Dexrazoxane for anthracycline extravasation

Accidental extravasation of anthracycline-containing anticancer chemotherapy is a feared complication that may lead to progressive tissue damage. The condition may require extensive surgical intervention and often has severe long-term effects. Until a short while ago, there has been no effective treatment against the devastating effect of extravasated anthracycline. However, dexrazoxane has proven highly effective in preventing necrosis in both preclinical and clinical studies and is now approved in Europe (Savene), and has orphan drug status in the USA (Totect) for this indication. Hence, it is the first and only proven effective antidote against anthracycline extravasation injuries.     

Dexrazoxane for anthracycline extravasation

Accidental extravasation of anthracycline-containing anticancer chemotherapy is a feared complication that may lead to progressive tissue damage. The condition may require extensive surgical intervention and often has severe long-term effects. Until a short while ago, there has been no effective treatment against the devastating effect of extravasated anthracycline. However, dexrazoxane has proven highly effective in preventing necrosis in both preclinical and clinical studies and is now approved in Europe (Savene?), and has orphan drug status in the USA (Totect?) for this indication. Hence, it is the first and only proven effective antidote against anthracycline extravasation injuries.     

Treatment of anthracycline extravasation from centrally inserted venous catheters

The treatment of accidental extravasation of anthracycline-based chemotherapy has markedly improved with the recent introduction of a systemic anti-dote, Savene. However, efficacy data on this treatment is mainly based on extravasation from peripheral catheters. This review presents data on 7 cases of Savene treatment of anthracycline extravasations from central venous catheters.     

右丙亚胺成功治疗蒽环类药物外渗的临床研究

背景与目的:化疗过程中蒽环类药物的意外外渗是蒽环类药物的严重并发症,可导致组织严重创伤.以往,蒽环类药物外渗所致的较大创伤需要外科清创术和(或)皮肤移植而没有其他更好的治疗方法.近年来,临床前和临床资料显示右丙亚胺对于蒽环类药物导致的皮下损伤高度有效.本研究旨在观察右丙亚胺治疗蒽环类药物外渗的有效性和安全性.方法:80岁女性非何杰金淋巴瘤患者1例,蒽环类药物外渗后左手背红肿、溃破、剧烈疼痛,给予右丙亚胺静脉注射治疗(1 000 mg/m2,第1～2天,500 mg/m2,第3天).其有效性评定由彩色摄影和临床随访(1个月)评定.结果:患者应用右丙亚胺后,创面恢复迅速,治疗后第19天创面完全愈合,后遗症为局部轻微疼痛和色素沉着,手部功能无影响.但右丙亚胺可以增加化疗药物的骨髓抑制作用,对症处理后能缓解,未观察到其他不良反应.结论:尽管右丙亚胺治疗蒽环类药物外渗尚处于试验阶段,但其疗效令人鼓舞.本例临床研究表明该方法是有效的、安全的.     

Treatment of anthracycline extravasation with dexrazoxane.

Accidental extravasation of anthracyclines is a feared complication. Present treatment consists of local cooling and extensive surgical debridement, which often results in severe morbidity. All clinically important anthracyclines are topoisomerase II poisons that are antagonized by topoisomerase II catalytic inhibitors such as dexrazoxane. Therefore, we investigated whether dexrazoxane protects against extravasation lesions caused by anthracyclines. B6D2F1 mice received s.c. daunorubicin, doxorubicin, or idarubicin followed by systemic treatment with dexrazoxane or saline. One single systemic dose of dexrazoxane immediately after s.c. administration of doxorubicin, daunorubicin, or idarubicin reduced the tissue lesions (expressed as area under the curve of wound size times duration) by 96% (P < 0.0001), 70% (P < 0.0001), and 87% (P = 0.0004), respectively. Moreover, the treatment resulted in a statistically significant reduction in the fraction of mice with wounds as well as the duration of wounds. The induction of wounds was dose-dependent, as was the degree of protection by dexrazoxane. Dexrazoxane could be administered up to 3 h after the anthracycline without loss of protection. Triple-dosage of dexrazoxane tended to be more effective than a single injection. Dexrazoxane had no effect on lesions induced by hydrogen peroxide. This is the first report of use of a topoisomerase II catalytic inhibitor such as dexrazoxane in the treatment of anthracycline extravasation injuries. These convincing preclinical data represent a novel nontoxic approach that can easily be implemented into the clinical handling of accidental extravasation of anthracyclines.     

Dexrazoxane use in the prevention of anthracycline extravasation injury

Accidental extravasation injury from the use of the anthracycline anticancer drugs doxorubicin, daunorubicin, epirubicin and idarubicin can be a serious complication of their use. As yet, there is little consensus on the way that anthracycline extravasation injury should be clinically managed. Dexrazoxane, which is currently clinically used to reduce doxorubicin-induced cardiotoxicity, has also been shown in preclinical studies to be highly efficacious in preventing anthracycline-induced extravasation injury. Several clinical case reports of dexrazoxane for this use have also indicated positive outcomes. There are currently two multicenter Phase II/III clinical trials underway. Dexrazoxane is a prodrug analog of the metal chelator EDTA that most likely acts by removing iron from the iron-doxorubicin complex, thus preventing formation of damaging reactive oxygen species.     

