What are the potential side effects of Trastuzumab (Herceptin)?

Potential Side Effects of Trastuzumab (Herceptin)

Cardiotoxicity: The Most Critical Adverse Effect

Cardiotoxicity is the most concerning side effect of trastuzumab, manifesting as left ventricular dysfunction and heart failure, with incidence rates of 7-34% for cardiac dysfunction and 0-4% for severe heart failure (NYHA class III or IV) in clinical trials. 1

Cardiac Dysfunction Characteristics

• Trastuzumab-induced cardiotoxicity is classified as Type II, meaning it is generally reversible, unlike anthracycline-induced cardiotoxicity (Type I). 2

• The mechanism involves blockade of ErbB2-ErbB4 signaling in cardiac myocytes, deactivating protective and growth-promoting pathways in the myocardium, with structural and functional changes in contractile proteins and mitochondria that rarely lead to cell death. 1, 2

• Cardiac myocytes appear histologically normal, with visible changes only under electron microscopy, explaining the potential for reversibility. 2

• Unlike anthracyclines, trastuzumab cardiotoxicity is not cumulative dose-related, though twice the rate of left ventricular dysfunction was reported when patients were treated for 24 rather than 12 months. 1, 2

Risk Factors for Cardiotoxicity

• The risk increases dramatically to 27% when trastuzumab is combined with anthracyclines and cyclophosphamide, compared to 4% with monotherapy. 2, 3

• Previous exposure to anthracyclines, short time interval (3 weeks vs. 3 months) between anthracycline and trastuzumab treatment, pre-existing arterial hypertension, low LVEF, and older age all increase cardiotoxicity risk. 1

• Left chest wall irradiation significantly increases cardiac event rates (31.4% vs. 15.4% without radiotherapy). 4

• In real-world registries, the cumulative incidence of cardiac dysfunction or heart failure in patients treated with anthracyclines and trastuzumab was 6.2% at 1 year and 20.1% at 5 years. 1

Infusion Reactions

• Severe infusion reactions can occur, requiring pre-medication with antihistamines and/or corticosteroids in patients who experienced prior reactions. 5

• Some patients had recurrent severe infusion reactions despite pre-medications, and prior severe reactions may necessitate treatment discontinuation. 5

Pulmonary Toxicity

• Trastuzumab can result in serious and fatal pulmonary toxicity, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency, hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. 5

• Patients with symptomatic intrinsic lung disease or extensive tumor involvement of the lungs appear to have more severe toxicity. 5

• Interstitial pneumonitis occurred in 0.2% of patients in the HERA trial. 5

Embryo-Fetal Toxicity

• Trastuzumab can cause fetal harm when administered during pregnancy, resulting in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. 5

• Females of reproductive potential must use effective contraception during treatment and for 7 months following the last dose. 5

Hematologic Toxicity

• The incidence of NCI-CTC Grade 3-4 neutropenia and febrile neutropenia is higher when trastuzumab is combined with myelosuppressive chemotherapy compared to chemotherapy alone. 5

• In metastatic gastric cancer, neutropenia, anemia, and thrombocytopenia were among the most common adverse reactions (≥10%) increased by ≥5% compared to chemotherapy alone. 5

Common Non-Life-Threatening Side Effects

The most common adverse reactions in breast cancer patients include: 5

• Gastrointestinal: Diarrhea (7%), nausea (6%), vomiting (3.5%), constipation (2%)
• Constitutional: Fever (6%), fatigue, chills (5%), peripheral edema (5%), asthenia (4.5%)
• Respiratory: Cough (5%), dyspnea (3%), upper respiratory infections (3%), influenza (4%)
• Musculoskeletal: Arthralgia (8%), myalgia (4%), back pain (5%), bone pain (3%)
• Neurologic: Headache (10%), paresthesia (2%), dizziness (4%)
• Infections: Nasopharyngitis (8%), urinary tract infection (3%)
• Dermatologic: Rash (4%), pruritus (2%), nail disorders (2%)
• Cardiac (non-failure): Hypertension (4%), palpitations (3%), cardiac arrhythmias (3%)

Critical Management Considerations

• Cardiotoxicity is the most common reason for treatment interruption in 13.5% of patients, with treatment interruption associated with increased cancer recurrence. 1

• Trastuzumab-induced cardiac dysfunction usually responds to standard heart failure treatment or discontinuation of trastuzumab, and most patients improve with proper treatment. 1, 3

• Regular monitoring of cardiac function through physical examination and measurement of left ventricular ejection fraction is essential, with baseline evaluation required before starting treatment. 2

• Reintroduction of trastuzumab may be considered after improvement of cardiac function in selected cases. 2

• Treatment with angiotensin-converting enzyme (ACE) inhibitors is likely to improve trastuzumab-associated cardiac dysfunction, analogous to experience with anthracycline cardiotoxicity. 1