重组人促甲状腺激素辅助131I在儿童和青少年分化型甲状腺癌的临床研究

目的 评估重组人促甲状腺激素(rhTSH)辅助¹³¹I对治疗儿童和青少年分化型甲状腺癌的安全性和有效性。方法 本研究共纳入87例分化型甲状腺癌患者,¹³¹I疗前注射重组人促甲状腺激素的46例患者为实验组,¹³¹I疗前停用甲状腺素药物的41例患者为对照组,对其进行回顾性调查研究。结果 实验组患者在注射重组人促甲状腺激素后第1天、第3天和第6天血清中促甲状腺激素浓度间存在统计学差异,第三天的浓度最高。¹³¹I疗前两组患者的促甲状腺激素浓度存在统计学差异(t=2.362,P=0.023)。对于甲状腺球蛋白抗体阴性患者,对照组患者的血清甲状腺球蛋白浓度显著高于实验组rhTSH注射第3天浓度(1.5±1.2 vs. 0.7±1.4,P=0.034)。¹³¹I清甲3~8个月后全身显像结果显示,实验组34例(84%)患者无放射性物,对照组例40例(87%)患者无放射性物,实验组与对照组患者间不存在统计学差异(χ²=0.277,P=0.599)。实验组和对照组患者¹³¹I再次清甲的原因分析结果显示不存在统计学差异(P=0.875)。结论 在短期内重组人促甲状腺激素和停用促甲状腺激素对于¹³¹I清甲治疗在甲状腺清除、生化缓解、短期复发等结局不存在统计学差异。重组人促甲状腺激素介导¹³¹I清甲治疗对于儿童和青少年分化型甲状腺癌是一个更好的方法。     

2015年美国甲状腺学会《成人甲状腺结节与分化型甲状腺癌诊治指南》解读：分化型甲状腺癌131I治疗新进展

近年来,分化型甲状腺癌(differentiated thyroid carcinoma,DTC)的发病率呈逐年上升趋势。美国甲状腺学会(American Thyroid Association,ATA)于2006年制定了《成人甲状腺结节与分化型甲状腺癌诊治指南》,以规范甲状腺结节和DTC的诊断和治疗。2009年ATA对该指南进行了首次更新(《2009版指南》),近几年有关甲状腺结节的诊断评估及处置和DTC手术、术后¹³¹I治疗等研究取得了长足进展,ATA于2015年再次更新了指南(《2015版指南》)。该文重点针对《2015版指南》的¹³¹I治疗相关更新内容进行解读。     

131I联合甲磺酸阿帕替尼对难治性甲状腺癌细胞的抑制作用及机制研究

目的 探讨¹³¹I联合血管生成抑制剂甲磺酸阿帕替尼对难治性甲状腺癌细胞的抑制作用及其机制。方法 将难治性甲状腺癌细胞分为对照组、¹³¹I组、阿帕替尼组及¹³¹I联合阿帕替尼治疗组(联合组),使用噻唑蓝(MTT)法检测各组肿瘤细胞治疗24 h、48 h后的增殖率;采用免疫荧光方法及蛋白印迹法检测各组细胞凋亡蛋白Caspase-3和血管生成蛋白VEGF的表达。结果 联合组处理后细胞的增殖率明显低于其它各组,差异具有统计学意义(P＜0.05)。联合组Caspase-3蛋白的表达含量明显高于其它各组(P＜0.01),联合组VEGF蛋白的相对表达量显著低于其它各组(P＜0.01)。结论 ¹³¹I联合甲磺酸阿帕替尼作用于难治性甲状腺癌细胞时具有协同增效作用,¹³¹I联合甲磺酸阿帕替尼通过上调促凋亡蛋白Caspase-3,下调VEGF的表达水平以达到增强¹³¹I抑制难治性甲状腺癌的增殖作用,从而为难治性甲状腺癌的临床治疗提供较好的策略。     

