What is the role of Dexrazoxane in preventing cardiotoxicity in patients receiving anthracycline-based chemotherapy?

Dexrazoxane for Cardioprotection in Anthracycline Chemotherapy

Dexrazoxane should be used to prevent anthracycline-induced cardiotoxicity in patients with advanced/metastatic breast cancer who have already received a cumulative doxorubicin dose ≥300 mg/m² and require continued anthracycline therapy. 1

Mechanism and Efficacy

Dexrazoxane works by chelating free and bound iron, thereby reducing the formation of anthracycline-iron complexes and subsequent generation of reactive oxygen species that damage cardiac tissue. 1

The evidence for cardioprotection is robust:

• Meta-analysis of seven randomized controlled trials demonstrates that dexrazoxane reduces the risk of clinical cardiotoxicity by 79% (odds ratio 0.21; 95% CI 0.09-0.5; P=0.00037). 1
• In patients with advanced breast cancer previously treated with anthracyclines, dexrazoxane significantly reduces cardiac events (13% vs 39%, P<0.001) and congestive heart failure (1% vs 11%, P<0.05). 2
• The cardioprotective effect is substantial, preventing heart failure with a relative risk of 0.28 (95% CI 0.18-0.42, P<0.00001). 3

When to Initiate Dexrazoxane

For doxorubicin: Begin dexrazoxane after cumulative dose reaches 300 mg/m². 1, 4

For epirubicin: The American Society of Clinical Oncology recommends considering dexrazoxane for patients responding to anthracycline-based chemotherapy for advanced breast cancer when continued epirubicin therapy is clinically indicated. 1 While no specific cumulative dose threshold is established for epirubicin, applying the same proportional approach as doxorubicin (55% of maximum recommended dose) suggests initiating at approximately 550 mg/m² when the Canadian maximum is 1000 mg/m². 4

Critical Contraindication

Do NOT use dexrazoxane from the first cycle of chemotherapy in the curative/adjuvant setting. 1, 5 In patients with metastatic breast cancer receiving FAC (fluorouracil, doxorubicin, cyclophosphamide) with dexrazoxane from cycle 1, response rates were lower (48% vs 63%) and time to progression was shorter compared to placebo. 5

Dosing and Administration

Standard cardioprotection regimen: Administer dexrazoxane at a 10:1 ratio to anthracycline dose (e.g., 500 mg/m² dexrazoxane for 50 mg/m² doxorubicin) by IV infusion 15-30 minutes before anthracycline administration. 5

Renal impairment: Reduce dexrazoxane dose by 50% in patients with creatinine clearance <40 mL/min, as drug clearance is significantly reduced (2-fold increase in AUC). 1, 5

Important administration details:

• Infuse in a large vein away from any prior extravasation site. 1
• Remove topical cooling (ice packs) 15 minutes before dexrazoxane administration. 1
• Do NOT apply DMSO when using dexrazoxane. 1

Cardiac Monitoring Requirements

Continue cardiac monitoring despite dexrazoxane use, as it does not completely eliminate cardiotoxicity risk. 5 After cumulative doxorubicin doses of 400 mg/m², cardiac monitoring should be frequent, with repeat assessment after 500 mg/m² and subsequently after each additional 50 mg/m². 1

Monitor for:

• Left ventricular ejection fraction (LVEF) decline ≥5% to <55% with heart failure symptoms, or
• Asymptomatic LVEF decline ≥10% to <55%. 6

Safety Profile and Adverse Effects

Myelosuppression is the primary additional toxicity. Dexrazoxane increases severe leukopenia incidence (78% vs 68%, P<0.01) compared to anthracycline alone. 7 Other adverse effects include:

• Hematologic toxicity
• Hypertransaminasemia
• Nausea
• Local pain at infusion site 1

Obtain complete blood counts before and during each treatment cycle, administering dexrazoxane only when adequate hematologic parameters are met. 5

Tumor Response Concerns

The impact on antitumor efficacy remains controversial. While meta-analysis of five breast cancer trials (n=818) showed no significant difference in objective response rate (odds ratio 0.85; 95% CI 0.61-1.18, P=0.33) 1, and individual studies demonstrate preserved tumor response rates 2, the FDA label warns that dexrazoxane may interfere with chemotherapy antitumor activity when used from cycle 1. 5

No significant difference in overall survival has been demonstrated between dexrazoxane and control groups. 1, 3

Secondary Malignancy Risk

Dexrazoxane carries a risk of secondary malignancies, particularly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). 5 This risk is documented in:

• Pediatric patients receiving dexrazoxane with chemotherapy (though dexrazoxane is not indicated in pediatrics)
• Adult patients receiving dexrazoxane with known carcinogenic anti-cancer agents
• Patients treated chronically with oral razoxane (the racemic mixture) at cumulative doses of 26-480 grams over 42-319 weeks 5

Special Populations

Patients with preexisting cardiomyopathy: Off-label use of dexrazoxane from cycle 1 in patients with asymptomatic systolic LV dysfunction (baseline LVEF ~39%) permitted successful completion of planned anthracycline therapy (doxorubicin 280-300 mg/m²) with minimal LVEF decline (39% to 34%) and no symptomatic heart failure. 8 In contrast, similar patients treated without dexrazoxane experienced marked LVEF decline (42.5% to 18%), symptomatic heart failure requiring hospitalization, and two deaths from cardiogenic shock. 8

Patients with cardiac risk factors: Insufficient evidence exists to make specific recommendations for patients with pre-existing cardiac risk factors or underlying cardiac disease. 1

Adjuvant setting: Dexrazoxane use in the adjuvant setting should only occur within clinical trials due to concerns about potential reduction in anthracycline efficacy and lack of long-term toxicity data. 1, 4

Pediatric patients: Insufficient evidence exists for routine recommendation in pediatric malignancies. 1

Other Anthracyclines

Insufficient data exist to recommend dexrazoxane with mitoxantrone, daunorubicin, or liposomal doxorubicin. 1 Preclinical studies showed no cardioprotective effect with mitoxantrone. 4

Cost Considerations

Using dexrazoxane costs approximately $5,600 per cardiac event prevented in patients with metastatic breast cancer receiving doxorubicin-based chemotherapy. 1

Extravasation Management (Alternative Indication)

For anthracycline extravasation, dexrazoxane is administered IV in a 3-day schedule (1000, and 500 mg/m²) starting within 6 hours of extravasation, which prevented severe tissue damage in 98.2% of patients (only 1 of 54 required surgical debridement). 1