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.     

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel

Purpose: Results of several clinical studies suggest that the combination of doxorubicin (DOX) and paclitaxel (PTX) is highly active against solid tumors. Both drugs are known to cause adverse cardiac effects, cardiomyopathy in the case of DOX and acute changes in cardiac rhythm in the case of PTX. It has been suggested that the addition of dexrazoxane (DZR) to this regimen may reduce the risk of cardiotoxicity. A model of chronic cardiomyopathy in the rat was used to determine whether DZR was tolerated and cardioprotective in a DOX+PTX combination. Methods: Male rats were treated once weekly for 7 weeks with one of the following vehicle and/or drug sequences: Group A, M/6 sodium lactate/saline/Cremophor EL (CEL); Group B, lactate/DOX/CEL; Group C, DZR/DOX/CEL; Group D, lactate/DOX/PTX; and Group E, DZR/DOX/PTX. DZR and DOX or their respective vehicles were given i.v. whilst PTX or CEL were given i.p. DZR, DOX and PTX were administered at 16 mg/kg, 0.8 mg/kg and 2.4 mg/kg, respectively, doses which caused minimal noncardiac toxicities. The hearts were examined histologically 5 weeks following the last treatment. Results: There were no deaths and no signs of overt toxicity during the 12 weeks of study. There was a significant decrease (P < 0.01) in white blood cell count in rats treated with DZR+DOX, DOX+PTX or DZR+ DOX+PTX but not in those given DOX alone. Liver and kidney weights were increased in rats given DOX (P < 0.05) but not in those given DZR+DOX. PTX had no effect on the DOX-induced liver and kidney changes and did not interfere with the protective effect of DZR on the kidney. The severity and extent of cardiomyopathy expressed as the mean total score (MTS) for each treatment group, was similar for DOX and DOX+PTX (4.6 and 4.2, respectively). DZR provided significant cardioprotection (P < 0.01) when added to either DOX (MTS 2.0) or to DOX+PTX (MTS 2.1). Conclusions: The results suggest that PTX does not exacerbate the chronic cardiomyopathy caused by DOX and when added to the DOX+PTX combination, DZR retains its protective activity against DOX-induced cardiotoxicity without increasing noncardiac toxicity. Received: 7 October 1998 / Accepted: 3 December 1998     

Prevention of chronic anthracycline cardiotoxicity in the adult Fischer 344 rat by dexrazoxane and effects on iron metabolism

Purpose: Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1–IRE binding, may be an important mechanism of anthracycline cardiotoxicity. Methods: This study examined the role of IRP1–IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5–6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1–IRE binding. Results: Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin. Conclusions: IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.The authors state there are no conflicts of interest regarding the work in this paper.     

Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy

Management of anthracycline extravasation is problematic and most reports are anecdotal. On September 6, 2007, the U.S. Food and Drug Administration approved Totect 500 mg (dexrazoxane hydrochloride for injection) for the treatment of extravasation resulting from i.v. anthracycline chemotherapy. In two studies, a total of 57 evaluable patients experienced extravasation from peripheral vein or central venous access sites with local swelling, pain, or redness. The presence of anthracycline in skin biopsy tissue was confirmed by tissue fluorescence, and treatment with a 3-day schedule of dexrazoxane began within 6 hours of the event. The primary endpoint was a reduction in the need for surgical intervention. Only one patient required surgical repair of the injury site, and late sequelae in the remainder were absent or mild. Also, the sponsor, TopoTarget A/S, Copenhagen, Denmark, performed controlled nonclinical studies in support of dexrazoxane dose and timing for the reduction of tissue injury resulting from anthracycline extravasation. For this uncommon but serious complication of anthracycline therapy, the need for surgical intervention was 1.7% with this regimen.     

