转移性肾细胞癌的治疗进展

肾细胞癌 (renal cell carcinom a,RCC)早期症状不明显 ,多数患者在获得明确诊断之时 ,就已经出现了转移。转移性 RCC的平均生存期为 8月～ 10月。该肿瘤对放疗、化疗、内分泌治疗等多种肿瘤治疗手段均有明显的抗性 ,有效率低于 2 0 %。以白细胞介素 (IL- 2 )和干扰素 α(IFN- α)为主的免疫治疗有一定客观疗效。最近几年 ,采用化疗联合免疫治疗 ,如长春花碱 (Vinblastine,VL B)联合IFN、IL- 2以及维甲酸协同 IFN治疗转移性 RCC,疗效有所提高。树突细胞瘤苗治疗转移性肾细胞癌也有可喜进展。现就近年国外有关转移性 RCC治疗的新…     

转移性肾细胞癌分子靶向治疗进展

肾细胞癌是我国泌尿生殖系统最常见的肿瘤之一。约30%的肾细胞癌患者在就诊时或手术后可能出现转移,预后差。转移性肾细胞癌对放疗与化疗均不敏感。转移性肾癌的分子靶向治疗已经取得了显著进展。现将最新的相关进展进行总结。     

替西罗莫司治疗转移性肾细胞癌初探

目的探讨替西罗莫司治疗转移性肾细胞癌的效果。方法 2008年6月4日至2008年12月18日共入组12例转移性肾细胞癌患者,接受替西罗莫司单药治疗,25mg,静脉滴注30～50分钟,每周1次,直至肿瘤进展或出现不可耐受的毒副作用。结果 12例患者中,按MSKCC评分中高危占75%(9/12),其中10例为多程治疗失败。最佳疗效:PR 2例(16.7%),另有6(50%)例患者出现不同程度的肿瘤缩小,PD 2例(16.7%)。临床受益率(CR+PR+SD≥24周)为41.7%(5/12)。中位PFS为8.4个月,中位OS 16.4个月。4例索拉非尼失败的患者的PFS分别为9个月、15个月、2.2个月和18.8个月。主要不良反应包括:皮疹、瘙痒、指甲改变、发热、口腔溃疡、高血糖、胆固醇和甘油三酯升高等。1例患者发生了V度间质性肺炎。结论替西罗莫司治疗转移性肾癌有效,对索拉非尼或舒尼替尼失败的患者的疗效值得进一步研究。代谢异常和间质性肺炎是需要重视的不良反应。     

舒尼替尼一线治疗转移性肾细胞癌的临床观察

目的:观察舒尼替尼一线治疗转移性肾细胞癌的有效性及安全性.方法:16例未经治疗的转移性肾细胞癌患者接受舒尼替尼治疗.14例患者口服舒尼替尼50 mg/d,服用4周休息2周,6周重复;2例患者口服37.5 mg/d,持续服用.结果:16例患者均可评价疗效和毒性.PR 5例,SD 9例,PD 2例;ORR为31.3％(5/16),DCR为87.5％(14/16).中位PFS和OS分别为10.5(95％CI:1.5～19.5)和17.5个月(95％CI:1.6～33.4).常见非血液学不良反应为手足综合征(12/16,75.0％)、乏力(11/16,68.8％)、口腔炎(8/16,50.0％)、高血压(8/16,50.0％)、纳差(9/16,56.3％)以及蛋白尿(6/16,37.5％);血液学主要不良反应为白细胞下降(10/16,62.5％)、血小板下降(9/16,56.3％).3～4级不良反应主要有口腔炎(3/16,18.8％)、高血压(2/16,l2.5％)、手足综合征(2/16,12.5％)、白细胞减少(2/16,12.5％)和血小板减少(2/16,12.5％).结论:舒尼替尼对未经治疗的中国人晚期肾细胞癌疗效确切,毒副反应可预见、可控制和可逆转,值得临床推荐使用.     

