## First-Line Neoadjuvant Chemotherapy for Osteosarcoma **Key Point:** Cisplatin and doxorubicin (with or without methotrexate in high-dose regimens) is the gold-standard neoadjuvant and adjuvant chemotherapy for osteosarcoma. This combination has been the backbone of treatment since the 1980s and has dramatically improved survival from <20% to >70% in localized disease. ### Standard Regimen The most commonly used protocol is **MAP (Methotrexate, Adriamycin/doxorubicin, Cisplatin)** or **AP (Adriamycin/doxorubicin, Cisplatin)** depending on institutional preference and patient tolerance. **High-Yield:** Neoadjuvant chemotherapy is given for 10–12 weeks before surgical resection, followed by adjuvant chemotherapy. The degree of tumor necrosis at histology (>90% necrosis = good response) predicts long-term survival. ### Why This Combination Works - **Cisplatin:** Platinum-based alkylating agent with proven efficacy in osteosarcoma; crosses blood-brain barrier poorly but effective in bone. - **Doxorubicin:** Topoisomerase II inhibitor; synergistic with cisplatin; cardiotoxicity is a known side effect requiring monitoring. - **Methotrexate (in MAP):** High-dose regimen with leucovorin rescue; adds additional activity, particularly in pulmonary micrometastases. ### Clinical Pearl Survival benefit is greatest when chemotherapy is started promptly after diagnosis and surgical resection is performed within 10–12 weeks of starting neoadjuvant therapy. Delayed surgery is associated with worse outcomes. **Warning:** Cisplatin nephrotoxicity and ototoxicity require baseline renal function and audiometry; doxorubicin cumulative dose must be monitored (max ~450 mg/m²) to prevent cardiomyopathy. [cite:Robbins 10e Ch 26]
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