In vivo antitumor efficacy and cardiotoxicity of novel anthracycline ID6105 (11-hydroxy-aclacinomycin X, Hyrubicin)

Hybrid biosynthetic approach produced a new anthracycline ID6105 (11-hydroxyaclacinomycin X, Hyrubicin), which has potent antitumor activities against a broad range of cancer cell lines. Like other anthracyclines, ID6105 has the inhibitory effects on DNA synthesis as well as topoisomerase II. As preclinical studies of ID6105, we investigated ID6105’s efficacy on human tumors, and cardiotoxicity. In human tumor xenografts, the ID6105’s antitumor effects were greater than other anticancer drugs. ID6105 induced tumor regression in Hep G2 human hepatoma model, and slowed down the tumor growth rates in several tumor models. Doxorubicin-refractory tumors such as PC-3, DU-145, and CX-1 were sensitive to ID6105, and the growth of EKVX, lung cancer, which did not respond to paclitaxel, was also inhibited by ID6105, but tumor mass in CFPA, MCF7, and HCT-15 was not reduced by ID6105. The cardiotoxicity of ID6105 has also been assessed in rats. ID6105 did not induce any remarkable histopathological changes in hearts, and its lipid peroxidation in rat cardiac muscles did not occur as much as doxorubicin, indicating that the cardiotoxicity of ID6105 is remarkably lower than that of doxorubicin. Taking all into account, our results suggest that ID6105 would be a promising candidate for a novel anthracycline chemotherapeutic agent. An erratum to this article can be found at     

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent

Purpose The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide.Methods Etoposide plasma levels were determined by HPLC.Results The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses.Conclusions The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.Abbreviations AUC_0– Area under the curve from time zero to infinity - C_max Maximum plasma concentration of drug - Cl_tot Total plasma clearance - HPLC High-pressure liquid chromatography - P_oct Octanol-water partition coefficient - t_1/2 Beta phase plasma elimination half-time - t_r Retention time Patricia Schroeder and Kenneth Hofland contributed equally to this work.     

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.     

右丙亚胺用于乳腺癌术后化疗所致患者心肌损害的有效性和安全性

目的 探讨右丙亚胺对乳腺癌患者采用蒽环类化疗时心肌的保护作用.方法 选择乳腺癌术后接受CAF(环磷酰胺+阿霉素+5-氟尿嘧啶)方案和TE(多西他赛+表柔比星)方案化疗的患者98例.按照随机数字法将患者分为试验组和对照组各49例.对照组及实验组均采用CAF方案和TE方案化疗,试验组在给予阿霉素或表柔比星30 min前给予右丙亚胺(奥诺先)静脉滴注(右丙亚胺:阿霉素或表柔比星=10:1),30 min内滴完.结果 与治疗前比较,试验组治疗12个月以后出现血清BNP升高,对照组治疗6个月以后出现升高,差异有统计学意义(P<0.05);治疗6个月,12个月及24个月,试验组血清BNP低于对照组,差异有统计学意义(P<0.05).与治疗前比较,2组患者治疗6个月以后血清cTnT升高,差异有统计学意义(P<0.05);治疗6个月,12个月及24个月,试验组血清cTnT低于对照组,差异有统计学意义(P<0.05).试验组患者治疗后血清CK-MB与治疗前差异无统计学意义(P>0.05);对照组治疗12个月以后升高,差异有统计学意义(P<0.05).试验组治疗期间,LVEF与治疗前差异无统计学意义(P>0.05);对照组治疗6个月以后LVEF下降,差异有统计学意义(P<0.05);治疗6个月以后,对照组LVEF低于观察组,差异有统计学意义(P<0.05).2组患者不良反应发生情况差异无统计学意义(P>0.05).结论 右丙亚胺用于乳腺癌术后化疗可以明显减轻蒽环类药物的心脏毒性,保护心肌细胞,且不增加化疗的不良反应,提高患者化疗药物耐受性.     

