白蛋白结合型紫杉醇与紫杉醇脂质体治疗复发性卵巢癌近期疗效及对Twist蛋白和血管内皮生长因子表达的影响

目的：分析白蛋白结合型紫杉醇与紫杉醇脂质体治疗复发性卵巢癌近期疗效及对Twist蛋白和血管内皮生长因子（VEGF）表达的影响。方法回顾性分析2013年4月至2014年3月本院收治的76例复发性卵巢癌患者的临床资料。按照治疗方法不同将其分为观察组和对照组，每组各38例。观察组患者予以白蛋白结合型紫杉醇联合奈达铂治疗，对照组患者予以紫杉醇脂质体联合奈达铂治疗。分析两组患者癌抗原125（CA125）、肿瘤病灶的变化情况，不良反应的差异以及Twist和VEGF的表达。结果观察组患者CA125下降和病灶缩小的有效率明显高于对照组（P＜0.05）。观察组患者各不良反应发生率均明显低于对照组（P＜0.05）。观察组患者Twist、VEGF阳性表达率均明显高于对照组（P＜0.05）。Twist和VEGF阳性表达率和淋巴结是否转移呈正相关（P＜0.05），而Twist和VEGF阳性表达率和患者的年龄以及肿瘤直径无关（P＞0.05）。结论白蛋白结合型紫杉醇治疗复发性卵巢癌近期疗效优于紫杉醇脂质体，患者的耐受性较好；同时，Twist和VEGF在复发性卵巢癌近期发生发展中有重要作用。     

Randomized phase 2 study of concomitant chemoradiotherapy using weekly carboplatin/paclitaxel with or without daily subcutaneous amifostine in patients with locally advanced head and neck cancer

BACKGROUND:

A randomized phase 2 study was performed to investigate the efficacy/toxicity of combining concomitant boost radiation and weekly carboplatin/paclitaxel with or without amifostine in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

METHODS:

Patients with newly diagnosed, locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin (area under the curve, 1.5) and paclitaxel (45 mg/m²) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks (every day for 18 days, twice a day for 12 days) (grading determined according to the TNM staging system). All patients were randomized to subcutaneous daily amifostine at a dose of 500 mg (Arm A) or no amifostine (Arm B). Toxicity data were collected weekly, and saliva collection was performed with and without citric acid stimulation. To evaluate the correlation between serum cytokine levels and the severity of oral mucositis, we evaluated a subset (13 patients in Arm A and 11 patients in Arm B) of subjects at baseline and then on alternate weeks.

RESULTS:

Fifty‐eight patients were enrolled, 29 in each arm. The majority of patients were men (90%), had stage IV disease (82%), and had the oropharynx as the primary tumor site (60%). Major toxicities encountered were similar in both arms and included grade 3 (as determined by Common Terminology Criteria for Adverse Events, version 3.0) mucositis (75% in Arm A and 70% in Arm B) and grade 2 xerostomia (41% in both arms). The median number of amifostine doses delivered was 28, with skin toxicity (grade 3 in 11 patients) as the limiting factor. Saliva production showed no difference between the arms. The median follow‐up was 34 months, and only 5 failures had been encountered (2 local and 3 distant) at the time of last follow‐up, with an overall survival rate of 89%. Neck dissection was performed in 25 patients; 5 patients demonstrated persistent disease and 4 patients were alive without disease recurrence at the time of last follow‐up. The median time to percutaneous endoscopic gastrostomy removal was 9.6 months in Arm A and 10.4 months in Arm B. Only 1 patient remained percutaneous endoscopic gastrostomy–dependent at the time of last follow‐up. A correlation was noted between levels of selected cytokines and mucositis severity, in which higher levels of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]‐1, and IL‐6) and lower levels of anti‐inflammatory cytokines (IL‐13) were noted. No changes in C‐reactive protein levels were noted.

CONCLUSIONS:

Four weekly doses of carboplatin/paclitaxel with concomitant boost radiation was found to be a highly effective regimen in this patient population with advanced SCCHN. The overall survival rate was 89%. The time to percutaneous endoscopic gastrostomy removal was prolonged. Amifostine given subcutaneously did not improve the rates of xerostomia and mucositis with this fairly intensive chemoradiotherapy regimen. Cancer 2009. © 2009 American Cancer Society.     

Long-term glutamate supplementation failed to protect against peripheral neurotoxicity of paclitaxel

Toxic peripheral neuropathy is still a significant limiting factor for chemotherapy with paclitaxel (PAC), although glutamate and its closely related amino acid glutamine were claimed to ameliorate PAC neurotoxicity. This pilot trial aimed to evaluate the role of glutamate supplementation for preventing PAC-induced peripheral neuropathy in a randomized, placebo-controlled, double-blinded clinical and electro-diagnostic study. Forty-three ovarian cancer patients were available for analysis following six cycles of the same PAC-containing regimen: 23 had been supplemented by glutamate all along the treatment period, at a daily dose of three times 500 mg (group G), and 20 had received a placebo (group P). Patients were evaluated by neurological examinations, questionnaires and sensory–motor nerve conduction studies. There was no significant difference in the frequency of signs or symptoms between the two groups although neurotoxicity symptoms presented mostly with lower scores of severity in group G. However, this difference reached statistical significance only with regard to reported pain sensation ( P  = 0.011). Also the frequency of abnormal electro-diagnostic findings showed similarity between the two groups (G: 7/23 = 30.4%; P: 6/20 = 30%). This pilot study leads to the conclusion that glutamate supplementation at the chosen regimen fails to protect against peripheral neurotoxicity of PAC.     