慢性淋巴细胞性甲状腺炎对分化型甲状腺癌放射性碘清甲治疗效果的影响

背景与目的：慢性淋巴细胞性甲状腺炎（chronic lymphocytic thyroiditis，CLT）是常见的甲状腺自身免疫炎性反应，本研究探讨其对分化型甲状腺癌(differentiated thyroid cancer，DTC）放射性碘-¹³¹（¹³¹I）治疗效果的影响。方法：回顾性分析了2014—2016年就诊于北京协和医院的中低危DTC患者128例，根据术后病理学检查是否伴CLT分为CLT1组与CLT0组。采用卡方检验、秩和检验等对比两组患者一般临床病理特征，依据2015版美国甲状腺协会（American Thyroid Association）效果反应体系对两组患者¹³¹I治疗的治疗反应进行评价，并对CLT与¹³¹I治疗效果进行相关性分析，探讨CLT对¹³¹I治疗效果及预后的影响。结果：CLT1组原发灶较小（P=0.028）且女性多见（P=0.011），而在年龄、多灶性、淋巴结分期、被膜外侵犯及TNM分期方面，差异无统计学意义（P>0.05）。CLT1组与CLT0组患者¹³¹I治疗后疗效满意、疗效不确定、血清学疗效不满意、结构性疗效不满意率分别为72.7%（40/55） vs 68.5%（50/73）、14.5%（8/55） vs 13.7%（10/73）、3.6%（2/55） vs 6.8%（5/73）和9.1%（5/55）vs 10.9%（8/73），对比分析提示两组间治疗效果与短期预后未见明显差异。相关性分析显示CLT与治疗效果不相关（P=0.519）。结论：CLT不是影响DTC患者¹³¹I治疗效果及预后的因素。     

首次131I治疗前刺激性甲状腺球蛋白在预测颈部及远处转移性分化型甲状腺癌的意义

背景与目的：由于受到残余甲状腺等多种因素的影响,刺激性甲状腺球蛋白(stimulated thyroglobulin,sTg)在首次¹³¹I治疗前对分化型甲状腺癌(differentiated thyroid carcinoma,DTC)复发转移的诊断价值尚有争议。该研究旨在探讨sTg在首次¹³¹I治疗前预测DTC患者颈部及远处转移的意义。方法：106例行甲状腺全切术及颈淋巴结清扫术的DTC患者,首次¹³¹I治疗前1天测sTg水平,¹³¹I治疗后5~7 d行¹³¹I全身显像和SPECT/CT断层融合显像。根据是否存在转移,将所有患者分为无转移组(M0)和颈部淋巴结转移组(M1)和远处转移组(M2),比较组间sTg值差异有无统计学意义,并通过ROC曲线及最佳诊断界值点(diagnostic critical point,DCP)评估sTg值预测转移的价值。结果：M0组、M1组和M2组的sTg值的四分位数间距分别为0.47~9.57、12.34~50.86和69.47~462.00 ng/mL。M1组、M2组与M0组的sTg相比差异均有统计学意义(P<0.01和P<0.01)。sTg值的ROC曲线下面积分别为0.872、0.964,DCP分别为23.95和20.93 ng/mL,灵敏度、特异度、准确度分别为68.42%、100%、92.31%和85.71%、100%、95.40%。结论：首次¹³¹I治疗前检测sTg值对DTC转移有重要的预测价值,对远处转移的预测价值更大。     

