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.     

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.     

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 extravasations using dexrazoxane

Extravasation of cytotoxic agents is a true medical emergency. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasations. Dexrazoxane proved to be effective and moderately well tolerated. However, alternative approaches for the management of anthracycline extravasations are available such as topical DMSO and cooling. There appears to be general agreement about dexrazoxane usefulness when extravasations involve large volumes of anthracycline and/or central venous access device. Nevertheless, the non-invasive combination of DMSO and cooling is the most commonly described therapy, particularly in small anthracycline extravasations. Further research is still needed to establish unequivocal situations where dexrazoxane must be initiated.     

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 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.     

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 experimental extravasation of amrubicin, liposomal doxorubicin, and mitoxantrone with dexrazoxane

Purpose  

Dexrazoxane is an established treatment option in extravasation of the classic anthracyclines such as doxorubicin, epirubicin, and daunorubicin. However, it is not known whether the protection against the devastating tissue injuries extends into extravasation with new types of anthracyclines, the anthracenediones, or the liposomal pegylated anthracycline formulations. We therefore tested the antidotal efficacy of dexrazoxane against extravasation of amrubicin, mitoxantrone, and liposomal pegylated doxorubicin in mice.     

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.     

Good clinical and cost outcomes using dexrazoxane to treat accidental epirubicin extravasation

A 75-year-old man diagnosed with lower esophageal adenocarcinoma suffered from epirubicin extravasation during the second cycle of neoadjuvant chemotherapy with epirubicin and oxaliplatin. A full recovery was achieved after treatment with dexrazoxane (Cardioxane? ). This is the first time in our hospital that extravasation of an anthracycline has been treated with dexrazoxane. We used Cardioxane? , approved for the prevention of anthracycline-induced cardiotoxicity, while Savene? is indicated for the treatment of anthracycline extravasation. The treatment was effective, and the selection of Cardioxane? (seven-fold cheaper than Savene? ) yielded a cost saving. Consequently, Cardioxane? has been included in our guidelines for anthracycline extravasation.     

Cardioprotective effect of early dexrazoxane use in anthracycline treated pediatric patients

Abstract

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.     

Intrapleural extravasation of epirubicin, 5-fluouracil, and cyclophosphamide, treated with dexrazoxane

The extravasation of DNA-binding vesicant drugs, such as epirubicin, is a feared complication of chemotherapy and can lead to extensive damage at injury sites. We describe a 56-year-old woman with breast cancer who received adjuvant chemotherapy after a breast-preserving surgical procedure. Due to catheter tip misplacement, epirubicin, 5-fluouracil, and cyclophosphamide were administered intrapleurally. To minimize long-term sequelae, flushing of the cavities and systemic administration of steroids were performed. Besides this treatment, empirically, 3-day therapy with dexrazoxane was added to prevent tissue damage and the risk of cardiac damage. Because of the potential benefits of dexrazoxane and its relatively mild side effects, its use should be considered in cases of the intrapleural extravasation of anthracyclines. We do emphasis the need for stringent surgical and oncological nursing procedures when using central venous access catheters in oncology.     

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.     

Topical dimethylsulfoxide may prevent tissue damage from anthracycline extravasation

Summary The optimal management of anthracycline extravasation remains unclear. Traditional topical measures to reduce local tissue damage, including corticosteroids, sodium bicarbonate, and ice applications, have not consistently demonstrated beneficial effects. This report describes our experience with four adult patients who suffered anthracycline extravasation and were treated with a regimen of ice, local glucocorticoid injection, and dimethylsulfoxide (DMSO) 55%–99% applied topically every 2–4h after extravasation for a minimum of 3 days. In all four cases, pain and erythema resolved within 2 days; in no case did tissue necrosis or skin ulceration occur. Topical DMSO is a safe, inexpensive agent that appears to reduce the risk of anthracycline-induced tissue damage. Further studies are needed to determine the optimal dose and schedule of DMSO application and to assess its efficacy in extravasation injuries from other vesicants.     

Treatment strategy and clinical experience

Nasopharyngeal carcinoma (NPC) is highly radiosensitive and patients presenting with early disease have a high cure rate after radiotherapy. For patients presenting with locoregionally advanced disease, despite a high initial control rate with radiotherapy, the subsequent failure rates are significant. Concurrent cisplatin-radiotherapy with or without adjuvant chemotherapy have been demonstrated to significantly improve survival and is currently the standard treatment strategy for patients with locoregionally advanced disease. Encouraging phase II trials have been reported on the use of neoadjuvant chemotherapy followed by concurrent chemotherapy-radiotherapy, which may provide the optimal way to deliver chemoradiation in NPC. Improved radiotherapy techniques using intensity modulated methods or three-dimensional conformal methods may further improve local control by reducing geographical misses while preserving normal organ functions.     

坎地沙坦联合小剂量卡维地洛或右丙亚胺对乳腺癌患者使用蒽环类化疗药物过程中的心脏保护作用对比研究

目的 对比研究坎地沙坦联合小剂量卡维地洛或右丙亚胺对乳腺癌患者使用蒽环类化疗药物过程中的心脏保护作用.方法 对104例乳腺癌患者的临床资料进行回顾性研究,按照不同治疗方式将患者分为试验组与对照组,每组52例.对照组患者在化疗方案中加用右丙亚胺;试验组患者在化疗方案中加用坎地沙坦联合小剂量卡维地洛.比较两组患者在治疗前以及治疗4、8个周期后心电图变化、肌钙蛋白水平、心肌重构指标以及不良反应发生情况.结果 化疗8个周期后,试验组患者QRS波群电压下降、心律失常、ST-T异常发生率明显低于对照组(P﹤0.01).化疗前两组患者LVEF、LVEDD及BNP比较,差异无统计学意义(P﹥0.05);化疗4、8个周期后,试验组患者LVEF下降程度低于对照组,LVEDD、BNP上升程度低于对照组(P﹤0.01).两组患者化疗4个周期后肌钙蛋白异常情况发生率比较,差异无统计学意义(P﹥0.05),化疗过程中两组患者未发生明显的肌钙蛋白异常情况(P﹥0.05).两组患者不良反应发生率比较,差异无统计学意义(P﹥0.05).结论 坎地沙坦联合小剂量卡维地洛能降低蒽环类化疗药物对癌症患者的心脏不良反应,且不良反应较轻,可在乳腺癌化疗患者中推广使用.     

Treatment of erythroleukemia with anthracycline antibiotics and cytosine arabinoside

The introduction of the anthracycline antibiotics and cytosine arabinoside have significantly improved the remission induction rate for patients with acute nonlymphocytic leukemia. Erythroleukemia (M6 by French-American-British classification) has long been considered to be resistant to chemotherapy. Since 1973 we have treated 14 patients with erythroleukemia with daunorubicin 45 mg/m2 or doxorubicin 30 mg/m2 for three days and cytosine arabinoside 100 mg/m2 by continuous infusion for 7 to 10 days. Six complete remissions (43%) were obtained with remission durations of 3+, 4+, 9, 13, 29+, and 35 months. While this remission rate is somewhat lower than that obtained with other types of acute nonlymphocytic leukemia, the combination of anthracycline antibiotics and cytosine arabinoside is clearly effective against erythroleukemia. Five patients treated before mid 1976 died soon after remission induction therapy was started. Four of these five patients were treated for 6 to 9 months with prednisone, halotestin, and/or splenectomy before remission induction chemotherapy was started and three of these patients died of systemic fungal infection, suggesting that these modalities of treatment may interfere with patient tolerance to remission induction therapy. It is suggested that erythroleukemia should be treated with intensive chemotherapy soon after the diagnosis is made.