Dexrazoxane makes doxorubicin-induced heart failure a rare event in sarcoma patients receiving high cumulative doses

Abstract

Doxorubicin remains a cornerstone in sarcoma treatment, but its dose-dependent cardiotoxicity limits its clinical use and therapeutic potential. Dexrazoxane, the only FDA-approved cardioprotective agent, has demonstrated substantial efficacy in preventing doxorubicin-induced cardiotoxicity. However, despite its proven benefits, dexrazoxane remains underutilized not only in clinical practice but also in contemporary trials. This review examines the role of dexrazoxane in recent oncology trials involving sarcoma patients treated with high cumulative doses of doxorubicin. The LMS 04 trial, a contemporary phase 3 sarcoma trial in which dexrazoxane use was prohibited, reported a 5.4% heart failure incidence at cumulative doxorubicin doses of 360–450 mg/m². In contrast, the trials, where dexrazoxane was used early or upfront, demonstrated rare heart failure incidences even at cumulative doses exceeding 600 mg/m², which is well beyond the conventional maximal limit. Additionally, dexrazoxane enables the safe administration of cumulative doxorubicin doses exceeding 1000 mg/m² without increasing cardiotoxicity. Concerns about secondary malignancies and reduced anti-tumor efficacy have not been supported by clinical trials and meta-analyses. The routine upfront use of dexrazoxane should be considered with doxorubicin treatment, especially in those requiring high cumulative doses or patients at high risk of cardiotoxicity, as each dose of doxorubicin incrementally contributes to the development of cardiotoxicity. Dexrazoxane not only mitigates cardiotoxicity but also allows for extended doxorubicin dosing, maximizing its therapeutic potential. Awareness and guideline updates are necessary to ensure its broader adoption in clinical practice.

Introduction

Doxorubicin remains a cornerstone in the treatment of various cancers, including solid tumors and hematologic cancers, despite rapid advances in targeted therapy and immunotherapy. However, its dose-dependent cardiotoxicity limits both clinical use and therapeutic potential. In contemporary oncology practice, doxorubicin-induced heart failure (HF) has become less common, largely due to dose restrictions and improved cardio-oncology care [1, 2]. Most patients with doxorubicin-associated cardiotoxicity are identified early and receive timely and appropriate cardiology care [3].

However, the curative potential of doxorubicin is also determined by appropriate dosing [4]. Cumulative doses exceeding 300 mg/m² remain standard in certain malignancies such as high-grade lymphomas and Hodgkin’s disease [5]. In advanced sarcomas, doxorubicin-based regimens have been the standard first-line treatment across nearly all subtypes [6]. High cumulative doses of 450–600 mg/m² (75 mg/m² per cycle) or more are often required for these patients [7, 8], making cardioprotection crucial not only to prevent the onset of HF but also to enable patients to complete their chemotherapy regimens with less acute cardiotoxicity. Currently, the threshold between low and high cardiotoxicity risk for cumulative doxorubicin dose is defined at 250 mg/m² [2, 9].

Dexrazoxane, approved by the FDA in 1995 for metastatic breast cancer patients receiving cumulative doxorubicin or equivalent doses exceeding 300 mg/m², is the only cardioprotective agent available in the United States, and is also approved by the European Medicines Agency (EMA). The 2022 European Society of Cardiology (ESC) guidelines do not recommend the routine use of dexrazoxane but expand its use as a Class IIa indication once cumulative doses exceed 250 mg/m², regardless of cancer type and stage [2]. The American Society of Clinical Oncology (ASCO) has issued a similar recommendation for the dexrazoxane use [10]. However, dexrazoxane remains underutilized in clinical practice, largely due to the oncologists’ limited awareness of its benefits and concerns over secondary malignancies, and potential impact on anti-tumor efficacy. As a result, the benefits of dexrazoxane are often underappreciated, even in contemporary clinical trials. Comprehensive reviews on dexrazoxane have been previously published [11,12,13]. In our previously published article, we discussed the potential role of dexrazoxane in preventing anthracycline-induced cardiotoxicity by analyzing the cardio-oncology trials, where low to moderate cumulative doses of doxorubicin or its equivalent (≤ 300 mg/m²) were used, and the incidence of HF was rare or low. In this article, we analyze the incidence of HF at high cumulative doxorubicin doses, with and without dexrazoxane in recent clinical trials involving patients with sarcoma. We aim to highlight the critical role of dexrazoxane in mitigating doxorubicin-induced HF and its potential to allow safe administration of much higher cumulative doses than conventional limits. Although epirubicin and other anthracycline analogues are also used in clinical trials in patients with sarcoma, this article only focuses on trials using doxorubicin-based therapies.

