晚期胃癌分子靶向治疗进展

我国胃癌发病率高,由于早期临床症状不典型以及早期胃癌的筛查重视度不够,多数患者确诊时已处于疾病晚期。传统化疗一直是晚期胃癌主要的治疗选择,然而单纯化疗的疗效仍十分有限且已达到瓶颈。随着肿瘤分子生物学的研究深入,分子靶向治疗为晚期胃癌的治疗带来了新的曙光和希望。本文拟就近几年胃癌靶向治疗的新进展作一综述,分析药物的有效性和安全性,为临床治疗提供一些参考。     

胃癌分子靶向治疗的研究新进展

分子靶向治疗是近几年来胃癌治疗领域的热点。目前,西妥昔单抗、帕尼单抗、吉非替尼、拉帕替尼、曲妥珠单抗等为胃癌治疗的主要靶向药物。本文结合最新研究报道对胃癌分子靶向治疗的最新进展作如下综述。     

进展期胃癌分子靶向治疗

进展期胃癌化疗效果不佳.分子靶向治疗是近年来进展期胃癌综合治疗的新手段.目前这些策略主要包括针对表皮生长因子受体(EGFR)通道的靶向治疗、针对血管内皮生长因子通道的靶向治疗、口服小分子靶向药物等.近期有关HER2、EGFR、VEGF、mTOR信号通路的靶向药物曲妥珠单抗、西妥昔单抗、贝伐单抗、阿帕替尼、索拉非尼、舒尼替尼、拉帕替尼、RAD001 (everolimus)等综合治疗进展期胃癌的报道结果令人鼓舞.     

进展期胃癌的综合治疗现状及进展

胃癌是世界范围内最常见的恶性肿瘤之一。据统计,全球每年新发胃癌约80余万例,占所有新发癌症病例的9％,仅次于肺癌、乳腺癌和肠癌之后,居第4位。每年约有60余万人因胃癌死亡,居癌症死因的第2位^[1]。胃癌在我国的发病率和死亡率分别约为25／10万和21／10万。据国内的回顾性研究表明,早期胃癌发现率仅占2％～4％,绝大多数为进展期胃癌^[2]。     

进展期胃癌分子靶向治疗

进展期胃癌化疗效果不佳。分子靶向治疗是近年来进展期胃癌综合治疗的新手段。目前这些策略主要包括针对表皮生长因子受体（EGFR）通道的靶向治疗、针对血管内皮生长因子通道的靶向治疗、口服小分子靶向药物等。近期有关HER2、EGFR、VEGF、mTOR信号通路的靶向药物曲妥珠单抗、西妥昔单抗、贝伐单抗、阿帕替尼、索拉非尼、舒尼替尼、拉帕替尼、RAD001（everolimus）等综合治疗进展期胃癌的报道结果令人鼓舞。     

胃癌分子靶向治疗进展

正0引言全世界每年新诊断的胃癌患者大约934 000人,占所有新发恶性肿瘤的8.6%,并且其中大部分病人就诊时已为局部晚期或存在转移,即使进行了根治性手术切除,仍有40%～60%的病人出现复发或转移。尽管外科手术技巧不断提高,临床诊断     

Her-2阳性进展期胃癌靶向治疗现状

研究发现进展期胃癌存在不同程度的表皮生长因子受体2(Her-2)基因扩增和/或蛋白过表达。Her-2在胃癌中的阳性表达主要与胃癌的组织学类型和原发部位等具有密切相关性,而Her-2状态与患者预后的关系目前仍存在争议。针对Her-2阳性胃癌的分子靶向治疗药物研究已取得一些成果。全文对于胃癌中Her-2表达、Her-2与胃癌预后相关性及抗-Her-2靶向药物在Her-2阳性进展期胃癌中的治疗现状作一综述。     

