[Protective effect of dexrazoxane on cardiotoxicity in breast cancer patients who received anthracycline-containing chemotherapy].

OBJECTIVE: To evaluate the cardioprotective effects of dexrazoxane (DEX) on breast cancer patients who received anthracycline-containing chemotherapy. METHODS: A total of 122 breast cancer patients after operation were randomly divided into two groups: The experimental group of 61 cases treated with EPI plus DEX (DEX:EPI = 10:1) as adjuvant chemotherapy regimen, and the control group of 61 cases treated with EPI but without DEX. All patients received four cycles of adjuvant chemotherapy and their changes of specific cardiac functional status and hematology status before and after chemotherapy, as well as non-cardiac toxicity were observed and analyzed. RESULTS: Brain natriuretic peptide (BNP) before chemotherapy and after four cycles of chemotherapy in the control group was (106.78 ± 4.52)×10(-6) µg/ml and (187.19 ± 8.71)×10(-6) µg/ml, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (102.34 ± 8.76)×10(-6) µg/ml and (105.29 ± 7.21)×10(-6) µg/ml, respectively, without a significant difference (P > 0.05). Cardiac troponin T (cTnT) before chemotherapy and after four cycles of chemotherapy in the control group was (12.55 ± 2.73)×10(-3) µg/ml and ( 31.05 ± 7.10 )×10(-3) µg/ml, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (12.70 ± 2.15)×10(-3) µg/ml and (13.65 ± 7.82)×10(-3) µg/ml, respectively, without a significant difference (P > 0.05). The hart rate (HR) before chemotherapy and after four cycles of chemotherapy in the control group, was 75.32 ± 7.14 bpm and 89.60 ± 9.21 bpm, respectively, with a significant difference (P < 0.05). It in the experimental group was 78.60 ± 6.29 bpm and 83.10 ± 7.56 bpm, respectively, without a significant difference (P > 0.05). The left ventricular ejection fraction (LVEF) before chemotherapy and after four cycles of chemotherapy in the control group was (65.23 ± 7.82)% and (55.21 ± 7.23)%, respectively, with a significant difference between them (P < 0.05). It in the experimental group was (64.12 ± 6.25)% and (59.6 ± 4.72)%, respectively, without a significant difference (P > 0.05). The absolute neutrophil count before chemotherapy and after four cycles of chemotherapy in the control group was (3.95 ± 1.36)×10(9)/L and (3.50 ± 1.52)×10(9)/L, respectively, without a significant difference (P > 0.05). It in the experimental group, was (4.96 ± 1.41)×10(9)/L and (3.10 ± 1.26)×10(9)/L, respectively, with a significant difference (P < 0.05). The incidence of grade I-IV bone marrow suppression in the experimental group was 21.3%, 16.4%, 24.6%, and 4.9%, respectively. It in the control group was 16.4%, 11.5%, 9.8%, and 5.5%, respectively, with a significant difference (P < 0.05). CONCLUSIONS: Cardiac toxicity after anthracycline treatment in breast cancer patients may be significantly reduced by DEX, without increase of non-cardiac and and non-hematologic toxicity. DEX combined with anthracycline increases the risk of bone marrow suppression, therefore, peripheral blood picture should be monitored or routine bone marrow support may be needed.

Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection.

SIGNIFICANCE: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. RECENT ADVANCES: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. CRITICAL ISSUES: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. FUTURE DIRECTIONS: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

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.

Savene® (dexrazoxane) use in clinical practice.

INTRODUCTION: Anthracycline extravasation (ACEV) is a rare but potentially devastating event which can result in severe injuries including ulceration and necrosis, slow-healing lesions, serious joint damage and permanent disfigurement. It can delay further scheduled chemotherapy and affect cancer treatment outcome. Savene® (dexrazoxane) is the only approved antidote for ACEV in Europe (Totect® in the USA) and is administered by intravenous infusion. Its efficacy has been demonstrated in clinical trials with biopsy-verified ACEV with a 98% success rate (no need for surgical debridement) allowing for immediate continuation of chemotherapy in 71% of patients. Adverse events, mainly haematological toxicity, were rapidly reversible. The objective of the study was to assess, in clinical practice, the efficacy and safety profile of Savene® for ACEV in different Belgian hospitals. PATIENTS AND METHODS: A survey of Savene® use was conducted in Belgium from 2007 to 2010 by using a questionnaire sent to 44 hospitals. MAIN RESULTS: Data were obtained for 41 cancer patients, 68% (28/41) had ACEV from central venous catheters. Surgical debridement due to ACEV could be avoided in 26 out of 28 extravasations from a central venous access and in 95% (39/41) of the total population treated with Savene®. Planned chemotherapy was maintained in 73% (30/41) of patients. Eight adverse events were reported in four patients treated with Savene®, six events were assessed to be of common toxicity criteria grades 1-2 (nausea, leucopenia and arm pain) and two events (neutropenia and pancytopenia) were assessed to be grade 3. CONCLUSION: These data are comparable with the data from previous clinical trials and confirm the efficacy and safety profile of Savene® in clinical practice for the treatment of anthracycline extravasation, including extravasations from central venous catheters.

