肝癌靶向治疗的研究进展

随着分子靶向药物的研发和临床应用,肿瘤的分子靶向治疗已成为肿瘤内科的研究热点。现有的研究结果已表明,肿瘤分子靶向治疗具有较好的安全性和有效性,尤其以多靶点Raf激酶抑制剂,表皮生长因子受体（EGFR）和血管内皮生长因子受体（VEGF）为靶点的治疗药物,已在临床中取得较好的疗效。本文就这几种治疗中具有代表性的药物进行综述,并提出今后的分子靶向治疗可能发展的方向。     

肺癌靶向治疗的新境界:活得更长,活得更好

分子靶向治疗是21世纪肺癌治疗最具希望的治疗策略,与传统的细胞毒药物不同,分子靶向治疗可以特异性地作用于肿瘤细胞的某些特定位点,高度选择性的杀死肿瘤细胞而不杀伤或仅很少损伤正常细胞,靶向治疗药物最大的特点是安全性和耐受性极好,毒副作用轻微,临床应用具有非常大的优势。近年来靶向治疗以惊人的速度和独特的疗效引起了广大从事肿瘤治疗的广泛关注,新的靶向治疗药物Et新月异,新的治疗方案、治疗策略层出不穷,本文对近来有关晚期肺癌靶向治疗的最新研究作一综述,希望对肺癌临床研究工作者有所帮助。     

西妥昔单抗联合同步放化疗治疗食管癌的研究进展

不断寻求能够提高疗效、降低毒性的有效药物是食管癌综合治疗追求的重要目标之一。与传统细胞毒性化疗药物相比,分子靶向药物以其靶点明确、特异性强、毒性小、安全性好,对转移瘤也有较好的疗效等特点,正成为肿瘤综合治疗研究的热点。近年来,分子靶向药物的研发为食管癌综合治疗提供     

抗肿瘤分子靶向药物导致手足皮肤反应的研究进展

摘 要：分子靶向治疗是针对肿瘤特异位点的治疗方法，旨在抑制肿瘤增殖、生长和存活。靶向药物治疗较常规化疗有更好的针对性和安全性；但是，靶向治疗会产生较多的皮肤不良事件，其中以手足皮肤反应最为常见。手足皮肤反应虽然不危及生命，但可导致靶向药物剂量改变、中断或终止治疗，从而限制靶向药物的抗肿瘤作用。全文总结了有关靶向药物导致手足皮肤反应的流行病学、发病机制、临床表现、预后以及防治方法。     

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.     

肿瘤的靶向治疗

靶向治疗是针对肿瘤细胞恶性表型的分子靶点,作用于促进肿瘤生长、存活的特异性细胞受体、信号传导等通道,实现抑制肿瘤细胞生长或促进凋亡的抗肿瘤作用。新的靶向治疗药物rituximab、伊马替尼、赫赛汀和全反式维甲酸已开始用于临床治疗,本文综述这些药物的作用机制、适应证、疗效及安全性。与传统细胞毒化疗不同,肿瘤靶向治疗具有特异性抗肿瘤作用,并且毒性明显减少。肿瘤靶向治疗令人鼓舞的初步成果为其进一步发展奠定了基础,提供了典范,开创了肿瘤化疗的新领域。     

T-DM1应用于乳腺癌的最新研究进展

T-DM1是由曲妥珠单抗、细胞毒药物DM1通过连接子偶联而成的抗体药物偶联物,具有靶向性和细胞毒杀伤双重抗肿瘤作用,是第4个被FDA批准上市的抗HER-2靶向治疗药物。在HER-2阳性晚期乳腺癌一线、二线以及多线治疗的临床研究中,T-DM1均显示出突出的抗肿瘤活性,且耐受性良好,NCCN指南推荐其作为曲妥珠单抗治疗失败后的二线首选治疗方案。目前正在进行的临床研究将明确T-DM1在早期乳腺癌治疗领域中的地位,以及与其他药物联合的疗效和安全性。本文综述了T-DM1的作用机制、疗效与安全性、与疗效相关的因素、克服耐药的策略以及应用前景,有助于指导T-DM1的临床应用。     

