DEXRAZOXANE USE SAFE IN CHILDREN

Use of the cardioprotectant dexrazoxane (DRZ) (multiple brands) is not linked to late mortality, second cancer–related mortality, or relapse after anthracycline use in survivors of pediatric blood cancers, according to a Children's Oncology Group (COG) study published online May 26 in the Journal of Clinical Oncology.

"We did not observe increased mortality or relapse among pediatric leukemia and lymphoma patients randomized to dexrazoxane compared with those treated without. This includes no significant differences in myeloid leukemia–related deaths," commented first author Eric Chow, MD, MPH, an assistant professor in hematology-oncology at the Fred Hutchinson Cancer Center, University of Washington, in Seattle.

Although the use of DRZ to protect against the cardiovascular toxicity of anthracyclines in adults is supported by the literature, its use in children remains controversial, the authors comment.

Use of DRZ in children has been limited over concerns that the topoisomerase inhibitor could interact with other cancer agents, decrease treatment efficacy, increase the risk for second cancers, and affect overall survival, they add.

Three past studies from the COG, however, suggest that DRZ does not affect overall survival and may be cardioprotective. The evidence remains inconclusive, though, because of the long follow-up needed to capture heart failure in survivors of childhood cancer.

Dr Chow and colleagues drew data from three phase 3 randomized, controlled trials conducted by the COG between 1996 and 2001: the P9404 study, in T-cell lymphoblastic leukemia/lymphoma (n = 537); the P9425 study, in intermediate- and high-risk Hodgkin's lymphoma (n = 216); and the P9426 study, in low-risk Hodgkin's lymphoma (n = 255). The trials randomly assigned participants to receive doxorubicin with or without DRZ given as an intravenous bolus before doxorubicin administration. Participants received DRZ and doxorubicin in a 10:1 ratio, with a cumulative doxorubicin dose of 100 to 360 mg/m². The researchers also used data from the COG and the National Death Index to look at overall and cause-specific mortality.

The analysis included 1008 patients, of whom 507 received DRZ. During a median follow-up of 12.6 years, 132 patients died, 67 of whom had received DRZ.

Results suggested that DRZ did not seem to affect cancer treatment efficacy in terms of relapse (16.1% with DRZ at 10 years vs 19.1% without; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.60 - 1.08), and overall mortality (12.8% with DRZ at 10 years vs 12.2% without; HR, 1.03; 95% CI, 0.73 - 1.45).

More than three quarters (76.5%) of all deaths resulted from the original cancer (HR, 0.90; 95% CI, 0.61 - 1.32), followed by death from second cancers (13.6% of deaths; HR, 1.24; 95% CI, 0.49 - 3.15). Deaths from primary or second cancer did not differ by DRZ administration (HR, 0.90; 95% CI, 0.61 - 1.32; and HR, 1.24; 95% CI, 0.49 - 3.15, respectively).

Deaths from acute myeloid leukemia/myelodysplasia and cardiovascular events were not linked to DRZ.

"I think our results will help allay some concerns about significantly increased risk of serious toxicities with dexrazoxane," commented Dr Chow.

However, he added: "What we don't have a good handle on is whether the drug really reduces long-term cardiac toxicity."

Postexposure data 5 years after receiving DRZ are "intriguing and promising," Dr Chow revealed, and they suggest improved cardiac function in DRZ-treated patients.

A new COG study (ALTE11C2: Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment [HEART]) could answer some of these questions. The HEART trial will look at the long-term effects of DRZ on second cancers and cardiac health of patients treated in the three COG trials included in this study.

"I think the challenge with pediatric cancer survivorship is that even after cure, these now young adults still have many decades of life ahead of them, and we want to emphasize the importance of continued follow-up for them," Dr Chow emphasized. "There are now many dedicated survivor long-term follow-up clinics across the country with specialized knowledge in care of these survivors, and we encourage these survivors and their primary healthcare providers to access these resources."

One or more of the authors reports receiving consulting fees, research funding, and/or other expenses from one or more of the following: Jazz Pharmaceuticals, Sigma Tau Pharmaceuticals, Merck, Clinigen Group, Roche Diagnostics, and Pfizer.