Disease Information

Solid Tumor: Osteosarcoma

Alternate Names: None

Definition

• Osteosarcoma is the most common type of bone cancer in children and adolescents.
• It occurs most often in the bones on either side of the knee and in the upper arm. It most commonly arises from the metaphysis (the wider part) of the bone.

Incidence

• Each year in the United States, osteosarcoma is diagnosed in approximately 400 children and adolescents younger than 20 years. 
• The peak incidence of osteosarcoma is in the second decade of life, during the adolescent growth spurt. It is extremely rare in children before the age of 5 years. 
• Osteosarcoma is somewhat more likely to affect males than females. 
• The incidence in black children is higher than that in whites.

Influencing Factors

• The cause of osteosarcoma is unknown; however, irradiation and genetic influences have been implicated in its development.
• Osteosarcoma occurs in long-term survivors of cancer who were treated with radiation therapy.
• The interval between irradiation and the appearance of osteosarcoma ranges from four to more than 40 years (median, 12-16 years).
• It is apparent that two suppressor genes, p53 and Rb, have major roles in tumorigenesis in osteosarcoma. Approximately 3-4 percent of children with osteosarcoma carry constitutional germline mutations in p53. The majority of these cases with germline p53 mutations occur in patients with a strong family history of cancer or with family histories suggestive of the Li-Fraumeni syndrome (a familial cancer syndrome) or in patients with multiple cancers. 
• By far the strongest genetic predisposition to osteosarcoma is found in patients with hereditary retinoblastoma. In hereditary retinoblastoma, germline mutations of the Rb gene are common.

Clinical Features and Symptoms

• Patients usually present with pain, swelling, and sometimes decreased joint motion.
• Occasionally, a patient may present with a fracture at the tumor site.
• Symptoms are usually present for several months before the diagnosis is made. 
• About 15-20 percent of the patients have metastatic disease at the time of diagnosis – usually in the lung and the bones.
• The work up of a patient with suspected osteosarcoma typically includes blood tests, plain x-rays and magnetic resonance imaging (MRI) of the affected bone, computerized tomography (CT) scan of the chest and a radionuclide bone scan.
• A biopsy is always required to make the diagnosis. It is preferable to have the biopsy done by the surgeon who will ultimately perform the definitive surgical treatment. Fine-needle aspiration and core-needle biopsy have been recommended at a number of centers, but most patients require open biopsy to obtain a generous sample of adequate and representative tissue.

Survival Rates

• Currently, the estimated 5-year survival for patients with osteosarcoma is 65 percent compared with 15 percent in the early 1960s.
• The presence of metastasis at diagnosis has a major impact on patient survival. The estimated survival rate for patients with localized osteosarcoma is about 75 percent compared to 30 percent for patients with metastatic disease.

Treatment Strategies

• Treatment of osteosarcoma includes surgery and chemotherapy.
• Surgical removal of all gross and microscopic tumor is required to prevent local tumor recurrence. Before the 1970s, amputation was the only surgical approach. Currently, 95 percent of patients with localized osteosarcoma of the extremity can be considered for limb-salvage surgery.
• When osteosarcoma is treated by surgery alone, the natural history is recurrence and more than 80 percent of patients will develop metastatic disease.
• The use of multi-agent chemotherapy has markedly improved the outcome of patients with osteosarcoma. Active agents against osteosarcoma include cisplatin, doxorubicin, high-dose methotrexate and ifosfamide used alone or in combination with carboplatin or etoposide.
    
  Studies done at St. Jude since 1968 have shown the importance of chemotherapy in the treatment of osteosarcoma. In 1986, we initiated a trial (OS86) of ifosfamide, cisplatin, doxorubicin, and high-dose methotrexate. The subsequent trial (OS91), which was completed in 1997, substituted carboplatin for cisplatin. The five-year survival estimates for patients with localized osteosarcoma were 69.2 percent ± 7.4 percent for those treated on OS86 and 74.5 percent ± 6.3 percent for those treated on OS91. The results of OS91 demonstrated that the carboplatin and ifosfamide combination has substantial antitumor activity. When used with doxorubicin and high-dose methotrexate to treat patients with localized osteosarcoma, this combination yielded outcomes comparable to those of trials using cisplatin-based therapy, with less long-term toxicity. The OS91 study also showed that dynamic contrast-enhanced MR imaging (DEMRI) may be useful in predicting tumor response to chemotherapy. Our most recently completed trial (OS99) used ifosfamide, carboplatin, and doxorubicin for treatment of patients with localized and resectable osteosarcoma. High-dose methotrexate, which may interfere with the dose-intensive delivery of other agents, was eliminated from the protocol. OS99 is the first St. Jude trial conducted as an international collaboration (with Chile) through our International Outreach Program and serves as a model for international collaborations particularly with developing countries. Twenty-two of the 72 eligible patients were treated in Chile and patients treated in Chile had similar treatment tolerance and outcome compared to patients treated at St. Jude. 

Current Research

• Results of studies suggest that the outcome of patients with localized osteosarcoma has reached a plateau with no added benefit from intensifying or adding new cytotoxic chemotherapy, and the outcome of patients with metastatic or unresectable disease remains poor. We are currently conducting a trial (OS2008) which adopts a novel strategy for first-line treatment of osteosarcoma by combining chemotherapy with anti-angiogenic therapy using bevacizumab (Avastin®), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Bevacizumab stops tumor growth by inhibiting the function of VEGF, a natural protein that stimulates new blood vessel formation. Bevacizumab has improved the efficacy of chemotherapy in adult patients with various types of cancer by increasing tumor response and increasing the chances of survival. The primary objectives of OS2008 are: 1) to study the feasibility of combining bevacizumab with standard chemotherapy in patients with osteosarcoma, and 2) to study the effect of adding bevacizumab to chemotherapy on the event-free survival in patients with localized resectable osteosarcoma compared to historical controls treated with the same chemotherapy without bevacizumab. The importance of this study goes beyond the potential to improve treatment efficacy since it includes multiple secondary objectives related to:
  • Reproductive function
  • Angiogenic markers
  • Bevacizumab pharmacokinetics and pharmacogenomic studies
  • Imaging studies (dynamic-enhanced MRI and PET CT ) 
  • Tumor biology 
  • Surgical resection and reconstructive techniques
  • Quality of life
  • Functional outcome of the limb
  • Neuropathic pain management

• In addition, laboratory investigations are ongoing to better understand the biology of the disease and identify prognostic factors and new effective agents. Such investigations are essential to improve the treatment and outcome of osteosarcoma. 

   

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