MAP Chemotherapy for Osteosarcoma (Methotrexate, Doxorubicin, Cisplatin)

BoneNeoadjuvantSurgeryAdjuvant

MAP Chemotherapy for Osteosarcoma (Methotrexate, Doxorubicin, Cisplatin)

Osteosarcoma (osteoblastic, chondroblastic, fibroblastic, telangiectatic variants), high grade surface osteosarcoma, Paget's sarcoma

Overview

  • MAP (Methotrexate, Doxorubicin/Adriamycin, Cisplatin) is the international standard chemotherapy regimen for high-grade osteosarcoma
  • Used in both neoadjuvant (pre-operative) and adjuvant (post-operative) settings
  • Standard regimen as per EURAMOS-1 and COG protocols
  • Neoadjuvant chemotherapy allows assessment of histological response - the single most important prognostic factor
  • Good histological response defined as ≥90% necrosis of the resected specimen
  • Total treatment duration approximately 18–30 weeks depending on protocol

Regimen & Dosing

Regimen

  • Neoadjuvant phase (pre-surgery): 2–3 cycles of MAP chemotherapy over 10 weeks
  • Surgery: wide local excision or limb salvage after neoadjuvant chemotherapy
  • Adjuvant phase (post-surgery): further MAP cycles based on histological response
  • Poor responders (<90% necrosis): continuation of MAP or addition of ifosfamide/etoposide per trial protocol
  • Total doxorubicin cumulative dose capped at 450–550 mg/m² (cardiotoxicity risk)

Dosing

  • High-dose Methotrexate (HDMTX): 12 g/m² IV over 4 hours, with folinic acid rescue starting 24 hours after MTX infusion
  • Doxorubicin: 37.5 mg/m²/day IV on Days 1 and 2 (total 75 mg/m² per cycle)
  • Cisplatin: 120 mg/m² IV over 4 hours with aggressive hydration (Day 1 or split over 2 days)
  • HDMTX cycles: given on Days 1 and 8 of each MAP block
  • Cisplatin + Doxorubicin: given on Day 1 of each MAP block
  • Folinic acid rescue: 15 mg/m² orally/IV every 6 hours starting 24h post-MTX until MTX level <0.1 µmol/L
  • Monitor MTX levels at 24h, 48h, 72h post-infusion
  • Hold HDMTX if creatinine elevated >10% above baseline or significant pleural effusion/ascites (MTX toxicity risk)

Eligibility & Contraindications

Eligibility

  • Histologically confirmed high-grade osteosarcoma
  • Age <40 years (standard eligibility; used in selected older patients with performance status consideration)
  • Adequate renal function: eGFR ≥60 mL/min
  • Adequate cardiac function: LVEF ≥50% (doxorubicin cardiotoxicity)
  • Adequate hepatic function
  • No prior anthracycline exposure up to cumulative cardiotoxicity limit
  • ECOG performance status 0–2
  • Adequate bone marrow function: ANC ≥1.0, platelets ≥100

Contraindications

  • Renal impairment (eGFR <60): HDMTX contraindicated - risk of fatal MTX retention
  • Pleural effusion or ascites: MTX trapped in third space - contraindicated
  • Cardiac dysfunction (LVEF <50%): doxorubicin contraindicated
  • Pregnancy: all agents teratogenic
  • Prior cumulative anthracycline dose approaching 450–550 mg/m²
  • Active infection or sepsis
  • Known hypersensitivity to any component

Monitoring

  • Baseline: FBC, U&E, creatinine, LFT, ECHO (LVEF), audiogram (cisplatin ototoxicity)
  • HDMTX: MTX levels at 24h, 48h, 72h post-infusion; daily U&E, creatinine, and urine pH (maintain >7 with IV bicarbonate)
  • Hydration: aggressive IV hydration for cisplatin (1–2L pre and post cisplatin)
  • Renal function before each cisplatin cycle (audiogram every 2 cycles)
  • LVEF reassessment at cumulative doxorubicin 300 mg/m² and 450 mg/m²
  • FBC nadir monitoring; G-CSF support as per protocol
  • Audiogram before each cisplatin cycle - hold/reduce if high-frequency hearing loss
  • End of treatment: ECHO, audiogram, gonadal function assessment
  • Response assessment MRI at completion of neoadjuvant phase (before surgery)

Notes

  • Histological response (% necrosis) is the single most important prognostic factor
  • Good response (≥90% necrosis): 5-year survival ~70–80%
  • Poor response (<90% necrosis): 5-year survival ~40–50%
  • EURAMOS-1 trial: addition of pegylated interferon in good responders did not improve survival
  • Folinic acid rescue is mandatory with HDMTX - never omit
  • Alkalinisation of urine (IV bicarbonate) essential to prevent MTX nephrotoxicity
  • Parosteal and periosteal osteosarcoma (low/intermediate grade): MAP chemotherapy not routinely required
  • Secondary osteosarcoma (Paget's, radiation-induced): poorer chemotherapy response, consider clinical trial

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