Standard Treatment Approach for Pediatric Osteosarcoma
The standard treatment for pediatric osteosarcoma consists of neoadjuvant chemotherapy with the MAP regimen (high-dose methotrexate, doxorubicin, and cisplatin), followed by limb-sparing surgical resection with wide margins, and then adjuvant chemotherapy using the same agents for a total treatment duration of 6-10 months. 1
Chemotherapy Regimen
Neoadjuvant (Preoperative) Chemotherapy
High-dose methotrexate is administered at a minimum dose of 12 g/m² in children 2, 3
- This requires mandatory inpatient treatment with rigorous hydration, clinical surveillance, regular blood tests, and leucovorin rescue 2
- Methotrexate serum level monitoring is essential, with dialysis support available if needed 2
- The starting dose for high-dose methotrexate is 12 g/m², which may be escalated to 15 g/m² if peak serum concentrations do not reach 1,000 micromolar 3
Doxorubicin is given at 30 mg/m²/day IV for 3 days 3
Cisplatin is administered at 100 mg/m² IV 3
The MAP regimen is the most frequently used first-line treatment and has increased disease-free survival from <20% to >60% compared to surgery alone 1. Randomized trials have shown that cisplatin plus doxorubicin may be comparable to more complex multiagent regimens 2.
Alternative Considerations
- Ifosfamide plus cisplatin is listed as a standard combination option 2
- If methotrexate cannot be tolerated, a two-drug regimen of doxorubicin plus cisplatin is appropriate 2
- Some protocols add ifosfamide (at doses up to 18 g/m² per course) for patients with large tumor volumes or poor response to initial chemotherapy 4
Surgical Management
Timing and Approach
- Surgery is performed after neoadjuvant chemotherapy, with presurgical evaluation using the same imaging modalities as at presentation 2
- 90-95% of patients should be considered candidates for limb salvage rather than amputation 1
- The biopsy scar must be resected and the tumor removed en bloc without being opened 2, 1
Technical Requirements
- Wide, clear histological margins are mandatory 2
- A sample of proximal marrow must be taken for analysis 2
- Surgery must be performed by an experienced surgeon familiar with bone tumor surgery and reconstructive options 2, 1
- Amputation is only performed under exceptional circumstances when limb-conserving surgery is contraindicated 2
Reconstructive Options
- Reconstructive surgery using prostheses 2
- Reconstruction using autologous or allogeneic bone graft 2
- Rotationplasty 2
- Growth-preserving techniques for skeletally immature patients 1
Adjuvant (Postoperative) Chemotherapy
- Use the same chemotherapy regimen as given preoperatively 2, 1
- Total treatment duration is 6-10 months 1
- If methotrexate and doxorubicin were given preoperatively, alternative agents active in osteosarcoma may be considered postoperatively 2
Special Populations and Scenarios
Metastatic Disease at Presentation
- Approximately 30% of patients with primary metastatic osteosarcoma can become long-term survivors with complete surgical resection of all disease sites 1, 5
- The existence of metastases at presentation, particularly if single, should not lead to abandoning curative treatment 2
- Aggressive surgery to lung metastases following primary chemotherapy is appropriate 2
- The same MAP chemotherapy regimen is used even when surgery is not immediately possible 5
Inoperable Tumors
- High-dose radiotherapy (55-70 Gy) may be indicated for inoperable tumors 2, 5
- Options include photon or neutron therapy 2
- Radiotherapy may also be useful for palliation of locally recurrent disease 2
Critical Safety Considerations
Methotrexate Administration
- Use only preservative-free formulation for high-dose therapy 3
- The preserved formulation contains benzyl alcohol and must not be used for high-dose therapy 3
- Facilities for rigorous hydration, clinical surveillance, regular blood tests, and folinic acid rescue must be in place at all times 2
Monitoring for Toxicity
- Close monitoring for bone marrow, liver, lung, and kidney toxicities is mandatory 3
- Unexpectedly severe bone marrow suppression, aplastic anemia, and gastrointestinal toxicity can occur, particularly with concomitant NSAIDs 3
- Methotrexate-induced lung disease (acute or chronic interstitial pneumonitis) may occur at any time and is not always reversible 3
- Diarrhea and ulcerative stomatitis require interruption of therapy to prevent hemorrhagic enteritis and intestinal perforation 3
Prognostic Factors
Adverse prognostic indicators include 1:
- Detectable metastases at presentation
- Proximal extremity or axial tumor location
- Large tumor size
- Elevated serum alkaline phosphatase or lactate dehydrogenase
- Older age
- Poor histological response to neoadjuvant chemotherapy (defined as <90% tumor necrosis)
Follow-Up Surveillance
Imaging Schedule
- Chest X-ray every 2 months for years 1-2, every 3 months for years 3-4, every 6 months for years 5-6, then annually 2, 1
- CT scan every 6 months for the first year if lung metastases were present at presentation, then annually until year 4 2, 1
- Plain X-ray of bone and MRI only for local symptoms 2, 1
- Technetium bone scan may be performed every 4 months for years 1-2, every 6 months for years 3-4, then only for symptoms (though its role remains debatable) 2
Long-Term Monitoring
- Long-term surveillance for chemotherapy, surgery, and radiotherapy toxicities should continue for >10 years 1
Common Pitfalls to Avoid
- Never use preserved methotrexate formulation for high-dose therapy - this contains benzyl alcohol and can cause severe toxicity 3
- Do not abandon curative intent in metastatic disease - 30% can achieve long-term survival with complete surgical resection 1, 5
- Do not perform amputation routinely - 90-95% of patients are candidates for limb salvage 1
- Do not give high-dose methotrexate without proper monitoring facilities - methotrexate level measurement and dialysis support must be available 2
- Do not continue chemotherapy in the presence of diarrhea or ulcerative stomatitis - this can lead to hemorrhagic enteritis and death 3