Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits.

Despite incomplete understanding to its mechanism of action, dexrazoxane (DEX) is still the only clearly effective cardioprotectant against chronic anthracycline (ANT) cardiotoxicity. However, its clinical use is currently restricted to patients exceeding significant ANT cumulative dose (300mg/m(2)), although each ANT cycle may induce certain potentially irreversible myocardial damage. Therefore, the aim of this study was to compare early and delayed DEX intervention against chronic ANT cardiotoxicity and study the molecular events involved. The cardiotoxicity was induced in rabbits with daunorubicin (DAU; 3mg/kg/week for 10 weeks); DEX (60mg/kg) was administered either before the 1st or 7th DAU dose (i.e. after ≈300mg/m(2) cumulative dose). While both DEX administration schedules prevented DAU-induced premature deaths and severe congestive heart failure, only the early intervention completely prevented the left ventricular dysfunction, myocardial morphological changes and mitochondrial damage. Further molecular analyses did not support the assumption that DEX cardioprotection is based and directly proportional to protection from DAU-induced oxidative damage and/or deletions in mtDNA. Nevertheless, DAU induced significant up-regulation of heme oxygenase 1 pathway while heme synthesis was inversely regulated and both changes were schedule-of-administration preventable by DEX. Early and delayed DEX interventions also differed in ability to prevent DAU-induced down-regulation of expression of mitochondrial proteins encoded by both nuclear and mitochondrial genome. Hence, the present functional, morphological as well as the molecular data highlights the enormous cardioprotective effects of DEX and provides novel insights into the molecular events involved. Furthermore, the data suggests that currently recommended delayed intervention may not be able to take advantage of the full cardioprotective potential of the drug.

Cardioprotective effect of early dexrazoxane use in anthracycline treated pediatric patients.

Anthracyclines play a major role in chemotherapeutic regimens for a variety of pediatric cancers, but produce undesirable dose-related cardiotoxicity. Dexrazoxane reduces early myocardial injury during anthracycline treatment, but data remain insufficient to fully understand its cardioprotective effectiveness in treating pediatric cancers and additional research is necessary to find efficient methods of dexrazoxane administration. Therefore, we retrospectively evaluated the cardioprotective effect of dexrazoxane against anthracyclines in 258 pediatric cancer patients who had received any anthracyclines from January 1997 to May 2005 at a tertiary teaching hospital in Korea. The results of this study suggest that the early use of dexrazoxane protects against the development of cardiotoxicity during anthracycline treatment in pediatric cancer patients. Further studies involving larger pediatric cancer patients are needed to evaluate the cardioprotective effect of dexrazoxane at higher cumulative doses of anthracyclines and on late-onset cardiotoxicity in long-term survivors.

Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children's Oncology Group.

BACKGROUND: Hodgkin lymphoma is highly curable but associated with significant late effects. Reduction of total treatment would be anticipated to reduce late effects. This aim of this study was to demonstrate that a reduction in treatment was possible without compromising survival outcomes. METHODS: Protocol P9426, a response-dependent and reduced treatment for low risk Hodgkin lymphoma (stages I, IIA, and IIIA(1) ) was designed in 1994 based on a previous pilot project. Patients were enrolled from October 15, 1996 to September 19, 2000. Patients were randomized to receive or not receive dexrazoxane and received two cycles of chemotherapy consisting of doxorubicin, bleomycin, vincristine, and etoposide. After two cycles, patients were evaluated for response. Those in complete response (CR) received 2,550 cGy of involved field radiation therapy (IFRT). Patient with partial response or stable disease, received two more cycles of chemotherapy and IFRT at 2,550 cGy. RESULTS: There were 294 patients enrolled, with 255 eligible for analysis. The 8-year event free survival (EFS) between the dexrazoxane randomized groups did not differ (EFS 86.8 ± 3.1% with DRZ, and 85.7 ± 3.3% without DRZ (P = 0.70). Forty-five percent of patients demonstrated CR after two cycles of chemotherapy. There was no difference in EFS by histology, rapidity of response, or number of cycles of chemotherapy. Six of the eight secondary malignancies in this study have been previously reported. CONCLUSIONS: Despite reduced therapy and exclusion of most patients with lymphocyte predominant histology, EFS and overall survival are similar to other reported studies. The protocol documents that it is safe and effective to reduce therapy in low-risk Hodgkin lymphoma based on early response to chemotherapy with rapid responding patients having the same outcome as slower-responding patients when given 50% of the chemotherapy.