131I联合甲磺酸阿帕替尼治疗分化型甲状腺癌肺转移的短期疗效及安全性研究

目的 探讨¹³¹I联合甲磺酸阿帕替尼治疗分化型甲状腺癌肺转移的短期疗效及安全性。方法 回顾分析2018年10月—2020年10月于我院就诊治疗的分化型甲状腺癌肺转移患者57例,分为对照组(n=30)和联合治疗组(n=27),对照组单纯使用¹³¹I治疗,联合治疗组行¹³¹I联合阿帕替尼治疗。每半年观察并记录两组患者的甲状腺球蛋白(Thyroglobulin,Tg)水平、靶病灶(Target lesions,TL)的基线直径变化情况及靶病灶浓聚放射性灶计数/本底计数(Concentration range count/background count,C/B)的变化情况,同时记录两组患者的不良反应情况。结果 随访结束后联合治疗组Tg水平(36.34±19.72 μg/L)较对照组(122.18±22.98 μg/L)明显降低,差异具有统计学意义(P＜0.001);联合治疗组TL的直径均值(3.55±0.39 mm)较对照组(14.01±1.44 mm)明显缩小,差异具有统计学意义(P＜0.001)。24个月后,联合治疗组DCR和ORR高于对照组(P＜0.01)。联合治疗组C/B值(2.98±0.54)较对照组(25.45±3.00)明显降低,差异具有统计学意义(P＜0.001)。联合治疗组阿帕替尼常见的不良反应为手足综合征6例,高血压4例,皮疹2例,未观察到与阿帕替尼相关的Ⅲ级以上严重不良反应。结论 ¹³¹I联合甲磺酸阿帕替尼治疗分化型甲状腺癌肺转移疗效确切,具有明显的缩瘤效果,达到较高的生化缓解率,同时副作用轻微可控,安全性较高。     

经验性131I治疗Rx-WBS阴性伴生化耐药分化型甲状腺癌患者的疗效观察

目的 观察经验性¹³¹I治疗在治疗后全身显像(Rx-WBS)阴性伴生化疗效不佳(BIR)分化型甲状腺癌(DTC)患者中的疗效。方法 回顾性收集2013-09-01-2020-09-30在山东省肿瘤医院行甲状腺全切或近全切术及二次放射性碘治疗(RAI)后Rx-WBS阴性、疗效评价为BIR的DTC患者的临床资料,共纳入52例甲状腺球蛋白(Tg)阳性的患者,26例行经验性¹³¹I治疗患者纳入经验性RAI组,另26例纳入对照组。应用χ²检验或Fisher确切概率法和Mann-Whitney U检验分析经验性RAI组和对照组患者血清Tg水平的变化趋势及¹³¹I治疗的疗效。结果 在Tg水平持续阳性的患者中,经验性RAI组抑制性Tg水平(iTg)为0.89(0.67～1.71) ng/mL,低于对照组的2.46(1.56～4.23) ng/mL,Z=-3.056,P=0.002。经验性RAI组生化缓解率为53.85%(14/26),高于对照组的15.38%(4/26),χ²=8.497,P=...     

可疑甲状腺球蛋白增高性分化型甲状腺癌患者经131I治疗后的临床转归

背景与目的： 分化型甲状腺癌（differentiated thyroid cancer,DTC）中可疑甲状腺球蛋白（thyroglobulin,Tg）水平增高但无明确结构性病灶者预后差异大,临床治疗决策存在较大争议,本研究拟探究¹³¹I治疗及不同治疗剂量对于这类患者临床转归的影响。方法： 回顾并分析2007—2021年就诊于北京协和医院核医学科的138例DTC全切术后可疑Tg水平增高的患者,依据首次¹³¹I治疗剂量分为低（剂量为1.11 GBq）、中（1.11 GBq<剂量≤3.70 GBq）、高（3.70 GBq<剂量≤7.40 GBq）3组,观察不同剂量¹³¹I治疗后6个月的短期及后续未再行其他干预患者的长期疗效,并进一步观察经初始治疗评估为生化疗效不佳（biochemical incomplete response,BIR）患者的临床转归。采用受试者工作特征（receiver operating characteristic,ROC）曲线评估预测结构性疗效不佳（structural incomplete response,SIR）和远处转移的刺激性Tg（stimulated Tg,sTg）的最佳界值点。结果： 低、中、高3个剂量组中分别有6.7%、13.5%、7.0%的患者短期疗效达到疗效满意（excellent response,ER）,3组间总体疗效差异无统计学意义（H=1.02,P=0.60）。常规随访下3组患者的长期疗效同样差异无统计学意义（H=2.94,P=0.23）。经初始治疗评估为BIR的患者经常规随访和再次¹³¹I治疗后的临床转归差异无统计学意义（U=324.5,P=0.15）。预测SIR和远处转移的sTg最佳界值点分别为27.5和61.7 ng/mL。结论： 可疑Tg水平增高的DTC患者复发率较高,以27.5 ng/mL为sTg界值点有助于尽早识别这部分患者。¹³¹I治疗有助于术后可疑Tg水平增高患者快速达到ER,但高剂量¹³¹I治疗未对患者的预后产生增益效应;再次¹³¹I治疗对于BIR患者未显示出进一步获益。     

