Research Progress on Effects of Different Treatments on Prostate Cancer with Atrial Fibrillation and Prevention Strategies
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摘要:
心房颤动(AF)是临床上最常见的心律失常。随着人口老龄化,发病率呈逐年上升趋势。AF风险增加的相关危险因素包括老年、肥胖、糖尿病、高血压和癌症等。研究表明,在所有年龄组中,伴发AF癌症患者的死亡率、住院费用和住院时间均高于非AF患者。前列腺癌(PCa)患者全身炎性反应增加、电解质异常和神经激素变化,导致其AF发生率明显高于其他癌症。前列腺癌手术、化疗和放疗也可能增加AF的风险。本综述系统收集相关文献,了解PCa患者发生AF的机制,确定PCa与AF之间的关系及其对住院预后的影响,为防治PCa患者发生AF提供策略。
Abstract:Atrial fibrillation (AF) is one of the most common clinical arrhythmias. As the population ages, there is an upward trend in its prevalence. The risk factors associated with increased risk of AF include old age, diabetes, hypertension, and cancer. Studies have shown that in all age groups, the risk of death, hospitalization expenses, and hospitalization time of cancer patients with AF were higher than that without AF. Thus, increased systemic inflammation, electrolyte abnormalities, and neurohormonal changes in patients with prostate cancer (PCa) lead to a significantly higher incidence of AF than other cancers. However, the treatment of prostate cancer, including surgery, chemotherapy and radiotherapy, may also increase the risk of AF. In this review, relevant literatures are collected to understand the mechanism of AF in patients with PCa, determine the relationship between PCa and AF and its effect on hospitalized prognosis, and provide strategies for the prevention and treatment of AF in patients with PCa.
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Key words:
- Atrial fibrillation /
- Prostate cancer /
- Treatment /
- Risk /
- Prognosis
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0 引言
心房颤动(atrial fibrillation, AF)是心房内异常的电活动导致的心律失常,近年来发病率逐渐上升,产生不良预后,增加医疗费用[1-3]。癌症患者发生AF的风险会增加,尤其在癌症诊断后的前3个月,这与癌症检查期间心脏检测增多相关,机制可能是全身炎性反应和抗肿瘤药物的使用[4]。前列腺癌(prostate cancer, PCa)是男性最常见的恶性肿瘤,也是第二大癌症相关的死亡原因[5]。癌症和心血管疾病之间的关系研究被称为肿瘤心脏病学[6],成为近年来的研究热点。本文梳理PCa与AF发病相关研究成果,探索患者诊断PCa后发生AF的相关机制以及PCa的各种治疗方法对产生AF的影响,为防治PCa患者发生AF提供理论依据。
