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