Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: A systematic review and meta-analysis

BackgroundCardiotoxicity is a well-recognised complication of chemotherapy with anthracycline and/or trastuzumab, and its prevention remains an important challenge in cancer survivorship. Several successful preventative strategies have been identified in animal trials. We sought to assemble the clinical evidence that prophylactic pharmacological interventions could prevent left ventricular (LV) dysfunction and heart failure in patients undergoing chemotherapy.MethodsWe undertook a systemic review of the evidence from randomised trials and observational studies where a prophylactic intervention was compared with a control arm in patients with a normal ejection fraction and no past history of heart failure. The primary outcome was development of heart failure (HF), a drop in ejection fraction (EF) or both. A random-effects model was used to combine relative risks (RR) and 95% confidence intervals (CIs), and a meta-regression was undertaken to assess the impact of potential covariates.FindingsData were collated from 14 published articles (n = 2015 paediatric and adult patients) comprising 12 randomised controlled trials and two observational studies. The most studied chemotherapeutic agents were anthracyclines, and prophylactic agents included dexrazoxane, statins, beta-blocker and angiotensin antagonists. There were 304 cardiac events in the control arm compared to 83 in the prophylaxis arm (RR = 0.31 [95% CI: 0.25–0.39], p < 0.00001). Cardiac events were reduced with dexrazoxane (RR = 0.35 [95% CI 0.27–0.45], p < 0.00001), beta-blockade (RR = 0.31 [95% CI 0.16–0.63], p = 0.001), statin (RR = 0.31 [95% CI 0.13–0.77], p = 0.01) and angiotensin antagonists (RR = 0.11 [95% CI 0.04–0.29], p < 0.0001).InterpretationProphylactic treatment with dexrazoxane, beta-blocker, statin or angiotensin antagonists appear to have similar efficacy for reducing cardiotoxicity.     

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.     

应变率成像监测肿瘤患者蒽环类药物化疗后心脏毒性的研究

目的 探讨应变率成像早期检测和评估葸环类药物（ATC）对肿瘤患者心脏毒性的临床价值。方法比较52例恶性肿瘤患者ATC化疗前和化疗后3～6个月的常规超声心动图心肌缩短率（FS）、射血分数（EF）舒张早期最大流速和收缩期最大流速的比值（E／A）指标以及心肌基底段和中间段前间隔、左室后壁、后间隔和左室侧壁中间段和基底段8个位点的收缩期最大应变率（SRs）、舒张早期最大应变率（SRe）。结果与化疔前比较,化疗后所取8个位点的SRs、SRe降低,E／A降低,差异均有统计学意义（P〈0．05）,化疗前后Fs、EF差异无统计学意义（P〉0．05）。结论在早期评价ATC对肿瘤患者心脏功能损害方面,SRs、SRe是较敏感的指标,E／A也有一定参考意义。     

Phase I dose finding study evaluating the combination of bendamustine with weekly paclitaxel in patients with pre-treated metastatic breast cancer: RiTa trial

Purpose  The aim of the RiTa trial is to establish a feasible combination of bendamustine and paclitaxel in a weekly schedule in anthracycline pre-treated metastatic breast cancer patients. Methods  Starting dose of bendamustine was 50 mg/m2 and was stepwise increased by 10 mg/m2 up to 70 mg/m2. The starting dose of paclitaxel was 60 mg/m2 and was increased up to 90 mg/m2. There are five pre-defined dose levels with three patients per dose level (maximum six patients) and six patients in the last dose level according to the Goodman design. Dose-limiting toxicities were defined as severe neutropenia and thrombocytopenia as well as non-haematological toxicities ≥NCI-CTC grade 3 in the first cycle. Results  No dose-limiting toxicity up to 70 mg/m2 bendamustine and 90 mg/m² paclitaxel occurred during the first cycle. Over all cycles, the following severe haematological toxicities (grade 3 and 4) were documented: neutropenia five patients and anaemia one patient. Relevant grade 3 and 4 non-haematological toxicities over all cycles were fatigue two patients, dyspnoea one patient, infection four patients and bone pain in one patient. Five serious adverse events, but no therapy related death occurred. Five patients showed a complete or partial remission, six patients stable disease and six progressed during treatment. The median progression-free survival was 8 months. Conclusion  Treatment with weekly bendamustine and paclitaxel is a feasible and effective regimen in patients with metastatic breast cancer. The recommended dose for forthcoming phase II study is 70 mg/m² bendamustine and 90 mg/m² paclitaxel. In part presented at the congress of the German Cancer Society on February 2008 in Berlin.     

