We reviewed data on 315 patients enrolled on two COG OS trials (P9754 and AOST0121), all of whom received higher cumulative dose doxorubicin with dexrazoxane cardioprotection. None of the 315 patients enrolled on either study had reported clinical cardiac toxicity after treatment with 450–600 mg/m2 of doxorubicin as per NCI-CTCAE (Common Terminology Criteria for Adverse Events) version 2, with or without trastuzumab and concomitant dexrazoxane [12, 13]. We also reviewed detailed cardiac function data of in 81 patients enrolled on the two trials who had such data available. Many patients, especially girls, had echocardiographic abnormalities or elevated concentrations of NT-proBNP after treatment. Left ventricular end-diastolic septal thickness and LV mass were significantly smaller for BSA than normal for both sexes. These echocardiographic changes persisted: one-third of children evaluated > 81 days after the METT had significantly smaller LV posterior wall thicknesses for BSA than normal controls. Girls also had a significantly smaller LV dimension Z-score which indicates greater susceptibility to doxorubicin cardiotoxicity [7, 15, 28, 29].
Anthracyclines target topoisomerase IIβ to cause DNA double-strand breaks, impairing transcription and translation, and they also couple with iron to generate reactive oxygen species. These species, in turn, cause an irreversible cardiomyocytic mitochondriopathy [8, 9]. Dexrazoxane chelates myocardial iron, preventing it from coupling with anthracyclines, thus preventing the mitochondriopathy [19].
Dexrazoxane is an effective cardioprotectant in children with acute lymphoblastic leukemia (ALL) [25, 30,31,32]. In an early use of dexrazoxane in children with sarcomas, 38 children were randomly assigned to receive doxorubicin with or without dexrazoxane [33]. Those children receiving dexrazoxane were less likely to have subclinical cardiotoxicity and had smaller declines in LV ejection fraction [33]. In the current cohort of patients with OS, none experienced clinical heart failure [12, 13], and none had any marked changes in LV fractional shortening Z-scores (Table 5 P = 0.30), or in LV end diastolic septal thickness Z-scores (Table 5 P < 0.01) despite treatment with trastuzumab and/or with cumulative doxorubicin doses up to 600 mg/m2. Although our study was not randomized, we believe the minimal cardiac changes noted are likely attributable to the significant cardioprotective benefit of dexrazoxane.
In studies of women with breast cancer, trastuzumab plus doxorubicin had rates of clinical cardiotoxicity as high as 27% [34]. Trastuzumab alone had a relative risk of 5.11 for severe heart failure in a meta-analysis of women with breast cancer [35]. A retrospective study of women with HER2-positive breast cancer who received doxorubicin and trastuzumab showed that the 25% who received dexrazoxane had significantly fewer cardiac events [36]. Our study supports this impression that dexrazoxane may mitigate the cardiotoxicity of doxorubicin given with trastuzumab.
In the > 200 children with ALL randomly assigned to receive doxorubicin alone or with dexrazoxane, cTnT and NT-proBNP concentrations increased significantly in children who received doxorubicin alone [31]. These increases were related to abnormal echocardiographic findings 4 years later [25]. In the OS studies reported here, all patients received dexrazoxane, and none of the evaluable children and adolescents had elevated concentrations of cTnT. The NT-proBNP concentrations overall did not reach levels of concern for heart failure risk in either study, with only one girl having a value in the range of heart failure risk (Figures 2 and 3). In P9754, NT-proBNP concentrations were significantly higher in girls than in boys at the end of therapy and remained high but never indicated heart failure (Figure 2). In AOST0121 we had few NT-proBNP measurements available for analysis. At the end of therapy some measurements were elevated for boys, which decreased with time. The findings in boys are consistent with the acute cardiotoxicity profile of trastuzumab, as the cardiotoxicity is often reversible once it is stopped [34, 35, 37, 38]. In the girls NT-proBNP slightly increased yet overall the concentration did not reach cardiomyopathy risk (Fig. 3).
Our finding that girls had more progressive abnormalities of LV structure (decreased LV wall thickness Z-scores, LV mass Z-scores and LV end-diastolic dimension Z-scores) than boys indicates that doxorubicin-treated girls have hearts that are disproportionately small for body size, increasing their ventricular stress as indicated by a statistically significant increase in NT-proBNP concentration. These results indicate that the dexrazoxane’s cardioprotection was incomplete for girls as reflected by the gender difference correlating with the smaller and more vulnerable hearts of girls. Other studies have also reported that female sex is an independent risk factor for late cardiac effects [7, 15, 28].
The 5-year cumulative incidence of SMNs in P9754 and AOST0121 combined was similar to historical controls from the INT-0133 study (Fig. 4). Doxorubicin itself is shown to increase SMN risk, as highlighted in a review of > 6000 childhood solid tumor survivors, which found a doxorubicin-dose-dependent increased SMN risk [39].
Some clinicians have hesitated to use dexrazoxane in children and adolescents with cancer because of a reported possible association between dexrazoxane and an increased risk of SMNs in patients with Hodgkin’s lymphoma [10]. In those studies, uniquely, three topoisomerase inhibitors (etoposide, doxorubicin, and dexrazoxane) were used simultaneously. Chow et al. reviewed these same Hodgkin’s lymphoma studies (POG 9425 and 9426), and the POG 9404 T-cell lymphoblastic lymphoma/leukemia study. With longer follow-up there was no increase in secondary AML/MDS attributable to dexrazoxane use [40]. In a multicenter study of 205 patients with high-risk ALL, half of whom received dexrazoxane with doxorubicin chemotherapy, dexrazoxane did not compromise the efficacy of doxorubicin [31, 32, 40], and there was no increase in the cumulative incidence of SMNs associated with dexrazoxane after a median follow-up of 6.2 years [41]. Similar findings were seen in other studies [30, 42], one of which examined 15,532 anthracycline-treated pediatric cancer patients, of whom 1406 received dexrazoxane, and found no increased risk of secondary AML [42]. In yet another set of sequential childhood protocols, among 553 high-risk ALL patients treated with dexrazoxane the only SMN was a single case of AML. The overall 5-year confidence interval of SMNs for patients was lower than the range in most historical studies, indicating SMNs were rare [43]. This updated SMN data led the European Medicines Agency (EMA) to withdraw its prohibition of dexrazoxane use in children aged 0–18 years. It now allows the use of dexrazoxane in Europe for children from the start of anthracycline chemotherapy if the planned cumulative dose is over 300 mg/m2. Their review also did not show evidence of dexrazoxane interference with chemotherapy, and led to removal of a safety warning for early death associated with dexrazoxane [44].
Our study was prospective, and all echocardiograms were centrally reviewed. However, the studies were not randomized so there were no comparison arms, and the numbers of children and adolescents with available data after the expected completion of treatment were small (echo data is missing in 74%, troponin in 78% and BNP in 81% of patients). Also, as the follow up period was short it is possible patients may have developed cardiotoxicity later in follow up. The substantial amount of missing data could have biased our results. Nonetheless, the absence of cardiotoxicity in children and adolescents receiving high-dose anthracycline therapy supports the conclusion that dexrazoxane is cardioprotective. There was no suggestion of an increased incidence in SMN.
