A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir

IntroductionTwo solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored.MethodsAdult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0.ResultsModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC_0–48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment.ConclusionOral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.     

多西紫杉醇作为晚期非小细胞肺癌的二线治疗药物的系统评价

目的系统评价多西紫杉醇作为晚期非小细胞肺癌二线治疗药物的疗效、不良反应、生存质量及给药方案。方法电子检索Medline（1991～2008．2）、Pubmed、CBMDisc等数据库，对符合纳入标准的研究，采用RevMan4．2软件进行Meta分析。结果共有8篇文献纳入研究。多西紫杉醇治疗晚期非小细胞肺癌疗效与支持性疗法相比，疾病进展期和中位生存期明显延长，分别是10．6周和6．7周（P〈0．001）、7．0月和4．6月（P〈0．001），1年生存率分别为37％和11％。不良反应研究中，3—4级血液学不良反应在多西紫杉醇组中发生率较高，其中高剂量组（100mg／m^2）发生率高于低剂量组（75mg／m^2）；3～4级非血液学不良反应，多西紫杉醇组和支持治疗组发生率相似。另外以长春瑞滨或异环磷酰胺为对照的研究显示，多西紫杉醇组反应率、疾病进展时间和生存率优于对照；4级血液学不良反应多西紫杉醇组高于对照组，其他3～4级非血液学不良反应的发生率无明显规律。生存质量评价（LCSS、QLQ—C30或QLQ—LC13）方面，患者自评和观察者评价均显示多西紫杉醇组优于支持治疗组。不同给药方案（3周给药和1周给药）的Meta分析结果可以看出不同给药方案在疾病控制率、反应率及1年生存率方面没有统计学差异（P〉0．05）；在嗜中性白细胞减少症、白细胞减少症的发生率上，1周给药组发生率均低于3周给药组（P〈0．01）；在非血液学不良反应如虚弱、恶心／呕吐的发生率上，不同给药方案没有统计学差异（P〉0．5）。结论多西紫杉醇可以认为是在晚期非小细胞肺癌的二线治疗中疗效确切的药物；不同的多西紫杉醇给药方案（3周vs1周），在疗效方面差异不明显，在不良反应发生率上略有差异，因此，在发生严重血液学不良反应的情况下，可以用1周给药代替3周给药进行治     

表柔比星联合多西他赛或紫杉醇治疗乳腺癌效果差异分析

目的探讨表柔比星联合多西他赛或紫杉醇治疗乳腺癌的效果差异。方法选取2018年2月至2019年7月本院收治的86例乳腺癌患者,根据动态随机分组法将其分为对照组(n=43)和观察组(n=43),对照组采用表柔比星联合紫杉醇治疗,观察组采用表柔比星联合多西他赛治疗,比较两组临床缓解率、1年内复发率、生存时间以及不良反应发生率。结果两组患者临床缓解率差异经统计学软件检验显示无统计学意义(P>0.05);观察组1年内复发率和不良反应发生率低于对照组,生存时间长于对照组,差异经统计学软件检验显示有统计学意义(P<0.05)。结论表柔比星联合多西他赛或紫杉醇对乳腺癌的治疗效果相近,但联合多西他赛的不良反应风险更低,还可延长患者生存时间。     

Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms

Background

Breast cancer patients initiating TEC (including docetaxel, epirubicin, and cyclophosphamide) treatment were genotyped for CYP3A4, CYP3A5, and ABCB1 to identify variability factors of side effects for docetaxel.

Methods

The planned dose of docetaxel per course was formulated according to each patient's height and weight. Each participant had received TEC treatment for 6 consecutive cycles. The single nucleotide polymorphisms (SNPs) of CYP3A4?4 (352A > G), CYP3A4?5 (653C > G), and CYP3A4?18A (20070T > C) for the CYP3A4 gene, CYP3A5?3A (6986A > G) for the CYP3A5 gene, and − 41A > G, − 145C > G, 1236C > T, 2677G > T(A), and 3435C > T SNPs for the ABCB1 gene were determined by using the restriction fragment length polymorphism of polymerase chain reaction products and the restriction enzymes.

