蒽环类抗肿瘤药物的心脏毒性及保护剂的研究进展

由于蒽环类药物显著的抗肿瘤作用和广泛的临床应用,其临床应用的安全性越来越受到重视.该类药物的心脏毒性表现为剂量限制性的特点.目前唯一获批的蒽环类药物心脏毒性保护剂只有右丙亚胺,其心脏保护作用已经得到了广泛认可,并被美国临床肿瘤实践指南及其他多种国内外指南推荐应用于蒽环类药物心脏毒性的预防和治疗.有关右丙亚胺的临床应用策略,目前仍存在一定争议.本文探讨了右丙亚胺对蒽环类药物抗肿瘤效价的影响、右丙亚胺用药时机的选择、右丙亚胺临床应用的安全性以及正在研究中的可能具有心脏保护功能的药物.     

右丙亚胺对蒽环类抗肿瘤抗生素心脏保护作用的研究进展

自二十世纪60年代阿霉素（Doxorubicin,又名Adriamycin,ADM）、柔红霉素（Daunoribicin,又名Daunomycin，DNR）、阿克拉霉素（AclacinomycinA,ACM）等蒽环类抗肿瘤抗生素相继问世以来,因其抗瘤谱广、抗瘤活性强,成为在肿瘤化疗中获得很高评价的一类药物。然而,该类药物除具有骨髓抑制、胃肠道反应、脱发等毒性外,长期使用还可发生剂量依赖性的心脏毒副作用。病理表现轻者为心电图异常、心律失常、心肌受损,重者可出现充血性心力衰竭而导致死亡[1]。临床研究表明,柔红霉素心脏毒性发生率为4％～12％,阿克拉霉素为6％～17％,阿霉素更高,当其累积剂量超过600mg/m2时，心脏毒性发生率为41％[2～4]。由于此类药物心脏毒性发生率与累积剂量明显相关,因而成为提高疗效的主要障碍。临床研究结果表明,在VitC、VitE、右丙亚胺、谷胱甘肽以及某些酚类化合物中,在减轻蒽环类抗肿瘤抗生素所致心脏毒性方面，右丙亚胺是最有前途的药物之一[5]。     

蒽环类化疗药物所致心脏毒性的研究进展

蒽环类化疗药物是临床广泛应用的抗肿瘤药物之一,作为恶性肿瘤化疗方案的基础用药,其致命性的不良反应是心脏毒性,单位体表面积累积药物剂量引发的心脏毒性在很大程度上影响了肿瘤患者的治疗和预后,因此限制了其在恶性肿瘤治疗中的应用。随着医学水平的不断提高和医学技术的不断发展,与蒽环类化疗药物引起的心脏损害相关的药物结构、作用机制、病理改变、保护性制剂和监测方法的研究不断展开,早期亚临床心脏损害的出现逐渐引起了人们的重视。随着新型蒽环类化疗药物--脂质体制剂的研发与应用,心脏毒性的发生率和病死率均较传统蒽环类化疗药物有所下降,但仍无法避免由于多次低剂量的累积而引发的早期无症状的心脏损害。因此,本文对蒽环类化疗药物引起患者出现心脏损害的相关影响因素、表现形式和发生发展机制等作一综述,并通过对多种针对化疗后肿瘤患者的心功能检测和检查方式进行分析,评价早期监测蒽环类化疗药物对化疗后肿瘤患者的价值,从而为临床早期监测和诊疗蒽环类化疗药物引起的心脏毒性提供参考。     

