Simultaneous Modulated Accelerated Radiation Therapy and Concurrent Weekly Paclitaxel in the Treatment of Locally Advanced Nasopharyngeal Carcinoma

Objectives: To evaluate the feasibility and efficacy of simultaneous accelerated radiation therapy (SMART) andconcurrent weekly paclitaxel in the treatment of locally advanced nasopharyngeal carcinoma. Methods: Fortyonepatients with pathologically confirmed nasopharyngeal carcinoma were treated by SMART with concurrentweekly paclitaxel. Daily fraction doses of 2.5 Gy and 2.0 Gy were prescribed to the gross tumor volume (GTV)and clinical target volume (CTV) to a total dose of 70 Gy and 56 Gy, respectively. Paclitaxel of 45 mg/m2 wasadministered concurrently with radiation therapy every week. Adjuvant chemotherapy was given four weeksafter the completion of the radiotherapy (RT) if the tumor demonstrated only a partial response (PR). Results:All patients completed the radiotherapy (RT) course. Adjuvant chemotherapy was administered to 12 patientsdue to PR. The CR (complete remission) rate was 82.9% three months after RT. Thirty-nine (95.1%) patientscompleted the concurrent weekly chemotherapy with paclitaxel, and two patients skipped their sixth course.Seven patients had a 15% dosage reduction at the fifth and sixth course due to grade 3 mucositis. The medianfollow-up was 30 (range, 14-42) months. The three-year overall survival (OS), metastases-free survival (MFS),and local control rates were 77.0%, 64.4%, and 97.6%, respectively. No correlation between survival rate and Tor N stage was observed. Grade 3 acute mucositis and xerostomia were present in 17.1% and 7.1%, respectively.Conclusion: SMART with concurrent weekly paclitaxel is a potentially effective and toxicity tolerable approachin the treatment of locally advanced NPC.     

Radiation, Hyperthermia, and Their Combination in Treatment of Chemically Induced Autochthonous Tumors in Mice

All autochthonous tumors induced chemically in the thighs of C3H/He mice showed recurrence after single X-irradiation with 20–60 Gy when they were 10 mm in diameter, although this treatment caused temporary, dose-dependent regression. Hyperthermia for 30 min at 43.0° alone had little effect. However, in 2 of 16 mice, hyperthermia after irradiation at 60 Gy resulted in complete cure, i.e., survival of mice without recurrence for more than 120 days after treatment. These results indicate that the combined treatment of radiation and hyperthermia is necessary to obtain the cure of mouse autochthonous tumors.     

Different Fractionation Schedules in Radiation Treatment of Cerebral Metastases

Multiple daily fractionation (MDF) was compared, in a cooperative study, with conventional fractionation (CF) in the radiation treatment of brain metastases. The 103 patients treated by MDF and the 44 given CF showed a similar response, in terms of neurologic improvement, survival, quality of residual life, and treatment-related morbidity. The hypothesis that MDF might give a better therapeutic ratio than CF was not confirmed in the present series. The short time period required gives MDF advantages in clinical practice.     

Paclitaxel induced apoptosis in breast cancer cells requires cell cycle transit but not Cdc2 activity

Purpose Paclitaxel (PTX) is a widely used chemotherapy agent and may cause cell death by apoptosis subsequent to microtubule (MT) disruption. In this paper, we have investigated whether cell cycle transit and or Cdc2 (Cdk1) activity is required for the apoptosis induced by PTX.Methods Cell cycle was analyzed by flow cytometry, Cdc2 was assayed bio chemically. Cdc2 activity was decreased by siRNA and dominant negative (dn) Cdc2 expression. Cells were arrested by chemical or biological inhibitors in a G₁or S phase. Apoptosis was measured by DNA fragmentation and examination of nuclei by microscopy. JNK and AKT activations were assessed as well.Results Cell cycle inhibition was highly effective in decreasing PTX induced apoptosis. MT morphology was not altered by these inhibitors. PTX induced JNK activity or AKT mediated BAD phosphorylation was unaffected by cell cycle inhibitors. Abrogation of Cdc 2 activity was without effect on PTX induced apoptosis.Conclusions While cell cycle transit is required for PTX induced apoptosis; Cdc2 activity is not required.     