转移性乳头状肾细胞癌的临床特征及预后分析

  目的  探讨转移性乳头状肾细胞癌（papillary renal cell carcinoma,pRCC）的临床特征、酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）及雷帕霉素靶蛋白（mechanistic target of rapamycin kinase,mTOR）抑制剂系统性靶向治疗疗效及预后情况。  方法  回顾性分析2003年1月至2018年3月93例北京大学肿瘤医院收治的转移性pRCC患者的临床资料,采用国际转移性肾细胞癌联合数据库（international metastatic renal cell carcinoma database consortium,IMDC）预后模型对患者进行预后危险分层。采用Kaplan-Meier法及Cox比例风险回归模型对生存及影响因素进行分析。  结果  93例转移性pRCC患者中Ⅱ型占95.7%（89/93）,Ⅰ型占4.3%（4/93）,伴肉瘤分化占11.8%（11/93）,中位年龄为50.0（22~87）岁,中位随访时间为23.1个月,中位总生存（overall survival,OS）时间为（31.5±5.9）个月（95% CI为19.9~43.1）。采用IMDC预后模型进行分层,低、中、高危患者分别占14.0%（13/93）、46.2%（43/93）、39.8%（37/93）,低、中、高危患者的中位OS分别为（100.0±32.8）、（38.3±8.2）、（16.4±1.2）个月,高危与低、中危患者的OS相比差异具有统计学意义（P < 0.001）,低危与中危患者的OS相比差异无统计学意义（P=0.015）。93例pRCC患者的一线靶向治疗的总中位无疾病进展（progression free survival,PFS）时间为（6.6±0.5）个月,低、中、高危患者一线靶向治疗的PFS分别为（17.5±5.7）、（7.1±2.3）、（5.2±1.5）个月,高危与低危患者、高危与中危患者的PFS相比差异具有统计学意义（P=0.002、P=0.01）。  结论  转移性pRCC具有独特的生物学特点,IMDC预后模型可用于预测转移性pRCC患者的TKI一线靶向治疗的疗效和预后生存。      

肾细胞癌治疗药物的研发进展

肾细胞癌(renal cell carcinoma, RCC)是一种致命的恶性肿瘤,其治疗方式包括手术切除、靶向治疗、免疫治疗和联合治疗等。近年来,随着分子生物学和药物研发技术的不断发展,肾细胞癌的药物治疗取得了长足的进展,包括靶向治疗药物的不断更新、免疫治疗的革命性突破以及联合治疗的策略优化。该文将对肾细胞癌的靶向治疗、免疫治疗以及联合治疗进行系统综述。     

肾细胞癌靶向治疗研究现状

肾细胞癌被认为是最难治的恶性肿瘤之一。由于对肾细胞癌分子发病机制研究的进一步深入,在晚期肾细胞的治疗中出现了一系列成功范例。在过去20年,非特异性免疫治疗被认为是晚期肾细胞癌治疗标准。近年,随着分子靶向药物的研发和临床使用,肿瘤的分子靶向治疗已成为肿瘤治疗的研究热点,同时由于对肾细胞癌进一步了解,肾细胞癌的治疗已开始转向抗-血管内皮生长因子及其相关通路研究,大量的临床研究试验,证明了分子靶向治疗在晚期肾细胞癌的疗效,其中Sorafenib(索拉非尼)和Sunitinib(舒尼替尼)分别于2005年和2006年经美国FDA批准用于晚期肾细胞癌。本文将围绕VEGF在肾细胞癌的重要性和Bevacizumab(贝伐单抗)、Sunitinib和So-rafenib治疗晚期肾细胞癌研究进展等问题进行简要阐述。     

转移性肾细胞癌的靶向治疗

抗血管生成治疗是转移性肾细胞癌的标准治疗。近年来,肿瘤新生血管通路的众多抑制剂纷纷进入临床研究,部分靶向药物取得良好的临床疗效。其他信号通路阻断剂如哺乳动物雷帕霉素靶蛋白与成纤维生长因子受体通路抑制剂也取得一定的成果。     

索拉非尼治疗21例转移性肾细胞癌的临床观察

由于转移性肾细胞癌(renal cell carcinoma,RCC)对放化疗具有抗拒性,故白细胞介素2(IL-2)和于扰素α(INF-α)一直是治疗转移性肾癌的主要药物,但不良反应阻碍了其临床应用.     