急性肿瘤患者右丙亚胺单药与联合华蟾素注射液治疗对阿霉素所致相关性心脏毒性的影响

目的：探讨恶性肿瘤患者右丙亚胺单药与联合华蟾素注射液治疗对阿霉素所致相关性心脏毒性的影响,并对比其疗效。方法选取恶性肿瘤患者166例为研究对象,随机分为单药组（右丙亚胺单药,61例）、联合用药组（联合应用右丙亚胺与华蟾素注射液,75例）与对照组（不予用药处理,30例）。3组患者均采用含蒽环类药物阿霉素的化疗方案。对照组化疗前不予用药处理;单药组化疗前30 min给予注射用右丙亚胺,按与阿霉素剂量比20∶1确定右丙亚胺剂量;联合用药组在化疗前同时给予右丙亚胺与华蟾素注射液15 ml,右丙亚胺用法用量同单药组。结果经4个化疗周期,（1）心脏毒性发生率方面：对照组53．3％,显著高于单药组（29．51％）、联合用药组（8．0％）,P＜0．05;单药组显著高于联合用药组,P＜0．05。（2）心电图方面：3组病例在化疗开始前心电图均无异常改变。化疗过程中右丙亚胺单药组心电图异常者9例（14．75％）、联合用药组7例（9．33％）,均显著低于对照组22例（73．3％）;联合用药组的心电图异常比例显著低于单药组,P＜0．05。（3）CK、CK-MB、TnI方面：单药组与对照组化疗后较本组化疗前显著上升（P＜0．05）;联合用药组化疗后CK、TnI较本组化疗前显著上升（P＜0．05）,CK-MB与化疗前比较差异不显著,P＞0．05。化疗前3组差异不显著（P＞0．05）。化疗后单药组、联合用药组显著低于对照组,P＜0．05;联合用药组显著低于单药组,P＜0．05。（4）超声心动图参数LVIDD、LVISD、A／E、LVEF、FS方面：单药组与对照组化疗前、后均有显著差异（P＜0．05）,但联合用药组化疗后较本组治疗前无显著差异（P＞0．05）。化疗前3患者各超声心动图参数均无显著差异（P＞0．05）,化疗后3组间两两比较均有明显差异（P＜0．05）。结论右丙亚胺与华蟾素注射液对阿霉素所致心脏毒性具有一定的保护作用,联合用药可明显降低心脏毒性的发生率以及毒性程度,维持正常的心电图、心肌酶以及心功能变化,从而增强恶性肿瘤患者对化疗药物毒副作用的耐受能力、提高肿瘤患者的治疗效果。     

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。     

乳腺癌患者术后化疗所致早期心脏毒性监测指标的研究

目的：观察乳腺癌术后辅助化疗患者的早期心脏毒性监测指标（左室射血分数、心肌做功指数、心电图以及心肌钙蛋白）的变化,评价其敏感性及临床意义。方法：选取42例乳腺癌患者,随机分为两组：干预组21例,患者接受TAC（多西紫杉醇＋吡喃阿霉素＋环磷酰胺）方案加右丙亚胺（右丙亚胺对吡喃阿霉素比值为10：1）;化疗组21例,常规接受TAC方案加安慰剂治疗。采用重复测量设计资料的方差分析化疗前、化疗后每周期以及化疗结束后3个月的心脏毒性指标变化情况。结果：两组患者不同周期左室射血分数（LVEF）变化无统计学意义（P〉0.05）;心肌做功（Tel）指数随着化疗周期的增加其测量结果存在统计学差异（P〈0.05）,且干预组患者Tel指数明显低于化疗组（P〈0.05）;两组患者心电图检查主要表现为一过性改变,均未出现明显特异性改变;在未达到吡喃阿霉素最大累积量前,血清中心肌钙蛋白（cTnI）与体内吡喃阿霉素累积量呈现零相关性（P〉0.05）。结论：蒽环类药物从第一次应用时对心脏就产生了明显的毒性,使用右丙亚胺对蒽环类药物所致心脏毒性有一定的防护作用。对两组患者心脏彩超、LVEF、心电图、cTnI等检查研究发现,上述指标对评价蒽环类药物所造成的亚临床左室结构与功能异常方面的敏感性与特异性较差,在临床上并不能及早有效评估化疗后患者早期心脏毒性,而Tel指数较之传统心脏超声、心电图、cTnI等能够更早、更敏感地评价蒽环类化疗药物对化疗患者心脏早期毒性。     

多柔比星心脏毒性机制及防治研究进展

多柔比星(ADM)是一种广谱、高效的蒽环类抗肿瘤药物,长期应用容易导致累积性、不可逆性心脏病变.有关ADM心脏毒性的机制较复杂,主要涉及氧化应激、线粒体病变、心肌细胞凋亡等.近年来一系列减少ADM心脏毒性而不影响其抗肿瘤活性的措施被人们采用.文章就ADM心脏毒性的发病机制及防治措施方面的进展作一综述,期望为改善肿瘤患者的长期生存率提供借鉴.     