胃癌靶向治疗进展

胃癌是消化系统常见的恶性肿瘤之一,每年新发病例近百万,其中约2／3的患者来自发展中国家,仅中国就占到了42％,同时胃癌又是世界第二大癌症致死原因,在日本、韩国、中国等亚洲国家胃癌的死亡率更是位居恶性肿瘤之首。尽管提高了手术技术,改进了诊疗技术,应用了新的化疗方法,但晚期胃癌和胃食管结合部腺癌的预后仍然不好,5年生存率很低。近年来分子靶向药物不断研发,以其低毒、高效的优势应用于临床,在常见肿瘤综合治疗中已经占有越来越重要的地位,包括对胃肠道间质瘤、非小细胞肺癌、大肠癌、肾癌等治疗都取得了令人瞩目的结果。然而在胃癌分子靶向治疗领域,尚未取得突破性进展,尽管在一项Ⅲ期临床试验中,证实了赫赛汀在治疗晚期胃癌中里程碑性的价值,但仍需要不断开发和探索更有效,更安全的靶向药物应用于胃癌的临床治疗。目前靶向药物主要分为以下几种：表皮生长因子（EGFR）抑制剂、人类表皮生长因子受体2（HER一2）抑制剂、抗血管生成药物、细胞周期相关抑制剂、下游信号抑制剂、环氧化酶抑制剂、基质金属蛋白酶抑制剂等,本文针对胃癌靶向药物的最新进展进行阐述。     

胃癌分子靶向药物治疗的研究进展

胃癌是最常见的恶性肿瘤之一,手术切除是胃癌首选的治疗方法,但由于缺乏典型早期症状,多数患者就诊时已有远处转移,失去手术治疗的机会.目前,晚期胃癌的治疗主要是以化疗联合靶向治疗为主的综合治疗.过去几十年,随着肿瘤生物学的快速发展以及肿瘤分子标志物的不断涌现,使众多靶向药物应运而生,如表皮生长因子(EGFR)、血管生成、免疫关键位点阻滞剂、细胞周期、细胞凋亡、关键酶、C-MET、mTOP等信号通路,以及胰岛素样生长因子受体(IGF-IR)等.分子靶向药物作用机制的深入研究将为胃癌的治疗提供新的认识.     

晚期胃癌的化疗及分子靶向治疗

在晚期胃癌的一线化疗方案中,蒽环类药物+铂类药物+氟尿嘧啶类药物组成的方案依然具有疗效和安全性;紫杉类药物+铂类药物+氟尿嘧啶类药物组成的化疗方案疗效和毒性并存;以S-1为基础的化疗方案显示了有效性和安全性.氟尿嘧啶类药物在非一线方案以及体力状况较差的患者中有效且安全.分子靶向药物联合化疗具有临床获益.疗效预测分子对选择化疗药物或分子靶向药物具有重要的意义.     

VEGF靶向治疗在胃癌中的临床研究进展

血管内皮生长因子（VEGF）是已知最强的刺激血管生成因子之一,其通过刺激血管内皮细胞增殖和血管通透性增加,促进肿瘤血管的形成。在实体肿瘤的发生、发展和转移中起重要作用。近年来以VEGF受体和VEGF传导通路中酪氨酸激酶为靶点的药物研究在胃癌治疗中有较大进展,是分子靶向治疗的热点。     

胃癌靶向治疗与免疫治疗的新进展

近几年,癌症基因组图谱计划的研究者们依据胃癌患者不同的临床与分子生物学特点将胃癌分为四种不同的亚型,以此来指导靶向药物的临床试验和应用。该分型的主要目的在于靶向药物的个体化治疗。有两种靶向药物,分别为曲妥珠单抗和雷莫卢单抗,已被批准用于晚期胃癌患者的治疗。而且,胃癌免疫治疗也取得了许多进展。虽然晚期胃癌的许多免疫治疗药物尚处于临床研究阶段,但是免疫治疗仍是一个充满应用前景的治疗手段。本文主要对胃癌领域靶向治疗与免疫治疗的最新研究进展做一系统综述。     

胃癌分子靶向治疗的研究进展

目前晚期胃癌的治疗方式是以全身化疗为主的综合治疗。尽管化疗能够延长肿瘤患者的生存期,但副作用较明显,近年来,随着对胃癌的各种相关分子的信号转导通路的逐渐认识,在分子水平抑制肿瘤生长的治疗方式越来越受到人们关注,众多靶向药物应运而生,如曲妥珠单抗、阿帕替尼、Claudin18.2等,各种靶向药物为晚期胃癌的治疗提供了良好的前景。     

Systemic therapy for advanced gastric cancer: a clinical practice guideline

Question

What is the optimal chemotherapy regimen in advanced gastric cancer?