肾细胞癌靶向治疗的临床研究进展

肾细胞癌（RCC ）是难治的恶性肿瘤之一,对放化疗不敏感,免疫治疗方式有效率一直徘徊于10% ～15% 。随着对肿瘤分子机制的深入以及多种分子靶向药物的深入研究,靶向治疗取得了重大进展。肾癌的发病机制与VHL 、Ras、PTEN等抑癌基因的突变有关,可诱导其下游的蛋白激酶受体表达异常。而蛋白激酶抑制剂可以通过干扰细胞内信号传导通路及改变肿瘤细胞微环境而影响肿瘤细胞的存活和增殖,是当前研发最集中的靶向治疗药物之一。近年来,多项靶向药物临床试验的可喜结果为转移性肾细胞癌（mRCC）治疗带来了新希望。本文就2009年NCCN 肿瘤治疗指南中介绍的舒尼替尼、索拉非尼、Temsirolimus、贝伐单抗等四种药物在肾细胞癌靶向治疗方面的临床研究最新进展展开综述。     

转移性肾癌靶向治疗和免疫治疗的现状与进展

近年来,转移性肾癌的治疗方式从细胞因子药物的治疗,到现在的针对血管生成、哺乳动物的雷帕霉素途径、免疫应答的药物的应用发生了巨大的变化。尽管耐药仍然是一个巨大的挑战,但通过对这些药物的应用及药物联合应用,转移性肾癌的治疗疗效得到大大的提高。目前新的治疗方法正在迅速发展,治疗前景一片大好。     

Current status of cytoreductive nephrectomy in metastatic renal cell carcinoma

The incidence of metastatic renal cell carcinoma (mRCC) continues to rise. While treatment options have increased dramatically in the last few years, few patients achieve a cure. The standard of care for mRCC in cytokine-eligible candidates is nephrectomy followed by high-dose IL-2. High-dose IL-2 can induce durable complete remissions, but only select patients can enjoy its benefits owing to toxicities. While not curative, the newer targeted therapies offer a broader patient population the chance for treatment response and prolonged survival. This review highlights the historical background of cytoreductive nephrectomy in mRCC, discusses the available treatment options and considers alternative treatment paradigms, such as the integration of the targeted agents with nephrectomy and the use of systemic therapy as medical selection for determining appropriate nephrectomy candidates.     

Cytoreductive nephrectomy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma is associated with a poor prognosis and a median survival time of only 6–12 months. However, the emergence of immunotherapies has rekindled interest in cytoreductive nephrectomy as a therapeutic option. Phase III randomized trials have demonstrated that cytoreductive nephrectomy significantly improves overall survival in selected patients with metastatic renal cell carcinoma treated with interferon immunotherapy. While cytokine-based immunotherapy may be considered the standard systemic therapy, clinical studies are ongoing to develop molecular biomarkers and new therapies with improved efficacy and tolerability. With further advances in our understanding of the pathogenesis, behavior and molecular biology of renal cell carcinoma, cytoreductive nephrectomy, in combination with molecular targeted therapies, may become the new standard of care for patients with metastatic renal cell carcinoma.     