131I难治性分化型甲状腺癌分子靶向治疗进展

放射性碘难治性分化型甲状腺癌患者因病灶摄碘功能不佳而无法从131I等传统治疗方法中获益。近年来,甲状腺癌分子病理学研究新成果为甲状腺癌的分子诊断和靶向治疗提供了新的契机,相关分子靶向治疗的临床试验和荟萃分析均取得了可喜的结果。本文从临床角度对放射性碘难治性分化型甲状腺癌分子靶向治疗的最新进展进行综述。     

不同年龄儿童及青少年分化型甲状腺癌患者的临床病理学特征与131I治疗分析

背景与目的： 既往研究已发现18岁以下的儿童及青少年分化型甲状腺癌（differentiated thyroid carcinoma,DTC）与成人DTC在临床病理学特征、远期预后等方面存在差异,但对其内部不同年龄段之间,特别是青春期前、围青春期和青春期之间的特征研究较少,因此本研究旨在探讨不同年龄组儿童及青少年DTC的临床病理学特征及首次¹³¹I治疗效果的差异。方法： 回顾性分析四川大学华西医院2006年7月—2022年1月收治的156例儿童及青少年DTC患者。根据年龄分为青春期前（0岁<年龄≤10岁）、围青春期（10岁<年龄≤14岁）及青春期（14岁<年龄≤18岁）3组,比较3组的临床病理学特征、初始复发危险度分层、首次¹³¹I治疗后动态风险评估及刺激性甲状腺球蛋白（stimulated thyroglobulin,sTg）水平在首次¹³¹I治疗后的变化。结果： 3组患者的性别、原发肿瘤最大直径、包膜侵犯、T分期、N分期及切除淋巴结阳性转移比例差异无统计学意义（P>0.05）。3组患者的远处转移率分别为63.2%、42.1%和20.2%（χ²=16.839,P=0.000）,高危患者分别占88.9%、60.5%和46.4%（χ²=12.447,P=0.009）。3组患者首次¹³¹I治疗后动态风险评估的差异有统计学意义（χ²=21.744,P=0.001）,其中3组患者的疗效满意（excellent response,ER）比例分别为10.5%、25.0%和38.1%;结构性疗效不佳（structural incomplete response,SIR）比例分别为68.4%、52.8%和25.8%;生化疗效不佳（biochemical incomplete response,BIR）比例分别为21.1%、13.9%和14.4%。63例患者接受了第2次¹³¹I治疗且TgAb低于40 U/mL,首次¹³¹I治疗后3组的中位sTg降幅分别为41.31%、38.02%和60.38%（H=4.642,P=0.098）。结论： 儿童及青少年DTC中0~10岁组患者的远处转移率和高危复发风险最高,首次¹³¹I治疗后ER的结局最少,青春期前儿童DTC的发生、发展机制和治疗值得进一步研究。     

Lenvatinib for the treatment of radioiodine-refractory differentiated thyroid carcinoma: a systematic review and indirect comparison with sorafenib

Introduction: Thyroid carcinoma is the most prevalent endocrine malignancy, with an increasing incidence over the past decades. Treatment of differentiated thyroid cancer consists of surgery followed by radioactive iodine (RAI) ablation of the thyroid remnant, and TSH suppression. Among new therapeutic solutions for patients with advanced RR-DTC stage, the most promising seem to be sorafenib and lenvatinib, up to now considered to be orphan drugs.

Areas covered: We performed a systematic review of medical databases to collect all eligible clinical trials referring to the topic of our analysis. Due to the lack of direct clinical trials comparing the drugs we used an adjusted indirect comparison of efficacy and safety of tyrosine kinase inhibitors (TKIs) by Bucher method.