Semisolid formulations containing dimethyl sulfoxide and α-tocopherol for the treatment of extravasation of antiblastic agents

The topical treatment with dimethyl sulfoxide (DMSO) and/or α-tocopherol (α-T) is widely used in order to prevent the local complications of extravasation of cytostatic drugs and protect patients against skin ulceration. Till now, DMSO and α-T have been mainly used in solution. The goal of this study was to formulate semisolid preparations for cutaneous application differing in the hydrophilic and lipophilic properties and containing DMSO and α-T in combination. With respect to solutions, the use of semisolid preparations containing DMSO and α-T could be advantageous in patients having extravasation as DMSO and α-T can remain in contact with the skin over an extended period of time. As a consequence, the action of the active principles can be limited specifically on the injured skin area, reducing the cutaneous irritative effects of DMSO. The following types of semisolid formulations containing 50% m/m DMSO and 2.5% m/m α-T were prepared: hydrophilic ointment, o/w emulsion, hydrophilic gel and lipophilic gel. The ex vivo skin permeation of DMSO and α-T was evaluated by using modified Franz’s diffusion cells and human stratum corneum and epidermis (SCE) as a membrane. The permeated and retained amounts of DMSO and α-T were determined. The oleogel preparation, the hydrophilic gel and the o/w emulsion were uniform in colour and aspect, without any evidences of phase separation over the period of the study. Hydrophilic ointments were discarded as they showed phase separation after 12 h. All formulations had a different behaviour in terms of skin permeability. In particular, hydrogel and o/w emulsion showed the best control on the drug release considering the interactions of the vehicle components with the SCE and the drugs partition between the vehicle and the SCE. The DMSO permeated amount after 24 h was 4.1 mg/cm² for hydrogel and 2.5 mg/cm² for emulsion while the permeated amount of pure DMSO after 24 h was 47.5 mg/cm². Therefore, aiming to reduce side effects after the topical application of the antidotes DMSO and α-T, these results suggested that hydrogel and o/w emulsion could be considered the most promising formulations for further clinical evaluations in managing of extravasation of anthracyclines.     

多西紫杉醇对蒽环类耐药性晚期乳腺癌的疗效分析

目的观察国产多西紫杉醇(Taxotere,TXT)为主的联合化疗方案治疗蒽环类耐药的晚期乳腺癌的疗效与安全性。方法晚期乳腺癌患者46例,其中21例给予多西紫杉醇联合顺铂(TXT DDP)方案化疗,17例给予多西紫杉醇联合吡喃阿霉素(TXT THP)方案化疗,8例给予多西紫杉醇联合米托蒽醌(TXT MIT)方案化疗。21天为1周期,2周期后评价疗效,有效患者治疗4周期以上。结果46例均可评价疗效,完全缓解(CR)4例(8.7%),部分缓解(PR)22例(47.9%),稳定(SD)18例(39.1%),进展(PD)2例(4.3%),总有效率(CR PR)为56.6%,中位肿瘤进展时间(TTP)为7.5个月。结论以多西紫杉醇为主的联合化疗可以作为治疗蒽环类耐药性晚期乳腺癌的补救方案。     