Results

Fifty-nine Taiwanese women (mean age, 46 y; range, 30-64 y) treated for breast cancer with TEC were recruited. We found that patients carrying the CYP3A5?1/?3 genotype demonstrated more side effects of fever, pleural effusion, and febrile neutropenia than those with the CYP3A5?3/?3 genotype (p = 0.075, 0.077, and 0.030, respectively); moreover, patients with the ABCB1 2677G/G genotype also showed more side effects of fever and febrile neutropenia than those with other genotypes (p = 0.024 and 0.027), In regard to ABCB1 3435C > T, patients with ABCB1 3435C/C tended to suffer leucopenia (p = 0.057).

Conclusions

There could be correlations between certain side effects of docetaxel treatment and polymorphisms of these metabolic enzymes. Unfortunately, there is not so much evidence due to the small sample size of this study which restricts the statistical power.     

芪胶升白胶囊对曲妥珠单抗和多西紫杉醇治疗转移性乳腺癌的影响

目的 探讨芪胶升白胶囊对曲妥珠单抗和多西紫杉醇治疗转移性乳腺癌的影响。方法 选择我院肿瘤内科转移性乳腺癌患者100 例,分为对照组与观察组,各50 例。对照组给予曲妥珠单抗和多西紫杉醇治疗;观察组给予芪胶升白胶囊联合曲妥珠单抗和多西紫杉醇治疗：疗程均25 周,疗程结束时观察两组临床疗效、生活质量和不良反应,并观察1 年内生存情况。结果 两组临床效果比较,差异无显著性（Z=-1.50,P＞0.05）;两组1 年内生存情况比较,差异无显著性（χ2=1.00,P＞0.05）;两组生活质量比较,观察组高于对照组（t=2.37,P＜0.05）;两组治疗后骨髓抑制比较差异有显著性（χ2=4.76,P＜0.05）,而肝肾功能损害比较差异具有显著性（χ2=7.90,P＜0.01）。结论芪胶升白胶囊可提高曲妥珠单抗和多西紫杉醇治疗转移性乳腺癌患者的生活质量,显著减轻化疗所引起的肝肾损伤和骨髓抑制。     

XELOX与DF方案治疗晚期胃癌临床疗效比较

目的比较XELOX和DF方案对晚期胃癌的临床疗效和毒副反应。方法132例晚期胃癌患者随机分为XELOX组和DF组。所有病例治疗4周期以上,按WHO标准评价并比较两组的客观疗效和毒副反应。结果XELOX组总有效率52．3％,DF组总有效率47．8％（P〉0．05）。XELOX组手足综合征的发生率为36．92％,明显高于DF组的13．43％（P〈0．05）;而骨髓抑制的发生率为41．54％,显著低于DF组的85．07％（P〈0．05）;其余各项常见的副作用未见明显差异,无统计学意义（P〉0．05）。结论XELOX方案与DF方案治疗晚期胃癌疗效相当,而XELOX方案骨髓抑制副反应小,耐受性好,更易为老年患者所接受。     

Tumor targetability and antitumor effect of docetaxel-loaded hydrophobically modified glycol chitosan nanoparticles

Hydrophobically modified glycol chitosan (HGC) nanoparticles, a new nano-sized drug carrier, were prepared by introducing a hydrophobic molecule, cholanic acid, to water soluble glycol chitosan. The HGC nanoparticles were easily loaded with the anticancer drug docetaxel (DTX) using a dialysis method, and the resulting docetaxel-loaded HGC (DTX-HGC) nanoparticles formed spontaneously self-assembled aggregates with a mean diameter of 350 nm in aqueous condition. The DTX-HGC nanoparticles were well dispersed and stable for 2 weeks under physiological conditions (pH 7.4 and 37°C) and a sustained drug release profile, in vitro. In addition, the DTX-HGC nanoparticles were reasonably stable in the presence of excess bovine serum albumin, which suggested that the DTX-HGC nanoparticles might also be stable in the blood stream. The DTX-HGC nanoparticles exhibited a distinctive deformability in aqueous conditions, in that they could easily pass through a filter membrane with 200 nm pores despite their mean diameter of 350 nm. We also evaluated the time-dependent excretion profile, in vivo biodistribution, prolonged circulation time, and tumor targeting ability of DTX-HGC nanoparticles by using a non-invasive live animal imaging technology. Finally, under optimal conditions for cancer therapy, the DTX-HGC nanoparticles showed higher antitumor efficacy such as reduced tumor volume and increased survival rate in A549 lung cancer cells-bearing mice and strongly reduced the anticancer drug toxicity compared to that of free DTX in tumor-bearing mice. Together our results showed that the anticancer loaded nano-sized drug carriers are a promising nano-sized drug formulation for cancer therapy.     

