Treatment of Metastatic Osteosarcoma in an 18-Year-Old
An 18-year-old with metastatic osteosarcoma should receive the MAP regimen (high-dose methotrexate, doxorubicin, and cisplatin) as neoadjuvant chemotherapy, followed by aggressive surgical resection of both primary and metastatic sites, then adjuvant chemotherapy using the same agents. 1
Chemotherapy Regimen and Dosing
First-Line Treatment: MAP Protocol
The standard chemotherapy backbone consists of three agents 1:
High-dose methotrexate: Starting dose of 12 g/m² IV as a 4-hour infusion 2
- If peak serum concentration does not reach 1,000 micromolar at end of infusion, escalate to 15 g/m² in subsequent treatments 2
- Administered at weeks 4,5,6,7,11,12,15,16,29,30,44,45 after surgery 2
- Critical safety requirement: Leucovorin rescue at 15 mg orally every 6 hours for 10 doses starting 24 hours after methotrexate infusion 2
- Must have facilities for methotrexate level monitoring, rigorous hydration, and dialysis capability 1
Doxorubicin:
Cisplatin: 100 mg/m² IV at weeks 20,23,33,36 2
Alternative Regimens
If methotrexate is contraindicated, doxorubicin plus cisplatin is an acceptable alternative 1. Other standard combinations include high-dose methotrexate + cisplatin or ifosfamide + cisplatin 1.
Treatment Schedule
Phase 1: Neoadjuvant Chemotherapy
- Duration: 2-6 cycles of combination chemotherapy before surgery 1
- Purpose: Facilitate surgical resection, assess tumor response, and treat micrometastases 1, 3
Phase 2: Surgery
- Timing: After neoadjuvant chemotherapy completion 1
- Approach: Simultaneous resection of primary tumor and all metastatic lesions when feasible 4, 5
- Surgical principles:
Phase 3: Adjuvant Chemotherapy
- Duration: Additional 6-10 months of chemotherapy 1
- Total treatment time: 6-12 months overall 1
- Regimen: Continue with same agents used preoperatively 1
Critical Prognostic Considerations
For metastatic disease specifically, survival correlates strongly with 4, 6:
- Number of metastases: Patients with 1-2 lung nodules have 78% 2-year disease-free survival versus 28% for those with ≥3 nodules 4
- Unilateral versus bilateral lung involvement: Unilateral disease shows 75% 5-year event-free survival versus 35.7% for bilateral 6
- Elevated alkaline phosphatase: Predicts inferior outcomes 7
- Surgical margin status: Positive margins significantly worsen overall survival 7
Treatment Modifications for Metastatic Disease
Primary metastatic osteosarcoma patients are treated with curative intent following the same principles as non-metastatic disease 1. However:
- Approximately 30% of all patients with primary metastatic osteosarcoma and >40% of those achieving complete surgical remission become long-term survivors 1
- Complete surgical resection of all disease sites (primary and metastatic) remains essential for survival 5
- Aggressive surgery to lung metastases following primary chemotherapy is appropriate 1
- The existence of metastases at presentation should not lead to abandoning curative treatment, particularly if single metastases 1
Additional Considerations
Immunotherapy Option
Mifamurtide (L-MTP-PE) may be added for patients <30 years with completely resected localized disease, though this patient has metastatic disease 1, 3. It is approved in Europe but not FDA-approved in the USA 3.
Monitoring Requirements
Prior to therapy, document 1:
- Alkaline phosphatase and LDH levels
- Renal function (creatinine, GFR)
- Cardiac echocardiogram
- Electrolytes including magnesium
Common Pitfalls to Avoid
- Do not alter adjuvant chemotherapy based on histologic response - this has not improved outcomes 1
- Do not delay metastasectomy indefinitely - complete surgical clearance is critical for survival 1, 5
- Do not use radiotherapy routinely - surgery is the primary local control modality, though RT may be considered for unresectable disease 1
If Disease Progresses
Second-line options include ifosfamide ± etoposide ± carboplatin, gemcitabine + docetaxel, or targeted agents like sorafenib or regorafenib 1.