Second-line chemotherapy with paclitaxel for ovarian cancer]

The authors summerize the results of second-line combination chemotherapy with paclitaxel (175 mg/m2, 3h) and carboplatin (AUC 5 mg/ml.min) in patients with recurrent epithelial ovarian cancer. The paclitaxel/carboplatin therapy was applied in 57 patients in 297 courses (median course/patient was 5, range 2, 12). Complete response (CR) was found in 3 patients (3/57 = 5%), however the tumorous process progressed after some time. The median progression free interval (PFI) was found to be 15 (range 3,130) weeks, with an average of 24.3 +/- 26.5 weeks. The authors conclude, that second-line paclitaxel combination therapy produces poorer results than the first-line treatment. These results, which are similar to the literature data have led to the agreement: paclitaxel can be applied in ovarian cancer patients only in first-line chemotherapy in Hungary from the year 2000.     

Spotlight on Paclitaxel in Ovarian Cancer

Paclitaxel belongs to the group of antitumor agents called the taxanes. Its efficacy in advanced ovarian cancer has been established in large, randomized phase III clinical trials. When used in combination with cisplatin for first-line treatment of advanced ovarian cancer, it is superior to cyclophosphamide/cisplatin, with gains in median survival of around 1 year. Paclitaxel plus carboplatin has similar efficacy to paclitaxel plus cisplatin. There is now consensus that paclitaxel plus either carboplatin or cisplatin is the recommended first-line therapy for patients with advanced ovarian cancer. The particular combination employed may vary between institutions and geographical regions, although paclitaxel plus carboplatin is generally better tolerated (i.e. lower incidence of non-hematologic adverse events) than paclitaxel plus cisplatin and is widely used in many countries. Paclitaxel is also used as monotherapy in second-line (salvage) treatment of ovarian cancer.Pharmacoeconomic analyses performed to date have primarily focused on first-line therapy comparing the combination of paclitaxel/cisplatin with cyclophosphamide/cisplatin. All studies incorporated clinical outcomes data, most commonly from the Gynecologic Oncology Group (GOG) 111 trial, showing a survival advantage for paclitaxel/cisplatin. These studies report incremental cost-effectiveness ratios (ICERs) ranging from $US6395 per additional life-year gained (LYG) in Spain (1995/96 values) to US$44 690 per additional progression-free LYG in France (year of costs not reported). Five studies were based in the US and Canada and these reported very similar ICERs of $US13 135 (year of costs not reported) to $US25 131 (1993 costs) per additional LYG. In all of these studies the incremental costs of paclitaxel/cisplatin therapy fall well within the commonly cited threshold limit of $US50 000 for new therapies and compare well with incremental costs reported for other oncologic and life-saving therapies.Patient preferences and quality of life are important issues due to the short survival of patients with ovarian cancer. Two cost-utility studies reported similar incremental cost-utility ratios (ICURs). In the study based on US costs, the ICUR of paclitaxel/cisplatin treatment was $US18 200 per additional quality-adjusted life-year (QALY) [1995 drug costs]. In a Canadian study the ICUR ranged from 11 600 Canadian dollars ($Can) to $Can24 200 (1996 costs) per additional progression-free QALY depending on the choice of second-line treatment. Conclusions: Paclitaxel used in combination with cisplatin offers survival and utility gains versus cyclophosphamide plus cisplatin, when used as first-line treatment in patients with stage III or IV ovarian cancer. The incremental cost for these gains is within the accepted range for healthcare interventions. However, pharmacoeconomic analyses of paclitaxel plus carboplatin — a combination widely accepted for use in women with advanced ovarian cancer and with clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile — are currently lacking. Nevertheless, results of available pharmacoeconomic data support the clinical use of paclitaxel/platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced ovarian cancer.     

Carboplatin in the treatment of ovarian carcinoma; as effective and less toxic in comparison with cisplatin

The efficacy and toxicity of a combination of carboplatin and cyclophosphamide (CC) were studied in a group of 76 patients with advanced ovarian cancer. Progression-free (PFS) and overall survival (OS) were compared with a historical group of 68 patients treated with cyclophosphamide, adriamycin and cisplatin (CAP-5). Subjective toxicity was compared by measurement of TWIST, the Time Without Symptoms of Treatment or Disease. Of 75 evaluable patients treated with CC, 18 (24%) had a pathologically complete remission (pCR), and 31 (41%) a partial remission (PR). CC led to grade 3 leukopenia in 38% and grade 4 in 3% of 421 treatment cycles. Thrombocytopenia grade 3 was seen after 7% and grade 4 after 2% of cycles. Treatment delay occurred in 11.5% and dose reduction in 21% of cycles. Nephro- or neurotoxicity did not occur. After a median followup of 18 months, the median PFS was greater than or equal to 22 and the OS was greater than or equal to 25 months. Median duration of TWIST was greater than or equal to 22 versus greater than or equal to 10 months after CAP-5 (p less than 0.01). Compared with historical controls, treatment with CC is equivalent to CAP-5. It is free of nephro- and neurotoxicity, but is more myelosuppressive. Quality of life, measured by TWIST, is significantly better during CC. Owing to its equivalent efficacy with lower subjective toxicity, carboplatin should replace cisplatin in treating patients with advanced ovarian cancer.     

