多西他赛联合重组人血管内皮抑素治疗非小细胞肺癌的临床效果

目的：探讨多西他赛联合重组人血管内皮抑素治疗非小细胞肺癌（NSCLC）的临床效果。方法选择2010年1月~2013年3月收治的76例一线化疗初治后进展或不能耐受毒性反应的NSCLC患者,观察组38例给予多西他赛联合重组人血管内皮抑素治疗,对照组38例采用单药多西他赛治疗,比较两组的疾病进展时间（TTP）、客观缓解率（ORR）、临床受益率（CBR）及不良反应情况。结果观察组及对照组的ORR均为0,CBR分别为63.2%（24/38）和52.6%（20/38）（P=0.712）。观察组及对照组的TTP分别为（2.6±0.4）、（2.0±0.8）个月（P=0.083）。观察组及对照组初治后进展的TTP分别为（1.3±0.4）、（1.6±0.8）个月（P=0.907）;不能耐受毒性的TTP分别为（4.7±0.1）、（3.1±0.8）个月（P=0.092）。观察组及对照组经治疗后获疾病稳定患者的TTP分别为（6.2±0.4）、（3.2±0.8）个月,观察组较对照组长（P=0.038）。观察组及对照组的不良反应比较差异无统计学意义（P>0.05）。结论对于初治后进展或不能耐受毒性反应的NSCLC患者,重组人血管内皮抑素在不增加毒副作用的情况下可延长多西他赛化疗获益患者的TTP。     

互为内标法测定紫杉醇和多西紫杉醇血浆药物浓度及临床应用

摘 要 目的： 建立高效液相色谱（HPLC）法测定人血浆中紫杉醇、多西紫杉醇浓度为临床个体化给药方案、疗效及不良反应评价提供实验依据。方法: 紫杉醇和多西紫杉醇互为内标,血浆样品采用乙腈提取法,以DikMA Diamonsil C₁₈反相色谱柱分离样品,流动相为乙腈∶水（55∶45）,检测波长为227 nm,流速为1.2 ml·min^-1,柱温为25℃。结果: 紫杉醇和多西紫杉醇血药浓度在0.078～10.0 mg·L^-1范围内线性关系良好;最低定量下限为0.039 mg·L^-1;平均方法回收率分别为99.85%和100.35%;日内、日间相对标准差均低于5%;短期稳定性、长期稳定性和反复冻融稳定性相对标准差均低于10%。紫杉醇临床样本血浆药物浓度监测结果范围为0.18～6.16 mg·L^-1,临床监测结果存在明显个体差异。结论:紫杉醇和多西紫杉醇血浆药物浓度差异明显,进行两药治疗药物监测十分必要。本方法灵敏、准确、便捷、快速,适用于紫杉醇和多西紫杉醇的临床常规治疗药物监测及药动学研究。     

Retrospective efficacy and safety analyses of erlotinib,pemetrexed, and docetaxel in EGFR-mutation-negative patients with previously treated advanced non-squamous non-small-cell lung cancer

ObjectiveSeveral guidelines recommend erlotinib, pemetrexed, or docetaxel for second-line chemotherapy in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The aim of this study was to retrospectively evaluate the efficacy of erlotinib, pemetrexed, and docetaxel in epidermal growth factor receptor (EGFR) mutation-negative patients with previously treated advanced non-squamous NSCLC.Materials and methodsWe analyzed the efficacy of these agents in patients with previously treated advanced non-squamous NSCLC who had EGFR wild-type tumors, performance status (PS) of 0, 1, or 2 and received erlotinib, pemetrexed, or docetaxel between December 2007 and September 2011. Variability among patient backgrounds was evaluated using propensity scores to assess comparability. The efficacy of these agents was evaluated in patient subgroups with low variability.ResultsThe propensity scores showed that the backgrounds of the groups that received second-line therapy with each agent had low variability and were adequate for comparison. Patients were divided into the PS0/1 and PS2 groups for analysis. The median progression-free survival (PFS) in patients treated with erlotinib was 2.8 months in the PS0/1 group, as compared with 1.0 month in the PS0/1/2 group and 0.90 months in the PS2 group. PFS in PS0/1 patients who received erlotinib was comparable to that in PS0/1 patients who received pemetrexed (2.5 months) or docetaxel (1.9 months). Overall survival (OS) in erlotinib-, pemetrexed-, and docetaxel-treated PS0/1 patients was 16.1, 7.4 and 10.0 months, respectively. The study had limited power to detect differences in PFS and OS because of the small sample size.ConclusionsErlotinib appears to be a useful second-line option in PS0/1 patients with EGFR mutation-negative advanced non-squamous NSCLC given its mild adverse effects. The results should be carefully interpreted because of the small sample size, limited power, and retrospective nature of the study.     

Docetaxel-Ifosfamide Combination in Patients with Advanced Breast Cancer Failing Prior Anthracycline- Based Regimens: Results of a Phase I-II Study