实体肿瘤靶向药物疗效评价标准的现状和展望

近几年抗肿瘤靶向药物的研究取得了突破性的进展,基于基因水平的肿瘤分子诊断技术的发展及特异性靶向药物的应用,推动了癌症治疗进入精准医学新时代。传统的肿瘤治疗评价体系如WHO 或RECIST标准不能准确地对靶向药物治疗进行疗效评价,无法准确地反映患者的生存获益,因此,探索并建立适用于肿瘤靶向药物的疗效评价标准迫在眉睫。本文将回顾抗肿瘤药物疗效评价标准发展历史,介绍针对各类肿瘤的不同靶向药物疗效评价标准的发展及演化历程,并重点介绍结合免疫指标评价的新标准,对该新标准的具体定义、指导原则和临床应用进行详细阐述。有理由相信,随着肿瘤靶向药物疗效评价体系的不断完善,会给个体化肿瘤治疗带来新的进展。     

靶向端粒端粒酶的抗肿瘤治疗研究进展*

端粒是人类染色体末端由重复核酸序列组成的保护性结构,会随着细胞成功的分裂进行性的缩短。超过85% 的肿瘤细胞通过激活在大多数正常体细胞中被抑制的端粒酶来阻止端粒的无限缩短,维持细胞的永生化。肿瘤细胞跟正常细胞相比,有着更短的端粒和被重新激活的端粒酶,这些简单却又特殊的生物学差异促进了靶向端粒/ 端粒酶抗肿瘤治疗的发展。近年来许多成功的治疗药物经过临床前的筛选,在多种肿瘤中取得Ⅰ/ Ⅱ期临床试验的成功,GRN 163L 和GV1001等药物已进入Ⅲ期临床试验。联合传统药物治疗是目前的发展方向,未来靶向端粒/ 端粒酶治疗联合放射治疗可能在取得抗肿瘤疗效叠加的同时,提高治疗的安全性。      

肝移植术后新发或合并恶性肿瘤患者化疗及靶向治疗的疗效与安全性

目的 总结分析7例肝移植后新发或合并恶性肿瘤患者化疗及靶向治疗的疗效与安全性。方法 收集复旦大学附属中山医院肿瘤内科诊治的7例肝移植后新发或合并恶性肿瘤患者的临床资料及诊治过程，观察并分析疗效与不良反应情况。结果 7例患者根据肿瘤病理类型、基因检测结果等选择化疗方案及靶向药物治疗，获得疾病控制，部分患者达到部分缓解，治疗不良反应以皮疹及消化道反应为主，未出现严重肝损及移植肝脏排斥反应，药物剂量下调后不良反应减轻。结论 肝移植术后新发或合并恶性肿瘤患者，包括移植肝出现转移病灶，可以继续化疗和(或)联合分子靶向治疗，未见肝移植相关特殊并发症，肝移植状态可耐受化疗及靶向治疗。     

Role of randomized phase III trials in an era of effective targeted therapies

In the era of cytotoxic therapies, tumor regression has rarely been observed in phase I trials and randomized controlled trials have usually been required to demonstrate modest improvements over prevailing standards of care. In the era of effective targeted therapies, drugs such as vemurafenib and crizotinib have demonstrated convincing efficacy in early clinical testing, raising the question of whether randomized phase III trials are necessary and feasible before drug approval. Since 1992, the FDA has approved a number of drugs without data from confirmatory clinical trials as part of the accelerated approval process. While this initiative has largely been successful in bringing effective drugs to the market more quickly, there is much to be learned from case studies of drugs, such as gefitinib, which subsequently failed to gain full approval. In this Review, we use a number of historical examples to make the case that it may be reasonable to consider foregoing randomized phase III trials for certain drugs before drug approval. We explore the consequences (both good and bad) of foregoing randomized phase III trials and propose criteria that might be used to select drugs for consideration of such an approach.     