肿瘤化疗药物心脏毒性的预防策略

化疗药物的心脏毒性越来越受到关注。在临床实践中,可以通过降低药物剂量、调整给药管理和使用低毒剂型等优化化疗方案对策降低心脏毒性反应的发生率和严重程度。心脏保护剂的应用也非常重要,目前常用的药物包括右丙亚胺、心血管药物和中药制剂等,但这些药物作为心脏保护剂的应用具有局限性,且其有效性和安全性尚需要进一步验证。     

Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies

Although conventional doxorubicin demonstrates broad activity, its clinical use is limited by cardiotoxicity. A more recent analysis suggests conventional doxorubicin-related cardiotoxicity occurs more frequently and at lower cumulative doses than previously reported. Pegylated liposomal doxorubicin, designed to maintain or improve conventional doxorubicin activity while reducing toxicities, has demonstrated improved cardiac safety versus conventional doxorubicin. In this prospective study, we evaluated endomyocardial biopsies to determine the cardiac effects of pegylated liposomal doxorubicin in patients with advanced malignancies receiving doxorubicin-equivalent doses ≥ 550 mg/m² (including pegylated liposomal doxorubicin) or ≥ 400 mg/m² pegylated liposomal doxorubicin alone. Eight patients were enrolled, and 10 biopsy scores were obtained (two patients had two biopsies). Median biopsy score (Billingham scale) was 0.75 (range, 0-1.5) after a median pegylated liposomal doxorubicin dose of 707.5 mg/m² and median total anthracycline exposure of 908.5 mg/m². These results suggest that pegylated liposomal doxorubicin minimizes doxorubicin-related cardiotoxicity, even at doses exceeding the recommended lifetime cumulative conventional dose (450-550 mg/m²).     

Multicenter Experience of Nonpegylated Liposomal Doxorubicin Use in the Management of Metastatic Breast Cancer

BackgroundThis study aimed to investigate the use of nonpegylated liposomal doxorubicin (NPLD) in the management of metastatic breast cancer (MBC) within routine UK clinical practice and to assess its efficacy and tolerability.Patients and MethodsAll patients that received NPLD for MBC at 5 institutions were identified. Clinicopathologic details, echocardiographic data, and toxicities were documented. Response to treatment, outcome, cardiotoxicity, and safety were assessed.Results63 patients (median age at NPLD therapy, 53.5 years) who had received NPLD were identified; 18 (29%) were anthracycline-naïve, and 42 (67%) were anthracycline-pretreated (median cumulative dose of epirubicin, 450 mg/m²). In 3 cases, prior treatment history was not available. NPLD was most frequently (16 [25%] of 63 patients) administered as first-line chemotherapy (median, third-line; range, 1-9), although it was given later in anthracycline-pretreated patients (median, fourth-line; range, 1-9). Overall, 14 (29%) of 49 evaluable patients achieved an objective response, which increased to 10 (71%) of 14 when NPLD was given first-line (anthracycline-naïve, 8 [100%] of 8; anthracycline-pretreated, 2 [50%] of 4; adjuvant treatment unknown, 2). Median progression-free survival was 7 months (first-line, 18 months, vs. ≥ second-line, 6 months; P = .0066), and median overall survival was 10 months (first-line, 18 months, vs. ≥ second-line, 10 months; P = .0971). Toxicities tended to be grade 1 or 2. Three patients had cardiotoxicity (left ventricular ejection fraction < 50% or a fall of ≥ 10% from baseline), which resolved during treatment.ConclusionNPLD was used in both anthracycline-naïve patients and those with prior exposure. There is evidence of clinical activity in those with prior exposure to anthracyclines, with a low incidence of cardiotoxicity.     

Comparison of the protective effects of amifostine and dexrazoxane against the toxicity of doxorubicin in spontaneously hypertensive rats

