Dexrazoxane Significantly Reduces Anthracycline-induced Cardiotoxicity in Pediatric Solid Tumor Patients

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Abstract

Cardiotoxicity is a dose-limiting and potentially lethal complication of anthracycline administration. Previous studies failed to determine definitive toxic doses or cardioprotective factors. Current dosing strategies may utilize unnecessarily high anthracycline doses, such that survival benefit may not outweigh increased toxicity rates. A systematic review of randomized controlled trials and prospective/retrospective studies investigating anthracycline treatment in pediatric solid tumors was performed from PubMed/MEDLINE and Cochrane databases. Generalized linear models mapping survival, cardiotoxicity and cardiotoxicity-free survival adjusted for male-to-female ratio, follow-up time, and concomitant chemotherapeutic drugs or cardioprotective agents (dexrazoxane) were generated using R. Survival rose linearly with increasing cumulative anthracycline dose while cardiotoxicity demonstrated exponential increases both without (dose >200mg/m 2) and with (dose >400mg/m 2) dexrazoxane. Maximum cardiotoxicity-free survival was 268.2 mg/m 2 without and 431.8 mg/m 2 with dexrazoxane. Despite increasing cardiotoxicity-free dose by >150mg/m 2, dexrazoxane minimally improved projected survival (71.9% vs. 75.4%). Cardiotoxicity increased linearly as a function of follow-up time with rates doubling from 5 to 20 years, without evidence of plateau. Based on our model, current dosing regimens — doxorubicin doses >375 mg/m 2 without dexrazoxane — overvalue increased anthracycline administration and may contribute to devastating cardiotoxicity. The linear increase of cardiotoxicity without evidence of plateau confirms the necessity for lifelong cardiac monitoring.

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G Curigliano, D Cardinale, T Suter … (2012)

Cardiovascular (CV) toxicity is a potential short- or long-term complication of various anticancer therapies. Some drugs, such as anthracyclines or other biological agents, have been implicated in causing potentially irreversible clinically important cardiac dysfunction. Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy agents, rare but serious complications have been described, and longer follow-up is needed to determine the exact profile and outcomes of related cardiac side-effects. Some of these side-effects are irreversible, leading to progressive CV disease, and some others induce reversible dysfunction with no long-term cardiac damage to the patient. Assessment of the prevalence, type and severity of cardiac toxicity caused by various cancer treatments is a breakthrough topic for patient management. Guidelines for preventing, monitoring and treating cardiac side-effects are a major medical need. Efforts are needed to promote strategies for cardiac risk prevention, detection and management, avoiding unintended consequences that can impede development, regulatory approval and patient access to novel therapy. These new ESMO Clinical Practice Guidelines are the result of a multidisciplinary cardio-oncology review of current evidence with the ultimate goal of providing strict criteria-based recommendations on CV risk prevention, assessment, monitoring and management during anticancer treatment.

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To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

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Osteosarcoma is the most common primary tumor of bone. Approximately 2/3 of patients who present with localized osteosarcoma can be expected to be cured of their disease with surgery and routine chemotherapy. Only 1/3 of patients with metastases detectable at presentation will be cured. These survival trends have stagnated over the past 20 years using conventional chemotherapy. New agents need to be rationally investigated to strive for improvement in the survival of patients diagnosed with osteosarcoma. This manuscript will review the rationale for conventional chemotherapy used in the treatment of osteosarcoma, as well as agents in varying stages of development that may have promise for treatment in the future. Copyright © 2012 Elsevier Inc. All rights reserved.