care

  • Echocardiogram (performed to document normal cardiac function prior to starting anthracycline therapy)

Radiograph of the affected area is often sufficient in making the diagnosis of osteosarcoma strongly suspected. The tumor has a very characteristic appearance on plain film. Specifically, the lesion will have a mixed lytic and sclerotic appearance. Osteosarcoma more commonly develops in the metaphyses of long bones, unlike Ewing’s Sarcoma which more commonly develops in the diaphyses. Periosteal new bone formation with the lifting of the bone cortex (commonly referred to as Codman’s Triangle) is common. Classically, a “sunburst” appearance is seen on plain film and refers to radiating calcification at the site of disease.

MRI of the site is essential for evaluating extent of local disease. A chest CT scan evaluates for pulmonary metastasis while bone scintigraphy evaluates sites of bone metastasis.

If you are able to confirm that the patient has osteosarcoma, what treatment should be initiated?

  • A complete staging work up includes Chest CT, MRI of the primary lesion, and bone scintigraphy. Echocardiogram should be performed to document normal cardiac function prior to beginning anthracycline therapy.

  • A central line (usually a port a catheter) should be placed.

  • Standard chemotherapy includes high dose methotrexate, doxorubicin and cisplatin.

Once the diagnosis of localized osteosarcoma is made, treatment is multimodal and involves intensive chemotherapy – neoadjuvant and adjuvant – in conjunction with complete surgical resection. Studies have shown a clear benefit to the addition of systemic chemotherapy to full surgical control. It has been well documented in historical studies of osteosarcoma that patients treated with surgery alone will develop metastatic recurrence in up to 85-90% of cases.

Chemotherapy administered in the neoadjuvant setting includes doxorubicin, cisplatin, and high dose methotrexate. After approximately 10 weeks of this treatment, surgical resection of the primary lesion is performed. Subsequent to definitive surgery, adjuvant therapy is instituted for approximately 30 weeks (“maintenance”). Maintenance chemotherapy also includes doxorubicin, cisplatin and high dose methotrexate. Augmenting maintenance chemotherapy (by adding agents or increasing the dose of specific agents) has not been shown to improve overall survival and EFS for those with poor necrosis at the definite surgery. Effective surgical control is essential for cure of osteosarcoma. En bloc resection of the entire lesion is necessary with negative margins to achieve local control. Osteosarcoma is not radiosensitive, and radiation for local control is usually not indicated for this tumor. Historically, patients with osteosarcoma had mutilating amputations to achieve local control. In more recent years, however, limb sparing procedures have been developed that similarly achieve effective local control while preserving adequate limb function in the majority of cases.

Limb sparing procedures after neoadjuvant chemotherapy have been shown to be as effective as mutilating procedures in achieving cure. Indeed, studies have shown that radical procedures, like amputation, have not correlated with improved outcome. Improvements in orthopedic techniques and prosthetic devices and implants have allowed limb sparing procedures to replace amputation as standard of care.

Metastatic disease at presentation is similarly treated with aggressive chemotherapy and surgical control. Newly diagnosed patients with metastatic disease will have tumor metastases that are similarly sensitive to neoadjuvant therapy. At definitive surgery, full surgical resection should be attempted at all sites of disease to optimize chances of survival with maintenance adjuvant chemotherapy as above.

Several studies have been done to improve the outcome for patients with recurrent ostoesarcoma. Solitary pulmonary recurrences are treated with full surgical resection. Adjuvant strategies using systemic and inhaled chemotherapeutic agents and immunomodulators have been attempted but have not been shown to correlate with improved survival. In multiply recurrent cases, treatment is generally palliative with surgery and systemic chemotherapy. The outcome for recurrent and/or metastatic osteosarcoma is poor.

What are the adverse effects associated with each treatment option?

There are multiple side effects possible with the chemotherapy agents used in the treatment of osteosarcoma.

High Dose methotrexate: renal toxicity, myelosuppresion, mucositis, infection, dermatitis, and hepatic toxicity, among others.

Doxorubicin: cardiac toxicity with high cumulative exposure (450 mg/m2 is standard in Osteosaracoma, a dose rarely associated with clinically significant acute cardiotoxicity but with a high risk for late cardiotoxicity). Alopecia, myelosuppression, infection, nausea and vomiting, extravasation, and very rarely, secondary leukemia.

Dexrazoxane prevents acute and possibly long term cardiac toxicity.

Cisplatin: renal toxicity, ototoxicity, nausea and vomiting, electrolyte abnormalities (particularly hypomagnesemia), peripheral neuropathy, Raynaud’s Phenomenon, and very rarely – encephalopathy.

Ifosfamide: myelosuppression, hemorrhagic cystitis, infection, nausea and vomiting, SIADH, sterility at high doses – more pronounced in males, secondary leukemia (rare), and neurotoxicity. Ifosfamide induced neurotoxicity is a rare side effect, is usually temporary and reversible, and can range from mild symptoms such as disorientation and hallucinations to more pronounced symptoms such as seizures, encephalopathy, and coma. Methylene blue is an antidote to the toxic metabolite thought to induce neurologic symptoms.