Purpose: To compare the protective effects of amifostine and dexrazoxane against the chronic toxicity induced by doxorubicin in spontaneously hypertensive rats (SHR). Methods: The animals were pretreated with amifostine (200 mg/kg, i.p.), dexrazoxane (25 mg/kg, i.p.) or saline 30 min before the administration of doxorubicin (1 mg/kg, i.v.), once-weekly for 12 weeks. Control animals received similar amounts of amifostine or saline. The SHR underwent necropsy examination 1 week after the last dosing, and cardiac, renal, and gastrointestinal lesions were graded semiquantitatively. Results: Amifostine and dexrazoxane provided equal degrees of protection against the renal toxicity of doxorubicin. However, dexrazoxane was more cardioprotective than amifostine, and prevented the mortality induced by doxorubicin. This mortality was not decreased by pretreatment with amifostine. The loss of body weight caused by doxorubicin was actually worsened by coadministration of amifostine. Conclusions: Compared to dexrazoxane, amifostine provided a comparable degree of protection against the nephrotoxicity of doxorubicin, but was less cardioprotective and did not prevent the mortality and loss of body weight produced by doxorubicin. These differences may be related to the fact that amifostine may act as a scavenger of reactive oxygen species, whereas dexrazoxane may prevent their formation. Received: 20 May 1999 / Accepted: 14 October 1999     

右丙亚胺对复发平滑肌肉瘤患者化疗的心脏保护作用研究

目的：观察右丙亚胺（dexrazoxane,DEX）对平滑肌肉瘤复发患者接受蒽环类药物辅助化疗所致心脏毒副反应的保护作用.方法：将29例复发平滑肌肉瘤患者随机分成治疗组（DEX组）和对照组.两组患者均接受以蒽环类药物为基础的辅助化疗5个周期,治疗组在使用蒽环类药物化疗的基础上加用右丙亚胺（右丙亚胺∶表柔比星=10∶1）,在第一次应用蒽环类药物时即给予右丙亚胺.监测各时期心肌肌钙蛋白（cTnT）和左心室射血分数（LEVF）,统计临床心功能不全的发生率以进行心脏功能评估,同时观察治疗的非心脏毒副反应及疗效.结果：两组患者在年龄、体重、ECOG评分等方面没有统计学差异（P＞0.05）.从表柔比星（EPI）治疗的第一个周期开始cTnT明显上升,到治疗结束时达到最高,直到治疗后2年仍然维持在较高水平.加用DEX组（即治疗组）在治疗期间及治疗后cTnT水平都较低,两组比较差异有显著性（P＜0.05）.而LEVF在两组的各个治疗阶段水平都没有统计学差异（P＞0.05）.两组的非心脏毒副反应没有差异.结论：EPI从第一次应用时对心脏便产生了明显的毒副反应,加用DEX后可以降低这种心脏毒副反应.     

In vitro antileukemic effect of a new anthracycline analogue,MEN 11079

The biological activity of MEN 11079, a new daunorubucin analogue with a fluorine atom in C₈ of ring A, was investigated in the human leukemic cell lines K-562 and in mononuclear cells (MNCs) of 40 patients with acute myeloid leukemia (AML) and the activity compared to two well-characterized anthracyclines, idarubicin (IDA) and doxorubicin (DOXO). IDA and MEN 11079 were more active than DOXO in cytotoxicity tests (WST-1 assay). IDA and MEN 11079 ID₅₀ values were also significantly different from each other (K-562: P=0.038; MNCs: P=0.003). Moreover, the range was 0.002–4.300 μM for IDA and 0.002–0.670 μM for MEN 11079, in the MNCs. Therefore, the latter appeared to assure a smaller variability of response in the AML cells. Apoptosis assays (performed using Annexin-V assay and propidium iodide) and cell cycle studies demonstrated that the MEN 11079 effective concentration was 10-fold lower than the DOXO and IDA ones. MDR (Pgp and MRP1 proteins), as measured by semiquantitative RT-PCR, cytofluorimetric and functional analysis of proteins, was similarly elicited by IDA and MEN 11079.

In conclusion, the response of the cells to the new anthracycline indicates that there is greater cytotoxic activity of this molecule than IDA and DOXO. Its narrower ID₅₀ range may allow for a more predictable response in the clinical setting.     