Paclitaxel suppresses the growth of primary prostate tumours (RM-1) and metastases in the lung in C57BL/6 mice

Paclitaxel has potent anti-cancer effects through its ability to block metaphase/anaphase transition during cell mitosis. This study shows that paclitaxel can significantly suppress both primary orthotopic murine (RM-1) prostate tumour growth (up to 60%) and the formation of pseudometastatic tumour colony formation in the lungs (by up to 46%) in C57BL/6 mice in vivo. Tumour growth suppression was associated with increased RM-1 cell apoptosis in the primary prostate tumours. In vitro studies found that the duration of exposure time to Paclitaxel was correlated with its ability to suppress cell proliferation and induce G2/M arrest.     

紫杉醇诱导急性白血病细胞S期特异性凋亡

背景与目的:化疗药物的细胞周期特异性是临床设计化疗方案的重要依据。一般认为,紫杉醇为G2/M期特异性化疗药物。但是近来的相关研究却表明,药物在体内的细胞周期特异性可能与体外不同。本研究旨在观察紫杉醇作用于不同生长状态下白血病细胞的细胞周期特异性有无改变。方法:利用流式细胞分析技术,对紫杉醇作用于人急性淋巴细胞性白血病细胞株Molt-4以及作用于17例急性白血病细胞所诱导的凋亡效应进行了观察。结果:紫杉醇诱导在对数生长状态下的Molt-4细胞株G2/M期特异性凋亡,在高密度状态下培养的Molt-4细胞为G0/G1期特异性凋亡,而在临床标本中诱导S期特异性凋亡。结论:紫杉醇在不同模型诱导不同的细胞周期特异性凋亡。与一般认为的不同,紫杉醇引起患者白血病细胞S期特异性凋亡。这些不同很可能与细胞处于不同的生长状态有关。     

The Dynamics of Tumor Cords in an Irradiated Mouse Mammary Carcinoma with a Large Hypoxic Cell Component

The tumor cord model represents a histologically based framework for interpretation of radiobiological phenomena, particularly the resistance to radiation conferred by absence of oxygen. For the mammary carcinoma T50/80 grown in B6D2F1 male mice, average oxygenation was poor, based on tumor growth delay after irradiation. There was no improvement in radiobiological oxygenation for several days after a high dose of radiation. This was consistent with events in the cords of the tumor, where although up to 20% of all cells became pyknotic by 8 hr, the cords did not shrink for at least 2 days. The cellular kinetics of populations of intact and dead cells, adjacent to and remote from the capillaries of the cords, were examined for up to 60 hr after irradiation and it was found that: (i) before treatment, average LI (adjacent) was 13% and LI (remote) was 2%, (ii) after irradiation, cells expressed pyknosis after passing through the S phase of the cell cycle, so that (iii) at early intervals there was a larger proportional rise in pyknotic cells in the adjacent than the remote zone. However, (iv) at later intervals there was always a higher proportion of dead cells in the remote zone.     

Treatment Outcomes of Paclitaxel for Refractory or Recurrent Epithelial Ovarian Cancer Patients in Thailand

Background: To study the response rate, toxicity profiles, and survival of refractory or recurrent epithelialovarian cancer (EOC) patients treated with paclitaxel. Materials and Methods: Patients with refractory orrecurrent EOC who were treated with paclitaxel between January 2002 and December 2011 at the Departmentof Obstetrics and Gynecology, Faculty of Medicine, Vajira Hospital were identified. Clinicopathological featuresof the patients including detailed data of paclitaxel treatment were collected. Results: During the study period, atotal of 44 patients were identified, with a mean age of 52.9±8.2 years. Some 13.6% (six patients) had refractorycancer to first-line chemotherapy while 86.4% (38 patients) had recurrent cancer. Among these, 35 (79.6%)and 9 (20.4%) patients were considered as platinum-sensitive and platinum-resistant, respectively. Threepatients (6.8%) received fewer than 2 cycles of paclitaxel due to loss to follow-up, leaving 41 patients evaluablefor response. The overall response rate observed in all 41 patients was 41.5% (17 patients; 12 complete andfive partial responses): 12.5% or 1/8 patients with refractory or platinum-resistant cancer and 48.5% or 16/33patients with platinum-sensitive disease. Stable disease was demonstrated in 17.0% (seven patients) whileprogressive disease was apparent in 41.5% (17 patients). Median time to progress was 4.5 months (range, 0.67-58.6 months). Median progression-free survival was not reached while median overall survival was 16.3 months(95% confidence interval, 11.0 months -21.6 months). Common toxicities were neutropenia, neuropathy, andalopecia. Conclusions: Paclitaxel is an active agent for refractory or recurrent EOC. Neutropenia, neuropathyand alopecia are common side effects.     