Etoposide: myelosuppression, alopecia, infection, peripheral neuropathy, hepatic enzyme fluctuation, hypersensitivity, hypotension with the infusion which usually responds to fluid administration, and rarely secondary AML.

Most acute side effects are temporary and can be effectively managed. Long term side effects include cardiomyopathy from anthracyclines, renal toxicity from cisplatin and high dose methotrexate, peripheral neuropathy and ototoxicity from cisplatin, and risk of secondary malignancy.

The risk of infertility in males is primarily of concern when ifosfamide is used in therapy. It warrants consideration of sperm banking and counseling prior to starting therapy. In female patients, the risk of infertility is low with conventional treatment for osteosarcoma. They are at risk for early menopause, however, and should be counseled appropriately at diagnosis.

Surgical complications are possible, as always, and include infection, bleeding, and pain. Long term function of the extremity involved will be dictated by what limb sparing procedure is used to achieve full resection with negative margins at definitive surgery.

What are the possible outcomes of osteosarcoma?

Patients with a new diagnosis of non metastatic osteosarcoma have an overall survival of approximately 65-70% with conventional multimodal therapy. Patients with metastatic disease have an overall survival of between 10% and 20%. By far, the most important predictor of overall survival at diagnosis is the presence of metastatic disease at presentation.

Recurrent osteosarcoma after conventional treatment has a grim prognosis.

A full discussion of all potential side effects should be had with the patient and family prior to beginning therapy, including all of the side effects discussed above, among others. Patients or their surrogates should sign informed consent to treatment at the start of treatment.

What causes this disease and how frequent is it?

Osteosarcoma has an incidence of 4.4 cases per million in adolescents and young adults. The age distribution, as described above, is bimodal with a peak in adolescence and young adulthood and second peak later in life in the sixth decade or after. There is no known seasonal variation to the incidence of osteosarcoma.

There is no known infectious cause of osteosarcoma. There have been studies that have shown that bone sarcomas can be induced in select animals by viruses. At this time, however, a relationship between infectious agents and osteosarcoma is not thought to exist.

There are no known activities or environmental exposures thought to lead to osteosarcoma, aside from ionizing radiation or a prior history of receiving alkylator or anthracycline based chemotherapy, as discussed above.

There are more than 900 new cases of osteosarcoma diagnosed in the United States each year, with more than 400 being diagnosed in the pediatric population. Osteosarcoma makes up less than 1 % of all cancers diagnosed in the United States each year. The peak incidence is 4.4 cases per million in adolescents and young adults.

Osteosarcoma has been well documented to have a bimodal age distribution with peaks of incidence in adolescents and young adults and a second peak later in life after the sixth decade. A relationship may exist between osteosarcoma and periods of rapid bone growth evidenced by the peak incidence in adolescence and the predisposition the tumor has for the metaphysis of long bones. Patients with osteosarcoma are, in general, taller than the general population which adds fuel to this debate. In addition, osteosarcoma in dogs is significantly more common in larger breeds than smaller.

In adolescents and young adults, there is a slight female to male preponderance, although in girls, the incidence peaks at a younger age. The metaphyseal plate closure occurs at a younger age in females, consistent with the hypothesis of a relationship between osteosarcoma and times of rapid bone growth.

Ionizing radiation is the most well documented exposure known to predispose patients to osteosarcoma. Exposure to alkylator and/or anthracycline based regimens of chemotherapy has also been found to be associated with the development of osteosarcoma, after controlling for radiation. There are no other infectious or environmental exposures that have been associated with the development of osteosarcoma.

There are multiple genetic factors that have been associated with osteosarcoma, some of which are listed above. Specifically, osteosarcoma has been associated with multiple inherited cancer syndromes including Li Fraumeni Syndrome (germline mutation of the tumor suppressor oncogene p53 on chromosome 17p), Hereditary Retinoblastoma (germline mutation of the tumor suppressor gene Rb on chromosome 13q), Rothmund-Thomson Syndrome, Bloom Syndrome, and Werner Syndrome. Both p53 and Rb are critical to cell cycle regulation and apoptosis.

Osteosarcoma has also been shown to be associated with mutations at loci on chromosomes 13q and 18p. The mechanism by which these genetic mutations specifically translate into the development of osteosarcoma is unknown and the subject of ongoing research.

In later life, secondary osteosarcoma can develop following malignant transformation of Paget’s Disease of Bone or other benign bone lesions. Paget’s Disease of bone is a condition where there is breakdown of normal bone turnover. Malignant transformation to osteosarcoma occurs in approximately 1-2% of all cases. Secondary osteosarcoma that develops after a diagnosis of Paget’s Disease has been well documented to have a much worse prognosis than primary osteosarcoma.

Despite the strong relationship with inherited cancer syndromes, the vast majority of cases of osteosarcoma in adolescents and young adults are sporadic with no known genetic risk factor.