表柔比星引起急性心脏毒性一例

乳腺癌是女性常见的恶性肿瘤，化疗是乳腺癌综合治疗的重要手段之一，其中蒽环类抗肿瘤药物是乳腺癌化疗的基本用药。蒽环类药物的慢性心脏毒性很早便引起了学者们的关注，其主要表现为慢性充血性心力衰竭，而急性心脏毒性少有报道，现报道1例表柔比星引起的急性心脏毒性病例。     

右丙亚胺对表柔比星所致心脏毒性防治作用的观察

目的:观察右丙亚胺对表柔比星所致心脏毒性的防治作用。方法:对84例应用含表柔比星方案化疗的患者,以心电图作为观察指标,先单独化疗4个周期,然后将已出现心电图异常者归入右丙亚胺治疗组、心电图正常者分为单独化疗组及右丙亚胺联合化疗组继续单独化疗或用右丙亚胺联合化疗2个周期,观察心电图变化。结果:单独化疗4个周期过程中,心电图异常发生率为26.2%(22/84)。继续化疗2个周期,单独化疗组心电图异常发生率为38.7%(12/31),右丙亚胺联合化疗组心电图异常发生率为16.1%(5/31),RIDIT公式统计,u=1.977,P<0.05,差异有统计学意义;右丙亚胺治疗组有13.6%(3/22)患者异常心电图转为正常,有18.2%(4/22)患者异常心电图保持稳定,其余68.2%患者心脏损害加重。结论:右丙亚胺对表柔比星所致心脏毒性的发生有一定的防护作用,并且对已经形成的损害有一定的治疗作用。     

麻醉处理对蒽环类抗肿瘤药物心脏毒性影响的研究进展

蒽环类抗肿瘤药物是一类对造血系统和实体肿瘤具有高效作用的广谱抗癌药物，是临床化疗方案中常用的药物之一。该类药物有一个严重的不良反应，即随着剂量的增加会产生显著的心脏毒性。临床上应用具有心肌保护作用的药物是安全使用蒽环类药物的重要策略之一。很多癌症患者在化疗期间还要进行手术治疗，全身麻醉是患者手术时主要的麻醉方法。对术前已行蒽环类药物化疗的患者实施全麻手术时，可能正处于蒽环类药物所致心肌损害的急性或慢性期，而麻醉药物对蒽环类药物所致心脏毒性的影响，将对患者术后心肺功能的恢复产生重要作用。目前，有关麻醉药物对蒽环类药物心脏毒性的影响已开始受到关注，本文即从蒽环类抗肿瘤药物的心脏毒性、心肌保护以及麻醉药物对其心脏毒性影响的研究现况进行综述。      

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.     

Pegylated liposomal doxorubicin in elderly patients with metastatic breast cancer

Breast cancer incidence is increasing among elderly patients. Age is a risk factor for toxicity after chemotherapy for breast cancer. In particular, anthracycline-induced cardiac toxicity is increased in elderly patients. Novel liposomal anthracyclines are associated with less cardiotoxicity. Pegylated liposomal doxorubicin (PLD) is active in breast cancer patients and, has shown comparable efficacy to conventional doxorubicin in clinical trials. Most toxicities during PLD treatment are hematological and mucocutaneous (in particular stomatitis and palmo-plantar erythrodysesthesia), and cardiac toxicity is rare. Tolerability of this agent in elderly patients has been confirmed by clinical trials in the advanced disease. Due to its efficacy and safety profile, PLD is an appealing treatment option for elderly breast cancer patients.     

