小细胞肺癌药物治疗进展

小细胞肺癌（SCLC）约占肺癌患者的13%。与非小细胞肺癌相比具有早期转移倾向及对一线细胞毒性化疗药物敏感的特点。目前的治疗方式包括手术、胸部及脑部放疗和化疗。以铂类联合依托泊苷为标准一线化疗,治疗后复发率较高。《中国肿瘤临床》2016年第10期来“专家共识”栏目中,自北京协和医院呼吸内科的张力教授结合近年临床工作,对SCLC药物治疗方法进行综述,以期对小细胞肺癌的治疗有新的突破。     

小细胞肺癌的治疗进展与现状

肺癌为一种恶性程度较高的肿瘤性疾病,其病死率居各种恶性肿瘤之首,发病率逐年上升,近年随着禁烟教育力度的增强和普及,发病率已出现下降势头。小细胞肺癌(SCLC)是一种以生长迅速、早期转移、高度侵袭性为特点的肺癌类型。小细胞肺癌的肿瘤细胞对化疗和放疗都非常敏感,但几十年来多方案的临床试验并没能找到彻底治愈小细胞肺癌的有效方法,多数患者在一线治疗以后仍会复发或转移。局限期小细胞肺癌的一线治疗包括双药化疗(足量EP方案:依托泊甙 顺铂/卡铂)联合胸腔放射治疗(TRT)。当联合方案达完全缓解(CR)或疗效较好的部分缓解(PR)患者,应后续应用预防性脑照射(PCI),可明显降低未来复发性脑转移的风险。日本和德国的临床研究显示含有伊立替康的IP方案及IC方案(伊立替康 顺铂/卡铂)治疗广泛期小细胞肺癌效果可比标准EP方案。各种强化疗法并不能提高小细胞肺癌患者的生存率。胸腔放疗方案的研究显示局限期小细胞肺癌患者早期同步应用超分割放疗方案配合化疗可以改善预后,可能与放疗越早介入越能有效减少耐药克隆株的发生有关。对于小细胞肺癌复发患者,可依据是敏感复发或是难治复发相应选择再次应用首次化疗方案或用二线单药化疗方案。培美曲塞联合铂类方案已应用于SCLC的一线及二线治疗。PET-CT的应用对小细胞肺癌的精确分期非常重要。真正符合Ⅰ_A期及Ⅰ_B期(TNM分期)的小细胞肺癌患者可考虑手术治疗,术后应行正规化疗。生物靶向治疗小细胞肺癌的若干研究性试验正在进行之中,这些生物制剂及其衍生物有可能会为未来小细胞肺癌的治疗带来一线曙光。     

分子靶向治疗在Ⅲb/Ⅳ期非小细胞肺癌一线治疗中的应用

Ⅲb/Ⅳ期非小细胞肺癌一线化疗的疗效已进入瓶颈期.分子靶向药物的出现,给晚期非小细胞肺癌的一线治疗带来了划时代的变革,极大地改善了晚期非小细胞肺癌患者的生活质量、提高了生存期.全文就分子靶向治疗在晚期非小细胞肺癌一线治疗中的应用作一综述.     

化疗在晚期非小细胞肺癌治疗中的地位和价值

摘 要：化疗于晚期非小细胞肺癌治疗依然具有举足轻重的作用。以IPASS研究为代表的一系列靶向治疗与化疗头对头对比研究,也证实了化疗依旧是EGFR野生型及突变未明患者一线治疗的首要选择。DELTA研究及CTONG0806研究结果则表明二线治疗中化疗比靶向治疗疗效更优。而LUX-LUNG3/6研究生存数据则表明21外显子突变患者可能更适合于一线化疗。总而言之,化疗是晚期非小细胞肺癌治疗全程管理中不可或缺的。     

