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Doxorubicin is among the most effective chemotherapeutic agents, and is active against a wide variety of cancers. However, it also is highly cardiotoxic so that any effective use of this agent requires a strategy to limit the toxicity. Dexrazoxane is the only drug approved specifically to counter the cardiac toxicity of doxorubicin because of its ability to interfere with the molecular mechanisms causing the cardiac injury. Although other mechanisms, namely iron chelating properties, were originally thought to be responsible for its cardiac protection, recent studies suggest that dexrazoxane’s interaction with topoisomerase II, an enzyme important for the function of DNA during mitosis is most likely the major mechanism. While it had been thought that the mechanism of doxorubicin’s cardiac toxicity and the mechanism of doxorubicin’s tumor effectiveness are different, more recent studies have suggested that some of the most important mechanisms are similar. Because of this uncertainty, dexrazoxane is underutilized in patients where it could be useful. Thus, studies comparing tumor efficacy in patients taking doxorubicin randomized to dexrazoxane comparing progression-free survival and mortality as well as cancer treatment-related cardiac dysfunction (CTRCD) are needed to give oncologists data to support aggressive use of dexrazoxane in their patients.
School of Medicine, Washington University, St. Louis, Missouri, USA
Azim Merchant
School of Medicine, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri, USA
Joshua D. Mitchell
School of Medicine, Washington University, St. Louis, Missouri, USA
*Address all correspondence to: rkrone@wustl.edu
1. Introduction
Doxorubicin, a member of a class of cancer chemotherapeutic agents derived from Streptomyces bacterium, is among the most effective chemotherapeutic agents active against a wide variety of cancers [1, 2], primarily solid tumors (breast, lymphomas, lung [1, 2] and especially sarcomas [3]. It is also effective against leukemias but often in combination with other agents and with more limited dosing. Unfortunately, the development of chemo-resistance and the development of cardiac toxicity limits its widespread applicability. A number of strategies have been developed to limit cardiotoxicity to allow more of the drug to be safely administered. Dexrazoxane is the only drug approved specifically to counter the cardiac toxicity of doxorubicin. Only dexrazoxane is able to directly interfere with the molecular mechanisms causing the cardiac injury. Originally proposed for its iron chelating properties, dexrazoxane more likely acts by inhibiting the effect of doxorubicin on topoisomerase IIB (TOPIIβ), though other mechanisms have also been suggested. While it has been held that the mechanisms of doxorubicin’s cardiac toxicity and the mechanism of doxorubicin’s tumor effectiveness are different, more recent studies have suggested that some of the most important mechanisms are similar. Because of this uncertainty, additional studies are needed to compare tumor efficacy in patients taking and not taking dexrazoxane to establish whether dexrazoxane, in addition to protecting the heart, does not reduce progression-free survival and increase cancer-related mortality.
Doxorubicin kills tumor cells through several unrelated mechanisms (Figure 1 and Table 1). After diffusing into the nucleus, it disrupts many targets: intercalating into DNA and interrupting DNA synthesis, inhibiting RNA synthesis and binding with TOPII, an enzyme essential to the reproduction of DNA, with subsequent DNA damage and induction of apoptosis [2, 4, 5, 6, 7]. Doxorubicin’s intercalation into DNA ultimately leads to inhibited synthesis of macromolecules. Interaction with TOPII impedes DNA resealing during mitosis and is a major mechanism for tumor destruction as well as cardiac toxicity. Doxorubicin also makes changes in the surface markers of the tumor allowing the dendritic cells to recognize the tumor and activate the immune system by stimulating killer cells and by other less-understood mechanisms. It binds to the inner mitochondrial membrane phospholipid, inhibiting aspects of the electron transporter chain and leading to the generation of reactive oxygen species (ROS) [8]. These molecules damage multiple cellular components such as lipids, proteins and DNA [9] and in severe exposures can lead to apoptosis. Doxorubicin also reacts with iron and the doxorubicin-iron complex catalyzes the conversion of H2O2 and O2 into reactive hydroxyl radicals that also lead to DNA, lipid and protein damage [10]. In addition to these effects on the tumor, anthracyclines can increase the concentration of iron within cardiac myocytes, which contributes to the formation of ROS-producing hydroxyl radicals. Finally, anthracyclines disrupt calcium metabolism, further interfering with cardiac contraction [11].
Figure 1.