Maximal cumulative dose limit of doxorubicin and minimal dose for cardiotoxicity

Doxorubicin-associated cardiotoxicity is well known to be dose-dependent. Von Hoff et al. [14] reported that 7% of patients developed HF at a cumulative dose of 550 mg/m², rising to 18% at 700 mg/m², while Swain et al. [15] reported much higher rates of 26% and 48%, respectively. It is generally accepted that the incidence of HF exceeds 5% when cumulative doses of doxorubicin reach 450 mg/m²[16]. These observations led to the empirical dose limit of 450–550 mg/m² for doxorubicin [17]. Oncologists are often bound by these dose limits to mitigate the risk of doxorubicin-induced HF. As a consequence, treatment with doxorubicin may be prematurely discontinued or substituted with less effective alternatives [16].

However, despite the assumed dose limits, there is no completely safe dose for doxorubicin. Billingham et al. [18] demonstrated substantial cardiac tissue damage at doses as low as 220–400 mg/m² through electron microscopy of endomyocardial biopsies. In a later study, 13 of the 30 patients who received a cumulative dose of 465 mg/m² (range 290–680 mg/m²) exhibited severe morphologic changes in biopsy specimens, precluding further doxorubicin use [19]. Moreover, myocardial damage has been observed as early as four hours after the first dose of doxorubicin [20]. This is supported by the clinical observation that troponin release can occurs soon after doxorubicin infusion [3]. Thus, the dose-dependent cardiotoxicity of doxorubicin aligns with a pathophysiologic model in which early subclinical myocardial cell injury progresses to an asymptomatic decline in the left ventricular ejection fraction (LVEF) and, if unaddressed, ultimately culminates in overt HF with or without continued doxorubicin use. This continuum of cardiac injury likely begins early in the course of anthracycline treatment [21].

These findings suggest that cardiotoxicity begins with the first dose of doxorubicin and progresses based on individual patient risk factors, characteristics, and, most importantly, the cumulative dose of doxorubicin. This highlights the importance of early and proactive use of cardioprotective agents in patients scheduled to receive high cumulative dose of doxorubicin.

Cardiac outcomes in two trials for advanced sarcoma with and without dexrazoxane use

The LMS 04 trial [22, 23] (2017–2023) (Table 1), a phase 3 randomized trial, involved 149 patients with advanced leiomyosarcoma treated with either single-agent doxorubicin (75 mg/m² for six cycles) or doxorubicin (60 mg/m² for six cycles) plus trabectedin, followed by trabectedin maintenance therapy for those without disease progression. This trial was the first to demonstrate overall survival and progression-free survival benefits compared to doxorubicin alone. However, cardiotoxicity was barely mentioned in the article except for indicating that one patient died of HF, which was the only treatment-related death reported. In the online supplemental appendix, 8 cases of HF (8/149, 5.4%) were reported, and 4 additional cases of cardiac dysfunction were noted. Notably, 76% of patients received cumulative doxorubicin doses of 360–450 mg/m². Despite the high cumulative doses, the trial protocol prohibited the use of dexrazoxane due to concerns about myelosuppression. Cardiac monitoring, initially limited to baseline and post-treatment echocardiograms, was amended later to include evaluations at cumulative doxorubicin doses of 300 mg/m² and as needed for clinical signs of HF (see online supplemental appendix). Nevertheless, 5.4% incidence of HF is high for contemporary oncology trials [13]. The absence of dexrazoxane use raises concerns, especially given that hematologic toxicities were closely monitored and reported in detail, and G-CSF was routinely used to protect against much less consequential hematologic events than HF. The 1-year post-discharge mortality rate is 35.2% among patients ≥ 65 years who were hospitalized for HF with reduced LVEF in the U.S., [24] and the 5-year mortality is more than 50%, [25] surpassing the mortality rates of many types of cancer.