软组织肉瘤靶向治疗进展

化学治疗晚期软组织肉瘤疗效似已达到平台,靶向药物是进一步提高疗效的关键.尽管第1代靶向治疗药物开发的种类繁多,但仅有少数药物在前瞻性、随机的Ⅲ期临床试验中显示出生存优势.第2代靶向治疗药物多靶点抑制剂可同时阻断肿瘤多个信号传导,临床试验的初步结果表明,不良反应可以耐受,效果较好,治疗软组织肉瘤已显示出较好的应用前景.     

Targeted therapies and non-small cell lung cancer: methodological and conceptual challenge for clinical trials

PURPOSE OF REVIEW: Targeted therapies are emerging as important drugs in the treatment of advanced non-small cell lung cancer (NSCLC). Within the past months, there have been considerable contributions to this topic. The results of several important clinical trials have been published. Furthermore, laboratory results have significantly contributed to clear out some molecular mechanisms regulating sensitivity or resistance to these drugs and to provide rational basis for further clinical studies. RECENT FINDINGS: A great part of recently published research on targeted agents in NSCLC regards EGFR inhibitors. Following the demonstration of activity of gefitinib in patients pretreated with chemotherapy, four large randomized trials testing the addition of gefitinib or erlotinib to first-line chemotherapy have been conducted, but failed to show any advantage. Interestingly, erlotinib has shown efficacy compared with placebo in pretreated patients. Mutations in the EGFR gene have shown a strong predictive role for sensitivity to EGFR inhibitors. A number of other targeted agents are currently under investigation: most of the phase II trials maintain a traditional methodology, with response rate as primary measure of activity. SUMMARY: Recent advances will lead to a rapid expansion of further studies aimed to define the best way to use targeted agents in NSCLC. Several methodological issues are still open. The proper selection of patients, the choice of the best study design and the most appropriate end-point for early clinical trials, and the correct modality to integrate these drugs with traditional chemotherapy represent the most challenging points that research is called to answer in the near future.     

晚期胃肠间质瘤新药相关Ⅰ期临床试验进展

酪氨酸激酶抑制剂如伊马替尼的应用显著延长了晚期胃肠间质瘤(gastrointestinal stromal tumor,GIST)患者的生存,但因为肿瘤基因突变位点的不同,现有靶向药物敏感性各有差异.并且随着治疗后继发耐药性突变位点的出现,传统的靶向药物已经难以为继.瑞派替尼和阿泊替尼的出现进一步改善了晚期GIST患者...     

Optimal treatment of metastatic colorectal cancer

For over 40 years, fluorouracil has been the only drug registered for the treatment of metastatic colorectal cancer. During the past 5 years, combination chemotherapy regimens including either irinotecan or oxaliplatin have proven to be superior to fluorouracil monotherapy in randomized clinical trials, in terms of response rate, progression-free survival and overall survival. Both doublets demonstrated similar efficacy, therefore either combination can be considered standard first-line treatment for metastatic colorectal cancer. Recently, a new orally active fluorouracil analog, capecitabine, and two targeted biological agents, cetuximab and bevacizumab, have been added to the armamentarium of drugs active against metastatic colorectal cancer, thus making the scenario more complex. Moreover, ongoing clinical trials are currently testing new promising molecularly targeted agents. Thus, we are facing a new era in which the rapid clinical development of novel agents is outpacing the ability to perform Phase III clinical trials. At present, there is no single standard treatment suitable for all patients. However, general principles of management can be derived from the available clinical data in order to guide the therapeutic choice and individualize treatment.     

