What is the typical dosing regimen of epirubicin (EPI) and cyclophosphamide (CYC) for a patient with breast cancer?

Epirubicin and Cyclophosphamide Dosing for Breast Cancer

For adjuvant treatment of breast cancer, the standard epirubicin and cyclophosphamide regimen is epirubicin 100 mg/m² IV on day 1 plus cyclophosphamide 500 mg/m² IV on day 1, repeated every 21 days for 6 cycles (FEC-100), or epirubicin 60 mg/m² IV on days 1 and 8 plus cyclophosphamide 75 mg/m² PO on days 1-14, repeated every 28 days for 6 cycles (CEF-120). 1

FDA-Approved Dosing Regimens

The FDA label for epirubicin specifies two validated regimens used in adjuvant trials for axillary node-positive breast cancer 1:

FEC-100 Regimen (Preferred for Most Patients)

• 5-Fluorouracil: 500 mg/m² IV on day 1
• Epirubicin: 100 mg/m² IV on day 1
• Cyclophosphamide: 500 mg/m² IV on day 1
• Cycle length: Every 21 days for 6 cycles 1

CEF-120 Regimen (Alternative with Split Dosing)

• Cyclophosphamide: 75 mg/m² PO on days 1-14
• Epirubicin: 60 mg/m² IV on days 1 and 8
• 5-Fluorouracil: 500 mg/m² IV on days 1 and 8
• Cycle length: Every 28 days for 6 cycles
• Requires prophylactic antibiotics (trimethoprim-sulfamethoxazole or fluoroquinolone) 1

Guideline-Based Context

The NCCN and ESMO guidelines list epirubicin/cyclophosphamide (EC) as an acceptable adjuvant chemotherapy regimen for breast cancer, though it is categorized as "other recommended" rather than "preferred" in more recent guidelines 2. The preferred regimens have evolved to dose-dense AC (doxorubicin/cyclophosphamide) followed by taxanes 3, 4.

For metastatic breast cancer, ESMO guidelines list epirubicin/cyclophosphamide as an available anthracycline-containing regimen, with typical dosing of epirubicin 50-100 mg/m² plus cyclophosphamide 500-600 mg/m² every 21 days 2.

Dose Modifications

For Bone Marrow Dysfunction

• Heavily pretreated patients or pre-existing bone marrow depression: Consider lower starting doses of 75-90 mg/m² epirubicin 1

For Hepatic Dysfunction

• Bilirubin 1.2-3 mg/dL or AST 2-4× ULN: Use ½ of recommended starting dose
• Bilirubin >3 mg/dL or AST >4× ULN: Use ¼ of recommended starting dose 1

For Renal Dysfunction

• Severe renal impairment (creatinine >5 mg/dL): Consider lower doses, though no specific recommendation exists 1

For Hematologic Toxicity During Treatment

• If nadir platelet count <50,000/mm³, ANC <250/mm³, neutropenic fever, or Grade 3/4 non-hematologic toxicity occurs: Reduce day 1 dose in subsequent cycles to 75% of current dose 1
• For split-dose regimens (day 1 and day 8):
  • If day 8 platelets 75,000-100,000/mm³ and ANC 1,000-1,499/mm³: Give 75% of day 1 dose
  • If day 8 platelets <75,000/mm³, ANC <1,000/mm³, or Grade 3/4 toxicity: Omit day 8 dose 1
• Delay next cycle until: Platelets ≥100,000/mm³, ANC ≥1,500/mm³, and non-hematologic toxicities recovered to ≤Grade 1 1

Critical Safety Considerations

Cardiac Toxicity

The risk of congestive heart failure with epirubicin increases with cumulative dose: approximately 0.9% at 550 mg/m², 1.6% at 700 mg/m², and 3.3% at 900 mg/m² 1. The maximum cumulative dose used in adjuvant trials was 720 mg/m² 1. Cardiac toxicity may occur at lower cumulative doses in patients with active or dormant cardiovascular disease, prior mediastinal radiation, previous anthracycline therapy, or concomitant cardiotoxic drugs 1.

Secondary Leukemia Risk

The cumulative risk of treatment-related AML or MDS in breast cancer patients receiving epirubicin-containing regimens was 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years 1.

Myelosuppression

Severe myelosuppression is the main dose-limiting toxicity, with Grade 3-4 neutropenia occurring in the majority of patients 1. The CEF-120 regimen requires prophylactic antibiotics due to higher myelosuppression risk 1.

Clinical Pitfalls to Avoid

• Never administer epirubicin intramuscularly or subcutaneously due to severe local tissue necrosis risk with extravasation 1
• Do not exceed 900 mg/m² cumulative dose except with extreme caution, as cardiac toxicity risk increases rapidly beyond this threshold 1
• Monitor cardiac function before and during therapy, particularly in patients approaching cumulative doses of 550-700 mg/m² 2, 1
• The FEC-100 regimen is generally preferred over CEF-120 in contemporary practice due to simpler administration (single IV day vs. split dosing and oral cyclophosphamide) and no requirement for prophylactic antibiotics 1