Table 1 Heart failure and Cardiac Dysfunction incidence in contemporary trials with high cumulative doses of Doxorubicin

In contrast, the ANNOUNCE trial (2015–2018) [26], a phase 3 randomized trial, included 509 patients with advanced soft-tissue sarcoma. The trial allowed for up to eight cycles of doxorubicin (75 mg/m² per cycle), resulting in a higher cumulative dose of 600 mg/m². Importantly, dexrazoxane was allowed starting from the first cycle of doxorubicin at the investigator’s discretion, and recommended for patients receiving five or more cycles of doxorubicin. The trial implemented comprehensive cardiac monitoring. Cardiac evaluations, including echocardiograms or MUGA scans, were performed at specified intervals, and electrocardiograms were conducted from baseline through follow-up.

The assessment of doxorubicin-associated cardiotoxicity in this trial was presented separately [27] (Table 1). The median cumulative dose of doxorubicin was 450.3 mg/m² (range, 72.3–634.0 mg/m²). Dexrazoxane was used in 63% of doxorubicin + olaratumab patients and 65% of doxorubicin + placebo patients, particularly at higher cumulative doses (38.6% for receiving < 450 mg/m2, 88.5% for 450–600 mg/m², and 90% for ≥ 600 mg/m²). About one third of patients who received dexrazoxane initiated with the first cycle of doxorubicin. Notably, dexrazoxane had no negative impact on treatment efficacy. Although HF was not well defined in the protocol, only one case of treatment-related HF resulting in death occurred in a patient with a cumulative dose of 450 mg/m², and did not receive dexrazoxane despite the protocol recommendation. Overall, the incidence of CTCAE 4.0 (the NCI Common Terminology Criteria for Adverse Events) grade ≥ 3 cardiac dysfunction (a HF equivalent event) was low, 1.9% and 2.4% in the doxorubicin + olaratumab and doxorubicin + placebo groups, respectively. Median follow-up for cardiac events was 28 weeks. Notably, grade ≥ 3 cardiac dysfunction occurred in only 1.1% of patients who received a very high cumulative dose of ≥ 600 mg/m², with 90% of these patients receiving dexrazoxane. Treatment-related cardiac adverse events were low across all dose ranges.

Upfront use of dexrazoxane allows very high cumulative doxorubicin doses

An interim analysis of a phase II trial [28] tested the upfront use of dexrazoxane with doxorubicin on progression-free survival and cardiac function in patients with soft-tissue sarcoma. This is a non-inferiority trial compared to historical controls for progress free survival. This analysis was conducted after 33 of 65 patients were enrolled. Dexrazoxane was administered from cycle 1, at a 10:1 ratio to doxorubicin (750 mg/m²), over 15 min, no more than 30 min prior to doxorubicin. The trial included comprehensive cardiac surveillance, with echocardiograms, including global longitudinal strain, performed at baseline and before every other treatment cycle. All echocardiograms were reviewed by an expert cardiologist and confirmed by a blinded core laboratory. Cardio-oncology referrals were made for patients receiving over 300 mg/m² of doxorubicin or experiencing changes in LVEF.

The results showed that the upfront use of dexrazoxane allowed patients to receive very high cumulative dose of doxorubicin. The median doxorubicin dose was 450 mg/m² (interquartile range 300–750 mg/m²) over six cycles. High cumulative doses of doxorubicin with the upfront use of dexrazoxane allowed for a progress-free survival of 8.4 months, non-inferior to the historical control of 4.6 months for doxorubicin treatment. Among the entire study cohort, there was no difference between LVEF measured at baseline, the end of the study treatment, and the end of the follow-up period. Only 3 patients (9.1%) were removed from the study due to cardiotoxicity (LVEF drops to below 50%), having received cumulative doses of 1200 mg/m², 600 mg/m², and 675 mg/m², respectively. All 3 patients recovered LVEF above 50% with cardio-oncology care, and none required hospitalization. Notably, no case with more than grade 3 cardiac dysfunction or HF was reported.