Protective effects of dexrazoxane against acute ischaemia/reperfusion injury of rat hearts.

Dexrazoxane (DEX), an inhibitor of topoisomerase II and intracellular iron chelator, is believed to reduce the formation of reactive oxygen species (ROS) and protects the heart from the toxicity of anthracycline antineoplastics. As ROS also play a role in the pathogenesis of cardiac ischaemia/reperfusion (I/R) injury, the aim was to find out whether DEX can improve cardiac ischaemic tolerance. DEX in a dose of 50, 150, or 450 mg·(kg body mass)(-1) was administered intravenously to rats 60 min before ischaemia. Myocardial infarct size and ventricular arrhythmias were assessed in anaesthetized open-chest animals subjected to 20 min coronary artery occlusion and 3 h reperfusion. Arrhythmias induced by I/R were also assessed in isolated perfused hearts. Only the highest dose of DEX significantly reduced infarct size from 53.9% ± 4.7% of the area at risk in controls to 37.5% ± 4.3% without affecting the myocardial markers of oxidative stress. On the other hand, the significant protective effect against reperfusion arrhythmias occurred only in perfused hearts with the dose of DEX of 150 mg·kg(-1), which also tended to limit the incidence of ischaemic arrhythmias. It is concluded that DEX in a narrow dose range can suppress arrhythmias in isolated hearts subjected to I/R, while a higher dose is needed to limit myocardial infarct size in open-chest rats.

Dexrazoxane for the prevention of cardiac toxicity and treatment of extravasation injury from the anthracycline antibiotics.

The cumulative cardiac toxicity of the anthracycline antibiotics and their propensity to produce severe tissue injury following extravasation from a peripheral vein during intravenous administration remain significant problems in clinical oncologic practice. Understanding of the free radical metabolism of these drugs and their interactions with iron proteins led to the development of dexrazoxane, an analogue of EDTA with intrinsic antineoplastic activity as well as strong iron binding properties, as both a prospective cardioprotective therapy for patients receiving anthracyclines and as an effective treatment for anthracycline extravasations. In this review, the molecular mechanisms by which the anthracyclines generate reactive oxygen species and interact with intracellular iron are examined to understand the cardioprotective mechanism of action of dexrazoxane and its ability to protect the subcutaneous tissues from anthracycline-induced tissue necrosis.

Isolated subcutaneous metastasis of osteosarcoma 5 years after initial diagnosis.

The pediatric malignancies most likely to metastasize to the skin are neuroblastoma, leukemia, and rhabdomyosarcoma. Cutaneous and subcutaneous metastases from osteosarcoma are extremely rare, with only a few cases reported in pediatric patients with multifocal synchronous osteosarcoma. We describe the case of a 19-year-old woman with a single subcutaneous nodule of the abdominal wall that, on histologic evaluation, proved to be a metastatic high-grade osteosarcoma 5 years after her initial diagnosis.

Pharmacokinetics of dexrazoxane in subjects with impaired kidney function.

Dexrazoxane is approved as a cardioprotective agent for use in female patients with breast cancer who are receiving doxorubicin. The effect of renal insufficiency on elimination is not known. The pharmacokinetics of dexrazoxane 150 mg/m(2), given as a 15-minute constant-rate intravenous infusion, were assessed in 24 men and women with varying degrees of renal function in a single-dose, open-label, parallel-group study. Blood and urine samples were measured by a validated liquid chromatography/mass spectrometry assay. Dexrazoxane pharmacokinetic parameters were derived by standard noncompartmental methods. The effect of kidney function and effect of body surface area on the pharmacokinetics of dexrazoxane were analyzed using linear and nonlinear regression in the SPSS statistical program. Dexrazoxane clearance is decreased in subjects with kidney dysfunction. Compared with normal subjects (creatinine clearance [CL(CR)] >80 mL/min), mean area under the concentration curve from time 0 to infinity (AUC(0-inf)) was 2-fold greater in subjects with moderate (CL(CR) 30-50 mL/min) to severe (CL(CR) <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC(0-inf)) could be achieved if dosing were reduced by 50% in subjects with CL(CR) less than 40 mL/min compared with control subjects (CL(CR) >80 mL/min). Modeling study results suggested that equivalent exposure could be achieved if dosing was halved in subjects with CL(CR) less than 40 mL/min compared with controls.