Expert commentary: Lenvatinib and sorafenib are drugs with strong evidence on efficacy in treatment of RR-DTC. Based on the currently available clinical data lenvatinib occurred more efficacious then sorafenib in RR-DTC therapy. Safety profile of the drugs was acceptable and comparative. Kinase inhibitors constitute a substantial progress in treatment of advanced thyroid cancer, have achieved long-lasting response and have improved survival without progress of the disease. In the near future we will deal with a range of therapeutic options for patients.     

18F-FDG PET/CT在评价索拉非尼治疗131I难治性分化型甲状腺癌疗效中的应用

背景与目的：肿瘤的疗效评价是阻碍确定肿瘤治疗最佳策略的因素之一。在淋巴瘤及其他实体肿瘤,基于正电子发射断层显像/电子计算机断层扫描(positron-emission tomography/computed tomography,PET/CT )的疗效评价的价值已经显现,尤其是对于靶向治疗(导致肿瘤活性改变而肿瘤大小可能未变)的疗效评价。通过对比实体瘤反应评价标准(Response Evaluation Criteria in Solid Tumors,RECIST 1.1)和欧洲癌症研究和治疗组织(European Organization for Research and Treatment of Cancer,EORTC)标准,研究18F-FDG PET/CT在评价索拉非尼(sorafenib)治疗131I难治性分化型甲状腺癌(radioiodine-refractory differentiated thyroid cancer,RR-DTC)疗效中的作用。方法：回顾性分析2011年—2014年索拉非尼治疗前和治疗3个月后均行18F-FDG PET/CT检查的14例RR-DTC 患者(男性6例,女性8例,平均年龄55.6岁)。用Wilcoxon符号秩和检验分析靶病灶直径之和与∑SUVmax变化百分比的差异。用χ2检验比较两种标准的疗效评分有无差异。用Wilcoxon 秩和检验比较按照RECIST 1.1或 EO-RTC 标准不同反应组间的无进展生存期(progression-free survival,PFS)有无差异。用Spearman 秩相关评估 PFS与形态学(RECIST 1.1)或功能学(EORTC criteria)反应分组的相关系数。结果：不同反应组间靶病灶直径之和与∑SUVmax变化百分比差异无统计学意义(Z=-0.408,P=0.683)。根据两种评价标准,14例患者中10例的评价结果是一致的(χ2=2.345,P=0.424),其余4例中,2例为SD/PMR,2例为SD/PMD。无论是按照RECIST 1.1(χ2=8.571, P=0.003)还是按照EORTC标准(χ2=8.781,P=0.003),各反应组间的PFS均有差异。PFS既与形态学评价结果相关(r=0.741,P=0.002),也与代谢学评价结果相关(r=0.816,P=0.0004)。结论：18F-FDG PET/CT可用于RR-DTC患者索拉非尼治疗后的疗效评价。尽管71.4%的患者RECIST 1.1和 EORTC 标准结果一致,但是基于PET的代谢学评价标准在预测治疗效果方面更为准确,可能比形态学评价标准更适用于靶向治疗的疗效评估。     

Lenvatinib: A Review in Refractory Thyroid Cancer

Lenvatinib (Lenvima®) is an oral, multi-targeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, platelet-derived growth factor receptor alpha, and RET and KIT signalling networks, which are implicated in tumour growth and maintenance. In the EU and USA, lenvatinib is indicated for the treatment of locally recurrent or metastatic progressive, radioiodine-refractory differentiated thyroid cancer (RR-DTC). This approval was based on the results of the randomized, double-blind, multinational, phase 3 SELECT study, in which lenvatinib significantly improved median progression-free survival (PFS) and overall response rate compared with placebo in patients with RR-DTC. The PFS benefit with lenvatinib was seen in all pre-specified subgroups, including patients who had received either one or no prior VEGF-targeted therapy. Moreover, the PFS benefit with lenvatinib was maintained regardless of BRAF or RAS mutation status. The safety and tolerability profile of lenvatinib in SELECT was consistent with that of other VEGF/VEGF receptor-targeted therapies and was mostly manageable. Hypertension was the most common treatment-related adverse event in lenvatinib-treated patients, but only infrequently led to discontinuation of the drug. Although not collected in SELECT, information on quality of life would be useful in assessing the overall impact of therapy on the patient. This notwithstanding, the data which are available indicate that lenvatinib is an effective and generally well-tolerated treatment option for patients with RR-DTC. Lenvatinib, therefore, offers an acceptable alternative to sorafenib — currently, the only other TKI approved for this indication.