Diagrammatic representation of the mechanisms of action of doxorubicin. The large red X represents the areas where dexrazoxane blocks the action of doxorubicin on the cardiac myocytes. The blue X marks where dexrazoxane may block the effect of doxorubicin on TOP2α which is the major action in destroying the tumor.
Doxorubicin kills tumor cells through several unrelated mechanisms.
DNA in the nucleus intercalates into DNA, and
interrupts DNA synthesis.
Inhibits RNA synthesis.
binds with TOPII with subsequent DNA damage and induction of apoptosis [2, 4, 5, 6].
leads to inhibited synthesis of macromolecules.
Interaction with TOPII impedes DNA resealing during mitosis.
Changes the surface markers of the tumor allowing dendritic cells to recognize the tumor-- activating the immune system.
Binds to the inner mitochondrial membrane phospholipid and generates (ROS) which damages the cell and leads to apoptosis which exposes tumor proteins activating the immune system [8].
Complexes with iron producing reactive hydroxyl radicals with DNA, lipid and protein damage [10].
Increases the concentration of iron in cardiac myocytes, producing hydroxyl radicals.
Disrupts calcium metabolism, further interfering with cardiac contraction [11].
Cardiac toxicity manifested as cancer treatment-related cardiac dysfunction (CTRCD) is common with doxorubicin and is dose related [12]. Toxicity to other organs, liver, kidneys and brain can also occur [6]. As early as 1987 Schwartz et al. reported that 16% of patients deemed at high risk for cardiotoxicity because of a high administered doxorubicin dose or a decline in left ventricular (LV) ejection fraction developed congestive failure. Of these, five continued with persistent LV dysfunction and one person died from cardiac failure [13]. An excellent history of the discovery of the toxicity of doxorubicin and the development of strategies to limit the toxicity is discussed by Benjamin and Minotti [14].
Careful monitoring of LV function with advanced imaging strategies to identify the earliest appearance of cardiac toxicity is recommended before severe cardiac dysfunction has developed. This facilitates the initiation of cardioprotective strategies either with dose modification or with cardioprotective medications hopefully before irreversible dysfunction develops [15]. Early treatment of CTRCD allows recovery of function in many patients, which may not happen if treatment is delayed [16]. Strategies of surveillance have been described [17]. This includes baseline evaluation of biomarkers, and especially measures of LV function. Echocardiography is currently recommended with careful measurement of LV ejection fraction using two-dimensional (2D) evaluation using Simpson’s rule. The use of echo contrast when images are inadequate is strongly encouraged [15, 18, 19]. Three-dimensional (3D) imaging has been recommended as a technique which may be more reproducible and is being investigated. However, it depends on high-quality imaging which may be less available in the clinical setting than in a research laboratory [20]. Measurement of global longitudinal strain has been promoted as a measure of ventricular function and may identify CTRCD before cardiac dysfunction manifests with the ejection fraction [18, 21, 22]. Other measures of LV function, such as cardiac magnetic resonance imaging can be used when echo images cannot be obtained [15] and offer the advantage of being able to image myocardial abnormalities such as edema or fibrosis. In high-risk patients, imaging usually with every other dose of doxorubicin has been recommended [15].
Cardiac toxicity, in the form of a depression of primarily LV function is a major consideration when using doxorubicin. Cardiac toxicity can lead to serious morbidity and even death in persons who otherwise may have survived their cancer. Where doxorubicin is holding the tumor in check but not eliminating it, the development of cardiotoxicity will require stopping the doxorubicin with the likely result that control may be lost over the tumor.
An early approach to reducing doxorubicin cardiotoxicity was to limit the dose to less than 550 mg/M2 [12, 23]. Of course, this has the disadvantage of restricting the use of doxorubicin. Such a strategy is especially problematic if the doxorubicin is controlling the tumor and is the most effective chemotherapeutic option. This is especially true in the management of sarcomas. More recently there have been a large number of controlled studies evaluating drugs which are used in the treatment of heart failure (GDMT) to determine if they can protect against CTRCD from doxorubicin [16, 24, 25, 26, 27].
