Cardioprotective Outcomes Evident With Dexrazoxane in Children Treated With Doxorubicin

For pediatric patients with cancer, treatment with dexrazoxane was associated with a long-lasting cardioprotective effect following treatment with an anthracycline, according to findings from a multi-institutional cooperative group study published in the Journal of Clinical Oncology.¹

Eric J Chow, MD, MPH

Findings from the study showed that among patients who received dexrazoxane and doxorubicin (n = 99), the combination was associated with superior left ventricular systolic function fractional shortening as well as superior ejection fraction compared with patients who received doxorubicin alone (n = 96), with absolute differences of +1.4% (95% CI, 0.3%-2.5%) and +1.6% (95% CI, 0.0%-3.2%), respectively.

Additionally, lower myocardial stress per B-type natriuretic peptide was observed among patients who received dexrazoxane compared with non-recipients (–6.7 pg/mL [95% CI, –10.6 to –2.8]). The protective effect associated with dexrazoxane treatment was mostly seen among patients who received the agent at a cumulative dose of at least 250 mg/m².

“We believe this study provides evidence that dexrazoxane offers measurable long-term cardioprotection for children and adolescents with cancer receiving anthracycline-based chemotherapy,” wrote Eric J Chow, MD, MPH, an attending physician at Seattle Childrens Hospital, and co-investigators, in the study. “Per a recently published international consensus guideline, oncology providers should consider administering dexrazoxane to children and adolescents expected to receive [at least] 250 mg/m² of cumulative doxorubicin, or an equivalent amount of other anthracyclines.”

According to study authors, most therapies for pediatric cancer rely on anthracyclines and other cytotoxicity chemotherapies, although there have been advances with molecularly targeted agents. For patients who receive anthracyclines, cardiomyopathy is a major late toxicity, and late cardiovascular morbidity still represents a significant threat to long-term survivors.

Therefore, this multi-institutional cooperative group study sought to evaluate whether dexrazoxane was an effective regimen in mitigating anthracycline-related cardiotoxicity in survivors.

Eligible patients were enrolled on legacy Children’s Oncology Group protocols P9404, P9425, P9426, and P9754, and Dana-Farber Cancer Institute Childhood Acute Lymphoblastic Leukemia Consortium protocol 95-01, all of which included treatment withdoxorubicin at doses ranging from 100 mg/m² to 600 mg/m². These protocols were all phase 3 clinical trials for patients with acute lymphoblastic leukemia (ALL)/lymphoma or Hodgkin lymphoma in which patients were randomly assigned upfront to receive treatment with or without dexrazoxane. Intravenous dexrazoxane was given uniformly as a single bolus in a 10:1 mg/m² dose ratio across all 5 trials.

Patients included as part of the study had to be in remission from their primary cancer. They also could not have experienced a subsequent malignant neoplasm that was treated with a cardiotoxic agent.

A total of 195 patients were enrolled and most were exposed to dexrazoxane (51%), with a cumulative dose of 297 ± 91 mg/m². They were assessed approximately 20 years (18.1 ± 2.7) postcancer diagnosis for cardiotoxicity

Participants underwent a 1-time assessment, consisting of anthropometric measurements and a fasting blood draw lasting at least 10 hours. Samples were then analyzed for ardiomyocyte injury and myocardial stress. Medical histories were also updated to include the presence of cardiovascular and other related diseases.

A standardized 2-dimensional, M-mode and Doppler echocardiogram was performed on all patients. The primary echocardiographic outcome was end-diastolic wall thickness-to-dimension ratio as a measure of left ventricular pathologic remodeling. Secondary outcomes included left ventricular systolic and diastolic function.

Between May 2014 and March 2021, 201 potentially eligible patients were enrolled. Two had a history of relapse, 2 consented but did not complete any study assessments, and 2 consented to self-report questionnaire submission only; all these patients were deemed to be ineligible.

Clinical characteristics were well-balanced between the dexrazoxane and no dexrazoxane arms; most patients were men (54.5% vs 52.1%) and White (82.8% vs 84.4%). Patients had a median age at diagnosis of 10.7 years (range, 0.9-19.8) and 12.3 years (range, 0.5-20.7), respectively.

The dexrazoxane arm enrolled patients with ALL (58.6%), lymphoblastic leukemia (10.1%), Hodgkin lymphoma (27.3%), and osteosarcoma (4.0%). Radiotherapy exposure to the heart occurred in 22.2% of patients. The median age at the time of the study was 27.8 years (range, 17.3-39.2).

In the arm that did not receive dexrazoxane, patients were diagnosed with ALL (44.8%), lymphoblastic leukemia (13.5%), Hodgkin lymphoma (35.4%), and osteosarcoma (6.3%). Radiotherapy exposure to the heart occurred in 32.3% of patients. The median age at the time of the study was 39.0 years (range, 16.1-40.5).

Of note, the dexrazoxane and non-dexrazoxane arms underwent similar protocol-specified doxorubicin doses, at 305 ± 92 mg/m² vs 288 ± 90 mg/m², respectively.

Additional findings showed that the dexrazoxane group surpassed the no dexrazoxane arm in terms of left ventricular fractional shortening (34.7 ± 3.6% vs 33.4 ± 4.1%; P = .02), ejection fraction(63.6 ± 5.2% vs 62.2 ± 5.7%; P = .08), and fewer patients with lower left ventricular function (4.1% vs 12.5%; P = .04). Left ventricular structure, including wall thickness-dimension ratio, was not significantly effected.

One limitation of this study was that it did not assess anthracyclines besides doxorubicin. Moreover, study authors noted that although dexrazoxane appears to offer some cardioprotection, the protection is not complete. They recommended periodic echocardiographic surveillance for all patients treated with anthracyclines, and for those who experienced radiotherapy exposure of the heart.

In December 2022, the International Late Effects of Childhood Cancer Guideline Harmonization Group wrote that the benefits of dexrazoxane probably outweigh the risk of subsequent neoplasms when the cumulative doxorubicin or equivalent dose is at least 250 mg/m². This was deemed to be a moderate recommendation. No recommendation was offered for patients who received cumulative doxorubicin or equivalent doses of lower than 250 mg/m², because of a lack of evidence.²

References

1. Chow EF, Aggarwal S, Doody Dr, et al. Dexrazoxane and long-term heart function in survivors of childhood cancer. J Clin Oncol. Published online January 20, 2023. doi:10.1200/JCO.22.02423
2. De Baat EC, van Dalen EC, Mulder RL, et al. Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
   Lancet Child Adolesc Health. 2022;6(12):P885-894. doi:10.1016/S2352-4642(22)00239-5