Open image in new window

     

Outcomes and Prognostic Factors in Radioiodine Refractory Differentiated Thyroid Carcinomas

Background.

Outcomes vary among patients with radioiodine refractory (RR) differentiated thyroid cancer (DTC). The prognostic factors for survival are not well-known, resulting in difficulty in selecting patients for new targeted therapies. We assessed overall survival (OS) and cancer-specific survival (CSS) from RR-DTC to identify prognostic factors associated with survival.

Patients and Methods.

The data on all cases of metastatic RR-DTC treated in our center from 1990 to 2011 were retrospectively reviewed. Survival was estimated using the Kaplan-Meier method; associated prognostic factors were assessed using Cox’s model.

Results.

Of 153 cases of metastatic DTC, 59% (n = 91) met a criterion for RR: that is, 60% (n = 55) had at least 1 metastasis without ¹³¹I uptake; 21% (n = 19) had progressive disease (PD) despite ¹³¹I; 19% (n = 17) had persistent disease despite a cumulative activity of ¹³¹I of ≥600 mCi. After the diagnosis of RR, median OS was 8.9 years (95% confidence interval [CI]: 5.4-NR); median CSS was 9.6 years (95% CI: 6.01-NR). In multivariate analyses, PD despite ¹³¹I as a criterion for RR disease and the time from initial diagnosis of DTC to diagnosis of RR <3 years were the only independent prognostic factors for poor OS and CSS. Thyroglobulin doubling time (Tg-DT) was assessed in 31 of 91 cases. Among the 11 patients with Tg-DT for <1 year or undetectable Tg, 6 deaths occurred, whereas only 3 died of 20 patients with Tg-DT >1 year or negative Tg-DT.

Conclusion.

The identification of prognostic factors for decreased survival in RR-DTC may improve the selection of patients for targeted agents.

Implications for Practice:

This study shows a great heterogeneity in terms of prognosis in radioiodine refractory differentiated thyroid carcinoma. Poorer prognosis is observed in patients with tumor progression or with a diagnosis of radioiodine resistance within 3 years after the initial diagnosis of thyroid cancer. Those findings could lead to improvements in the selection of patients for targeted therapies.     

Integration of EGFR inhibitors with radiochemotherapy

Laboratory studies that led to the development of epidermal growth factor receptor (EGFR) inhibitors indicated that such inhibitors would be effective when given to patients with tumours that are driven by activated EGFR. However, initial clinical studies have shown modest responses to EGFR inhibitors when used alone, and it has not yet been possible to clearly identify which tumours will respond to this therapy. As a result, EGFR inhibitors are now used in combination with radiation therapy, chemotherapy and, more recently, with concurrent radiochemotherapy. In general, these clinical trials have been designed without much preclinical data. What do we need to know to make these combinations successful in the clinic?     

晚期胃癌免疫检查点抑制剂治疗的临床研究进展

[摘要] 晚期胃癌治疗方法有限,预后较差。2017 年,针对程序性死亡蛋白-1（programmed cell death protein-1, PD-1）和程序性死亡配体-1（programmed death ligand-1, PD-L1）的免疫检查点抑制剂获批用于晚期胃癌治疗,提示胃癌免疫治疗时代已经到来。然而,相对于肺癌,免疫检查点抑制剂尚未获批用于胃癌一、二线治疗。目前,大量胃癌免疫治疗临床试验正在进行中,其模式还在进一步优化,包括免疫联合化疗、免疫检查点抑制剂联合其他免疫治疗及新型免疫检查点抑制剂的应用等,同时寻找合适的肿瘤标志物,筛选优势人群用于胃癌精准免疫治疗。本文着重讨论晚期胃癌免疫检查点抑制剂治疗的临床研究最新进展。     