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.

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.

Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity.

Dexrazoxane is a derivative of the powerful metal-chelating agent ethyl enediamine tetra acetic acid. Its cardioprotective effect is thought to be due to its ability to chelate iron and reduce the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals. Preclinical studies have confirmed that dexrazoxane has significant activity as a cardioprotective agent against anthracycline-induced cardiotoxicity. Dexrazoxane is well-tolerated, with myelosuppression being the dose-limiting toxicity in Phase I trials. The cardioprotective utility of dexrazoxane has been further illustrated in a number of randomized trials. In addition no significant difference in survival has been observed between the dexrazoxane and control arms of these trials but, in one, a significantly lower response rate was observed in the dexrazoxane compared to placebo arm. Further trials are required to evaluate the efficacy of dexrazoxane in hematological malignancies as well as the adjuvant treatment of breast cancer. Its use in the paediatric setting and in the management of elderly patients with cardiac comorbidity also requires investigation. Recently, interest has focused on the use of dexrazoxane as an antidote for anthracycline extravasation. In addition the general cytoprotective activity of this drug requires further assessment, as well as selectivity in this context.

The use of dexrazoxane for the prevention of anthracycline extravasation injury.

BACKGROUND: The use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin sometimes results in accidental extravasation injury and can be a serious complication of their use. OBJECTIVE: The object of this review was to evaluate the preclinical and clinical literature on the use of dexrazoxane in preventing anthracycline-induced extravasation injury. METHODS: A review of the literature was carried out using PubMed. RESULTS/CONCLUSIONS: Dexrazoxane, which is clinically used to reduce doxorubicin-induced cardiotoxicity, has been shown in two clinical studies and in several case reports to be highly efficacious in preventing anthracycline-induced extravasation injury. Dexrazoxane is a prodrug analog of the metal chelator EDTA that likely acts by removing iron from the iron-anthracycline complex, thus preventing formation of damaging reactive oxygen species.

Dexrazoxane: a second look. Prevention of anthracycline cardiotoxicity: useful for some patients.

In patients treated with anthracyclines, the addition of dexrazoxane moderately reduces the risk of symptomatic heart failure. But dexrazoxane increases the haematological toxicity induced by chemotherapy and might also reduce its antitumour efficacy.

Razoxane and vindesine in advanced soft tissue sarcomas: impact on metastasis, survival and radiation response.

BACKGROUND: The treatment options in advanced soft tissue sarcomas (STS) are limited. In a pilot study, an antimetastatic and radiosensitizing treatment concept was explored. PATIENTS AND METHODS: Twenty-one patients with unresectable and/or oligometastatic STS received the drugs razoxane and vindesine supported by radiotherapy and surgery. Long-term treatment was intended in metastatic disease. Forty-one patients with comparable stages of STS treated with contemporary chemotherapy served as non-randomised controls. The prognostic parameters of the groups were comparable. RESULTS: In the study group, the median number of new metastases after 6 months was 0 (range, 0-40) and after 9 months likewise 0 (0-70). The corresponding numbers in the control group were 4.5 (range, 0-40) and 9 (0->100) (p<0.001). The progression-free survival at 6 months was 71% in the study group and 23% in the controls, and the median survival time from the occurrence of the first metastasis was 16 months versus 9 months. The rate of major responses under radiotherapy combined with razoxane and vindesine was 88%, and in the control group 62% (p=0.007). The combined treatment was associated with a low to moderate toxicity. CONCLUSION: The treatment combination inhibited the development of remote metastases in the majority of patients with STS and prolonged survival to some extent.

Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease.

PURPOSE: Pediatric Oncology Group (POG) studies 9426 and 9425 evaluated dexrazoxane (DRZ) as a cardiopulmonary protectant during treatment for Hodgkin's disease (HD). We evaluated incidence and risk factors of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and second malignant neoplasms (SMNs). PATIENTS AND METHODS: Treatment for low- and high-risk HD with doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC), respectively, was followed by low-dose radiation. The number of chemotherapy cycles was determined by rapidity of the initial response. Patients were assigned randomly to receive DRZ (n = 239) or no DRZ (n = 239) concomitantly with chemotherapy to evaluate its potential to decrease adverse cardiopulmonary outcomes. RESULTS: Ten patients developed SMN. Six of eight patients developed AML/MDS, and both solid tumors (osteosarcoma and papillary thyroid carcinoma) occurred in recipients of DRZ. Eight patients with SMN were first events. With median 58 months' follow-up, 4-year cumulative incidence rate (CIR) for AML/MDS was 2.55% +/- 1.0% with DRZ versus 0.85% +/- 0.6% in the non-DRZ group (P = .160). For any SMN, the CIR for DRZ was 3.43% +/- 1.2% versus CIR for non-DRZ of 0.85% +/- 0.6% (P = .060). Among patients receiving DRZ, the standardized incidence rate (SIR) for AML/MDS was 613.6 compared with 202.4 for those not receiving DRZ (P = .0990). The SIR for all SMN was 41.86 with DRZ versus 10.08 without DRZ (P = .0231). CONCLUSION: DRZ is a topoisomerase II inhibitor with a mechanism distinct from etoposide and doxorubicin. Adding DRZ to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS.

Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies.

BACKGROUND: The purpose of this study was to assess the efficacy and tolerability of i.v. dexrazoxane [Savene (EU), Totect (US)] as acute antidote in biopsy-verified anthracycline extravasation. PATIENTS AND METHODS: Two prospective, open-label, single-arm, multicentre studies in patients with anthracycline extravasation were carried out. Patients with fluorescence-positive tissue biopsies were treated with a 3-day schedule of i.v. dexrazoxane (1000, 1000, and 500 mg/m(2)) starting no later than 6 h after the incident. Patients were assessed for efficacy (the possible need for surgical resection) and toxicity during the treatment period and regularly for the next 3 months. RESULTS: In 53 of 54 (98.2%) patients assessable for efficacy, the treatment prevented surgery-requiring necrosis. One patient (1.8%) required surgical debridement. Thirty-eight patients (71%) were able to continue their scheduled chemotherapy without postponement. Twenty-two patients (41%) experienced hospitalisation due to the extravasation. Mild pain (10 patients; 19%) and mild sensory disturbances (nine patients; 17%) were the most frequent sequelae. Haematologic toxicity was common as expected from the fact that the extravasation occurred during a chemotherapy course. Other toxic effects were transient elevation of alanine aminotransferases, nausea, and local pain at the dexrazoxane injection site. CONCLUSION: Dexrazoxane proved to be an effective and well-tolerated acute treatment with only one out of 54 assessable patients requiring surgical resection (1.8%).

Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy.

Dexrazoxane (Cardioxane, Zinecard, a cyclic derivative of edetic acid, is a site-specific cardioprotective agent that effectively protects against anthracycline-induced cardiac toxicity. Dexrazoxane is approved in the US and some European countries for cardioprotection in women with advanced and/or metastatic breast cancer receiving doxorubicin; in other countries dexrazoxane is approved for use in a wider range of patients with advanced cancer receiving anthracyclines. As shown in clinical trials, intravenous dexrazoxane significantly reduces the incidence of anthracycline-induced congestive heart failure (CHF) and adverse cardiac events in women with advanced breast cancer or adults with soft tissue sarcomas or small-cell lung cancer, regardless of whether the drug is given before the first dose of anthracycline or the administration is delayed until cumulative doxorubicin dose is > or =300 mg/m2. The drug also appears to offer cardioprotection irrespective of pre-existing cardiac risk factors. Importantly, the antitumour efficacy of anthracyclines is unlikely to be altered by dexrazoxane use, although the drug has not been shown to improve progression-free and overall patient survival. At present, the cardioprotective efficacy of dexrazoxane in patients with childhood malignancies is supported by limited data. The drug is generally well tolerated and has a tolerability profile similar to that of placebo in cancer patients undergoing anthracycline-based chemotherapy, with the exception of a higher incidence of severe leukopenia (78% vs 68%; p < 0.01). Dexrazoxane is the only cardioprotective agent with proven efficacy in cancer patients receiving anthracycline chemotherapy and is a valuable option for the prevention of cardiotoxicity in this patient population.

A small prospective study of chordomas treated with radiotherapy and razoxane.

PURPOSE: To evaluate the local effect of conventional photon irradiation in chordomas if the radiosensitizing agent razoxane is added. The rationale for this procedure were improved results previously seen in soft tissue and chondrosarcomas with this combination. PATIENTS AND METHODS: Between 1988 and 1996, five patients with histologically confirmed chordomas of the skull base or the spine (three females, two males) were irradiated with 6- and 25-MeV photons under razoxane medication, one patient was treated with a telecobalt unit. Single doses of 180-200 cGy were given five times a week. The median total tumor dose was 63 Gy (range 54-67 Gy). Concomitantly, the radiosensitizer razoxane was administered at a dose of 125 mg twice daily p.o., median total dose 7.6 g. The drug was started 3-5 days before the first irradiation, and continued until the end of radiotherapy. RESULTS: After a potential median follow-up time of 10 years, three of the five patients are alive and show neither symptoms nor signs of recurrence in CT or MR images. One patient with persistent sacral chordoma died after 8 years from cardiac insufficiency, and another patient died after 6.5 years from a bleeding complication following surgery for recurrence. The patients remained locally controlled for 5, 5.5+, 6.4, 11+, and 13+ years, respectively. Objective tumor regressions were noted in three of four patients with measurable disease. Acute side effects included mucosal reactions, two of five patients developed a leukopenia WHO grade 3 due to razoxane. Serious long-term complications were not observed. CONCLUSIONS: Although the patient series is small, there is an interesting trend in local control and survival. The cases are unselected, and the follow-up time is of considerable duration. The treatment can easily be performed at any institution and is tolerated fairly well.