A separate trial (P9754) [29] (Table 1) involving 242 pediatric and young patients (age 3–30 years) with non-metastatic osteosarcoma have also shown the feasibility and safety of increasing the cumulative dose of doxorubicin with concurrent dexrazoxane administration, without compromising the antitumor efficacy of doxorubicin. Dexrazoxane was administered with each doxorubicin doses. Upfront use of dexrazoxane enabled cumulative doxorubicin doses of 450–600 mg/m² with minimal cardiotoxicity. Five patients experienced grade 1 or 2 left ventricular dysfunction; one was lost to follow-up. The remaining four recovered LVEF to above 50%, and no patients required hospitalization for cardiac dysfunction. Two patients (< 1%) developed secondary leukemia, one as a first event, a rate similar to previous trials [30]. While the trial is not powered to evaluate the efficacy of high cumulative doses of doxorubicin exceeding 600 mg/m², it supports the safe use of high cumulative doxorubicin doses with concurrent use of dexrazoxane in pediatric patients, without increased cardiotoxicity or risk of secondary leukemia.

A long-term follow up of the P9754 and AOST0121 trials in children and adolescents with osteosarcoma [31] who received high cumulative dose of doxorubicin (450–600 mg/m²) with the upfront use of dexrazoxane (10:1 dexrazoxane: doxorubicin dosing) has been published. Among 315 patients with no reported cardiotoxicity at the completion of treatment, a follow-up over a mean period of approximately six years revealed no incidence of HF and no significant changes of LV systolic function, as assessed by LV fractional shortening. Dexrazoxane did not increase the risk of secondary malignant neoplasms. Additionally, a further long-term follow-up of survivors from P9754 trial indicated a sustained cardioprotective effect of dexrazoxane with a median follow-up of 18.4 years post-anthracycline exposure. Although HF incidence was not recorded, there were no cardiovascular-related deaths and heart transplants among the 144 survivors including the 110 patients who received a cumulative doxorubicin doses of 600 mg/m². In contrast, in a comparator group from the Childhood Cancer Survivor Study with osteosarcoma patients (n = 495) who did not receive dexrazoxane for doxorubicin treatment with a median cumulative dose of 379 mg/ m² (interquartile range 288–455 mg/ m²), 8 patients either received heart transplants or were on transplant waiting lists, and all events occurring within 20 years of cancer diagnosis and with a median cumulative doxorubicin dose of 509 mg/ m². This corresponded to a 20-year cumulative incidence of 1.6% of end-stage HF [32, 33].

Furthermore, neurohormonal treatments such as enalapril failed to demonstrate benefit in improving cardiac outcomes in a randomized trial on the pediatric patients with anthracycline-induced cariotoxicity [34]. In a long-term follow-up study on doxorubicin-induced cardiotoxicity, prolonged enalapril therapy did not result in sustained improvements in LV systolic function despite showing transient benefits [35]. Additionally, continuous doxorubicin infusion, which showed benefits to prevent doxorubicin-induced cardiotoxicity compared to bolus infusion [36], failed to offer a cardioprotective advantage over bolus infusion in children [37]. These findings further underscore the importance of dexrazoxane in preventing doxorubicin-induced cardiotoxicity in younger cancer patients.

Maximal dose of doxorubicin used with the upfront use of dexrazoxane

As demonstrated in the interim analysis of a phase II non-inferiority trial [28], five patients were able to receive more than 1000 mg/m² of doxorubicin with the upfront use of dexrazoxane, with 2 patients receiving over 2000 mg/m², up to a maximum of 2850 mg/m². Of these, only one patient discontinued the study at cumulative dose of 1200 mg/m² due to cardiotoxicity. This patient’s LVEF recovered to above 50% after proper cardiology care. The ability to safely administer such high cumulative doses of doxorubicin may explain the observed trends toward longer progression-free survival compared with historical data in similar treatment settings in this trial. The use of dexrazoxane allowed for these high doses without increased cardiac damage, suggesting its potential to extend the effectiveness of doxorubicin-based therapies.