The use of liposomal anthracycline analogues for childhood malignancies: A systematic review

In an effort to prevent or reduce anthracycline-induced cardiotoxicity, liposomal anthracyclines have been developed. The objective of this systematic review was to summarise all available evidence on the benefits and risks of liposomal anthracyclines in children with cancer.We searched databases (MEDLINE (1966-September 2009), EMBASE (1980-September 2009) and CENTRAL (The Cochrane Library, issue 3 2009)), reference lists of relevant articles and ongoing trial databases for relevant studies. Two reviewers independently performed study selection, data extraction and quality assessment of included studies.No randomised controlled trials (RCTs) or controlled clinical trials (CCTs) were found. Fifteen observational studies described the use of liposomal anthracyclines in children with cancer. Most patients had been treated extensively in the past. Some patients developed cardiotoxicity, serious allergic reactions, mucositis, infections, hematotoxicities and/or hepatotoxicity after single agent treatment. However, due to the low quality of the currently available research, it is unclear what the exact risks are.In conclusion, there is no evidence available from RCTs or CCTs about the benefits and risks of liposomal anthracyclines in children with cancer. Limited data from observational studies suggest that children treated with liposomal anthracyclines are at risk for developing cardiotoxicity and other serious toxicities. There is an urgent need for results of well-designed studies which accurately evaluate the benefits and risks of liposomal anthracyclines in children with cancer. Until high quality evidence is available, we recommend monitoring of cardiac function in childhood cancer patients treated with a liposomal anthracycline and awareness of other serious toxicities.     

The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium

Background

Dexrazoxane reduces the risk of anthracycline-related cardiotoxicity. In a study of children with Hodgkin lymphoma, the addition of dexrazoxane may have been associated with a higher risk for developing second malignant neoplasms (SMNs) including acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). We determined the incidence of SMNs in children and adolescents with acute lymphoblastic leukaemia (ALL) who were treated with dexrazoxane.

Methods

Between 1996 and 2010, the Dana-Faber Cancer Institute ALL Consortium conducted three consecutive multicentre trials for children with newly diagnosed ALL. In the first (1996-2000), high risk patients were randomly assigned to receive doxorubicin (30 mg/m²/dose, cumulative dose 300 mg/m²) preceded by dexrazoxane (300 mg/m²/dose, 10 doses), or the same dose of doxorubicin without dexrazoxane, during induction and intensification phases. In subsequent trials (2000-2005 and 2005-2010), all high risk and very high risk patients received doxorubicin preceded by dexrazoxane. Cases of SMNs were collected prospectively and were pooled for analysis. The frequency and 5-year cumulative incidence (CI) of SMNs were determined for patients who had received dexrazoxane.

Findings

Among 553 patients treated with dexrazoxane (1996-2000, N = 101; 2000-2005, N = 196; and 2005-2010, N = 256), the number of SMNs observed by protocol was 0 (median follow-up 9.6 years), 0 (median follow-up 5.2 years), and 1 (median follow-up 2.1 years). The only SMN was a case of AML, which developed in a patient with MLL-rearranged ALL 2.14 years after initial diagnosis. The overall 5-year CI of SMNs for all 553 patients was 0.24 ± 0.24%.

Interpretation

In a large population of children with high risk ALL who received dexrazoxane as a cardioprotectant drug, the occurrence of secondary AML was a rare event.     

Incidence and risk of cardiotoxicity in cancer patients treated with targeted therapies

BackgroundCardiotoxicity is a serious side effect of molecularly targeted agents. The purpose of this study was to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade cardiotoxicity in patients with solid tumors receiving targeted agents through a revised meta-analysis of available clinical trials.MethodsThe scientific literature regarding cardiotoxicity was extensively analyzed using MEDLINE, PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL). Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies.ResultsOur search yielded a total of 4998 clinical studies; of them, 31 trials were finally considered for this meta-analysis. A total of 28,538 patients were included; 7995 of these patients had breast cancer (28%), 6151 (22%) prostate cancer and 14,392 (50%) were treated for other malignancies. The highest RR of high-grade events was observed with Vandetanib (RR = 7.71, 95% CI 1.04–56.99), followed by Ramucirumab (RR = 5.0) and Aflibercept (RR = 4.1). Grouping by drug category, the highest incidence of high-grade cardiotoxicity was shown by anti-VEGFR-TKIs (RR 5.62, 95% CI 1.49–21.24) and anti-VEGF mAbs/VEGF-trap (RR 1.82, 95% CI 1.24–2.69). Grouping by tumor type, the highest incidence of cardiotoxicity was observed in thyroid cancer (8%), followed by gastric cancer (4%).ConclusionsTreatment with targeted agents in cancer patients is correlated with a significant increase in the risk of cardiotoxicity. Frequent clinical monitoring should be emphasized when using these and newer biological agents.     

