Clinical Research on Albumin-Bound Paclitaxel-Based Chemotherapy for Advanced Esophageal Cancer

Background: To evaluate the efficacy and safety of albumin-bound paclitaxel-based chemotherapy in treatmentfor patients with advanced esophageal cancer who failed in first-line chemotherapy. Materials and Methods: Wecollected29 advanced esophageal cancer patients who received albumin-bound paclitaxel-based chemotherapyfromJune 2009 to September 2013, and the efficacy and safety of the compound were evaluated. These patientswere treated with 100-150mg/m2 nab-paclitaxel on days 1,8.The cycle was repeated every 3 weeks. Clinicalefficacy was evaluated every two cycles. Results: Of the 29 patients, two persons interrupted treatment because ofadverse reactions, failed to evaluate efficacy effect. The rest of27 patients who could be evaluated for short-termresponse, 10 patients (37%) achieved partial response, 2 (7.4%) remained stable disease, and 15 (55.6%) hadprogressivedisease. The objective response rate was 37%, and the disease control rate was 44.4%.The mediantime to progression was 6.6 months.The major adverse reactions includedalopecia (62.07%), neutropenia (65.5%),gastrointestinalreaction (10.3%) andsensory neuropathy(6.8%). Conclusions: The albumin-bound paclitaxelbasedchemotherapy is efficacy and safety in treatment for patients with advanced esophageal cancer who failedin first-line chemotherapy.     

紫杉醇脂质体与多西紫杉醇对乳腺癌疗效及安全性临床观察

目的对比乳腺癌的新辅助化疗方案中紫杉醇脂质体与多西紫杉醇治疗效果和安全性的差异。方法对接受新辅助化疗后手术的乳腺癌174例患者的临床资料进行回顾性分析,根据患者自愿选择用药分为观察组（接受紫杉醇脂质体治疗）和对照组（接受多西紫杉醇治疗）,每组各87例,同时两组均给予环磷酰胺及表阿霉素的联合新辅助化疗方案,1个化疗周期为21天,共进行6个化疗周期,结束后过3周再给予手术切除,对两组的治疗效果及不良反应等进行统计分析。结果观察组的病理完全缓解率为10.3％（9/87）,客观缓解率分别为80.5％（70/87）,疾病控制率为95.4％（83/87）,对照组分别为9.2％（8/87）、79.3％（69/87）、93.1％（81/87）,两组比较差异均无统计学意义（P＞0.05）。观察组的白细胞减少（Ⅲ～Ⅳ级）、中性粒细胞减少（Ⅲ～Ⅳ级）、过敏反应、体液潴留、皮肤指甲毒性反应及口腔黏膜炎等的发生率均较对照组显著降低,差异均有统计学意义（均P＜0.05）。结论紫杉醇脂质体对于乳腺癌新辅助化疗的疗效与多西紫杉醇相近,但其化疗的不良反应发生率较低且程度轻,安全性要更高。     

叶酸偶联纳米紫杉醇脂质体在大鼠体内的药物代谢动力学研究

目的探讨叶酸偶联纳米紫杉醇脂质体在大鼠体内的药物代谢动力学。方法将SD大鼠尾静脉注射叶酸偶联纳米紫杉醇脂质体（实验组）及普通紫杉醇脂质体（对照组）,采用高效液相色谱分析紫外（HPLC—UV）法检测两组大鼠体内血药浓度经时变化,Excel绘制药物经时曲线。药物代谢统计分析软件（DAS）模拟房室模型并计算药代动力学参数。结果①紫杉醇标准品血样在0．07-30μg／ml浓度时呈良好的线性关系,浓度测定的日内、日间精密度的相对标准偏差（RSD）值〈6％,高（10．0μg／ml）、中（2．0μg／ml）、低（0．2μg／ml）浓度下的紫杉醇标准品血样的提取回收率均〉90％;②实验组血药浓度经时曲线符合1／C权重的三室模型,对照组符合1／C2权重的二室模型;③实验组药物快、慢分布相半衰期分别是（0．12±0．10）h和（0．40±0．08）h,消除半衰期是（3．29±1．02）h,血浆清除率（CL）是（1．37±0．04）L／（kg·h）,0～t时血药浓度一时间曲线下面积（AUC）及AUC（0～∞）分别是（12．19±0．40）mg／（L·h）和（14．61±0．40）mg／（L·h）;对照组药物分布相半衰期是（0．09±0．08）h,消除半衰期是（2．57±0．51）h,CL是（1．50±0．10）L／（kg·h）,AUC（0～t）及AUC（0～∞）分别是（9．30±0．48）mg／（L·h）和（13．39±0．92）mg／（L·h）;两组消除半衰期、CL、AUC（0-t）和AUC（0～∞）比较,差异均有统计学意义（P〈0．05）。结论叶酸偶联纳米紫杉醇脂质体与普通紫杉醇脂质体均能较快地分布于体内并达到平衡,但是前者半衰期较长,清除速度略快,生物利用度高。     