紫杉醇脂质体治疗非小细胞肺癌40例近期疗效及安全性分析

目的比较国产紫杉醇脂质体与紫杉醇联合顺铂治疗非小细胞肺癌的疗效和安全性。方法病理诊断明确的晚期非小细胞肺癌患者随机进入试验组和对照组。试验组每周期予以紫杉醇脂质体135 mg/m2,对照组每周期予以紫杉醇135 mg/m2。两组每周期均联合顺铂75 mg/m2,每三周为一周期,两周期后评价疗效及安全性。结果82例患者进入该研究。试验组40例,对照组42例。其中81例患者可评价疗效和不良反应。试验组总有效率27.5％,对照组总有效率24.4％,两组有效率差异无统计学意义。两组血液学毒性发生率差异无统计学意义。但周围神经病变及聚氧乙基代蓖麻油与无水乙醇的混合溶媒所产生的相关毒性,试验组发生率明显低于对照组,差异有统计学意义。结论紫杉醇脂质体联合顺铂治疗晚期非小细胞肺癌疗效与紫杉醇相当,但过敏反应和周围神经病变的发生率明显降低。     

紫素为主的化疗联合放疗增加乳腺癌患者放射性肺炎危险性的分析

目的：评价紫素为主的化疗联合放疗增加乳腺癌患者放射性肺炎的危险性。方法：回顾性分析276例行联合放化疗的乳腺癌患者放射性肺炎的发病率,其中215例患者为术后三野放疗,61例为保乳术后切线放疗,依照辅助化疗方案的不同分为3个组,即PA组（紫素与阿霉素）,CAF组（环磷酰胺,阿霉素,氟脲嘧啶）,CMF组（环磷酰胺,氨甲喋呤,氟脲嘧啶）,比较各组间放射性肺炎的发病率。结果：PA组放射性肺炎的发病率高于其它两组,而其他两组间比较差异无显著性。结论：紫素为主的化疗增加了乳腺癌患者放射性肺炎的发病危险。     

紫杉醇加5-氟脲嘧啶持续滴注治疗晚期鼻咽癌

目的：观察紫杉醇（Paclitaxel)，醛氢叶酸（Leucovorin),5-氟脲嘧啶（5－Fluorouraicl)持续滴注治疗晚期鼻咽癌的疗效及其不良好反应。方法：经病理组织学诊断的鼻咽癌患者20例（研究组），紫杉醇150mg/m^2，静脉滴注3h，第1天，醛氢叶酸200mg/m^2，静脉滴注2h，随后5－Fu375mg/m^2静脉推注10min再接5－Fu3.0g/m^2用输液泵连续滴注48h,以上治疗21天为1个周期，所有患者至少接受2个疗程治疗，结果：20例均可评价疗效，完全缓解（CR）3例（15．0％），部分缓解（PR）10例（50．0％），4例患者稳定（20．0％），主要不良反应为骨髓抑制，恶心、呕吐、肌肉疼痛和关节痛，黏膜炎等，经常规预防用药后，未出现严重的过敏反应，无治疗相关性死亡者，结论：该研究表明，紫杉醇加醛氢叶酸和5－Fu持续滴注治疗晚期鼻咽癌患者，缓解率较高，毒性相对较弱，值得进一步临床研究。     

Cytotoxicity Enhancement of Paclitaxel by Loading on Stearate-g-dextran Micelles on Breast Cancer Cell Line MCF-7

Objective: Paclitaxel (PTX) is a chemotherapeutic agent used for treating breast cancer. The study aimed to preparePTX loaded dextran stearate (Dex-SA) and evaluate its efficacy against human breast cancer cell line MCF-7. Methods:Dex-SA/PTX micelles were prepared by dialysis method. The micelles size, zeta potential and particle size distributionwere measured by dynamic laser light scattering method. Amount of loaded PTX on the polymer measured by HPLC.Release profiles of the drug from the micelles were obtained in buffer (phosphate pH=7.4). Then the cytotoxicity of blankmicelles, Dex-SA/PTX micelles and free PTX were evaluated in the MCF-7 cells by MTT method. Result: Loadingefficiency of PTX on the Dex-SA was measured about 84.24±9.07%. The smallest particles size was about 193.9±7.1nm but the other formulation with larger particle size had better zeta potential (-33.5±6.74 mV). The drug releasefrom the micelles was slowly and reached steady state after about 12 hours. The cytotoxicity experiment showed thatDex-SA/PTX micelles have more cytotoxicity compared to free PTX against MCF7 cell lines. Conclusions: Dex-SApolymeric micelle is a suitable carrier for hydrophobic cytotoxic drugs such as PTX.     