Treatment of anthracycline extravasation with dexrazoxane -- clinical experience

BACKGROUND: Accidental extravasation is a severe complication when administering anthracyclines. We describe 3 cases of extravasation with 3 different anthracyclines. PATIENTS AND METHODS: One patient came from another hospital for a second opinion after an epirubicin extravasation. Only surgical debridement of the necrotic tissue was possible. The other two extravasations occurred during treatment with doxorubicin and doxorubicin- EMCH, respectively, in our department. Both patients were treated with dexrazoxane within 6 h of the event. RESULTS: The 2 patients treated with dexrazoxane recovered completely without any sequelae. CONCLUSIONS: Treatment of antracycline extravasation with dexrazoxane is potentially useful and safe.     

右丙亚胺治疗蒽环类药物外渗2例疗效观察

蒽环类药物（Anthracyclines）由于其抗肿瘤谱广,疗效好,是乳腺癌、白血病、淋巴瘤、子宫癌、卵巢癌等多种恶性肿瘤的一线或基本用药,而乳腺癌大多数方案均以蒽环类药物为基础。既往化疗均为外周静脉化疗,而经外周静脉置入中心静脉导管术（ peripherally inserted central venous catheters, PICC）的开展,将很多患者从外周静脉化疗的痛苦中解脱出来,但仍然有部分病人因为经济原因、PICC 穿刺禁忌或维护不便等原因,选择外周静脉化疗。而蒽环类药物外渗一直是令医护人员倍感棘手的问题,目前还没有有效的方法解救其可能造成的毁灭性后果。欧盟及美国 FDA 分别于2006年和2007年批准右丙亚胺用于治疗葸环类药物外渗的适应症［1,2］,而国内仅见1例报道［3］。我科使用右丙亚胺治疗2例蒽环类药物外渗患者,对其疗效及安全性进行观察,报道如下。     

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%).     

Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone

Dexrazoxane has been reported to be protective against anthracycline induced subcutaneous ulceration in mice. It is currently under clinical investigation as an acute antidote in accidental anthracycline extravasation, for which indication topical dimethylsulfoxide (DMSO) and intralesional hydrocortisone are used empirically. We studied the effect in 72 mice of monotherapy with and combined therapy of intraperitoneal dexrazoxane, topical DMSO, and intralesional hydrocortisone as acute antidotes against ulceration after subcutaneous daunorubicin. Dexrazoxane completely prevented wounds from occurring, while neither DMSO nor hydrocortisone had any preventive effect. The addition of topical DMSO actually reduced the efficacy of dexrazoxane. In conclusion, the present study does not support the concomitant use of topical DMSO + systemic dexrazoxane or intralesional hydrocortisone + systemic dexrazoxane. Monotherapy with systemic dexrazoxane seems preferable and is highly efficacious in preventing ulceration.     

DNA damage by anthracycline drugs in human leukemia cells

Leukemia cells from 4 acute myelocytic leukemia (AML) and 1 acute lymphocytic leukemia (ALL) patients were incubated with a set of 6 anthracycline agents: Adriamycin (Am), 4′-epi-Adriamycin (4′-epi-Am), daunorubicin (Dm), 4-demethyoxy-daunorubicin (4-dDm), carminomycin (Cm) and N-trifluoroacetyl-Am-14-valerate (AD32). Cells were assayed for drug uptake after incubation for 2 h, and for DNA damage and drug retention 4 h later. Uptake and retention patterns were characteristic for each agent and fairly uniform for the different cell populations. In contrast, profiles of the amount of DNA damage produced reflected striking differences in each population of cells. These individual responses raise the possibility that leukemic cells resistant to one anthracycline may yet be sensitive to another.     

Angiotensin converting enzyme inhibitors may be protective against cardiac complications following anthracycline chemotherapy

Doxorubicin (DOX), despite causing cardiac toxicity, is an anthracycline chemotherapeutic agent that plays an important role in the treatment of breast cancer. Angiotensin-converting enzyme inhibitors (ACE-I) may protect against cardiac toxicity in patients receiving DOX chemotherapy. A total of 143 patients receiving DOX at the Masonic Comprehensive Cancer Clinic, University of Minnesota, who had two or more multigated blood pool imaging (MUGA) scans or echocardiograms performed between 2004 and 2007 were identified and reviewed. Patients with a 10% absolute drop in their ejection fraction (EF) or more to below 55% were identified and compared with those that did not have a 10% decline in EF. Impact of patient variables and the use of concurrent medications on EF drop were evaluated using logistic regression. Median age was 52 years old. 85 (60%) were female. Cancer diagnosis was breast (n = 26), lymphoma (n = 92), and other (n = 25). In spite of a similar baseline EF in all the patients, 22/142 (15%) patients had a significant drop in EF during DOX chemotherapy. Adjusting for age, the odds ratio of EF drop associated with the use of ACE-I is 0.267 (P = 0.0940), suggesting that ACE-I has a protective effect. Cumulative DOX dose, the use of beta-blockers, or aspirin did not appear to be predictive or protective. Although not statistically significant, this study suggests that the use of ACE-I when given with DOX chemotherapy protects against DOX chemotherapy and warrants further investigation.