晚期非小细胞肺癌一线治疗新进展

目的:总结近期晚期非小细胞肺癌一线治疗最新进展.方法:应用Medline和CKNI期刊全文数据库系统,以"晚期非小细胞肺癌、一线治疗、靶向治疗和维持治疗"为关键词,搜索近期发表的大型临床研究,选择以Ⅲ期研究为主的大型多中心随机临床研究.共计纳入文献29篇.结果:随着多项新药临床试验的完成,一线治疗方案和治疗理念有了新的突破--含铂两药化疗模式不再是唯一的一线治疗方法,化疗联合靶向、靶向单药正逐步成为一线治疗的选择.同时,非小细胞肺癌根据不同亚型选择不同的治疗已成为必然趋势.而通过基因突变筛选患者接受靶向治疗不仅提高了治疗的有效率,也避免了不必要的过度治疗.另外维持治疗概念的引入也成为一线治疗疗程模式的一大突破.结论:目前公认的晚期非小细胞肺癌一线治疗标准是含铂的两药联合方案.随着多项新药临床试验的完成,一线治疗方案和治疗理念有了新的突破.     

晚期非小细胞肺癌维持治疗的临床研究进展

 4～6个周期含铂类的一线化疗方案是晚期非小细胞肺癌目前的标准治疗,但对一线治疗后有效和稳定的患者,如何选择安全有效的药物来拓展一线治疗疗效及带来进一步的临床获益是目前值得关注的问题。文章就以化疗和分子靶向药物作维持治疗的临床进展作一介绍。     

小细胞肺癌新药物研究进展

小细胞肺癌约占肺癌的15％～20％,具有增殖快、转移早等特点。尽管其对放、化疗比较敏感,但几十年来的临床试验并没能找到彻底治愈SCLC的有效方法,EP／EC方案依旧是SCLC的标准一线化疗方案,多数患者在一线治疗以后仍会复发或转移。针对SCLC的新的化疗药物和生物靶向治疗药物的正在研究之中,这些药物为SCLC的治疗带来新的希望。     

2007年肺癌治疗新热点-来自ASCO的证据

 【摘要】　可手术切除非小细胞肺癌（NSCLC）术前化疗的价值尚未肯定，局部晚期NSCLC同期化放疗后巩固化疗仍需进一步验证。贝伐单抗与化疗联合应用一线治疗晚期NSCLC优于单用化疗，目前尚无证据显示吉非替尼二线治疗晚期NSCLC的总生存优于多西紫杉醇。细胞分子信号通路和药理基因组学的研究结果可能指导肺癌的个体化治疗。伊立替康与铂类联合一线治疗广泛期小细胞肺癌（SCLC）优于EP方案，所有化疗取得缓解的广泛期SCLC接受预防性脑放疗（PCI）可延长生存。     

平消胶囊联合化疗治疗肺癌初步临床疗效分析

目的 观察平消胶囊联合化疗治疗对一线治疗无效的小细胞及非小细胞肺癌的疗效及毒副反应。方法 从2002年5月至2003年3月应用平消胶囊联合其他常用化疗药物组成的联合化疗方案治疗非小细胞肺癌42例，小细胞肺癌11例。结果 总有效率(CR PR)为68．2％，血液毒性：WBC减少为68％，其中Ⅲ度占13．3％，无Ⅳ度反应。PLT减少为59％，其中Ⅲ度占9．1％，无Ⅳ度反应。无严重非血液毒性。结论 本组资料显示平消胶囊与其它化疗药物联合治疗小细胞及非细胞肺癌获得68．2％的疗效并且未有明显的血液及非血液系统毒副反应，是有效、经济和安全的。     

小细胞肺癌治疗回顾及展望

小细胞肺癌(small cell lung cancer,SCLC)是对放、化疗极为敏感的恶性实体肿瘤之一,依托泊苷联合铂类的方案仍然是广泛期小细胞肺癌的一线标准治疗方案,客观缓解率为50%～70%.联合放化疗可以使局限期小细胞肺癌完全缓解率增加到40%～50%,但大部分患者会复发.对于复发的患者,单药托泊替康化疗是到目前为止二线治疗较为合适的治疗药物.胸部联合放、化疗、对于放疗时间和分级的优化、预防性的脑放疗可使3年生存率明显提高.     

