VAC/IE Chemotherapy for Ewing Sarcoma (Vincristine, Doxorubicin, Cyclophosphamide / Ifosfamide, Etoposide)

BoneNeoadjuvantSurgeryAdjuvant

VAC/IE Chemotherapy for Ewing Sarcoma (Vincristine, Doxorubicin, Cyclophosphamide / Ifosfamide, Etoposide)

Ewing sarcoma (bone and soft tissue), BCOR-rearranged sarcoma, CIC-rearranged sarcoma (Ewing-like)

Overview

  • VAC/IE (alternating Vincristine-Doxorubicin-Cyclophosphamide / Ifosfamide-Etoposide) is the standard chemotherapy for Ewing sarcoma
  • Established by the landmark INT-0091 trial (IESS studies), subsequently refined by AEWS0031 (compressed interval)
  • Administered in a dose-dense compressed schedule every 2 weeks (with G-CSF support) rather than 3-weekly - improves survival
  • Neoadjuvant chemotherapy precedes local control (surgery and/or radiotherapy)
  • Adjuvant chemotherapy continues post-local control to complete full course
  • Total duration: approximately 48 weeks (17 cycles in AEWS0031 compressed schedule)

Regimen & Dosing

Regimen

  • Alternating cycles of VDC (Vincristine + Doxorubicin + Cyclophosphamide) and IE (Ifosfamide + Etoposide)
  • Neoadjuvant phase: 4–6 cycles (alternating VDC/IE) prior to local control
  • Local control (surgery and/or radiotherapy) after neoadjuvant phase
  • Adjuvant phase: continuation of alternating VDC/IE to complete total course
  • Compressed 2-weekly schedule with mandatory G-CSF support

Dosing

  • Vincristine: 2 mg/m² IV (max 2 mg) Day 1 of VDC cycles
  • Doxorubicin: 75 mg/m² IV over 24–48 hours Day 1 of VDC cycles (cumulative dose cap 375 mg/m²)
  • Cyclophosphamide: 1200 mg/m² IV with mesna uroprotection Day 1 of VDC cycles
  • Ifosfamide: 1800 mg/m²/day IV Days 1–5 with mesna uroprotection (IE cycles)
  • Etoposide: 100 mg/m²/day IV Days 1–5 (IE cycles)
  • G-CSF: filgrastim or pegfilgrastim from Day 3 until ANC recovery (mandatory in compressed schedule)
  • Mesna: dosed at 120% of cyclophosphamide/ifosfamide dose (divided doses)

Eligibility & Contraindications

Eligibility

  • Histologically confirmed Ewing sarcoma with EWSR1 rearrangement (or FUS-ERG/other rare fusions)
  • Any age (paediatric and adult protocols similar)
  • Adequate renal function: eGFR ≥60 mL/min
  • Adequate cardiac function: LVEF ≥50%
  • Adequate hepatic function: bilirubin ≤1.5× ULN
  • Adequate bone marrow: ANC ≥1.0, platelets ≥100
  • ECOG/Lansky performance status 0–2

Contraindications

  • Cardiac dysfunction (LVEF <50%): doxorubicin contraindicated
  • Severe renal impairment: ifosfamide/cyclophosphamide contraindicated
  • Pregnancy: all agents teratogenic - effective contraception required
  • Prior anthracycline cumulative dose approaching cardiotoxicity threshold
  • Active haemorrhagic cystitis: cyclophosphamide/ifosfamide contraindicated

Monitoring

  • Baseline: FBC, U&E, creatinine, LFT, ECHO (LVEF), gonadal function counselling, audiogram
  • FBC before each cycle (nadir monitoring); G-CSF mandatory
  • Renal function before each cycle containing ifosfamide (tubular function: phosphate, bicarbonate for Fanconi syndrome)
  • LVEF reassessment at cumulative doxorubicin 300 mg/m² and at end of treatment
  • Urinalysis before ifosfamide (haematuria - mesna dose adjustment)
  • Watch for ifosfamide encephalopathy: confusion, agitation - hold ifosfamide, give methylene blue
  • Gonadal function at end of treatment and annually (gonadotoxic regimen)
  • Annual renal function post-treatment (ifosfamide nephrotoxicity - tubular dysfunction long-term)
  • MUGA/ECHO 2, 4, and 6 years post-diagnosis (per LSESN follow-up guidelines)
  • Response assessment MRI before local control surgery

Notes

  • Compressed 2-weekly schedule (AEWS0031) superior to 3-weekly - requires G-CSF support
  • High-dose chemotherapy with autologous stem cell rescue (HDC-ASCT) for very high-risk/metastatic disease - clinical trial setting
  • Ifosfamide encephalopathy: treat with methylene blue 50 mg IV; hold ifosfamide
  • Fanconi syndrome (proximal tubular dysfunction) from ifosfamide: monitor phosphate, bicarbonate; supplement as needed
  • Sperm/egg cryopreservation should be offered before treatment (gonadotoxic)
  • Local control: surgery preferred over radiotherapy alone where feasible for resectable tumours
  • Whole-lung irradiation for pulmonary metastases at diagnosis: considered in selected patients
  • Extraskeletal Ewing sarcoma: treated identically to bone Ewing sarcoma

Medical disclaimer

The content on Sarcopedia is for educational and informational purposes only and does not constitute medical advice. It is not intended to be a substitute for professional medical diagnosis or treatment. Always consult with a qualified physician regarding any health concerns or before starting any new treatment. Reliance on any information provided on this site is solely at your own risk.