Beta blockers differ in their mechanism of actions, and their effectiveness in this role of protecting against LV depression from chemotherapy varies. Carvedilol a non-selective beta blocker with antioxidant activity [28] and nebivolol a cardioselective beta blocker with antioxidant activity and a nitric oxide donor [29] are somewhat protective but metoprolol [30, 31] did not protect. Enalapril among the ACE inhibitors in an early study was found to be protective [32] but in a larger study with 125 patients showed no effect [31]. The combination of enalapril and carvedilol prevented LV deterioration with doxorubicin. Valsartan [33], telemesartan [34] and candesartan [30] have also been shown protective efficacy.
Spironolactone has been shown to be protective when given simultaneously with doxorubicin [35]. Spironolactone may be a poor choice in breast cancer since it blocks adrenergic hormones. Presumably, eplerenone could be substituted in these patients since it does not affect adrenergic hormones but this has not been studied.
Statins have been explored as a possible cardioprotection agent and an association between statin use and decreased toxicity of anthracyclines has been shown in a meta-analysis [36, 37].
Sodium glucose co-transporter 2 (SGLT-2) inhibitors have more recently been reported to be beneficial. In a case-controlled study of 3033 patients with diabetes and cancer who were treated with anthracyclines, there was an incidence of cardiac events in 3% of patients taking SGLT-2 inhibitors compared to 20% incidence of cardiac events in the other patients, not taking SGLT-2 inhibitors [38]. Of course, these data are not conclusive. A prospective study would be needed to establish this relationship.
There are two approaches to limiting cardiotoxicity other than restricting the dose. One option is to monitor the patient for early signs of CTRCD [22] and then treat with medications with proven benefit for heart failure, commonly referred to as guideline-directed medical therapy (GDMT) [16, 39]. A second approach in persons thought to be at special risk would be to start the protective medication “up front” with the first dose of doxorubicin, continuing surveillance to avoid developing severe CTRCD. Treatment with the beta blockers and the ACE inhibitors or ARBs is often problematic as they can cause increased fatigue and relative hypotension, which seriously affects the quality of life. Even statins are associated with fatigue in some instances. The cardioprotective effect of these medications, at least with carvedilol, was greater if given within the first six months of cardiac dysfunction. Additionally, continuation of cardioprotective treatment is likely important. Withdrawal of carvedilol therapy after recovery of function, even after stopping the doxorubicin, was associated with deterioration of function that was not reliably reversed with resumption of the beta blocker [16]. GDMT drugs used to treat heart failure, may be difficult to use in patients with cancer as they may cause hypotension or fatigue, which are problematic in these patients. Often doses are limited or withheld unless there is a clear need for the protection.
A second, in many ways complementary approach to reducing the effect of doxorubicin on the heart, is to alter the administration of doxorubicin to limit cardiac toxicity while not depressing the effect on the tumor. One initial approach has been to modify the administration of doxorubicin to minimize high serum levels, which are thought to cause cardiac toxicity without improving tumor efficacy. Slow infusion [14, 40] that lowers peak serum levels of the doxorubicin has been used. Slow infusion is effective but expensive and requires more time in the hospital [14]. Liposomal formulations of doxorubicin have been developed to reduce the peak levels but have historically had limited availability and increased the cost of treatment.
Because the effects of doxorubicin on the cancer cells and the heart are thought to be different [41], it seemed reasonable that a drug could block the effects of doxorubicin on the heart without reducing its effect on tumors. Chelating agents, related to ethylene diamine tetra-acetic acid (EDTA), had been proposed as compounds which would possess antitumor activity [42]. Dexrazoxane, a bisdioxopiperazine derived from EDTA, was shown to be effective in pediatric cancer patients-achieving a complete remission in one patient with lymphocytic leukemia and cleared the blood of lymphoblasts in four [43].
In early clinical studies, dexrazoxane also appeared to ameliorate the cardiac toxicity of anthracyclines [44]. Several randomized studies, on relatively small numbers of patients, showed impressive cardiac protection without impairing tumor efficacy [45, 46]. It was subsequently accepted that dexrazoxane protected the heart from doxorubicin cardiotoxicity and likely did not decrease tumor efficacy, but because of the small size of the studies (130 randomized patients), the question of a possible reduction in tumor efficacy remained.