Perspectives

Gastric cancer is the second leading cause of cancer mortality worldwide. Despite low incidence rates for gastric cancer in Ontario, the overall prognosis is bleak, with 5-year survival rates of approximately 23% in Canada. Even with the considerable body of research available on chemotherapy for advanced gastric cancer, uncertainty remains. There is no recognized standard treatment, and there appears to be geographic variation in practice.

Outcomes

Outcomes of interest were overall survival, objective response rate (complete plus partial responses), time to disease progression, adverse effects, and quality of life.

Methodology

After a systematic review, a practice guideline containing clinical recommendations relevant to patients in Ontario was drafted. The practice guideline was reviewed and approved by the Gastrointestinal Disease Site Group (gi dsg) and the Report Approval Panel of the Program in Evidence-Based Care. External review by Ontario practitioners was obtained through a survey, the results of which were incorporated into the practice guideline.

Practice Guideline

The gi dsg makes the following recommendations:

• To improve survival, a platinum agent should be included in any combination chemotherapy regimen.
• Within a combination chemotherapy regimen, oral capecitabine is preferred over intravenous 5-fluorouracil (5fu)—that is, epirubicin–cisplatin–capecitabine is preferred over the prior standard regimen, epirubicin–cisplatin–5fu (ecf).
• Epirubicin–oxaliplatin–capecitabine (eox) is a reasonable alternative to ecf. The choice between ecf and eox should be based on patient preference.
• Trastuzumab in combination with cisplatin and a fluoropyrimidine (5fu or oral capecitabine) is recommended for advanced gastric cancer positive for the human epidermal growth factor receptor 2 (her2/neu).

     

Alternate-day oral therapy with TS-1 for advanced gastric cancer

Background TS-1 (1M tegafur-0.4M 5-chloro-2,4-dihydroxypyrimidine-1M potassium oxonate) has a high single-agent response rate, of more than 40%, for gastric cancer; however, the recommended regimen of 4 weeks of administration interrupted by 2 weeks of drug withdrawal frequently causes adverse effects. The alternate-day dosage of pyrimidine fluoride anticancer drugs could reduce their adverse effects without compromising their effects. We attempted an alternate-day therapy with TS-1 aiming at the avoidance of adverse effects and significantly longer duration of administration.Methods We observed patients for clinical effects and adverse effects under alternate-day dosage of TS-1, and determined blood 5-fluorouracil (FU) levels. The judgment of clinical effects was based on the New Guidelines to Evaluate the Response to Treatment in Solid Tumors (RECIST), whereas the evaluation of adverse effects was based on the National Cancer Institute NCI-common toxicity criteria (CTC).Results In 72 (78%) of 92 patients, the TS-1 regimen was converted to the alternate-day dosage because of adverse effects. Twenty patients were treated with the alternate-day dosage regimen from the start because of the fear of adverse effects. The alternate-day dosage was clinically effective, as 28 of 34 patients after relatively curative resection remained alive and free from recurrence. The median survival time of 58 patients after noncurative resection or with unresectable or recurrent cancer was 332 days. Fifty-three percent of these 58 patients achieved partial response and stable disease of more than 12 weeks duration. We followed time-dependent changes in blood 5-FU levels in 36 of the patients on alternate-day therapy, in whom TS-1 had been administered daily before being administered every other day. The trough level was significantly lower when TS-1 was administered on alternate days, and blood 5-FU reached a peak at sufficiently effective levels at 2h even after administration on the alternate-day basis.Conclusion This study demonstrated that, compared with daily administration, alternate-day administration of TS-1 reduces adverse effects, and simultaneously ensures effective blood levels and provides sufficient clinical effects.     

Progression of targeted therapy in advanced cholangiocarcinoma

It is necessary to establish an effective therapy to improve the survival of patients with advanced cholangiocarcinoma (CCA). Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.     

胃癌靶向治疗新进展

化疗是进展期胃癌最常见的治疗方法,但单纯化疗的疗效十分有限。随着对胃癌分子生物学研究的深入,多个胃癌“驱动基因”已被发现,针对这些基因的靶向药物也被尝试用于胃癌的治疗,目前已有多个大型Ⅲ期临床研究评价了这些靶向药物治疗胃癌的效果,本文拟对这些临床研究作一总结,并思考研究结果带给我们的启示。