Recommended Dosing of Epirubicin and Cyclophosphamide for Adjuvant Breast Cancer
For adjuvant treatment of early-stage breast cancer, the recommended dose of epirubicin is 100 mg/m² and cyclophosphamide is 500 mg/m² administered intravenously on day 1 every 21 days for 6 cycles (FEC-100 regimen), with fluorouracil 500 mg/m² also given on day 1. 1, 2
Standard Dosing Regimens
The ASCO guidelines explicitly recommend the following epirubicin-containing regimens for adjuvant therapy in early breast cancer 1:
FEC-100 Regimen (Preferred for High-Risk Disease Without Taxanes)
- Fluorouracil: 500 mg/m² IV on day 1
- Epirubicin: 100 mg/m² IV on day 1
- Cyclophosphamide: 500 mg/m² IV on day 1
- Schedule: Every 21 days for 6 cycles 1, 2
This regimen demonstrated superior 10-year disease-free survival (50.7% vs 45.3%) and overall survival (54.8% vs 50.0%) compared to the lower-dose FEC-50 regimen in the FASG-05 trial 3.
CEF-120 Regimen (Alternative High-Dose Option)
- Cyclophosphamide: 75 mg/m² orally days 1-14
- Epirubicin: 60 mg/m² IV on days 1 and 8
- Fluorouracil: 500 mg/m² IV on days 1 and 8
- Schedule: Every 28 days for 6 cycles 1, 2
This regimen requires prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or fluoroquinolone 1, 2.
Dose-Dense EC Followed by Paclitaxel (Optimal for Maximum Efficacy)
- Epirubicin: 90 mg/m² IV every 2 weeks for 4 cycles
- Cyclophosphamide: 600 mg/m² IV every 2 weeks for 4 cycles
- Followed by Paclitaxel: 175 mg/m² IV every 2 weeks for 4 cycles 1
This dose-dense sequential approach demonstrated superior recurrence-free survival compared to standard AC followed by paclitaxel 4.
Critical Cumulative Dose Limits
The cumulative dose of epirubicin must not exceed 720 mg/m² but should be at least 600 mg/m² for optimal efficacy in high-risk disease. 1
- Minimum effective cumulative dose: 600 mg/m² epirubicin 1
- Maximum safe cumulative dose: 720 mg/m² epirubicin 1
- For comparison, doxorubicin cumulative dose should not exceed 240 mg/m² in two-drug regimens 1
Clinical Decision Algorithm
When to Use Anthracycline-Taxane Sequential Regimens (Preferred)
Use dose-dense AC or EC followed by taxane for 1, 5:
- Node-positive disease requiring maximum efficacy
- High-risk node-negative disease
- Triple-negative breast cancer where maximum benefit is needed
- Patients who can tolerate anthracycline and taxane therapy
When to Use Anthracycline-Only Regimens (FEC-100 or CEF-120)
Use FEC-100 or CEF-120 for patients with 1:
- High-risk disease who cannot receive taxanes due to contraindications
- Strong contraindications to taxane therapy (severe neuropathy risk, hypersensitivity)
- Patient preference to avoid taxane-related toxicities
When to Avoid Anthracyclines Entirely
Use docetaxel-cyclophosphamide (TC) × 4 cycles instead for 1:
- Cardiac contraindications to anthracyclines
- Prior anthracycline exposure approaching cumulative limits
- Elderly patients with baseline cardiac dysfunction
Dose Modifications for Special Populations
Hepatic Dysfunction
The FDA label provides specific dose reductions 2:
- Bilirubin 1.2-3 mg/dL or AST 2-4× ULN: Use 50% of recommended starting dose
- Bilirubin >3 mg/dL or AST >4× ULN: Use 25% of recommended starting dose
Bone Marrow Dysfunction
Consider lower starting doses of 75-90 mg/m² epirubicin for 2:
- Heavily pretreated patients
- Pre-existing bone marrow depression
- Neoplastic bone marrow infiltration
Hematologic Toxicity During Treatment
If nadir platelet counts <50,000/mm³, ANC <250/mm³, neutropenic fever, or Grade 3/4 nonhematologic toxicity occurs 2:
- Reduce Day 1 dose in subsequent cycles to 75% of current cycle dose
- Delay Day 1 chemotherapy until platelets ≥100,000/mm³, ANC ≥1,500/mm³, and nonhematologic toxicities recover to ≤Grade 1
For divided-dose regimens (Day 1 and Day 8) 2:
- Day 8 dose should be 75% of Day 1 if platelets 75,000-100,000/mm³ and ANC 1,000-1,499/mm³
- Omit Day 8 dose if platelets <75,000/mm³, ANC <1,000/mm³, or Grade 3/4 nonhematologic toxicity occurred
Cardiac Monitoring Requirements
Baseline Assessment
Obtain echocardiogram with left ventricular ejection fraction (LVEF) evaluation before initiating treatment 6.
During Treatment Monitoring
Mandatory cardiac monitoring after cumulative doses of 6:
- Epirubicin 360 mg/m² in high-risk patients
- Monitor for LVEF reduction ≥10 percentage points with value <50%
Criteria to Discontinue Treatment
Stop anthracycline therapy if 6:
- LVEF reduction ≥10 percentage points with value <50%
- Development of clinical heart failure
Long-Term Cardiac Safety Data
The 10-year follow-up of the FASG-05 trial showed acceptable cardiac toxicity rates with FEC-100 3:
- Delayed cardiac toxicity (before relapse): 1.1% with FEC-100
- Cardiac toxicity after relapse: 4.1% with FEC-100
Common Pitfalls to Avoid
Do Not Use Suboptimal Doses
The FEC-50 regimen (epirubicin 50 mg/m²) is inferior to FEC-100 and should not be used for curative-intent adjuvant therapy 3. The 10-year data clearly demonstrate that the higher dose provides superior survival without unacceptable toxicity.
Do Not Exceed Maximum Cumulative Doses
Never exceed 720 mg/m² cumulative epirubicin dose, as this increases cardiac toxicity risk without additional benefit 1.
Do Not Use Three-Weekly AC Followed by Paclitaxel
Standard three-weekly doxorubicin-cyclophosphamide followed by paclitaxel (AC/T) is significantly inferior to both CEF and dose-dense EC/T, with 3-year recurrence-free survival of only 85.0% compared to 90.1% for CEF 4. If using sequential anthracycline-taxane therapy, use dose-dense schedules with growth factor support.
Require Prophylactic Antibiotics for CEF-120
The CEF-120 regimen (epirubicin 60 mg/m² on days 1 and 8) mandates prophylactic antibiotic therapy throughout treatment due to high rates of febrile neutropenia (22.3%) 1, 2, 4.
Growth Factor Support for Dose-Dense Regimens
Dose-dense regimens (every 2 weeks) require mandatory growth factor support to maintain schedule 1, 4. Do not attempt dose-dense schedules without G-CSF.
Comparative Efficacy Context
The ESMO guidelines note that anthracycline-based regimens like AC or EC are standard, with fluorouracil adding no efficacy benefit and increasing toxicity 1. However, the FEC-100 regimen remains guideline-recommended based on its proven 10-year survival benefit 1, 3.
For patients requiring maximum efficacy, anthracycline-taxane sequential regimens are superior to anthracycline-only regimens 1. The addition of sequential taxanes reduces breast cancer mortality by approximately one-third 1.
In triple-negative breast cancer specifically, dose-dense EC followed by paclitaxel provides optimal outcomes, with the MA.21 trial showing superior recurrence-free survival compared to standard CEF 4.