Two separate studies with the same protocol and same PI, in patients with breast cancer treated with fluorouracil, dexrazoxane and cyclophosphamide randomized to dexrazoxane or placebo were published in 1997, the response rate in one study was 46.8% in the dexrazoxane group compared to 60.5% in the placebo group, and in the second study was 57.3% vs. 49.3% [47]. There was no difference in “time to progression” or survival. During the study, after the cardioprotective effect was clear, a protocol amendment was introduced to allow patients randomized initially to placebo to be given dexrazoxane if additional doxorubicin was desired to continue to treat the cancer. With this change, giving dexrazoxane after a total of 300 mg/m2 of doxorubicin, patients receiving dexrazoxane had significantly less heart failure with higher doses of doxorubicin (3 vs. 22%) [48]. Based on this study, in 1995, dexrazoxane received approval for patients with breast cancer but only after 300 mg/M2 of doxorubicin had been administered.
There were genuine concerns with this more limited, dose-dependent approval, especially since it is known that cardiac damage can occur with the first infusion [49]. At a meeting of French and American oncologists and cardiologists in Paris in 2001 [50], the consensus opinion was that dexrazoxane was underutilized, in large part because of concern that dexrazoxane would decrease tumor efficacy. The participants further opined that the data did not support a decrease in tumor efficacy by dexrazoxane and they recommended that dexrazoxane be more widely utilized. It was recognized that the quality of the data even at that time was poor, reducing the confidence in these recommendations [51].
In the pediatric age group, dexrazoxane is begun at the onset of treatment in order to limit long-term cardiotoxicity because of the anticipated long-term survival in many patients and the anticipated high doses of doxorubicin required. For sarcomas in adults, doxorubicin remains the most effective treatment for advanced or metastatic sarcomas so that approaches to permit therapy by limiting cardiotoxicity are critical. A number of studies have evaluated “upfront” dexrazoxane, giving the dexrazoxane with the first dose of doxorubicin in sarcomas with no evidence for a reduction in efficacy. A preliminary analysis in a study of upfront dexrazoxane in patients with soft tissue sarcomas shows no decrease in progression-free survival in patients treated with upfront dexrazoxane [52] but more data are needed before this is established.
It has been believed that doxorubicin causes damage to the cardiac myocytes and the tumor through different mechanisms opening the possibility for a drug, which can protect the cardiac myocytes while not impairing the effectiveness of doxorubicin against the tumor. The initial construct suggested a major role in the production of free radicals by doxorubicin disrupting mitochondria and flooding the mitochondria with iron [53]. Dexrazoxane was introduced initially to chelate the iron and prevent this process. More recent studies show that doxorubicin manifests its tumorocidal actions and cardiotoxic actions primarily through interference with TOPII, an enzyme responsible for permitting the DNA to separate and come back together in mitosis [54]. There are two isomers: TOPIIα in the tumor and TOPIIβ in the heart and also in the tumor. Dexrazoxane, given before the doxorubicin, binds with the TOPIIβ so that the enzyme is not available to bind with the doxorubicin and the heart is protected. Dexrazoxane’s cardioprotection appears to depend primarily on this mechanism, binding with TOPII rather than iron chelation. Martin et al. tested a drug similar to dexrazoxane with its iron-binding properties but without interaction with TOPII. They found no cardioprotective effects of this drug in mice given doxorubicin [55]. Unfortunately, dexrazoxane also interacts to a lesser extent with TOPII2α in most tumors and may lower its levels in the tumors which would also reduce the target for doxorubicin [56]. However, the interaction of dexrazoxane with TOPIIα itself causes DNA damage response and DNA double-strand breaks, which are toxic to the tumor [57]. This interaction of dexrazoxane with the TOPIIα varies among tumor types so that one cannot predict with confidence that the tumor efficacy will be preserved uniformly across all cancers.
Dexrazoxane should be administered intravenously over 15 minutes rather than a one-time IV push [58]. The dosage ratio of dexrazoxane to doxorubicin is 10:1. It should be given 30 minutes to an hour before the doxorubicin. Dosing mechanisms are different in patients with renal and hepatic impairment. Typically, renal patients with estimated creatinine clearance lower than 40 mL/min have dexrazoxane dosages reduced by 50% [59]. The dosage ratio would also change to a 5:1 ratio. In terms of hepatic impairment, most notably in the setting of hyperbilirubinemia, dexrazoxane should also be dose reduced along with doxorubicin to maintain a 10:1 ratio. Dexrazoxane is only approved for use in patients with breast cancer who have gotten doses of doxorubicin of 300 mg/m2 or more and continuing treatment with doxorubicin [7]. Of course, it is widely used in many types of cancer, especially soft tissue sarcomas where doxorubicin is the mainstay of therapy and strategy is to maximize the dose which can only be done safely if the heart is protected with dexrazoxane [14, 60]. Case reports in patients with severe cardiomyopathy prior to treatment and ongoing larger studies in patients with cancers other than breast are challenging the limitations of the original FDA approval [60, 61].