How do these pathogens/genes/exposures cause the disease?

Other clinical manifestations that might help with diagnosis and management

Several adverse prognostic factors have been identified for osteosarcoma at diagnosis:

1. The presence of metastatic disease at diagnosis (adverse).

2. Pathologic subtypes of osteosarcoma may be associated with improved or worse prognosis but do not dictate or change therapy, however.

3. Poor necrosis at definitive surgery after neoadjuvant chemotherapy (adverse).

4. Tumors that cannot be resected with negative margins.

5. Tumors that arises in sites of previous irradiation.

6. Large primary extremity tumors (> one third the size of the limb involved).

7. High serum LDH has also been correlated with adverse outcome.

8. Children diagnosed under age 10 may also have a worse outcome, perhaps attributable to primary sites that are not amenable to full resection.

Patients who present with symptoms for a long period of time prior to diagnosis have been found to have a better prognosis and probably have more indolent tumors.

What complications might you expect from the disease or treatment of the disease?

Are additional laboratory studies available; even some that are not widely available?

There are no additional laboratory studies that can aid in the diagnosis of osteosarcoma.

How can osteosarcoma be prevented?

There are no known strategies or treatments to prevent the development of osteosarcoma as the disease is most often sporadic with no known risk factor. If the patient has an inherited cancer predisposition syndrome associated with osteosarcoma as listed above, a full genetics evaluation should be done with appropriate genetic counseling. These are extremely rare, however.

Current trends in pediatric oncology that limit or reduce use of high does radiation to bone (eg. in the treatment of Ewing sarcoma) may reduce the risk of secondary osteosarcoma.

What is the evidence?

Broadhead, ML, Clark, JC, Myers, DA. “The Molecular Pathogenesis of Osteosarcoma: A Review”. Sarcoma. 2011. pp. 1-12.

Chou, AJ, Merola, PR, Wexler, LH. “Treatment of Osteosarcoma at First Recurrence after Contemporary Therapy The Memorial Sloan Kettering Experience”. Cancer,. vol. 104. 2005. pp. 2214-2221.

Dorfman, HD, Czerniak, B, Dorfman, HD, Czerniak. “Bone Tumors”. 1998. pp. 128

Geller, DS, Gorlick, R. “Osteosarcoma: A Review of Diagnosis, Management, and Treatment Strategies”. Clinical Advances in Hematology and Oncology. vol. 8. 2010. pp. 705-718.

Goorin, AM, Harris, MB, Bernstein, M. “Phase II/III Trial of Etoposide and High-Dose Ifosfamide in Newly Diagnosed Metastatic Osteosarcoma: A Pediatric Oncology Group Trial”. Journal of Clinical Oncology. vol. 20. 2002. pp. 426-433.

Hurley, C, McCarville, B, Shulkin, BL. “Comparison of 18F-FDG-PET-CT and bone scintigraphy for evaluation of osseous metastases in newly diagnosed and recurrent osteosarcoma”. Pediatric Blood and Cancer,. vol. 63. 2016. pp. 1381-1386.

Janeway, KA, Grier, HE. “Sequelae of osteoseosarcoma medical therapy: a review of rare acute toxicities and late effects”. Lancet Oncology,. vol. 11. 2010. pp. 670-678.

Link, MP, Goorin, AM, Miser, AW. “The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity”. New England Journal of Medicine,. vol. 314. 1986. pp. 1600-1606.

Link, MP, Meyers, PA, Gebhardt, M, Pizzo, PA, Poplack, DG. “Osteosarcoma”. Principles and Practice of Pediatric Oncology. 2006. pp. 1074-1115.

Marina, NM, Smeland, S, Bielack, SS. “Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial”. Lancer Oncology. vol. 16. 2016. pp. 1-13.

McKenna, RJ, Schwinn, CP, Soong, KY. “Sarcomata of the osteogenic series (osteosarcoma, fibrosarcoma, chondrosarcoma, parosteal osteogenic sarcoma, and sarcoma arising in abnormal bone). An analysis of 552 cases”. Journal Bone Joint surg (Am). vol. 48. 1966. pp. 1-26.

Meyers, PA. “Malignant Bone Tumors in childhood: Osteosarcoma”. Hematology Oncology Clinics North Am,. vol. 1. 1987. pp. 655-665.

Meyers, PA, Schwartz, CL, Krailo, M. “Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate”. Journal of Clinical Oncology,. vol. 23. 2005. pp. 2004-2011.

Mirabello, L, Troisi, RJ, Savage, SA. “Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program”. Cancer,. vol. 115. 2009. pp. 1531-1543.

Ongoing controversies regarding etiology, diagnosis, treatment

The major issue confronting osteosarcoma research is resistance to chemotherapy. Poor necrosis, a marker of chemotherapy response, is known to be an adverse prognostic factor but attempts to improve outcome via intensification of therapy via dose escalation or additional agents has not been shown to improve outcome. It becomes essential to understand the mechanisms of such resistance in order to develop new approaches that might successfully treat those with drug resistance.

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