[Cardiotoxicity of conservative treatment of solid tumors].

With an increasing number of long-term breast cancer survivors, the number of patients experiencing anthracycline-induced cardiotoxicity increas too. Anthracycline--and nonanthracycline-induced cardiac toxicity--clinically significant and frequent adverse event of conservative treatment of cancer. Echocardiogram and multigated acquisition (MUGA) scan--modalities that may overlook early changes that could identify patients at risk for anthracycline-related cardiotoxicity. However, monitoring cardiac function before and during therapy, continuous infusions of drugs, limiting lifetime anthracycline dose, using cardioprotectants such as dexrazoxane, and developing lipid formulations, may decreased risk of cardiotoxicity.

Dexrazoxane as a cardioprotectant in children receiving anthracyclines.

Anthracyclines play a critical role in the treatment of a variety of childhood cancers. However, the cumulative cardiotoxic effects of anthracyclines limit the use of these agents in many treatment regimens. Dexrazoxane is a cardioprotectant that significantly reduces the incidence of adverse cardiac events in women with advanced breast cancer treated with doxorubicin-containing regimens. Clinical evidence for the efficacy of dexrazoxane as a cardioprotectant in children, especially from randomized clinical trials, is limited, but the available data support a short-term cardioprotective effect. Long-term follow-up in children treated with dexrazoxane has not been reported. Dexrazoxane's impact on the antitumor effect and toxicity profile of the anthracyclines and the role of dexrazoxane in the development of secondary malignant neoplasms in patients who received dexrazoxane are reviewed. Based on the available data, dexrazoxane appears to be a safe and effective cardioprotectant in children, and it does not appear to alter overall survival times in children with cancer. Continued follow-up from previous trials is needed to determine the long-term effect of dexrazoxane on cardiac outcomes and quality of life.

Safety of concurrent administration of dexrazoxane and doxorubicin in the canine cancer patient.

Doxorubicin may cause a rare but serious cardiotoxicity. Dexrazoxane is a cardioprotectant drug used to reduce the risk of cardiotoxicity in human patients. In this study, 25 tumour-bearing dogs were treated with concurrent doxorubicin and dexrazoxane. The total number of doses of dexrazoxane given was 54 (range 1-5 doses per dog, median 2 doses). Five dogs received more than 165 mg m(2) cumulative doxorubicin dose before starting dexrazoxane. Haematologic, gastrointestinal and cardiovascular toxicities were considered tolerable. The combination of doxorubicin with dexrazoxane was well tolerated with minimal side-effects in this patient cohort. Future studies are required to evaluate potential cardioprotective effects of dexrazoxane given concurrently with doxorubicin.

Can anthracycline therapy for pediatric malignancies be less cardiotoxic?

Anthracyclines have a central role in the treatment of cancer in pediatric patients but confer an increased risk of cardiac dysfunction. Several strategies have been employed to help reduce anthracycline-induced cardiotoxicity, including pretreating the patient with the iron chelator dexrazoxane and infusing the dose of anthracycline over a longer period. Much focus has also been placed on the development of methods that decrease the toxicity of parent compounds, specifically through the use of drug carriers such as liposomes, and on the development of new, potentially less toxic anthracycline derivatives, such as amrubicin and pixantrone. We provide a review of these strategies, focusing on studies in pediatric patients when available, and support the idea that anthracycline therapy can be less cardiotoxic in pediatric patients.

Comparison of doxorubicin cardiotoxicity in pediatric sarcoma patients when given with dexrazoxane versus as continuous infusion.