Abstract

The established clinical activity of docetaxel and ifosfamide as single agents in anthracycline pre-treated breast cancer, led us to conduct a phase I-II study to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and clinical activity of the docetaxel+ifosfamide combination in this setting. Patients with histologically confirmed metastatic breast cancer, after failure on prior anthracycline-based chemotherapy, were treated at successive dose levels (DLs) in cohorts of 3-6 with escalated doses of docetaxel 70-100 mg/m² over 1 h on day 1 followed by ifosfamide 5-6 g/m² divided over days 1+2 (2.5-3.0 g/m²/day over 1 h), every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. Between March 1997 and December 2002, 65 patients with a median age of 57 years (range, 32-72) and performance status (WHO) of 1 (range, 0-2) were treated at 5 DLs as follows; 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 44 were treated at DL4 (total of 50 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 62 for response. DLT (with the addition of G-CSF after DL2) was reached at DL5 with 2/3 initial patients developing febrile neutropenia. Clinical response rates (RRs), on an intention-to-treat basis, in phase II were: 56%; (95% CI, 42.2- 69.7%); 4 CRs, 24 PRs, 10 SD and 12 PD. The median response duration was 7 mo (3-24 mo), median TTP 6.5 mo (0.1-26 mo), and median OS 13 mo (0.1-33 mo). Grade 3/4 toxicities included: neutropenia in 72% of patients, with 60% developing grade 4 neutropenia (≤7 days) and in 10% of these febrile neutropenia, while no grade 3/4 thrombocytopenia was observed. Other toxicities included peripheral neuropathy grade 2 only in 10%, grade 1/2 reversible CNS toxicity in 16%, no renal toxicity, grade 2 myalgias in 8%, grade 3 diarrhea in 8%, skin/nail toxicity in 14%, and grade 2 fluid retention in 2% of patients. One patient in the study treated at phase II died as a result of acute liver failure after the first cycle.

The present phase I-II study has determined the feasibility, defined the MTD and demonstrated the encouraging activity of the docetaxel-ifosfamide combination in the phase II part of the study. Therefore, future randomized phase III studies versus single-agent docetaxel or combinations of the latter with other active agents are warranted.     

DP、EP化疗方案治疗非小细胞肺癌的临床疗效及其对血清血管内皮生长因子的影响

目的对比DP、EP化疗方案治疗非小细胞肺癌（NSCLC）的临床疗效及其对血清血管内皮生长因子（VEGF）的影响。方法102例晚期NSCLC患者随机分为DP组（n=58）和EP组（n=44）。DP组静脉注射多西紫杉醇75mg／m2，dl；静脉滴注顺铂75mg／m2，d1～4；EP组静脉滴注依托泊苷0．1g／d，d1～5；顺铂用法同上。两组28d为1个周期，治疗3个周期，化疗前后常规给予止呕类药物及对症治疗。检测两组临床疗效和血清VEGF水平。结果DP组、EP组，总有效率分别为74．14％和29．55％，DP组总有效率明显高于EP组。与治疗前比较，两组治疗后血清VEGF水平均明显降低。DP组治疗后血清VEGF水平明显低于EP组治疗后。结论DP治疗中晚期NSCLC临床疗效确切，有效率、生存率均较高。     

Analysis of patient-reported outcomes from the LUME-Lung 1 trial: A randomised,double-blind,placebo-controlled,Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer

IntroductionThe LUME-Lung 1 trial (NCT00805194; Study 1199.13) demonstrated a significant overall survival (OS) advantage for nintedanib plus docetaxel compared with placebo plus docetaxel as second-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and adenocarcinoma histology. Patient-reported outcomes (PROs) for symptoms and health-related quality of life (QoL) are reported here.MethodsPROs were assessed at screening, on Day 1 of each 21-day treatment cycle, at the end of active treatment, and at the first follow-up visit. PRO instruments were the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 supplement, and the EuroQol disease-generic questionnaire (EQ-5D and EQ-VAS). Analyses of PRO items for lung cancer-specific symptoms of cough, dyspnoea and pain were prespecified.ResultsRates of questionnaire completion were high. There was no significant difference in time to deterioration of global health status/QoL, or symptoms of cough, dyspnoea or pain, between the treatment groups for both the overall study population and the adenocarcinoma population. Time to deterioration of some gastrointestinal events was shorter with nintedanib versus placebo. Longitudinal analysis for the adenocarcinoma population showed comparable changes between the groups in symptom scores over time, with numerical differences in favour of nintedanib for cough and pain scales, and significant reductions in some pain items with nintedanib versus placebo. There was no statistically significant difference in EQ-5D or EQ-VAS between the groups.ConclusionThe significant OS benefit observed with the addition of nintedanib to docetaxel therapy was achieved with no detrimental effect on patient self-reported QoL.     

多西他赛联合基质金属蛋白酶抑制剂SB-3CT对前列腺癌移植瘤生长的影响

目的 探讨多西他赛联合基质金属蛋白酶抑制剂（SB-3CT）对前列腺癌移植瘤生长的影响及其可能的作用机制。方法 用前列腺癌PC-3细胞建立裸鼠皮下移植瘤模型，随机分为SB-3CT组（注射SB-3CT溶液25 mg/kg），联合用药组（SB-3CT 25 mg/kg+静脉注射多西他赛溶液 10 mg/kg）和空白对照组（注射等量生理盐水），每组5只。测量肿瘤体积和质量并绘制生长曲线。免疫组化检测移植瘤组织中PDK1和PFKFB4的表达。结果 联合用药组、空白对照组和SB-3CT组平均瘤体质量比较差异有统计学意义（F=29.556，P=0.001），且联合用药组的肿瘤生长速度明显较空白对照组和SB-3CT组慢。免疫组化结果显示，PDK1在联合用药组、空白对照组和SB-3CT组的染色评分分别为（2.33±0.47） 分、（6.00±0.81） 分和（4.33±0.48） 分，组间比较差异有统计学意义（F=18.200，P=0.003），且联合用药组评分低于SB-3CT组（P=0.017）；PFKFB4在3组的染色评分分别为（5.33±0.49） 分、（11.33±0.47） 分和（9.00±1.41） 分，组间比较差异有统计学意义（F=17.643，P=0.003），且联合用药组评分低于SB-3CT组（P=0.011）。结论 多西他赛联合基质金属蛋白酶抑制剂SB-3CT对前列腺癌移植瘤生长具有抑制作用，糖代谢相关酶PDK1和PFKFB4表达下调可能是潜在的分子机制。