紫杉醇加卡铂与紫杉醇加顺铂治疗晚期NSCLC的对比研究

目的　比较紫杉醇 卡铂与紫杉醇 顺铂治疗NSCLC疗效和毒性。方法　46例初治的NSCLC随机分入紫杉醇 卡铂组(A组)和紫杉醇 顺铂组(B组) ,化疗2周期后进行评价。结果　A组有效率为5 7% ,B组有效率为5 2 % ,二组疗效无显著差异(P >0 0 5 )。胃肠道反应、肾毒性和肌肉关节疼痛A组较B组轻(P <0 0 5 )。结论　紫杉醇 卡铂治疗NSCLC可能会取代紫杉醇 顺铂的联合化疗。     

紫杉醇联合顺铂方案治疗晚期乳腺癌疗效观察

目的　研究 2 1例晚期转移乳腺癌患者接受紫杉醇 顺铂方案治疗的临床疗效。方法　 2 1例病理确诊的晚期转移性乳腺癌 ,给予紫杉醇联合方案治疗。结果　 2 1例中完全缓解 1例 ,占 4.76%,部分缓解 9例 ,占 42 .8%。总有效率为 47.6%,平均缓解期 4.9个月。主要毒性是骨髓抑制所致白细胞下降。结论　紫杉醇 顺铂方案对晚期转移乳腺癌疗效较好 ,不良反应主要为血液毒性 ,但可耐受 ,可作为其治疗首选方案     

紫杉醇脂质体联合卡铂对宫颈癌的治疗效果及预后影响因素分析

目的：研究分析紫杉醇脂质体联合卡铂对宫颈癌的治疗效果及预后影响因素。方法158例首发的宫颈癌患者随机分为研究组和对照组,研究组100例,对照组58例。研究组给予患者紫杉醇脂质体联合卡铂方案,对照组给予患者紫杉醇注射液联合卡铂方案,2组患者均进行2个疗程的治疗。比较2组患者的疗效和不良反应,同时分析患者化疗预后与FIGO分期、肿瘤大小、年龄、病理类型、分化程度及血红的蛋白水平之间相关性。结果2组患者在总有效率、骨髓抑制发生率以及胃肠道反应发生率上不存在明显的差异（P＞0．05）,但研究组过敏反应发生率明显低于对照组（P＜0．05）。年龄、肿瘤直径、分化程度以及血红蛋白水平与患者预后效果之间有明显的相关性（P＜0．05）。结论紫杉醇脂质体联合卡铂方案治疗宫颈癌具有良好的疗效和可靠的安全性,其预后效果与肿瘤分化程度、分期以及是否患有贫血等多种因素有关,可给予患者一定的干预以提高预后效果。     

紫杉醇联合卡铂治疗卵巢癌的效果分析

目的探讨紫杉醇联合卡铂化疗治疗卵巢癌的效果。方法收集92例卵巢癌患者的临床资料,根据不同的治疗方法,将患者分为对照组与观察组,每组各46例。对照组患者单纯采取卡铂化疗,观察组患者采取紫杉醇联合卡铂化疗。分析2组患者临床疗效与不良反应发生率。结果观察组治疗总有效率为89.13%,对照组总有效率为63.04%,差异有统计学意义(P<0.05)。观察组不良反应发生率为26.09%,对照组为23.91%,差异无统计学意义(P>0.05)。结论紫杉醇联合卡铂治疗晚期卵巢癌的临床效果明显优于单纯卡铂治疗,患者均可耐受出现的不良反应,值得临床推广。     

Pharmacokinetics of Ifosfamide Administered According to Three Different Schedules in Metastatic Soft Tissue and Bone Sarcomas

Abstract

Ifosfamide is a leading drug in soft tissue sarcoma therapy. Recently high dose therapy (>9 g/m²) has been introduced in different schemes to obtain a higher response rate. All these higher doses can be administered following two different schedules: continuous infusion 24 hours a day for 4-5 days or bolus administration for 5 consecutive days. In this study we compare the differences in the pharmacokinetic profile between the two schedules. In both schemes we saw a very important autoinduction phenomenon, with a corresponding half-life decrease and total body clearance increase during the days of therapy. The clearances were not directly correlated with the administered dose. We can conclude that ifosfamide continuous infusion therapy is equivalent to fractionated administration, at least from a pharmacokinetic point of view. Short-term infusion is subjectively better tolerated and is therefore preferred.