Side Effects of Epirubicin and Cyclophosphamide
Epirubicin combined with cyclophosphamide causes dose-dependent hematologic toxicity (primarily neutropenia in 80% of patients), cardiotoxicity risk increasing sharply above 900 mg/m² cumulative dose, and significant gastrointestinal and dermatologic effects, with the FDA mandating cardiac monitoring and dose modifications based on organ function. 1
Hematologic Toxicity (Most Common and Dose-Limiting)
Neutropenia and leukopenia are the predominant acute toxicities:
- Grade 3-4 neutropenia occurs in 58.6-67.2% of patients receiving FEC-100/CEF-120 regimens 1
- White blood cell nadir typically occurs at 10-14 days after administration, with recovery by day 21 1
- Febrile neutropenia occurs in 6.1% of patients on high-dose regimens 1
- Grade 3-4 anemia affects 5.8% and thrombocytopenia 5.4% of patients 1
- Direct comparison shows EC produces grade 3-4 neutropenia in 50.71% of patients, which is non-inferior to docetaxel-based regimens 2
Clinical consequences include fever, infection, septicemia, septic shock, hemorrhage, and death, requiring colony-stimulating factor support and prophylactic antibiotics (trimethoprim-sulfamethoxazole or fluoroquinolone) for 120 mg/m² regimens 1
Cardiotoxicity (Cumulative Dose-Dependent)
Cardiac toxicity is the cumulative dose-limiting toxicity with two distinct patterns 1:
Early (Acute) Cardiac Effects
- Sinus tachycardia and non-specific ST-T wave ECG changes 1
- Tachyarrhythmias, premature ventricular contractions, ventricular tachycardia 1
- These rarely predict delayed cardiotoxicity and are not indications for treatment suspension 1
Delayed Cardiotoxicity (Most Serious)
Risk increases exponentially with cumulative dose 1:
- 0.9% risk of congestive heart failure (CHF) at 550 mg/m²
- 1.6% risk at 700 mg/m²
- 3.3% risk at 900 mg/m²
- Risk increases steeply after 900 mg/m² cumulative dose 1
In high-dose studies, cardiotoxicity occurred in 19% of patients at median cumulative dose of 720 mg/m² (range 120-1,440 mg/m²), with cumulative risk of 7.7% at 720 mg/m² and 48.7% at 1,080 mg/m² 3
Clinical manifestations include reduced LVEF, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, and gallop rhythm, typically developing within 2-3 months after completion but can occur years later 1
Mandatory monitoring requirements 4:
- Baseline LVEF assessment before treatment
- Repeated LVEF evaluations during therapy
- Monitoring after cumulative doses of 360 mg/m² in high-risk patients
- Treatment cessation if LVEF reduction ≥10 percentage points with value <50%
Gastrointestinal Toxicity
Nausea and vomiting are nearly universal 1:
- Occurs in 92.4% of patients (grade 3-4 in 25%) on FEC-100/CEF-120 1
- Prophylactic antiemetics should be used before each administration 1
Mucositis (primarily oral stomatitis) 1:
- Affects 58.5% of patients (grade 3-4 in 8.9%) 1
- Dose-dependent, appearing early after administration 1
- May progress to mucosal ulcerations if severe, with recovery typically by third week 1
- Hyperpigmentation of oral mucosa may occur 1
Other gastrointestinal effects 1:
- Diarrhea in 24.8% (grade 3-4 in 0.8%)
- Anorexia in 2.9%
- Severe vomiting and diarrhea can cause dehydration requiring intervention 1
Dermatologic and Alopecia
Alopecia is nearly universal 1:
- Occurs in 95.5% of patients (grade 3-4 in 56.6%) on FEC-100/CEF-120 1
- Usually reversible with hair regrowth within 2-3 months after treatment termination 1
Other cutaneous effects 1:
- Skin and nail hyperpigmentation
- Photosensitivity
- Radiation-recall reaction in previously irradiated areas 1
- Rash/pruritus in 8.9% of patients 1
- Nail changes more common with EC than other regimens 2
Injection Site and Vascular Complications
Extravasation risks 1:
- Can cause severe tissue lesions, vesication, severe cellulitis, and necrosis
- Burning or stinging sensation indicates perivenous infiltration requiring immediate termination and vein change
- Venous sclerosis may result from small vessel injection or repeated use of same vein 1
Thromboembolic phenomena including pulmonary embolism (sometimes fatal) have been reported 1
Endocrine and Reproductive Effects
Amenorrhea is common 1:
- Occurs in 71.8% of patients on FEC-100/CEF-120 1
- May be irreversible, leading to premature menopause 1
- Hot flashes affect 38.9% of patients 1
Fertility impact 5:
- Women under 35 have >80% chance of pregnancy after treatment, especially with fertility preservation
- Ifosfamide (structurally related to cyclophosphamide) carries high gonadotoxicity risk
- Men should use effective contraception during treatment due to chromosomal damage risk to sperm 1
Infectious Complications
Infection risk is substantial 1:
- Overall infection rate of 21.5% (grade 3-4 in 1.6%) on FEC-100/CEF-120
- Febrile neutropenia in 6.1% of patients
- One death from neutropenic sepsis reported in high-dose studies 6
Secondary Malignancies
Acute myeloid leukemia (AML) 1:
- Occurs in 0.8% of patients receiving FEC-100/CEF-120
- Two cases of acute lymphoid leukemia also observed, though causal relationship less established 1
Other Notable Toxicities
Comparative toxicity profile 2:
- EC causes significantly more anemia than docetaxel-based regimens (42.86% vs 22.96%, p=0.0007)
- More nausea/vomiting, hair loss, and nail changes compared to TC regimen (p<0.01) 2
Constitutional symptoms 1:
- Lethargy in 45.8% (grade 3-4 in 1.9%)
- Fever in 5.2%
- Conjunctivitis/keratitis in 14.8% 1
Urine discoloration: Red urine for 1-2 days after administration is expected and patients should be counseled not to be alarmed 1
Dose Modifications for Toxicity Management
Hepatic dysfunction requires specific reductions 4:
- 50% dose reduction for bilirubin 1.2-3 mg/dL or AST 2-4× ULN
- 25% dose reduction for bilirubin >3 mg/dL or AST >4× ULN
Bone marrow dysfunction: Lower starting doses of 75-90 mg/m² epirubicin recommended 4
Maximum safe cumulative dose: 900 mg/m² should be exceeded only with extreme caution, with optimal efficacy range of 600-720 mg/m² 4, 1