Discussion

Patients with sarcoma undergoing high cumulative dose of doxorubicin treatment are at high risk of HF. Dexrazoxane remains the most effective agent in preventing doxorubicin-induced cardiotoxicity [13]. Despite its efficacy, dexrazoxane remains underutilized not only in clinical practice but also in contemporary trials. The LMS 04 trial prohibited dexrazoxane use due to concerns about myelosuppression, resulting in a 5.4% HF incidence. In contrast, the ANNOUNCE and pediatric osteosarcoma trials, where dexrazoxane was used, reported rare cases of HF, despite doxorubicin doses exceeding 600 mg/m², which are well beyond the conventional maximal limit. It seems paradoxical in the LMS 04 trial that G-CSF is routinely used to manage reversible neutropenia, yet dexrazoxane is restricted from preventing potentially irreversible and lethal HF.

In a large observational study, despite prompt and optimal heart failure therapy, only 11% of patients had a full recovery (a LVEF equal to that before the initiation of chemotherapy); in the remaining 89% of patients, the LVEF was below the baseline value [3]. It emphasizes the importance of prevention of doxorubicin-induced cardiotoxicity.

The ability of dexrazoxane to allow very high cumulative doses of doxorubicin without increasing cardiotoxicity is remarkable. Empirical dose thresholds, such as the 450–550 mg/m² limit, are no longer restrictive when dexrazoxane is co-administered. There is no convincing evidence that dexrazoxane compromises doxorubicin’s anti-tumor efficacy or increases secondary malignancies [11, 38, 39], although long-term follow-up for secondary malignancies in pediatric survivors is still needed, given their much longer survival compared to adults. Furthermore, the association of dexrazoxane with worsened myelosuppression is controversial [11], if present, can be effectively managed. For patients with sarcoma who is scheduled to receive high dose of doxorubicin, the upfront use of dexrazoxane starting from cycle 1 should be strongly considered, particularly in younger patients. This strategy may also be applied to patients at high risk of cardiotoxicity [2], particularly those with preexisting LV dysfunction. A case series study [40] demonstrated that patients with preexisting cardiomyopathy (mean LVEF 39%) who received doxorubicin with upfront dexrazoxane experienced only a mild LVEF reduction (from 39 to 34%) and did not develop clinical HF. In contrast, those who did not receive dexrazoxane had a marked LVEF reduction (from 42.5 to 18%), and all developed clinical HF. The upfront use of dexrazoxane prevents the buildup of subclinical cardiotoxicity or cardiac vulnerability in the early stage of doxorubicin treatment and allows patient to receive higher cumulative dose while minimizing the risk for developing overt HF. We believe this approach should be extended beyond sarcoma to any cancer patient planning on receiving high cumulative dose (≥ 250 mg/m²)² or at high risk of cardiotoxicity, as it both minimizes cardiotoxicity and maximizes doxorubicin’s therapeutic potential.

While dexrazoxane’s exact cardioprotective mechanism is not fully clear, its ability to chelate intracellular iron to prevent free radicals formation [41], and block topoisomerase-IIb-induced DNA damage likely play a significant role [42]. With nearly three decades of clinical use, dexrazoxane’s efficacy in preventing HF is well established. Other cardioprotective agents, including renin–angiotensin–aldosterone system inhibitors, beta-blockers, statins, or SGLT2 inhibitors have shown mixing results for the prevention of anthracycline-induced cardiotoxicity [13, 21, 43]. These trials are generally underpowered to demonstrate a significant effect on HF prevention and have not been tested in patients with sarcoma who required cumulative dose of doxorubicin more than 450 mg/m²5. Given dexrazoxane’s consistently proven efficacy, The US FDA should consider expanding its indications and clinical guidelines should be updated accordingly.

Conclusions

The evidence strongly supports the early or upfront use of dexrazoxane in patients receiving doxorubicin. Dexrazoxane enables patients to complete and optimize their doxorubicin treatment while maintaining cardiac function, without compromising antitumor activity. Therefore, the former maximal dose limit for doxorubicin no longer applies, and much higher cumulative dose of doxorubicin can be used when dexrazoxane is co-administered. With comprehensive cardio-oncology care, early-stage cardiotoxicity can be effectively identified and managed. By adopting this approach, doxorubicin-induced HF can become a rare event, allowing oncologists to optimize treatment and improve patient outcomes.