Recent advances with topotecan in the treatment of lung cancer

Topotecan is a semisynthetic derivative of camptothecin that specifically targets topoisomerase I. It has well-established antineoplastic properties and has been successfully combined with other antineoplastic agents with activity dependent on DNA disruption, such as cisplatin and etoposide. Topotecan is indicated for the treatment of small cell lung cancer (SCLC) sensitive disease after failure of first-line chemotherapy and metastatic ovarian carcinoma after failure of initial or subsequent chemotherapy. Since the approval of topotecan for the second-line treatment of SCLC, studies have been conducted in the first-line setting. Recent studies demonstrate the utility of i.v. topotecan in combination with cisplatin for untreated SCLC. Further, an oral formulation of topotecan is currently under investigation and may provide added convenience for patients. Oral topotecan has been studied in the first- and second-line settings for both SCLC and non-small cell lung cancer (NSCLC). Three recent phase III trials have demonstrated the activity of oral topotecan. In the first study of chemotherapy-na?ve patients with extensive-disease SCLC, oral topotecan plus cisplatin provided efficacy and safety similar to those of etoposide plus cisplatin. In a second study of patients with relapsed SCLC, treatment with oral topotecan showed a statistically significant and clinically meaningful longer overall survival time and improvement in dyspnea and quality of life compared with best supportive care alone in all prognostic groups. Finally, in previously treated patients with NSCLC, single-agent oral topotecan was shown to be noninferior in 1-year survival rate relative to the current standard of i.v. docetaxel. In future studies, oral topotecan will represent a good candidate for combination therapy with other i.v. or oral chemotherapy agents, monoclonal antibodies, and small molecule tyrosine kinase inhibitors.     

Second-line chemotherapy for small-cell lung cancer: a review

Small-cell lung cancer (SCLC) is an aggressive malignancy, and only a minority of patients survive 2 years. Although this cancer is sensitive to both chemotherapy and radiotherapy, the majority of patients relapse, and second-line treatment is an option for many. Currently in the United States, the combination of cisplatin/etoposide is the standard first-line therapy in SCLC. At this time, topotecan is the only Food and Drug Administration-approved chemotherapeutic agent for second-line treatment of SCLC. In this paper, we review studies of second-line chemotherapy for SCLC.     

伊立替康联合顺铂与依托泊苷联合顺铂方案一线治疗广泛期小细胞肺癌的多中心临床研究结果

背景与目的:依托泊苷联合顺铂(EP)方案是否是广泛期小细胞肺癌(small cell lung cancer,SCLC)的最佳治疗方案目前仍不确定,本研究的目的是比较伊立替康联合顺铂(IP)和EP方案一线治疗广泛期SCLC的疗效和生存期.方法:在开放、两组随机、多中心、前瞻性临床研究中,符合入组条件的广泛期SCLC患者,随机接受IP或EP一线化疗,用药方案IP组:伊立替康65 mg/m2,第1、8天,顺铂30 mg/m2,第1、8天,21 d为1个周期,连续4个周期;EP组:VP-16为100 mg/m2,顺铂25 mg/m2,第1～3天,21 d为1个周期,连续4个周期.比较两组患者的疗效、生存期及不良反应.结果:2008年12月-2010年7月,共64例广泛期SCLC患者进入研究,其中IP组35例,EP组29例.IP和EP组的客观缓解率分别是66.7％和60.7％ (P=0.202);无进展生存期分别是5.7和7.1个月(P=0.719);总生存期分别是未达到和12个月(P=0.591).IP组最常见的不良反应是粒细胞减少、腹泻、消化道反应和血小板减少,发生率分别是88.2％、40％、29.4％和26.5％; EP组最常见的不良事件是粒细胞减少、消化道反应和贫血,发生率分别是80.8％、73.1％和38.5％.结论:IP和EP方案一线治疗广泛期SCLC的疗效和生存期相同,不良反应可耐受.     

Chemotherapy-induced bowel obstruction in small cell lung cancer: a case report

This case report focuses on an elderly gentleman with extensive stage small cell lung cancer (SCLC) who experienced episodes of bowel obstruction shortly after commencing first-line chemotherapy with cisplatin and etoposide. The patient had no radiological or pathological evidence of intra-abdominal carcinomatosis or paraneoplastic bowel disease secondary to SCLC. Although neurotoxicity is commonly associated with platinum agents, the effect is predominantly peripheral as opposed to autonomic. The authors conclude that the observations documented in this case were secondary to etoposide; a podophyllotoxin that can bind microtubules and inhibit fast axonal transport. Although paralytic ileus is well recognised with podophyllotoxin poisoning, to our knowledge, this is the first report to associate bowel obstruction with standard doses of etoposide and highlights the need for physicians to be aware of such deleterious effects in patients treated with this cytotoxic agent.     