双诱导联合蒽环类抗生素治疗初治急性早幼粒细胞白血病疗效观察

目的观察以全反式维甲酸（all-trans retinoic acid,ATRA）和亚砷酸（As2O3）双诱导,联合蒽环类抗生素（anthracycline,ATC）为主的治疗方案治疗急性早幼粒细胞白血病（APL）的疗效。方法对初治APL患者以ATRA和Asz03进行双诱导,联合DA方案化疗,达完全缓解（CR）后,以ATC为主的方案巩固化疗6疗程,以后以化疗、ATRA、As2O3交替序贯维持治疗,化疗方案中仍以ATC为主。总治疗时间3年。14例患者接受了PML／RARα融合基因监测。结果21例初治APL患者中,除2例早期死亡外,其余19例诱导治疗后均达CR,经巩固、维持治疗,此19例患者至今均为持续完全缓解（CCR）状态,其中CCR5年以上2例,3年以上6例。无患者出现严重或不可逆的毒副反应。接受PML／RARα融合基因检测的14例患者,初诊时均为阳性,巩固治疗结束时均转为阴性,在以后监测中无一例转阳。结论双诱导联合ATC治疗初治APL,疗效可靠,毒副反应小。     

Left Ventricular Diastolic Filling Patterns Associated with Progressive Anthracycline-Induced Myocardial Damage: A Prospective Study

The objective of this study was to examine changes in diastolic function associated with progressive myocardial damage and their implications. We used prospective sequential Doppler echocardiographic studies of left ventricular (LV) function. The study included 125 consecutive children (median age 6.3 years) receiving anthracyclines to cumulative doses between 45 and 1150 mg/m² (median 270 mg/m²). We measured peak early (E) and atrial (A) phase filling velocities, EA ratio, deceleration and isovolumic relaxation times (EDecT and IVRT), heart rate, and fractional shortening (SF). Results were compared serially and with individually paired control data matched for body surface area. Progressive myocardial damage was evidenced by a mean SF decrease of 1 absolute %/100 mg/m² of anthracycline. Six patients developed cardiac failure. After 1–100 mg/m² of anthracyclines, the EA ratio decreased (mean 1.54–1.40, p= 0.02) and IVRT became prolonged (54 vs 52 msec in controls, p= 0.03). EA ratio increased again with the next dose, usually normalizing thereafter. Twelve patients ended treatment with an EA ratio <1 (1 cardiac death) and 17 with EA ratio >2 (2 cardiac deaths). Diastolic abnormalities were not strongly predictive of reduced SF. Modest changes in left ventricular diastolic filling patterns occur during anthracycline treatment of childhood malignancies. Although 20% of patients have significant abnormalities of diastolic filling by the end of treatment, considerable individual variability renders the pathophysiological and clinical implications of the early changes uncertain.     

多西紫杉醇联合顺铂治疗蒽环类耐药的晚期乳腺癌的临床疗效观察

目的观察多西紫杉醇联合顺铂治疗蒽环类耐药的晚期乳腺癌的疗效与不良反应。方法 2003年6月至2007年6月,我科以多西紫杉醇联合顺铂治疗蒽环类耐药的晚期乳腺癌36例。多西紫杉醇75mg/m2,静脉点滴,第1天;顺铂30mg/（m2.d）,静脉点滴,第1天至第3天;每21d为一周期,至少两个周期后评价疗效。本组中位化疗周期数为4（2-6）周期。结果 36例均可评价疗效。完全缓解（CR）2例（5.6%）,部分缓解（PR）18例（50%）,稳定（SD）9例（25%）,进展（PD）7例（19.4%）,总有效率（CR＋PR）55.6%,中位肿瘤进展时间6个月,一年生存率71%,中为生存时间16个月。主要的不良反应为胃肠道反应和骨髓抑制。结论多西紫杉醇联合顺铂治疗蒽环类耐药的晚期乳腺癌疗效较好,不良反应可以耐受,是蒽环类耐药的晚期乳腺癌的有效解救方案。     

紫红路南菌素A和B产生菌的分类、发酵和生物学特性研究

从我国云南省路南县采集的土壤样品中分离到一株链霉菌,编号为SIIA76-1289。它的孢子丝卷曲或螺旋,孢子球形或椭园形,表面带刺。经形态、培养特征和生理生化特性的研究和比较,认为SIIA76-1289菌株与紫色链霉菌(Streptomyces violaceus)基本相似。命名为紫色链霉菌路南变种(Streptomyces violaceus var.lunanensis var.nov.)。所产生两个蒽环类抗生素A和B,能够抗革蓝氏阳性细菌。在体外对白血病P388细胞DNA的合成有很强抑制作用。