Dexrazoxane 500mg powder and solvent for solution for infusion vials

PURPOSE: This study aimed to systematically assess the efficacy of cardioprotective agents in preventing anthracycline-induced cardiotoxicity in patients with breast cancer using a comprehensive network meta-analysis (NMA). METHODS: This study included patients with breast cancer undergoing anthracycline-based chemotherapy. Randomized controlled trials (RCTs) published before March 2020 were identified through systematic searches in MEDLINE, Cochrane CENTRAL, Web of Science, and CINAHL. The primary outcome was left ventricular ejection fraction (LVEF), assessed using cardiac magnetic resonance imaging, multigated radionuclide angiography, or echocardiography. The NMA integrated direct and indirect comparisons to estimate the relative effectiveness of pharmacological interventions. RESULTS: The systematic review included 31 RCTs with 3,228 participants, whereas the NMA synthesized 25 effect sizes from 15 RCTs. Mineralocorticoid receptor antagonists (MRAs) [standardized mean difference (SMD): -1.78, 95% confidence interval (CI): -2.81 to -0.75] and trimetazidine (SMD: -1.12, 95%CI: -2.32 to -0.09) exhibited the most substantial cardioprotective effects. Dexrazoxane (SMD: -0.53, 95%CI: -1.90 to -0.02) and β-blockers (SMD: -0.34, 95%CI: -0.70 to 0.02) showed potential benefits, albeit with greater uncertainty. Direct comparisons showed that dexrazoxane was more effective than β-blockers (SMD: -1.25, 95%CI: -2.22 to -0.48), with mineralocorticoid receptor antagonists (MRAs) outperforming both. Despite heterogeneity and potential publication bias, mineralocorticoid receptor antagonists (MRAs) and trimetazidine consistently ranked as the most effective interventions. LVEF findings confirmed the cardioprotective benefits of β-blockers, ARBs, ACE inhibitors, and dexrazoxane. CONCLUSIONS: RCT evidence suggested that cardioprotective drugs effectively mitigate anthracycline-induced LVEF decline. However, the lack of direct head-to-head trials limits definitive conclusions on comparative efficacy, warranting trials in patients with lower baseline LVEF to optimize cardioprotective strategies.

Abstract licence: CC BY

BACKGROUND: Anthracyclines are cornerstone chemotherapeutics, but cardiotoxicity limits their use. OBJECTIVE: This study aims to evaluate the efficacy of various drugs in preventing and treating anthracycline-induced cardiotoxicity (AIC). METHODS: We conducted an extensive search across seven databases to identify randomized controlled trials (RCTs) pertinent to the prevention and treatment of AIC with medications. Subsequently, a Bayesian Model-based network meta-analysis was performed in the R 4.4.0. RESULTS: A total of 128 RCTs involving 10,431 cancer patients treated with anthracyclines and 78 drug regimens were included in this study. The network meta-analysis results showed that, compared with patients who did not receive cardioprotective drugs, those treated with Calcium Dibutyryladenosine Cyclophosphate (Mean Difference [95% Credible Interval], 8.760 [0.5917, 16.92]), Carvedilol (4.024 [0.5372, 7.656]), Carvedilol + Candesartan (7.934 [3.159, 12.91]), Compound Salvia Miltiorrhiza + Levocarnitine (9.087 [0.9160, 17.25]), Dexrazoxane (5.066 [2.589, 7.540]), Dexrazoxane + Cinobufacini (11.61 [4.590, 18.70]), Dexrazoxane + Shenqi Fuzheng (13.05 [4.640, 21.40]), Nicorandil (14.24 [5.122, 23.31]), Qiliqiangxin (11.38 [2.826, 19.91]), and Xinmai Long (6.371 [1.735, 11.02]) experienced less decrease in LVEF after chemotherapy. The SUCRA ranking results indicated that the most effective treatment option for preserving LVEF was Nicorandil (SUCRA 91.76%). CONCLUSION: Apart from Dexrazoxane, Carvedilol, a β-blocker, also appears to show significant potential in preventing AIC. Furthermore, our results indicate that there is insufficient evidence to support the beneficial effects of statins, Sildenafil, Ivabradine, Levocarnitine, N-acetylcysteine, Glutathione, Coenzyme Q10, Vitamin E, and Vitamin C in preventing LVEF decline and exerting a positive effect on the prevention of AIC.

Abstract licence: CC BY

Cancer is one of the leading causes of morbidity and mortality in the pediatric population with the most common cancer being acute lymphoblastic leukemia. One of the most common drugs used in the treatment is the anthracycline group of chemotherapeutic agents, and a major side effect is cardiotoxicity. Dexrazoxane, a member of the cardioprotective agents' group of medications, is the only current FDA-approved medication to tackle cardiotoxicity. The mechanism of action in which dexrazoxane is cardioprotective is by halting necroptosis in cardiomyocytes after anthracycline therapy and concurrently binds with iron and reduces the formation of anthracycline-iron complexes and reactive oxygen species. The efficacy of dexrazoxane has been demonstrated in clinical trials within the pediatric population with roughly 60%-80% reduction in risk of developing cardiotoxicity with a very tolerable and limited side effect profile. Further research is required to not only establish the efficacy of dexrazoxane within the pediatric population but also to explore other medications that may serve alongside the function of dexrazoxane.

Abstract licence: CC BY

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.

Abstract licence: CC BY-NC-ND

Despite high anticancer activity, doxorubicin (DOX)-induced cardiotoxicity (DIC) limits the extensive utility of DOX in a clinical setting. Amongst various strategies explored, dexrazoxane (DEX) remains the only cardioprotective agent to be approved for DIC. In addition, altering the dosing regimen of DOX has also proved to be somewhat beneficial in decreasing the risk of DIC. However, both approaches have limitations and further studies are required to better optimize them for maximal beneficial effects. In the present work, we quantitatively characterized DIC as well as the protective effects of DEX in an in vitro model of human cardiomyocytes, by means of experimental data and mathematical modeling and simulation (M&S) approaches. We developed a cellular-level, mathematical toxicodynamic (TD) model to capture the dynamic in vitro drug-drug interaction, and relevant parameters associated with DIC and DEX cardio-protection were estimated. Subsequently, we executed in vitro-in vivo translation by simulating clinical PK profiles for different dosing regimens of DOX alone and in combinations with DEX and using the simulated PK profiles to drive the cell-based TD models to evaluate the effects of long-term, clinical dosing regimens of these drugs on the relative cell viability of AC16 and to determine optimal drug combinations with minimal cellular toxicity. Here, we identified that the Q3W (once every three weeks) DOX regimen with 10:1 DEX:DOX dose ratio over three cycles (nine weeks) may offer maximal cardio-protection. Overall, the cell-based TD model can be effectively used to better design subsequent preclinical in vivo studies aimed for further optimizing safe and effective DOX and DEX combinations to mitigate DIC.

Abstract licence: CC BY