1 发生机制
1.1 癌症与房颤
心血管疾病和癌症是全世界发病率和死亡率最高的两类疾病,最近有研究[7]显示,癌症患者心血管疾病患病率逐步上升。随着癌症患者生存时间的延长,癌症逐渐被认识到是一个重要的中长期心血管疾病危险因素[8]。癌症患者发生AF的危险因素包括高龄、高血压、糖尿病、高胆固醇血症、吸烟、饮酒、心力衰竭、心肌缺血、慢性肺部疾病等,癌症相关的特殊状态如水电解质异常、缺氧和代谢紊乱也容易诱发AF[9]。化疗、放疗、激素治疗和靶向治疗等多种治疗方式也与心脏毒性相关,其机制可能是全身炎性反应促进心房重构导致AF的发生,癌症患者中C-反应蛋白、肿瘤坏死因子-α和白细胞介素-2水平的增加支持了这一观点[9]。此外,Xi等[10]发现交感和副交感神经系统的不平衡活动与AF有关,这种自主神经系统功能障碍在癌症患者中也有一定程度的发生。
1.2 前列腺癌与房颤
PCa患者均为男性,发病率和死亡率在40~79岁呈现急剧上升的趋势[11]。引起PCa的内源性危险因素包括种族、年龄、家族史等[12],这与AF的危险因素一致。有研究发现PCa患者体内雄激素及雌激素水平异常,睾酮和孕酮具有使心室除极和复极激动时间(QT)间期缩短的作用,而雌二醇具有QT间期延长的作用[13]。内源性和外源性性激素对心室复极都有不同的影响,激素水平紊乱将会引发患者出现心律失常[14]。新型化疗药物、放疗和支持治疗,都增加了PCa患者心血管疾病的发生率[15]。PCa患者合并AF后,在抗凝治疗、抗心律失常药物治疗、继发心衰以及血栓栓塞和出血等不良预后方面存在巨大风险,生存期明显缩短[16]。
2 手术治疗
与保守治疗相比,前列腺癌根治术(radical prostatectomy, RP)明显提高PCa患者生存率[17]。一部分RP患者会经历术后并发症,最常见的围手术期并发症包括AF、静脉血栓栓塞、直肠损伤及伤口感染,发生的概率在很大程度上取决于手术的强度和患者本身的危险因素[18]。Mazzone等[19]在一项研究中证实,RP+淋巴结切除术与未处理淋巴结手术相比,其围手术期发生心血管疾病的风险较高。Nyberg等[20]发现机器人辅助前列腺癌根治术(robot-assisted radical prostatectomy, RARP)后心血管系统并发症发生率比开放前列腺癌根治术(open radical prostatectomy, ORP)高,他们认为RARP的急性期免疫和代谢反应相对衰减、组织创伤相对较少,将降低心血管并发症的风险。Wang等[21]发现PCa伴发AF患者围手术期心脏并发症如急性心肌梗死、严重心率失常等的发生率约为术前的16倍,RP术后合并AF的患者住院时间延长。这可能是因为AF会导致血流动力学不稳定,增加心脏负担。对于寻求手术治疗的PCa患者,考虑到发生心脏并发症的风险,应优先推荐RARP。随着RP患者的年龄越来越大,加强对AF的管理可以减少RP术后并发症。
3 放射治疗
放射治疗是一种局限性或局部进展期PCa的治愈性治疗方式,包括外放射治疗(external beam radiotherapy, EBRT)和近距离放射治疗(brachytherapy, BT)[22]。研究发现放射治疗通过激活细胞核相关因子、介导白介素-6的转录,影响血管功能,导致心脏缺血和心肌纤维化,进而发展为心脏传导系统紊乱[23-24]。Yusuf等[25]认为EBRT引发的血管内炎性反应增加了血管内的胶原水平,引发血管壁狭窄,导致心脏收缩和舒张功能减退,最终导致包括AF在内的严重心率失常,危及患者生命。Michalak等[26]发现在PCa高危患者中,EBRT联合化疗优于单独EBRT,包括糖尿病、吸烟和AF在内的因素对患者预后都有负面影响,其中伴发AF的患者需要进行抗凝治疗。Whalley等[27]的队列包括65例中度风险患者和36例高危患者,均使用高剂量BT+EBRT的方法治疗PCa,中位随访时间为56个月,患者出现的显著急性不良反应包括静脉血栓栓塞、AF和肺栓塞。Stone等[28]对1 669例中位年龄为66岁的T1~T3期PCa患者实施BT治疗,平均随访10年。发现AF的发生率较治疗前增加,伴有AF的患者生存期较低。为了延长患者的生存期,指南建议考虑抗凝治疗来预防癌症患者伴发AF的栓塞和卒中[29]。