Current standards of care in small-cell and non-small-cell lung cancer

Lung cancer is the leading cause of cancer-related death in the United States, accounting for over 30% of cancer deaths in men and 25% in women. Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are uniformly aggressive tumors, with rates of regional or distant metastases at diagnosis as high as 70%. Because the majority of these tumors are unresectable, patients with relatively good performance status receive platinum-based chemotherapy. Although no treatment consensus exists, currently recommended regimens for SCLC include PE (cisplatin and etoposide), CAV (cyclophosphamide, doxorubicin, and vincristine), CAE (cyclophosphamide, doxorubicin, and etoposide), and CAVE (cyclophosphamide, doxorubicin, vincristine, and etoposide). Of these, the PE regimen has been widely accepted in the United States, although CE (carboplatin and etoposide) provides better tolerability. For NSCLC, standard chemotherapy regimens have included platinum-based therapy (cisplatin and a vinca alkaloid or PE). Data from recent studies suggest that the addition of paclitaxel to platinum modestly improves tumor response and survival in NSCLC. Although SCLC and NSCLC are both responsive to first-line chemotherapy, most patients relapse and die from their disease, with 5-year survival rates of approximately 15%. Given the disappointing survival rates associated with SCLC and NSCLC, the introduction of new cytotoxic agents has been eagerly anticipated. Evidence of improved response and extended survival is mounting for various combinations of established regimens (e.g., PE) with newer drugs exhibiting novel mechanisms of action and single-agent antitumor activity, such as gemcitabine, paclitaxel, docetaxel, vinorelbine, and topotecan. This article reviews the current standards of care in SCLC and NSCLC, and introduces the potential role of newer agents given in combination with standard chemotherapy.     

伊立替康联合铂类药物治疗广泛期SCLC的研究进展

小细胞肺癌(Small cell lung cancer,SCLC)在肺癌中约占10%~15%,是一种恶性程度较高的肿瘤,具有进展快且转移早的特点,联合化疗是广泛期SCLC主要的治疗方法。依托泊苷(Etoposide,VP-16)联合顺铂(Cisplatin,DDP)的方案(简称EP方案)是治疗广泛期小细胞肺癌(Extensive disease small cell lung cancer,ED-SCLC)的标准方案,这些年来并未取得突破性的治疗进展。伊立替康联合铂类抗肿瘤药物的方案在治疗ED-SCLC方面显示出有效性和安全性,本文就伊立替康联合铂类药物治疗ED-SCLC的现状做一简要综述。     

Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer

Small-cell lung cancer (SCLC) easily recurs with multidrug resistance phenotype. However, standard therapeutic strategies for relapsed-SCLC remain unestablished. Human epidermal growth factor receptor 2 (HER2) expression correlates with poor prognosis in extensive disease-SCLC. We have reported previously that HER2 expression is upregulated when HER2-positive SCLC cells acquire chemoresistance, and also demonstrated that trastuzumab exerts significant antitumor activity toward HER2-upregulated chemoresistant SCLC, mainly via antibody-dependent cell-mediated cytotoxicity mechanism. Based on these preclinical data, we treated two patients with HER2-positive SCLC by combination of trastuzumab (6 mg/kg, day 1) and irinotecan (80 mg/m², days 1 and 8) every 21 days as the third-line chemotherapy following two prior regimens, first-line carboplatin plus etoposide and second-line amrubicin. One patient achieved partial response after the first cycle and received 6 cycles in total without disease progression for 4.5 months. The other also received 4 cycles and kept stable disease for 3.5 months. This treatment can be continued safely at an outpatient clinic without any severe adverse event. In conclusion, trastuzumab plus irinotecan chemotherapy is promising and feasible against HER2-positive relapsed SCLC. Further clinical studies are encouraged to confirm the antitumor efficacy of trastuzumab in SCLC.