Vorinostat increases carboplatin and paclitaxel activity in non‐small cell lung cancer cells

We observed a 53% response rate in non‐small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 hr of continuous drug exposure. Vorinostat (1 μM) inhibited growth by: 17% ± 7% in A549, 28% ± 6% in 128‐88T, 39% ± 8% in Calu1 and 41% ± 7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel led to significantly greater growth inhibition than chemotherapy alone in all 4 cell lines. Vorinostat (1 μM) synergistically increased the growth inhibitory effects of carboplatin/paclitaxel in 128‐88T cells. When colony formation was measured after drug withdrawal, vorinostat significantly increased the effects of carboplatin but not paclitaxel. The % colony formation was control 100%; 1 μM vorinostat, 83% ± 10%; 5 μM carboplatin, 41% ± 11%; carboplatin/vorinostat, 8% ± 4%; 2 nM paclitaxel, 53% ± 11%; paclitaxel/vorinostat, 46% ± 21%. In A549 and 128‐88T, vorinostat potentiated carboplatin induction of gamma‐H2AX (a DNA damage marker) and increased α‐tubulin acetylation (a marker for stabilized mictrotubules). In A549, combination of vorinostat with paclitaxel resulted in a synergistic increase in α‐tubulin acetylation, which reversed upon drug washout. We conclude that vorinostat interacts favorably with carboplatin and paclitaxel in NSCLC cells, which may explain the provocative response observed in our clinical trial. This likely involves a vorinostat‐mediated irreversible increase in DNA damage in the case of carboplatin and a reversible increase in microtubule stability in the case of paclitaxel.     

Phase 2 study of irinotecan and paclitaxel in patients with recurrent or refractory small cell lung cancer

BACKGROUND:

Patients with extensive stage small cell lung cancer (SCLC) who develop disease progression with standard cisplatin‐based therapy are reported to have a poor overall prognosis. Irinotecan and paclitaxel are active as single agents and exhibit preclinical synergy in SCLC cell lines. A phase 2 study was conducted to evaluate this combination in patients with recurrent or refractory SCLC.

METHODS:

Patients with SCLC who progressed with 1 prior chemotherapy regimen and had measurable disease present; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; and adequate bone marrow, hepatic, and renal function were included in the study. Paclitaxel (at a dose of 75 mg/m²) and irinotecan (at a dose of 50 mg/m²) were administered intravenously on Days 1 and 8 of each 3‐week treatment cycle. Therapy was continued until disease progression or unacceptable toxicity. The target response rate of interest was ≥30%.

RESULTS:

A total of 55 patients were enrolled, 51 of whom received at least 1 dose of therapy. The majority of the patients had an ECOG PS of 0 or 1 (96%). A median of 3 cycles of treatment was administered, and 15 patients received ≥6 cycles. Seventeen patients experienced toxicity of grade 3 or higher (neutropenia in 8 patients and fatigue in 5 patients). The overall response rate was 21%. The median survival was 25.4 weeks, and the 1‐year survival rate was 22%.

CONCLUSIONS:

The regimen of irinotecan and paclitaxel was found to be tolerated well in patients with recurrent or refractory SCLC. Although modest anticancer activity was noted, the efficacy failed to meet the primary endpoint of interest. Cancer 2010. © 2010 American Cancer Society.     

Ten‐year follow‐up of a phase 2 study of dose‐intense paclitaxel with cisplatin and cyclophosphamide as initial therapy for poor‐prognosis,advanced‐stage epithelial ovarian cancer

BACKGROUND:

The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced‐stage epithelial ovarian cancer (EOC) who were receiving dose‐intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule.

METHODS:

Patients with stage III/IV EOC received cyclophosphamide 750 mg/m², followed by a 24‐hour infusion of paclitaxel 250 mg/m² and cisplatin 75 mg/m² on Day 2. Filgrastim began on Day 3 at 10 μg/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel.

RESULTS:

Sixty‐two patients were enrolled. Thirty‐two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent‐to‐treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow‐up of 11.4 years, the median progression‐free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel.

CONCLUSIONS:

The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Oncology Group suggest that further study is warranted of dose‐dense or dose‐intense paclitaxel regimens in women with newly diagnosed, advanced‐stage EOC. Cancer 2010. © 2010 American Cancer Society.     

