What is the treatment for osteosarcoma (bone cancer)?

Osteosarcoma: Comprehensive Overview

Definition and Epidemiology

Osteosarcoma is the most common primary malignant bone tumor, with a bimodal age distribution peaking at 18 and 60 years, and is slightly more common in males. 1 It accounts for less than 1% of all diagnosed cancers annually but represents the most frequent bone sarcoma in children and young adults. 2 The disease typically arises in bones with rapid growth rates, most commonly affecting the metaphysis of long bones—specifically the distal femur, proximal tibia, and proximal humerus. 2

Pathophysiology

• Osteosarcoma arises from mesenchymal tissue with malignant cells producing osteoid (immature bone). 3
• The etiology involves multiple genetic drivers linked to bone formation that cause malignant progression and metastasis. 1
• The lungs are the most common site of metastatic spread. 2

Clinical Presentation and Diagnosis

Key Symptoms to Identify

• Persistent non-mechanical bone pain that worsens at night and does not resolve with rest. 4
• Progressive swelling at the tumor site. 4
• Functional impairment of the affected limb. 4
• Duration and intensity of pain are critical historical features. 4

Diagnostic Workup Algorithm

Step 1: Initial Imaging

• Plain radiographs are the preferred first diagnostic test, showing a poorly marginated lesion in patients with painful bone lesions. 4, 2

Step 2: Comprehensive Staging at Reference Center

• Local imaging: Plain radiographs AND MRI of the entire affected extremity. 4, 5
• Distant disease assessment: Chest CT scan (mandatory for lung metastases), bone scintigraphy, and/or whole-body MRI. 4, 5
• Laboratory markers: Serum alkaline phosphatase and lactate dehydrogenase (both are adverse prognostic factors when elevated). 4, 5

Step 3: Biopsy

• Must be performed under supervision of the surgical team or dedicated interventional radiologist at a specialized bone sarcoma reference center to avoid contamination. 4, 5
• Pathological diagnosis follows the 2013 WHO classification. 4

Critical Pitfall: Biopsy performed at non-specialized centers can contaminate tissue planes and compromise subsequent limb-salvage surgery. 4

Staging and Prognostic Factors

Adverse Prognostic Indicators

• Detectable metastases at presentation (most significant). 4, 5
• Axial or proximal extremity tumor location. 4, 5
• Large tumor size (>200 ml). 4
• Elevated serum alkaline phosphatase or lactate dehydrogenase. 4, 5
• Older age (>40 years). 4
• Poor histological response to neoadjuvant chemotherapy (<90% tumor necrosis). 4

Staging Systems

• The 2010 AJCC staging classification based on histologic grade (G), tumor size (T), and presence of metastases (N, M). 4
• The Musculoskeletal Tumor Society Surgical Staging System (SSS) may be used in addition. 4

Treatment by Disease Subtype

Low-Grade Osteosarcoma (Central and Parosteal)

These variants have low metastatic potential and should be treated by surgery alone. 4 No chemotherapy is indicated. 4

High-Grade Osteosarcoma (Localized Disease)

Curative treatment consists of multimodal chemotherapy combined with complete surgical resection. 4 This approach increases disease-free survival from <20% with surgery alone to >60% with combined treatment. 4, 5

Chemotherapy Regimen

First-Line Treatment:

• MAP regimen (high-dose methotrexate, doxorubicin, and cisplatin) is the preferred first-line treatment. 4, 5, 6
• High-dose methotrexate should be administered at ≥12 g/m² in children or ≥8 g/m² in adults with mandatory leucovorin rescue. 5
• Alternative regimens include doxorubicin plus cisplatin, or combinations with ifosfamide. 4

Age-Specific Considerations:

• In patients >40 years, preferred regimens combine doxorubicin, cisplatin, and ifosfamide, often without high-dose methotrexate. 4

Treatment Timeline:

• Neoadjuvant chemotherapy: 2-4 cycles before surgery. 6
• Total treatment duration: 6-12 months. 4, 5

Critical Caveat: High-dose methotrexate requires inpatient monitoring with adequate hydration, urinary alkalinization, and leucovorin rescue to prevent severe toxicity. 5, 7

Surgical Management

90-95% of patients should be considered candidates for limb-salvage surgery rather than amputation. 4, 5 The goal is complete tumor removal with wide, clear margins (at least wide by Enneking's definition—surrounded by unviolated normal tissue) while preserving maximum function. 5, 8

Surgical Principles:

• Complete en bloc resection including any soft tissue component. 4
• Surgery must be performed by experienced bone tumor surgeons with expertise in reconstructive options. 5
• For skeletally immature patients, growth-preserving techniques should be considered. 5

Management of Surgical Margins:

• Positive margins: Surgical re-resection with or without radiotherapy. 4
• Close or contaminated margins in pelvic osteosarcoma are associated with very poor outcomes. 8

Adjuvant Chemotherapy

• Continue the same chemotherapy agents used preoperatively. 5
• Histological response to neoadjuvant chemotherapy is a critical prognostic factor: Good responders (>90% tumor necrosis) have 5-year disease-free survival of 67.9% versus 51.3% for poor responders. 4, 6
• Attempts to improve outcomes in poor responders by modifying adjuvant chemotherapy have been largely unsuccessful. 4, 6