紫杉醇脂质体的制备及初步毒性、药效学研究

 目的 制备紫杉醇脂质体并对其理化性质、毒性及药效学进行初步研究。方法 将大豆卵磷脂（soybean Phosphatidylcholine,SPC）、培化磷脂酰乙醇胺（mPEG2000-DSPE）及紫杉醇以100∶0.5∶5（摩尔比）混合并溶解于氯仿中,采用油水相研磨成乳,然后高压均质的方法制备脂质体。采用低速离心法测定包封率,动态光散射法测定粒度分布,KM鼠进行毒性实验,H22/KM小鼠为模型进行药效实验。结果 脂质体平均粒径为（140±10） nm;药脂摩尔比在3%～6%内包封率均大于95%;毒性实验表明,紫杉醇脂质体（Pac-lipo）和紫杉醇游离药（Pac-free）对KM雄性小鼠的最大耐受剂量（MTD）分别为64.8和29.4 mg·kg^-1;药效实验表明,紫杉醇脂质体剂量依赖性的抑制鼠肝癌H22肿瘤生长。结论 紫杉醇脂质体具有较高包封率,与紫杉醇游离药相比可以显著提高治疗指数。     

紫杉醇联合顺铂或奈达铂新辅助化疗治疗局部晚期子宫颈癌的近远期疗效观察

目的 比较紫杉醇联合顺铂或奈达铂新辅助化疗治疗局部晚期子宫颈癌的疗效和不良反应.方法 49例局部晚期子宫颈癌患者随机分为顺铂组和奈达铂组,给予紫杉醇联合顺铂或奈达铂化疗,化疗2个疗程.评价两组的近、远期疗效和不良反应.结果 顺铂组总缓解率为79.2％,临床获益率为100.0％,奈达铂组总缓解率为76.0％,临床获益率为100.0％.两组比较差异均无统计学意义(P＞0.05).各组化疗前后肿瘤大小比较差异均具有统计学意义(P＜0.05),但两组组间比较差异无统计学意义(P＞0.05).顺铂组Ⅰ、Ⅱ级胃肠道反应、肌酐升高和血红蛋白下降的发生率明显高于奈达铂组(P＜0.05),但其Ⅰ、Ⅱ级血小板减少的发生率明显低于奈达铂组(P＜0.05).顺铂组1、2、3年生存率分别为91.7％、83.3％和79.2％,奈达铂组1、2、3年生存率分别为88.0％、84.0％和76.0％,两组比较差异均无统计学意义(P＞0.05).结论 紫杉醇联合顺铂或奈达铂新辅助化疗治疗局部晚期子宫颈癌患者的近、远期疗效相似,但奈达铂不良反应相对低,临床更易耐受.     

Potential Predictive Factors for Response to Weekly Paclitaxel Treatment in Patients with Metastatic Breast Cancer

Abstract

The authors compare results obtained from weekly paclitaxel treatment in advanced breast cancer patients with biological and clinical prognostic factors. Expression of c-erbB-2, Ki-67, p53 and hormone receptors (HR) was examined by immunohistochemistry in samples of breast tissue from 30 patients. Univariate analysis showed that Ki-67 positivity and low performance status (PS) were associated with poor outcome (P <0.05). We observed that expression of p53 and c-erbB-2 did not have any negative effect on response to chemotherapy and survival. HR-negative patients had better response and slightly statistically significant overall survival (OS) rates compared to HR-positive patients (P >0.05). In a multivariate analysis low PS was the only significant predictor of shorter survival (P <0.05). In conclusion, while the expression of p53 and c-erbB-2 did not have any effect on treatment results, negative Ki-67 expression and negative HR status were associated with better OS in this patient population. PS was the only significant predictor for OS.     

Drug-induced subacute cutaneous lupus erythematosus associated with nab-paclitaxel therapy

Drug-induced lupus erythematosus (dile) syndromes are documented complications of chemotherapeutic agents, including paclitaxel. Subacute cutaneous lupus erythematosus (scle) is a distinct dile syndrome presenting with characteristic annular or papulosquamous skin lesions in a photosensitive distribution with associated high anti-ssa titres. Previously, dile syndromes complicating paclitaxel therapy have been attributed to polyethoxylated castor oil (Kolliphor EL: BASF, Ludwigshafen, Germany), the biologic solvent included in the drug’s original formulation (Taxol: Bristol–Myers Squibb, Montreal, QC), rather than the parent chemotherapy molecule. Here, we report a characteristic case of drug-induced scle complicating treatment with nanoparticle albumin bound (nab)–paclitaxel (Abraxane: Celgene, Summit, NJ, U.S.A.), a solvent-free taxane formulation. The pertinent English-language literature is also discussed. This case report is the first to link solvent-free paclitaxel with scle, and it suggests that the parent molecule is responsible for the reaction.     

Intraperitoneal chemotherapy in the management of malignant disease

The intraperitoneal administration of antineoplastic agents has been proposed as a method to improve the efficacy of therapy of malignant disease principally confined to the peritoneal cavity. Phase I studies have demonstrated the safety and pharmacokinetic advantage for a number of drugs delivered directly into the body compartment, with surgically-defined responses documented in the Phase II trial setting. More recently reported randomized Phase III studies have revealed a survival benefit associated with the use of intraperitoneal cisplatin, compared to iv. drug delivery when employed as initial treatment of small volume residual advanced ovarian cancer. While there is far less experience with regional therapy of gastrointestinal cancers, limited data suggest intraperitoneal drug administration should be further explored as a potentially important strategy to improve the outcome for this group of malignancies.