异环磷酰胺联合方案治疗复发或耐药性妇科恶性肿瘤疗效分析

目的：评价异环磷酰胺（IFO）方案对复发或耐药性妇科恶性肿瘤的疗效和毒性反应。方法：以IFO为主联合化疗，治疗35例以往多药程联合化疗失败或复发的卵巢，宫颈，宫内膜及阴道恶性肿瘤。结果：完全缓解9例，部分缓解11例，总有效率为57．1％（20／35），主要毒性反应为骨髓抑制，消化道反应和脱发。结论：IFO联合方案对多药耐药性妇科恶性肿瘤均显示出较好疗效，是目前治疗耐药或复发性妇科恶性肿瘤的有效方案。     

Spotlight on Trastuzumab in Metastatic Breast Cancer Overexpressing HER2

Trastuzumab is a humanized monoclonal antibody developed to target the HER2 receptor which is over-expressed by some cancer cells, including 25 to 30% of breast cancers. Binding with high affinity to the extracellular domain of HER2, trastuzumab inhibits the proliferation of tumor cells that overexpress HER2. A large well designed multicenter study found that the addition of trastuzumab to either an anthracycline plus cyclophosphamide or to paclitaxel, as first-line therapy for metastatic breast cancer overexpressing the HER2 receptor, significantly increased time to disease progression, rate of objective response, duration of response and survival compared with chemotherapy alone. Single-agent trastuzumab was associated with an objective response in 15% of extensively pretreated patients with metastatic breast cancer overexpressing HER2, and 26% of previously untreated patients. Patients with a HER2 overexpression level of 3+ using immunohistochemical assay, or a positive HER2 result using fluorescence in situ hybridisation, benefit more from trastuzumab therapy than those with tumors overexpressing at a level of 2+. Trastuzumab has demonstrated synergistic action with several chemotherapy agents preclinically but the optimal combination clinically is yet to be determined. Trastuzumab is generally well tolerated by most patients; the most significant adverse effects being acute fever and/or chills and the potential to cause cardiac dysfunction. Serious adverse events, including anaphylaxis and death, have occurred in 0.25% of patients. Symptomatic or asymptomatic cardiac dysfunction occurred in 27% of patients receiving an anthracycline and cyclophosphamide combined with trastuzumab. Thus, combination therapy with anthracyclines is not recommended. Symptomatic or asymptomatic cardiac dysfunction occurred in 13% of patients receiving trastuzumab plus paclitaxel and in 4.7% of patients receiving trastuzumab alone. In conclusion, intravenous trastuzumab is effective as a single-agent, and in combination with chemotherapy it significantly improves the median time to disease progression and survival time in patients with metastatic breast cancer overexpressing the HER2 receptor compared with chemotherapy alone. Cardiotoxicity is the main concern with therapy; particularly in patients with pre-existing cardiac dysfunction, the elderly and in combination with, or following, anthracyclines. Trastuzumab is indicated for use with paclitaxel as first-line therapy or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2. Investigation is ongoing to ascertain the optimal combination regimen containing trastuzumab and antineoplastic agents. In addition, current research is focusing on the optimal timing, sequencing and duration of therapy as well as administration in the neoadjuvant and adjuvant setting.     

放射治疗与动脉插管化疗联合应用治疗晚期贲门癌的疗效观察

目的探讨晚期贲门癌的安全有效的治疗手段。方法对32例晚期贲门癌患者先进行一次经皮穿刺胃左或腹腔动脉的灌注化疗。然后对贲门癌和周围肿瘤病灶进行放射治疗,DT达60 Gy,生物有效剂量（BED）达72 Gy,随访观察患者临床症状改善情况,并对病灶进行X线、胃镜、CT检查和治疗前后对比。结果所有患者临床症状均有明显改善,影像学检查显示,肿瘤病灶明显缩小,患者生存质量提高,生存时间明显延长。结论动脉插管化疗和放射治疗联合应用治疗晚期贲门癌安全,疗效好,副作用小;动脉插管化疗与放射治疗间隔时间越短,疗效越佳,但全身毒副反应也越大;采取三维适形放疗精度高,并发症少,放射治疗增益比提高,从而能更好地提高晚期贲门癌的治疗效果。     

Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.     