4 激素治疗
PCa占男性癌症诊断的五分之一,大量患者接受激素治疗[15]。在使用外源性激素药物治疗癌症的背景下,有报道称患者出现AF等的电生理变化的情况[30]。在PCa中,雄激素剥夺疗法(androgen deprivation therapy, ADT)通过阻断睾酮对心室复极的作用,与长QT间隙和间断扭转性心动过速相关[31]。ADT使男性面临相当大的心血管风险,包括AF、室上速等重要的电生理变化[32]。阿比特龙和恩杂鲁胺是两种新型内分泌治疗药物,分别于2012年6月和2014年2月在法国上市,用于转移性去势抵抗性前列腺癌(castration-resistant prostate cancer, CRPC)的治疗。它们最近被推荐用于非转移性CRPC和激素敏感疾病阶段,而这两种药物最常见的不良反应是AF[33]。与恩杂鲁胺相比,使用阿比特龙发生心肌梗塞和卒中等心血管疾病的风险增加了31%[34]。Kulkarni等[35]推测风险的增加可能与阿比特龙抑制CYP17(一种细胞色素酶)有关,刺激促肾上腺皮质激素分泌,导致皮质醇合成下降和盐皮质激素前体合成增加。CRPC的患者在对ADT反应3~8年后才发生明显的并发症,延长ADT时间与心血管系统并发症发病率增加相关[36]。Dubinsky等[37]认为对于有抗凝指征的患者,如AF、静脉血栓栓塞和机械心脏瓣膜,在适当的监测下,可以与阿比特龙联合使用。
5 支持治疗
PCa的支持治疗包括使用糖皮质激素和双磷酸盐。糖皮质激素可诱发肥胖、胰岛素抵抗、葡萄糖耐受不良等危险因素导致AF的发生[38]。糖皮质激素诱导脂质分解,增加极低密度脂蛋白的产生,并加剧游离脂肪酸在肝脏的积累,导致血脂异常,长期使用皮质类固醇会通过加速动脉粥样硬化性血管疾病的发生和进展,以及诱发高血压直接影响心血管系统[39]。双磷酸盐广泛用于PCa骨转移患者,在最近的一项对9 386例患者的Meta分析中,未发现与心脏并发症相关[40]。支持治疗的范围和强度应基于多种因素,如年龄、抗癌药类型、患者目前和以前的心血管状态、其他合并症和伴随药物等。根据国际老年肿瘤学会指南,每例70岁以上的患者都应接受相关量表筛查,有助于对PCa治疗计划和强度的适当选择,根据健康状况评估做出治疗决定[41]。
6 预防措施
近年来,PCa患者发生AF等心血管疾病的风险已越来越受到重视,Bhatia等[42]制定干预措施如下:(1)增强患者对AF等心血管疾病的认识;(2)血压控制在小于140/90 mmHg;(3)血糖持续性监测;(4)应用他汀类药物控制既往心血管疾病史患者的胆固醇水平;(5)可使用阿司匹林等药物进行预防;(6)食用富含谷物与果蔬的食品,生活上要戒烟与避免过量饮酒。Curigliano等[43]强烈建议定期对PCa患者进行心脏事件评估,患者心血管系统合并症应得到良好的控制和最佳的治疗。在开始任何抗癌治疗之前,每例患者都应该进行高血压、血脂异常和糖尿病前期/糖尿病筛查,还有心电图和经胸超声心动图检查。如果出现AF相关的心血管系统并发症,治疗的决定应基于癌症预后、预期寿命和患者的选择。
7 小结
综上所述,PCa并发AF与患者全身炎性反应增加、激素水平异常相关,手术、放疗、激素和支持治疗也不同程度地影响AF的发生风险。研究PCa患者发生这种心律失常的机制和原因对于制定预防措施和有针对性的治疗非常重要。AF的适当管理和预防可以减少这类患者的住院率、发生严重并发症率和死亡率。对于AF患者必须做更仔细的评估和围手术期管理,RP前应进行风险分层、评估风险,对风险较高的AF患者应参照AF管理指南进行规范化治疗或术后管理。泌尿外科医生要了解更多潜在的风险,并重新评估相关心血管系统合并症发生的危险因素。对于高风险患者来说,由心血管内科、血液内科和泌尿外科专家参与的多学科治疗可能是一种合理的治疗方式。近年来新药物和新技术的使用,PCa患者并发AF的风险更应该得到重视,新的预测工具和量表需要在该类患者中得到验证。
Competing interests: The authors declare that they have no competing interests.作者贡献:徐希:文献检索、资料整理及论文撰写张振声:总体指导及论文修改 -
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