Dexrazoxane was originally developed as a chemotherapeutic agent, but was found to have serious toxicities at tumorocidal doses. Bone marrow suppression is one of the most common side effects. Much like with doxorubicin, leukopenia, neutropenia, granulocytopenia and thrombocytopenia may occur. The myelodysplastic syndrome has been reported. It can certainly be difficult to distinguish whether a side effect in a given patient is due to the dexrazoxane itself or doxorubicin, since both are given together [62]. However, aside from pain with injection, adverse effects are seen with about the same frequency as with doxorubicin alone [7]. Nonetheless, neutropenic fever (infection in the setting of decreased white blood cell count) has been reported in patients with dexrazoxane. Gastrointestinal distress such as nausea, vomiting and diarrhea have been described in patients taking the medication [63]. Injection site reactions such as pain, redness, swelling and irritation can also occur. Although rare, allergic reactions such as anaphylaxis, angioedema, skin reactions, bronchospasm, respiratory distress, hypotension and loss of consciousness have been reported [64]. Dexrazoxane might cause changes in liver function tests, indicating potential liver issues [65]. Some individuals may experience fatigue or weakness as a result of dexrazoxane treatment.
There have been concerns that dexrazoxane might increase the risk of secondary malignancies, especially in pediatric populations. More specifically, acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in patients given dexrazoxane. A randomized clinical trial by Tebbi et al. suggested that pediatric Hodgkin’s lymphoma patients have an increased risk of secondary malignancies stated above when treated with dexrazoxane [66]. However, Lipshultz et al. criticized this trial due to having weak statistical power [67] and the question remains in doubt. Dexrazoxane can cause damage to the fetus and in studies with pregnant rabbits and mice effects on the fetus and maternal toxicity were seen at lower doses than the clinically recommended dose. Dexrazoxane can be given to pregnant women but patients need to be appraised of the risk to the fetus. Infertility in males is also a concern with dexrazoxane [58, 68].
8. Extravasation injury of anthracyclines: treatment with dexrazoxane
Extravasation of doxorubicin causes necrosis of the tissue involved, which untreated may need surgical repair. The mechanism of this is not clear but may be related to damage to DNA binding mechanisms leading to local inflammation and tissue necrosis [69]. This damage is very similar histologically to the damage of ionizing radiation. Dexrazoxane intravenously, not locally, has been shown to limit this problem [70, 71]. The mechanism of how dexrazoxane promotes recovery from extravasation is not clear. Mice models have suggested that the interaction between dexrazoxane and TOPII is not important in protecting from anthracycline extravasation local injury/necrosis [72]. It is more likely that the iron-chelation or direct antioxidant effect likely plays a role in protection against extravasation. Thirty-six patients with anthracycline extravasation were given dexrazoxane intravenously in two clinical trials. These patients were then given multiple infusions of dexrazoxane with appropriate healing and recovery. Only one patient required surgical debridement in the treatment arm [73]. Because of these studies, the FDA quickly approved dexrazoxane to treat anthracycline extravasation.
Doxorubicin remains a very important drug in the cancer armamentarium, especially for soft tissue sarcomas, where it is the most important agent, but also in breast, lymphomas and pediatric cancers. In tumors responsive to doxorubicin, the main limitation to treatment is severe and progressive cardiac dysfunction. Thus, it is essential to protect against cardiac toxicity to permit effective dosing of the doxorubicin. While there are a number of therapeutic approaches to mitigating cardiac damage, namely medications used for GDMT for heart failure, as well as statins and possibly SGLT-2 inhibitors, the most effective approach is with dexrazoxane, which protects the heart without seriously impairing tumor efficacy. While more research is needed to better understand both the mechanism of doxorubicin’s tumorocidal effects as well as the mechanism of its cardiac toxicity, at present dexrazoxane given with doxorubicin appears to protect the heart without affecting tumor efficacy.
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Written By
Ronald J. Krone, Azim Merchant and Joshua D. Mitchell
Submitted: 20 October 2023Reviewed: 15 January 2024Published: 06 February 2024
Open access peer-reviewed chapter
