Late Mortality After Dexrazoxane Treatment: A Report From the Children's Oncology Group

Abstract

Purpose: Given concerns that dexrazoxane may reduce treatment efficacy, induce second cancers, and thus compromise overall survival among children, we examined long-term overall and cause-specific mortality and disease relapse rates from three randomized clinical trials.

Patients and methods: Children's Oncology Group trials P9404 (T-cell acute lymphoblastic leukemia/lymphoma; n = 537), P9425 (intermediate/high-risk Hodgkin lymphoma; n = 216), and P9426 (low-risk Hodgkin lymphoma; n = 255) were conducted between 1996 and 2001. Each trial randomly assigned patients to doxorubicin with or without dexrazoxane. The dexrazoxane:doxorubicin dose ratio was 10:1, and the cumulative protocol-specified doxorubicin dose was 100 to 360 mg/m(2). Dexrazoxane was given as an intravenous bolus before each doxorubicin dose. Data from all three trials were linked with the National Death Index to determine overall and cause-specific mortality by dexrazoxane status.

Results: Among 1,008 patients (507 received dexrazoxane) with a median follow-up of 12.6 years (range, 0 to 15.5 years), 132 died (67 received dexrazoxane). Overall mortality did not vary by dexrazoxane status (12.8% with dexrazoxane at 10 years v 12.2% without; hazard ratio [HR], 1.03; 95% CI, 0.73 to 1.45). Findings were similar when each trial was examined separately. Dexrazoxane also was not significantly associated with differential causes of death. The original cancer caused 76.5% of all deaths (HR, 0.90; 95% CI, 0.61 to 1.32) followed by second cancers (13.6% of deaths; HR, 1.24; 95% CI, 0.49 to 3.15). Specifically, dexrazoxane was not associated with deaths from acute myeloid leukemia/myelodysplasia or cardiovascular events.

Conclusion: Among pediatric patients with leukemia or lymphoma, after extended follow-up, dexrazoxane use did not seem to compromise long-term survival.

Trial registration: ClinicalTrials.gov NCT01790152.

Fig 1.

Cumulative incidence of relapse and overall mortality in the combined Children's Oncology Group randomized trials of dexrazoxane (DRZ). Cumulative incidences at 10 years were not significantly different by DRZ status for either outcome. DRZ+, exposed to DRZ; DRZ−, not exposed to DRZ.

Fig 2.

Cumulative mortality through 10 years attributed to (A) original cancer, (B) second cancer, and (C) other toxicity by dexrazoxane (DRZ) status. Cumulative mortality at 10 years was not significantly different by DRZ status for any of the three outcomes. The y-axis scales differ. DRZ+, exposed to DRZ; DRZ−, not exposed to DRZ.