High-Grade Craniofacial Osteosarcoma

• Should be treated identically to high-grade osteosarcoma of other sites with multimodal chemotherapy and surgery. 4
• Radiotherapy can be proposed when complete surgery is not feasible or for positive surgical margins. 4
• Heavy particle radiotherapy (proton/carbon ion) and IMRT should be considered for unresectable primary tumors. 4

Primary Metastatic Osteosarcoma

Patients with metastases at presentation should be treated with curative intent following the same principles as non-metastatic disease. 4 This includes:

• Full-dose multimodal chemotherapy (MAP regimen). 6
• Complete surgical resection of ALL disease sites (primary tumor and metastases). 4, 5
• Approximately 30% of patients with primary metastatic disease can become long-term survivors with complete surgical resection. 5

Prognostic Factors in Metastatic Disease:

• Number of metastases: 2-year disease-free survival is 78% for 1-2 lesions versus 28% for ≥3 lesions. 4
• Unilateral lung metastases have better outcomes than bilateral or bone metastases. 4
• Complete surgical resectability is the most important prognostic indicator. 4

Critical Reality: Despite aggressive treatment, 2-year event-free survival for metastatic disease remains only 21% compared to 75% for localized disease. 6

Radiotherapy Role

Radiotherapy is NOT standard for resectable osteosarcoma. 4, 5 However, it may be considered in highly selected cases:

• Unresectable primary tumors (heavy particle RT, IMRT, or proton therapy). 4
• Incomplete surgical resection with positive margins. 4
• Palliation of locally recurrent disease. 5
• Skull base locations where complete surgery is not feasible. 4

Caveat: Osteosarcoma is relatively radioresistant; surgical resection remains the gold standard for local control. 4

Recurrent/Relapsed Disease

Surgical Approach

The treatment of recurrent osteosarcoma is primarily surgical for isolated lung metastases or local recurrence. 4

• Complete surgical resection of all recurrent disease sites is the goal. 4
• Longer relapse-free interval and complete resectability are the most important prognostic indicators for survival. 4

Alternative Local Therapies

For patients unfit for surgery or with small metastases:

• Radiofrequency ablation (RFA). 4
• Stereotactic radiotherapy. 4
• Cryotherapy. 4

Second-Line Chemotherapy

Second-line chemotherapy options include: 4

• Ifosfamide or cyclophosphamide, possibly with etoposide and/or carboplatin. 4
• Gemcitabine and docetaxel. 4
• Sorafenib (tyrosine kinase inhibitor). 4
• Regorafenib (tyrosine kinase inhibitor). 4
• Samarium-153 EDTMP for relapsed/refractory disease beyond second-line. 4

Reality Check: Response rates to second-line chemotherapy are modest, and prognosis for recurrent disease remains poor. 9

Multidisciplinary Team Requirements

All patients must be evaluated and treated by a multidisciplinary team at a reference center with demonstrated expertise. 4 Required team members include:

• Pediatric and/or medical oncologists experienced in sarcoma treatment. 4
• Orthopedic surgeons with bone tumor expertise. 4, 5
• General surgeons (for metastasectomy). 4
• Pathologists with sarcoma expertise. 4
• Radiologists. 4
• Radiation oncologists (when indicated). 4
• Specialist nurses. 1

Critical Point: Fertility preservation should be discussed with appropriate patients BEFORE starting treatment. 4

Surveillance and Follow-Up

Monitoring Schedule

Recommended surveillance includes: 5

• Chest X-ray every 2-6 months. 5
• Chest CT scan every 6 months. 5
• Local imaging (plain radiographs and MRI) only for symptoms. 5

Long-Term Considerations

• Long-term surveillance for chemotherapy, surgery, and radiotherapy toxicities should continue for >10 years. 5
• Extended follow-up is necessary to address potential late effects including cardiotoxicity (doxorubicin), nephrotoxicity (cisplatin), ototoxicity (cisplatin), and secondary malignancies. 4
• Survivors require specialized medical follow-up as curative treatment has significant long-term adverse effects affecting quality of life. 1
• Patients should receive a survivorship prescription scheduling follow-ups with the multidisciplinary team. 4

Emerging Therapies

While conventional chemotherapy and surgery remain the standard of care, several investigational approaches are being studied:

• Immune checkpoint inhibitors (limited efficacy to date). 3
• Adoptive cellular therapy. 3
• Cancer vaccines. 3, 10
• Tyrosine kinase inhibitors (sorafenib, regorafenib showing some activity). 4, 3
• Monoclonal antibodies targeting surface antigens. 10

Reality: Despite these investigations, no breakthrough therapies have emerged to significantly improve outcomes beyond conventional treatment, particularly for metastatic disease. 3, 1

Prognosis Summary

• Localized high-grade osteosarcoma: 60-75% event-free survival with multimodal treatment. 4
• Metastatic disease at presentation: <30% event-free survival. 1
• Recurrent disease: Poor prognosis, especially with bone metastases or short relapse-free interval. 4, 9
• Low-grade variants: Excellent prognosis with surgery alone. 4