右丙亚胺对联用吡柔比星化疗患者的心脏保护作用

目的：探讨右丙亚胺对行吡柔比星化疗乳腺癌患者的心脏保护作用。方法选择行吡柔比星药物化疗的乳腺癌患者80例,随机分为两组,各40例,其中观察组接受TAC（多西他赛＋吡柔比星＋环磷酰胺）方案加右丙亚胺静脉滴注,右丙亚胺的配制浓度为吡柔比星的10倍;对照组常规接受TAC方案加安慰剂治疗。分析并比较两组患者间不同治疗阶段的心电图、左室射血分数及不良反应。结果两组患者心电图异常差异、左室射血分数从第4周开始均有统计学意义（P＜0．05）;观察组在治疗前及治疗后1年随访期间,左室射血分数差异无统计学意义（P＞0．05）,观察组治疗期间消化道反应、脱发的发生率均明显低于对照组（P＜0．05）。结论右丙亚胺能提高行含吡柔比星药物化疗的乳腺癌患者的心脏耐受性,减少不良反应。     

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.     

Comparison of cardiac events associated with liposomal doxorubicin,epirubicin and doxorubicin in breast cancer: a Bayesian network meta-analysis

BackgroundAnthracyclines play a broad and important role in the care of patients with either operable or metastatic breast cancer. However cardiotoxicity narrows the therapeutic index of this drug class leading to potentially clinically meaningful treatment delays or discontinuations. We conducted a Bayesian network meta-analysis, a validated statistical methodology, allowing direct and indirect comparison of cardiotoxicity of different anthracycline and non-anthracycline regimens.MethodsWe conducted a systematic review of prospective randomised controlled trials through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Google Scholar comparing non-anthracycline based regimens (NON), doxorubicin (DOX), epirubicin (EPI) and liposomal doxorubicin (LD). We included studies published up to 1st January 2014 in both adjuvant and metastatic contexts. Notably, HER2/neu-targeted regimens were excluded. We assessed the studies’ eligibility criteria and data collection with consensus of two independent authors. Our primary outcome measure was cardiac events grade 3 or greater (CE3) in accordance with Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. A Bayesian pairwise and network meta-analysis was conducted to estimate pooled Odds Ratio (OR).FindingsNineteen randomised controlled trials met eligibility criteria and were included in this analysis. We found a trend showing that LD is less cardiotoxic than DOX with an OR of 0.60 (95% confidence interval (CI) 0.34–1.07) There was no difference between Epi and LD with an OR of 0.95 (95%CI 0.39–2.33). DOX is more cardiotoxic than Non with an OR of 1.57 (95%CI 0.90–2.72).InterpretationDOX has higher CE3 rates than NON does. LD statistically trended to lower cardiac event rates than DOX. Non-statistical significance among EPI, LD and DOX with regard to cardiac toxicity indicates that avoidance of CE3 should not motivate selection of a particular anthracycline in otherwise healthy women in whom total lifetime anthracycline exposure will likely be limited. Overall low incidence of CE3 with any type of anthracycline indicates that we can safely use any anthracycline if cumulative dose limits are not exceeded. While CE3 does not limit our choice of anthracycline LD appears to be the least cardiotoxic.FundingTakeo Fujii is supported by the grant named Young Investigator Award for Study Abroad in Clinical Epidemiology from St. Luke’s Life Science Institution.