Chemotherapy for gastric cancer

5-FU has been a key chemotherapeutic agent in the treatment of advanced or recurrent gastric cancer. In order to enhance the effect of 5-FU, biochemical modulation or combined chemotherapy has been developed. Although several phase III studies have been reported in 1990's, a standard chemotherapeutic regimen has not been established worldwide. Recently, newly developed anticancer agents such as CPT-11, TS-1, Paclitaxel, or Docetaxel can be clinically used for advanced gastric cancer either single agent or in combination that may further improve the quality of life and prolong the survival of patients with gastric cancer. In Japan, postoperative adjuvant chemotherapy has been actively developed to enhance survival benefit of surgery for patients with gastric cancer. There were a few positive single randomized controlled study showing benefit of adjuvant chemotherapy with a high evidence level. However, all reports of meta-analysis of adjuvant chemotherapy for gastric cancer indicated the survival benefit of adjuvant chemotherapy. At present, a nation-wide randomized controlled study in the postoperative adjuvant setting for gastric cancer using TS-1 (ACTS-GC) is under way that may clarify the effect of postoperative adjuvant chemotherapy in gastric cancer.     

氟尿嘧啶引起的心脏毒性9例报道附文献复习

目的 探讨氟尿嘧啶(5-FU)引起的心脏毒性机制和防治.方法 回顾性分析9例晚期胃肠道恶性肿瘤患者使用含氟尿嘧啶的FOLFOX6方案后出现的心脏毒性,并结合文献进行分析.结果 9例患者均出现心脏毒性,心脏毒性分级按CTCAE 4.0版本标准进行,心律失常约77.8％ (7/9),其次是心绞痛22.2％(2/9)和无症状性心肌缺血22.2％(2/9),多为1～2级,无3～5级的心脏毒性发生.其中3例患者更换雷替曲塞,2例心律失常缓解,另1例心律失常由2级降至1级.其余6例中有4例停用5-FU后,3例心脏毒性缓解,另1例心脏毒性持续,但未加重.另外2例暂停和推迟化疗后心脏毒性均缓解.结论 5-FU是临床上最常用、广谱和有效的抗肿瘤药物,心脏毒性不能被忽视.     

右丙亚胺对接受表柔比星化疗的胃癌患者的心脏保护作用

目的 观察右丙亚胺对接受表柔比星(EPI)联合化疗方案的胃癌患者的心脏保护作用.方法 将66例应用含表柔比星方案化疗的患者分成右丙亚胺联合EOX化疗组和EOX化疗组2组,分别采用EOX方案化疗6个周期,以及EOX联合右丙亚胺治疗6个周期,观察2组的心电图变化,并进行比较.结果 在心电图异常发生率方面,右丙亚胺联合EOX化疗组和EOX化疗组分别为12.1%(4/33)和36.4%(12/33),2组差异有统计学意义(P<0.05).EOX化疗组中,出现心电图异常的患者中有12例予以右丙亚胺治疗,经治疗,6例出现心脏损害加重,4例异常心电图保持稳定,2例心电图恢复正常.结论 右丙亚胺对使用表柔比星的胃癌患者的心脏有一定的保护作用,并且对已经形成的损害有一定的治疗作用.     

Risque élevé de dysfonction cardiaque des leucémies aiguës myéloïdes secondaires à un cancer du sein

Secondary acute myeloid leukaemia (AML) occurring after breast cancer is a rare long-term complication of the chemo- and/or radiation therapy required to treat breast cancer. The usually recognized curative option of these secondary AML includes courses of anthracycline-based chemotherapy followed by haematopoietic stem cell transplantation (HSCT). Cardiac dysfunction during AML treatment of these patients previously treated with anthracyclines for breast cancer has not been reported to date. We evaluated the evolution of cardiac function in seven patients treated with anthracyclines and/or autologous or allogeneic bone marrow transplantation for secondary AML occurring after breast cancer. All of the patients who received a cumulative anthracycline dose above the cardiac toxicity threshold developed cardiac symptoms during AML chemotherapy courses. Moreover, four of the five transplanted patients developed severe heart failure among which two were fatal. Thus, the risk of severe cardiac dysfunction after treatment of secondary AML following breast cancer must be taken in account as part of the therapeutic strategy of those patients. As discussed here, an accurate evaluation of risk factors, the use of sensitive detection tests and of cardioprotective drugs as well as that of non-cardiotoxic chemotherapy might decrease the occurrence and severity of this life-threatening complication.