骨肉瘤生物治疗基础研究的现状

随着新辅助化疗的广泛应用和手术技术的进展,骨肉瘤患者的5年生存率得到了很大提高,但受肿瘤细胞耐药机制和免疫逃逸的影响,目前骨肉瘤的疗效处于“瓶颈”状态。近期的研究显示,骨肉瘤细胞中存在着一些表达间充质干细胞和胚胎干细胞表面标志和表型的干细胞样肿瘤细胞,它们具有自我更新、广泛增殖的特点;同时,自骨肉瘤细胞分选出表达高水平ABCG2、能在NOD/SCID小鼠成瘤的SP细胞,显示骨肉瘤细胞耐药可能与SP细胞相关。研究针对上述标志物和降低ABCG2表达的治疗方法或药物,将有望进一步提高骨肉瘤的疗效。此外,研究主动和被动免疫疗法,以及针对Src蛋白酪氨酸激酶等靶点的靶向治疗也将为提高骨肉瘤的疗效提供新的途径。     

晚期肾癌靶向治疗的现状与进展

随着对肾癌发生发展过程的分子信号通路研究的不断深入,晚期肾癌的靶向治疗取得了重大进展.曾作为标准的细胞因子治疗效果不佳且有明显毒副作用,而靶向治疗已显示出在治疗晚期肾癌方面的明显优势.本文对舒尼替尼、索拉非尼、贝伐单抗、帕唑帕尼、Temsirolimus、依维莫司六种靶向药物的临床疗效,毒副作用以及对策,在贯序治疗、联合治疗和新辅助治疗方面的进展作一综述.     

Current status of studies on targeted therapy for renal cell carcinoma

Renal cell carcinoma (RCC) is regarded as one of the most refractory malignancies. A further study of the molecular mechanism of RCC formation has led to a series of successful examples for treatment of patients with advanced RCC. Over the past 20 years, a nonspecific immunotherapy, with cytokines, has been employed as the gold standard for therapy of metastatic RCC. However, with scientific development and clinical testing of new drugs, targeted molecular cancer therapy has become a focus of interest. At the same time, with a better understanding of RCC,the treatment method has converged on anti-vascular endothelial growth factor (VEGF) and related molecular-targeted pathways.A large amount of research and numerous clinical trials have demonstrated the clinical efficacy of the targeted molecular therapies in patients with metastatic RCC. For example sorafenib and sunitinib were approved, in 2005 and 2006 respectively, by the U.S. FDA for treating advanced RCC. In this report, issues such as the importance of VEGF in RCC and the studies of bevacizumab,sunitinib and sorafenib in treating metastatic RCC etc., are reviewed.     

The role of metastasectomy in renal cell carcinoma

Despite significant advances in the systemic treatment of metastatic renal cell carcinoma, long-term survival remains low. A potential way to improve outcomes in selected cases is the use of metastasectomy, which is part of the multimodal treatment of this disease. Although the evidence supporting this approach is limited, we believe it is a reasonable option for certain patients. This review summarizes the evidence supporting this approach.     

Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial

Background:

Preclinical investigations support combining sorafenib with IL-2 in the treatment of metastatic renal cell carcinoma (mRCC).

Methods:

In this open-label, phase II study, 128 patients with mRCC were randomised to receive oral sorafenib, 400 mg twice daily, plus subcutaneous IL-2, 4.5 million international units (MIU) five times per week for 6 in every 8 weeks, or sorafenib alone. After enrolment of the first 40 patients, IL-2 dose was reduced to improve the tolerability.

Results:

After a median follow-up of 27 months, median progression-free survival (PFS) was 33 weeks with sorafenib plus IL-2, and 30 weeks with sorafenib alone (P=0.109). For patients receiving the initial higher dose of IL-2, median PFS was 43 weeks vs 31 weeks for those receiving the lower dose. The most common adverse events were asthenia, hand–foot syndrome, hypertension, and diarrhoea. Grade 3–4 adverse events were reported for 38 and 25% of patients receiving combination and single-agent treatment, respectively.

Conclusion:

The combination of sorafenib and IL-2 did not demonstrate improved efficacy vs sorafenib alone. Improvements in PFS appeared greater in patients receiving higher-dose IL-2.