Overview

Most common primary bone malignancy in adolescents. Peak incidence age 15-19 during rapid skeletal growth. Arises in metaphysis of long bones (distal femur 40%, proximal tibia 20%). Standard treatment: neoadjuvant chemotherapy (MAP: high-dose methotrexate, doxorubicin, cisplatin), limb-salvage surgery when feasible, adjuvant chemotherapy. Histologic response (>90% necrosis) is prognostic. 5-year survival 60-70% localized, 20-30% metastatic. Mifamurtide (immune stimulant) used in Europe.

Clinical Management: Treatment individualized based on stage, histology, molecular profile, and patient factors. Multidisciplinary tumor board review recommended. Refer to NCCN guidelines and FDA package inserts for complete dosing and administration.

Epidemiology & Impact

Osteosarcoma is the most common primary malignant bone tumor with approximately 1,000 US cases annually. Bimodal age distribution peaks in adolescents (10-19) and adults over 60. Most common in distal femur, proximal tibia, and proximal humerus. Five-year survival is approximately 70% for localized disease but 20-30% for metastatic, unchanged in 40 years.

Molecular Biology & Biomarkers

Characterized by extreme genomic complexity with chromosomal chaos rather than recurrent mutations. TP53 disruption (approximately 90%) and RB1 alterations (30%) are most common. The chaotic landscape lacks targetable oncogene drivers, making precision medicine challenging. Li-Fraumeni and hereditary retinoblastoma predispose.

Osteosarcoma is characterized by extreme genomic complexity, with chromothripsis and kataegis occurring in over 80% of cases. Unlike many adult cancers, osteosarcoma is driven primarily by structural variants and copy number alterations rather than recurrent point mutations. TP53 pathway inactivation (via mutation, MDM2 amplification, or CDKN2A deletion) occurs in virtually all cases. RB1 loss is found in approximately 30% of tumors. The MYC oncogene is amplified in 10-15% of cases and correlates with poor prognosis. Emerging research has identified recurrent alterations in the PI3K/mTOR pathway, ATRX mutations (associated with alternative lengthening of telomeres), and IGF signaling dysregulation as potential therapeutic targets.

Evolving Treatment Landscape

Standard MAP chemotherapy (methotrexate, doxorubicin, cisplatin) plus surgery has been unchanged for 40 years. Limb salvage is possible in over 80% of cases. Multiple phase 3 trials of novel agents have failed. Regorafenib showed modest benefit in relapsed disease. Novel microenvironment-targeting approaches are under investigation.

Standard treatment combines neoadjuvant chemotherapy (MAP: high-dose methotrexate, doxorubicin, cisplatin) with surgical resection and adjuvant chemotherapy. Histologic necrosis response (≥90%) to neoadjuvant therapy is the strongest prognostic factor. Limb-salvage surgery is now possible in approximately 85% of patients. For relapsed disease, ifosfamide, etoposide, and gemcitabine-docetaxel combinations are used, though response rates remain modest. Emerging therapeutic strategies include immune checkpoint inhibitors (response rates of 5-10% as monotherapy), anti-GD2 antibodies, tyrosine kinase inhibitors targeting angiogenesis (regorafenib showed activity in the SARC024 trial), and HER2-targeted therapies for the subset with HER2 overexpression. The Pediatric MATCH trial and adult SARC trials continue to evaluate molecularly targeted approaches.

Approved Osteosarcoma Therapies

Note: There are no FDA-approved targeted or novel therapies specifically for osteosarcoma. Standard of care consists of neoadjuvant and adjuvant chemotherapy with the MAP regimen (high-dose methotrexate, doxorubicin/adriamycin, and cisplatin) combined with surgery. Mifamurtide (Mepact)
EMA-approved only — not approved by FDA is approved in Europe but not by the FDA.