TEC方案化疗后乳腺癌患者的早期心脏毒性

目的 观察多西他赛、表柔比星、环磷酰胺(TEC)联合化疗对乳腺癌患者早期心脏毒性影响.方法 收集2009年12月～2011年6月共71例乳腺癌患者,中位年龄48 (35～64)岁,术后予6个周期TEC方案化疗,化疗前及化疗结束时、结束后12h、24 h、48 h及72 h的分别检测血清心肌肌钙蛋白Ⅰ(cTnI)及检查心电图.结果 (1)患者化疗后不同时间点cTnI出现异常的比例均较化疗前明显升高(P＜0.01); (2)共有8(11.27％)例出现心电图改变,其中窦性心动过速4例(5.63％)、ST-T改变1例(1.41％)、窦性心动过缓2例(2.82％)、房室传导阻滞1例(1.41％),除1例为Ⅱ级毒性反应外,其余7例为Ⅰ级毒性反应.结论 TEC方案化疗后可引起早期心脏毒性反应.     

Four consecutive multicenter phase II trials of adjuvant chemoradiation in patients with completely resected high-risk gastric cancer: the experience of the German AIO/ARO/CAO group

Purpose

Feasibility and efficacy of four different adjuvant radiochemotherapy regimens in patients with completely resected gastric cancer were evaluated in consecutive cooperative phase II trials using different 5-fluorouracil (5-FU)-based combination chemotherapies (CTX) and 5-FU-enhanced radiotherapy.

Methods

Between 2000 and 2005, 157 patients with completely resected gastric adenocarcinoma were included. The study design was based on two cycles of CTX and irradiation with 45 Gy plus concomitant 5-FU 225 mg/m² per 24 h between these two cycles. CTX cycles consisted of 5-FU, folinic acid (FA), cisplatin plus paclitaxel (FLPP); 5-FU, FA and cisplatin (FLP); 5-FU, FA and irinotecan (FLI); or 5-FU, cisplatin plus docetaxel (FPD).

Results

Median follow-up for all four trials was 18 months (range, 1–64) without significant difference between the four regimens: FLPP 30 months (2–46+), FLP 18 months (1–64+), FLI 15 months (1–26), FPD 10 months (5–19+). Treatment associated toxicity was tolerable and did not differ significantly between the four CTX regimens. Across all patients grade ¾, toxicities during the first cycle/chemoradiation/second cycle consisted of leukocytopenia 4%/2%/30%, anorexia 5%/10%/6%, diarrhea 6%/1%/3%, nausea 2%/7%/2%. Early death occurred in one patient due to Pneumocystis carinii pneumonia. Median progression free survival was 23 months for FLPP, 18 months for FLP, 14 months for FLI, 9 months for FPD (not significant). One-year-overall survival rates were 95% for FLPP, 82% for FLP, 94% for FLI, 86% for FPD.

Conclusion

Adjuvant radiochemotherapy in patients with gastric cancer can be safely given continuous infusion of 5-FU at 225 mg/m² per day. In addition, a variety of 5-FU-based multiagent chemotherapy regimen with defined activity in gastric cancer appears both safe and effective when given prior and after radiochemotherapy in this setting.

     

比卡鲁胺联合化疗治疗去势抵抗性前列腺癌的临床分析

目的探讨晚期去势抵抗性前列腺癌安全、有效的治疗方法。方法以比卡鲁胺作为二线抗雄激素药物,联合多西紫杉醇加泼尼松化疗治疗26例去势抵抗性前列腺癌患者,观察疗效及毒副反应。结果 26例去势抵抗性前列腺癌患者25例有效,有效率为96.15%。最常见的毒副反应是骨髓抑制,可耐受。结论比卡鲁胺作为二线抗雄激素药物联合多西紫杉醇加泼尼松化疗治疗去势抵抗性前列腺癌的临床疗效明显,毒副反应轻,可作为晚期去势抵抗性前列腺癌的治疗策略。