Topoisomerase I inhibitors for the treatment of brain tumors

Patients with primary malignant brain tumors have a poor prognosis. Standard treatment includes surgical resection, radiation therapy and chemotherapy. Topoisomerase I inhibitors such as topotecan and irinotecan (CPT-11) represent one class of chemotherapy drugs that have been used in this disease. Recent clinical trials have shown major antitumor activity in recurrent glioblastoma when adding the antiangiogenesis drug bevacizumab with CPT-11. The combination of targeted agents to topoisomerase I inhibitors represent a novel and promising approach. This review will summarize clinical trials with topoisomerase I inhibitors and discuss new treatment strategies for primary malignant brain tumors.     

Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies

The efficacy of small-molecule kinase inhibitors has recently changed standard clinical practice for several solid cancers. Glioblastoma is a solid cancer that universally recurs and unrelentingly results in death despite maximal surgery and radiotherapy with concomitant and adjuvant temozolomide. Several clinical studies using kinase inhibitors in glioblastoma have been reported. The present study systematically reviews the efficacy, toxicity, and tissue analysis of small-molecule kinase inhibitors in adult patients with glioblastoma as reported in published clinical studies and determines which kinases have been targeted by the inhibitors used in these studies. Publications were retrieved using a MEDLINE search and by screening meeting abstracts. A total of 60 studies qualified for inclusion, of which 25 were original reports. A total of 2385 glioblastoma patients receiving kinase inhibitors could be evaluated. The study designs included 2 phase III studies and 37 phase II studies. Extracted data included radiological response, progression-free survival, overall survival, toxicity, and biomarker analysis. The main findings were that (i) efficacy of small-molecule kinase inhibitors in clinical studies with glioblastoma patients does not yet warrant a change in standard clinical practice and (ii) 6 main kinase targets for inhibitors have been evaluated in these studies: EGFR, mTOR, KDR, FLT1, PKCβ, and PDGFR.     

Treatment Options For Postmenopausal Women with Tamoxifen-Resistant Advanced Breast Cancer

Tamoxifen resistance can be classified into de novo (with disease progression within 6 months of treatment) and acquired (with an initial clinical benefit of at least 6 months followed by subsequent disease progression). Further endocrine therapy tends to be the treatment of choice when acquired resistance develops, especially when there has been a long duration of response to tamoxifen, in postmenopausal women with advanced breast cancer. These endocrine agents used to be progestogens (e.g. megestrol acetate) or aminoglutethimide. They have now been replaced by third-generation aromatase inhibitors (anastrozole, letrozole and exemestane) which have shown superior efficacy and tolerability compared with the traditional agents. The pure anti-estrogen, fulvestrant, has also been shown to be at least equivalent to anastrozole and is currently being evaluated in phase III trials. Recently, the third-generation aromatase inhibitors are challenging the role of tamoxifen as a first line endocrine agent. It is, therefore, envisaged that the use of endocrine agents at the time of tamoxifen resistance (when used as a second-line therapy) would become more complex and depend on the response of prior agents used. For patients with de novo resistance, chemotherapy is the standard treatment option, although for those who refuse chemotherapy or are deemed unfit a second-line endocrine agent could be tried. Newer biological therapies such as monoclonal antibodies (e.g. trastuzumab), tyrosine kinase inhibitors (ZD1839) and cell cycle inhibitors (e.g. CCI-779) are either available for clinical use or being investigated in trials.     

Topoisomerase I inhibitors for the treatment of brain tumors

Patients with primary malignant brain tumors have a poor prognosis. Standard treatment includes surgical resection, radiation therapy and chemotherapy. Topoisomerase I inhibitors such as topotecan and irinotecan (CPT-11) represent one class of chemotherapy drugs that have been used in this disease. Recent clinical trials have shown major antitumor activity in recurrent glioblastoma when adding the antiangiogenesis drug bevacizumab with CPT-11. The combination of targeted agents to topoisomerase I inhibitors represent a novel and promising approach. This review will summarize clinical trials with topoisomerase I inhibitors and discuss new treatment strategies for primary malignant brain tumors.