Clinical development of new molecular targeted therapeutics for cancer therapy

Recently much attention has been paid to clinical development of new drugs targeting the important molecules involved in cell growth, motility, invasion, metastatic formation of cancer cells and tumor angiogenesis. Among them, several drugs are designed to inhibit those activities, by which cancer growth and/or metastasis may be controlled. A major problem in developing new molecular targeted therapeutics is determining the optimal biological dose in Phase I studies. Appropriate surrogate markers should be employed to evaluate their therapeutic efficacy before entering the Phase III study. A future strategy to evaluate the efficacy of new drugs in combination with conventional anticancer therapy (surgery, radiotherapy and chemotherapy) is required. For this, careful consideration must be given to the design of clinical Phase III trials. This paper discusses the present status and future strategy for development of new molecular targeted therapeutics in clinics.     

Chemotherapy and signaling: How can targeted therapies supercharge cytotoxic agents?

In recent years, oncologists have begun to conclude that chemotherapy has reached a plateau of efficacy as a primary treatment modality, even if toxicity can be effectively controlled. Emerging specific inhibitors of signaling and metabolic pathways (i.e., targeted agents) contrast with traditional chemotherapy drugs in that the latter primarily interfere with the DNA biosynthesis and the cell replication machinery. In an attempt to improve on the efficacy, combination of targeted drugs with conventional chemotherapeutics has become a routine way of testing multiple new agents in early phase clinical trials. This review discusses the recent advances including integrative systematic biology and RNAi approaches to counteract the chemotherapy resistance and to buttress the selectivity, efficacy and personalization of anti-cancer drug therapy.     

二甲双胍抗肿瘤治疗的临床研究进展

二甲双胍不仅是最广泛使用的口服降糖药之一, 还表现出降血糖作用外的多种疗效, 如保护心脏作用、改善血脂作用及可能的抗癌作用。流行病学数据也显示服用二甲双胍的患者癌症发病率和死亡率均降低。随着研究的开展, 二甲双胍作为一种潜在辅助抗癌药物引起了广泛关注。围绕二甲双胍作用机制及疗效的临床试验在不同癌种中陆续开展, 随着更多临床试验的结果公布, 二甲双胍与化疗、放疗、分子靶向药物或免疫治疗等联合治疗的效果以及对治疗前后某些代谢分子的表达影响均获得验证, 为二甲双胍联合治疗癌症提供了更为明确的证据, 有助于促进二甲双胍作为辅助抗癌剂的临床应用。      

非小细胞肺癌的分子靶向治疗

与传统细胞毒性化疗相比,分子靶向治疗能更特异性作用于肿瘤而毒性反应较轻。新的靶向治疗药物得到发展,并相继在晚期非小细胞肺癌一线、二线治疗中进行临床试验,其中有的药物显示了较好的疗效。本文对近年来关于非小细胞肺癌靶向治疗的临床试验进行回顾。     

The role of surrogate markers in the clinical development of antiretroviral therapy: a model for early evaluation of targeted cancer drugs

Both CD4 cell counts and measurements of plasma HIV-1 RNA (i.e. viral load) have become established surrogate markers for predicting treatment and disease outcome in HIV infection, and are instrumental for the evaluation of new antiretroviral drugs in clinical trials. Recently, HIV drug-resistance testing has also become available and has been shown to have prognostic value in providing guidance with antiretroviral therapy. The identification of robust surrogate markers is also an essential requirement for the clinical development of targeted anticancer agents, which unlike their cytotoxic counterparts, are often devoid of the toxicities that have been traditionally used to monitor the efficacy of chemotherapy. In particular, biological or molecular markers that are predictive of a drug effect need to be integrated into early efficacy trials of targeted therapies in order to confirm that the drug is in fact “hitting” the intended target. The full clinical significance of many of the altered cell types or polymorphisms, which are selected by cytostatic agents, remains to be elucidated. However, molecular genotyping of these targets, akin to drug resistance testing for HIV infection, may constitute an important strategy to assist with the selection and monitoring of targeted chemotherapy in cancer patients. Thus, lessons from HIV/AIDS on the value of surrogate makers may assist with the development and optimization of targeted cancer therapy.