A phase 2 clinical trial of nab‐paclitaxel in previously treated and chemotherapy‐naive patients with metastatic melanoma

BACKGROUND:

nab‐Paclitaxel (ABI‐007, Abraxane), a 130‐nM, albumin‐bound (nab) particle form of Cremophor‐free paclitaxel, is approved for metastatic breast cancer. In the current study, the efficacy and safety of nab‐paclitaxel were evaluated in previously treated and chemotherapy‐naive patients with metastatic melanoma (MM).

METHODS:

Patients with histologically or cytologically confirmed, measurable MM were enrolled. nab‐Paclitaxel was administered intravenously weekly for 3 of 4 weeks at a dose of 100 mg/m² (in previously treated patients) or 150 mg/m² (in chemotherapy‐naive patients).

RESULTS:

Thirty‐seven patients were treated in each cohort. The response rate was 2.7% in the previously treated cohort and 21.6% in the chemotherapy‐naive cohort; the response plus stable disease rate was 37.8% and 48.6% in the previously treated and chemotherapy‐naive cohorts, respectively. The median progression‐free survival (PFS) was 3.5 months and 4.5 months, and the median survival was 12.1 months and 9.6 months, respectively. The probability of being alive and free of disease progression at 6 months was 27% for the previously treated cohort and 34% for the chemotherapy‐naive cohort; the probability of surviving 1 year was 49% and 41%, respectively, for the previously treated and chemotherapy‐naive cohorts. Approximately 78% of the previously treated patients and 49% of the chemotherapy‐naive patients were treated without dose reduction. Eight (22%) chemotherapy‐naive patients discontinued therapy because of toxicities. Drug‐related toxicities included grade 3 to 4 (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neuropathy, alopecia, neutropenia, and fatigue.

CONCLUSIONS:

nab‐Paclitaxel was found to be well tolerated and demonstrated activity in both previously treated and chemotherapy‐naive patients with MM. The response rate, PFS, and survival compared favorably with current standard dacarbazine therapy and combination therapies for melanoma. nab‐Paclitaxel therapy of MM should be investigated further in controlled clinical trials. Cancer 2010. © 2010 American Cancer Society.     

紫杉醇诱导子宫颈癌H eLa细胞自噬性凋亡的观察

目的观察紫杉醇对体外培养的子宫颈癌HeLa细胞自噬性凋亡的影响,并初步探讨其可能的机制。方法不同浓度（1.2、6、12、24、36 mg/L）的紫杉醇处理体外子宫颈癌HeLa细胞6、12、24、48、72小时后,用MTT法测定其生长抑制率,倒置显微镜及透视电镜观察细胞形态学变化,通过流式细胞术分别测定细胞凋亡率、细胞周期分布,RT-PCR检测自噬基因Beclin1表达的变化情况。结果紫杉醇呈剂量和时间依赖性抑制子宫颈癌HeLa细胞增殖;紫杉醇12 mg/L处理的HeLa细胞,早期（24小时内）可出现明显的细胞自噬性变化,细胞凋亡数明显增加,G2/M期阻滞,且自噬基因Beclin1的表达明显增高。结论紫杉醇具有抑制子宫颈癌HeLa细胞增殖、诱导细胞自噬性凋亡等作用,诱导子宫颈癌HeLa细胞发生自噬性凋亡,其机制可能与上调自噬基因Beclin1的表达水平有关。     

紫杉醇和顺铂联合放疗治疗老年晚期非小细胞肺癌疗效观察

目的研究紫杉醇和顺铂诱导化疗并同期联合放疗治疗不能手术的局部晚期非小细胞肺癌（NSCLC）的最佳治疗模式及疗效、预后和毒副反应。方法 82例局部晚期非小细胞肺癌患者,先给予紫杉醇和顺铂诱导化疗2周期,继之紫杉醇40 mg/m^2,静脉滴注,每周1次,并同期联合放疗,放疗结束后2月评价疗效。结果同步放疗、化疗的治疗总有效率为81.7%,1、2、3年生存率为78.6%、54.8%、38.1%,中位生存期19.6月,3年无进展生存率为26.8%（22/82）。治疗前后的QOL、KPS随机比较,差异有统计学意义（P〈0.01）。同步放疗、化疗期间入组患者其毒性可耐受,主要的急性毒副反应为白细胞下降、放射性肺炎和放射性食管炎;后期反应主要为肺纤维化和食管损伤,程度可接受,经对症处理均能耐受,均能顺利完成计划。结论每周紫杉醇联合同期放疗治疗局部晚期非小细胞肺癌有较好的疗效,值得临床应用。