Doxorubicin is an effective agent for many malignancies. To limit cardiotoxicity, doxorubicin can be given as prolonged infusion (PIDX) or bolus infusion following dexrazoxane (DZX). The authors report their institutional experience comparing PIDX and DZX in a sarcoma cohort. Retrospective record review for newly diagnosed sarcoma patients at the University of Texas M.D. Anderson Cancer Center from June 1998 to June 2006. There were 23 Ewing's sarcoma (EWS) patients treated with DZX and 40 osteosarcoma (OS) patients treated with PIDX. The DZX group had higher mean cumulative anthracycline dose (510 mg/m(2) [SD 120 mg/m(2)] versus 414 mg/m(2) [SD 99 mg/m(2)], P = .002), however mean lowest left ventricular ejection fraction (EF) values were higher for DZX (52.5% [SD 5.6%] versus 47.2% [SD 10.9%], P = .014). Fifteen of 19 patients with cardiac dysfunction were PIDX patients (P = .15). Five PIDX patients required cardiac medication, and 1 patient died of congestive heart failure (CHF). Sixteen patients with cardiac dysfunction had improvement, demonstrated by EF ≥ 50% at last echocardiogram. Although not statistically significant, there were 4 DZX patients with cardiac dysfunction. Prospective studies are required to determine which strategy has long-term advantages and if certain patients are at increased risk for cardiac dysfunction.

Successful dexrazoxane treatment of a potentially severe extravasation of concentrated doxorubicin.

Dexrazoxane is now authorized for the treatment of anthracycline extravasations. Several clinical cases of doxorubicin extravasation treated with dexrazoxane have been reported to date, but detailed cases have not been published. We report a case of a successful dexrazoxane treatment for a potentially severe extravasation of concentrated doxorubicin. We also describe objective outcome of this treatment, drug tolerance to dexrazoxane and long follow-up. A 29-year-old man diagnosed with Hodgkin's lymphoma was prescribed a regimen including 90 mg of doxorubicin in a 50 ml infusion using a reduced occlusion infusion pump. After this infusion, the patient complained of pain around the site of injection and presented a 10x6-cm swollen area with erythema and inflammation. A significant portion of doxorubicin was extravasated. Dexrazoxane was prescribed as an antidote. Side effects of dexrazoxane were restricted to reversible hematological toxicity, nausea, and vomiting. The next day, the inflammation of the extravasation area was reduced. On day 7, a painless mild induration in the extravasated area was the only remaining sign of the extravasation. On day 40, an arm nuclear magnetic resonance image showed no focal injuries. At 6-month follow-up, the patient has no sequelae. The two risk factors that could have increased the severity of the extravasation are the use of an infusion pump and the high drug concentration. Dexrazoxane proved to be effective and moderately well tolerated. A dexrazoxane stock in oncological facilities could help to promptly handle emergencies like this. Anthracyclines can be administered using reduced occlusion infusion pumps, but it seems preferable to always administer a free-running infusion to minimize accidents like this one.

Successful experience utilizing dexrazoxane treatment for an anthracycline extravasation.

OBJECTIVE: To describe a successful case of dexrazoxane treatment after an extravasation of doxorubicin and share a creative solution for formulary cost management. CASE SUMMARY: A 42-year-old female diagnosed with breast cancer was receiving doxorubicin as adjuvant treatment. The patient recently underwent a right mastectomy for a 3-centimeter grade 3 invasive ductal carcinoma. Three of 20 lymph nodes were positive, and the patient was stage 2B at presentation, with an estrogen receptor/progesterone receptor-positive and HER-2/neu-negative tumor. At an outside hospital, the patient was receiving doxorubicin through an infusion port when extravasation was noted after approximately 15 mL had been infused. She was transferred to Riverside Methodist Hospital and dexrazoxane treatment was initiated within 6 hours after extravasation. She received a full 3-day course of dexrazoxane treatment without complication and was discharged home. Significant delays in chemotherapy administration were avoided, and the patient successfully completed her planned chemotherapy course. DISCUSSION: Dexrazoxane has the potential to minimize tissue damage and treatment delays after an anthracycline extravasation. Although dexrazoxane is commercially marketed for 2 separate treatment indications, Totect is the Food and Drug Administration-approved product for anthracycline extravasations. Facilities administering anthracyclines should proactively resolve how to obtain, process, prepare, and administer this antidote to a patient within 6 hours of an extravasation event. Developing a preprinted chemotherapy extravasation order may facilitate the incorporation of the most recent Oncology Nursing Society guidelines to utilize dexrazoxane for an anthracycline extravasation. Cost sharing with other institutions may offer a creative solution to lessen the financial impact of stocking dexrazoxane therapy. CONCLUSIONS: Ensuring expedient treatment and accessibility to dexrazoxane therapy after an anthracycline extravasation is critical to the success of the treatment. All facilities utilizing anthracycline chemotherapy should purchase dexrazoxane or secure agreements with other facilities to guarantee the administration of this medication should extravasation occur.

Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for I(Ks).

INTRODUCTION: Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism. Results were compared with those obtained with a reference human ether-a-go-go (hERG) channel blocker, moxifloxacin. METHODS: The effects of moxifloxacin (100 microM) and doxorubicin (30 microM), with or without dexrazoxane (from 3 to 30 microM), have been evaluated on the QTc interval in guinea-pig isolated hearts and on I(Kr) (rapid component of the delayed rectifier current) and I(Ks) (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells. RESULTS: Moxifloxacin (100 microM), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 microM) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited I(Ks) (IC(50): 4.78 microM). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of I(Ks). CONCLUSION AND IMPLICATIONS: Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective I(Ks) blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting I(Ks) in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes.

Dexrazoxane: new indication. Anthracycline extravasation: continue using dimethyl sulfoxide.

1) Anthracycline extravasation can provoke extensive tissue necrosis, sometimes with serious consequences. Topical dimethylsulfoxide (DMSO) is the main antidote known to prevent this necrosis. It is used off-licence in France, based on the results of non-comparative trials. Among nearly 150 patients treated with dimethylsulfoxide, only one required surgery and about 10% of patients had sequelae; 2) A product based on dexrazoxane, an iron chelator, also approved to prevent anthracycline cardiotoxicity, has now been authorized for intravenous treatment of anthracycline extravasation; 3) Clinical evaluation of dexrazoxane in this setting does not include any trials versus dimethylsulfoxide. The combination of dexrazoxane plus dimethylsulfoxide is contraindicated, based on the results of animal studies; 4) Clinical evaluation of dexrazoxane only includes one case of anthracycline extravasation from a central venous line; 5) In two non-comparative trials in a total of 54 patients, only one patient required surgery for tissue necrosis. About one-third of patients had local complications (sensory disorders, pain, cutaneous atrophy, or restricted movement); 6) The only known adverse effect of topical dimethylsulfoxide is local irritation. In contrast, 10% of patients who received intravenous dexrazoxane had an infection that the investigators considered possibly linked to dexrazoxane. In addition to the known haematological effects of dexrazoxane (leukopenia and thrombocytopenia), other serious adverse events observed in the two trials included a major increase in hepatic transaminase activity, elevated creatinine levels, and hyper- or hypokalaemia; 7) Based on an evaluation that is neither sufficiently thorough nor rigorous, the risk-benefit balance of intravenous dexrazoxane appears to be less favourable than that of local dimethylsulfoxide, which should therefore continue to be used in this setting. In the meantime, preventive measures should be strictly followed in order to prevent extravasation from occurring. The assessment of dexrazoxane in anthracycline extravasation from a central line also remains inadequate.

Treatment of vascular soft tissue sarcomas with razoxane, vindesine, and radiation.

PURPOSE: In previous studies, razoxane and vindesine together with radiotherapy was proved to be effective in soft tissue sarcomas (STS). Because razoxane leads to a redifferentiation of pathological tumor blood vessels, it was of particular interest to study the influence of this drug combination in vascular soft tissue sarcomas. METHODS AND MATERIALS: This open multicenter Phase II study was performed by the Austrian Society of Radiooncology. Among 13 evaluable patients (10 angiosarcomas and 3 hemangio-pericytomas), 9 had unresectable measurable disease, 3 showed microscopic residuals, and 1 had a resection with clear margins. They received a basic treatment with razoxane and vindesine supported by radiation therapy. Outcome measures were objective response rates, survival time, and the incidence of distant metastases. RESULTS: In nine patients with measurable vascular soft tissue sarcomas (eight angiosarcomas and one hemangiopericytoma), 6 complete remissions, 2 partial remissions, and 1 minor remission were achieved, corresponding to a major response rate of 89%. A maintenance therapy with razoxane and vindesine of 1 year or longer led to a suppression of distant metastases. The median survival time from the start of the treatment is 23+ months (range, 3-120+) for 12 patients with macroscopic and microscopic residual disease. The progression-free survival at 6 months was 75%. The combined treatment was associated with a low general toxicity, but attention must be given to increased normal tissue reactions. CONCLUSIONS: This trimodal treatment leads to excellent response rates, and it suppresses distant metastases when given as maintenance therapy.