上皮性卵巢肿瘤血清中RASSF1A基因异常甲基化检测及其临床意义

目的:探讨上皮性卵巢肿瘤血清中RASSF1A基因异常甲基化的检测及其临床意义。方法:选择2009年2月～2012年2月期间,在该院妇科收治的卵巢肿瘤患者92例,其中上皮性卵巢癌43例,良性卵巢肿瘤49例。对两组患者RASSF1A基因异常甲基化进行检测。结果:与良性肿瘤患者相比,上皮性卵巢癌患者血清中RASSF1A基因异常甲基化比率显著提高,可达58.14%,差别具有统计学意义(P<0.05)。与WHO病理Ⅰ级患者相比,Ⅱ级和Ⅲ级患者血清中RASSF1A基因异常甲基化比率显著提高,分别可达66.67%和81.82%,差别均具有统计学意义(P<0.05)。与FIGO临床Ⅰ～Ⅱ期患者相比,Ⅲ～Ⅳ期患者血清中RASSF1A基因异常甲基化比率显著提高,可达86.67%,差别具有统计学意义(P<0.05)。讨论:RASSF1A基因异常甲基化的检测对于上皮性卵巢肿瘤的诊断、治疗和预后提供新的思路,对临床具有重要的参考辅助作用。     

Cytostatic treatment of ovarian carcinoma

Shortly after treatment with the cytostatic combination of cisplatin and paclitaxel was generally accepted as the standard therapy for patients with epithelial ovarian carcinoma, many have come to regard the combination of carboplatin and paclitaxel as a better choice. The latter combination causes fewer side effects and may be used in the outpatient clinic. Conceivably, the carboplatin-paclitaxel scheme will shortly have to be adjusted again owing to results of current research. The intensive basic research of recent years, namely, is beginning to yield benefits for the therapeutic arsenal against ovarian carcinoma. Possibilities are inhibitors of the breakdown of extracellular matrix (such as marimastat) and inhibitors of signal transduction (such as trastuzumab).     

卵巢癌的二线化疗

超过80%的晚期卵巢癌患者因复发需要接受二线化疗。目前多项大型随机对照试验表明,对于铂类敏感患者,以铂类为基础的联合化疗,如紫杉醇+卡铂或吉西他滨+卡铂,在有效率及改善生存方面优于铂类单药化疗,可作为首选。而对于铂类耐药患者,无论采用何种化疗,效果均不理想,临床上一般采用不良反应较小、使用方便的单药化疗作为姑息性治疗,联合化疗的价值有待更多随机对照试验证明。     

卵巢上皮性癌中mTOR信号通路蛋白的表达及其临床意义

目的:研究哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路蛋白在人卵巢上皮性癌中的表达及其临床意义。方法:选取武汉同济医院妇产科2005～2008间手术切除并经病理证实的人卵巢上皮性癌63例,其中Ⅰ级12例、Ⅱ级15例、Ⅲ级23例、Ⅳ级13例,应用免疫组织化学法检测卵巢上皮性癌组织中mTOR信号通路关键蛋白pm-TOR、pAKT的表达,分析其与卵巢癌患者临床病理特征的关系。结果:pmTOR在各级卵巢上皮性癌中的阳性率分别为:Ⅰ级41.7%(5/12)、Ⅱ级53.3%(8/15)、Ⅲ级65.2%(15/23)、Ⅳ级69.2%(9/13),pAKT在各级卵巢上皮性癌中的阳性率分别为:Ⅰ级33.3%(5/12)、Ⅱ级40.0%(6/15)、Ⅲ级52.2%(12/23)、Ⅳ级53.8%(7/13);各阳性表达率间无统计学差异(P>0.05),但其表达水平均随着卵巢上皮性癌病理级别的增高而升高,而与病理类型无关。结论:mTOR信号通路蛋白在卵巢上皮性癌的发生发展中起重要的作用,可能是卵巢癌治疗的潜在靶点。     

Experience with gemcitabine-carboplatin chemotherapy in relapsed ovarian cancer

Despite the progress that has been achieved in the primary therapy of ovarian cancer, unfortunately, the disease relapses resulting death in a lot of patients. This is the rationale for several new chemotherapy trials, however the expected results are awaited yet. The pyrimidine analogue drug gemcitabine belongs also to this group of hopeful therapies to increase the outcomes. PATIENTS AND METHODS: 22 patients with platinum-resistant, recurrent epithelial ovarian carcinoma, were treated with gemcitabine, in 98 courses in the Gynecologic Department at National Institute of Oncology, Budapest. Gemcitabine was applied in combination chemotherapy with carboplatin in the 2-8th line with the gemcitabine dose of 1000 mg/qm/d 1, 8 and carboplatin dose of AUC 4/d 1, in 3 week courses. Progression free interval was calculated by GraphPad Prism (version 2.0) program. RESULTS: A 39% overall response and a median 3 months progression free interval were resulted. Complete response was found only in one patient. CONCLUSION: Combination therapy with gemcitabine and carboplatin showed only limited responses in the authors' relapsed ovarian cancer patients. It seems to authors the lesser progression free interval is resulted by the resistant clones of the tumour due to the several (median 4) unsuccessful previous chemotherapies. The authors' early experience with gemcitabine underlines the good tolerability and the possibility of outpatient administration of the drug as well.     

白蛋白紫杉醇与紫杉醇注射液联合卡铂治疗宫颈癌的临床观察

目的比较白蛋白紫杉醇与紫杉醇注射液联合卡铂治疗宫颈癌的临床疗效。方法将98例宫颈癌患者随机分为白蛋白紫杉醇组和紫杉醇注射液组,各49例。白蛋白紫杉醇组采用白蛋白紫杉醇联合卡铂方案静脉化疗,紫杉醇注射液组采用紫杉醇注射液联合卡铂方案静脉化疗。比较两组的疗效和化疗不良反应。结果白蛋白紫杉醇组的治疗总有效率为73.47%,与紫杉醇注射液组的65.31%比较差异无统计学意义(P>0.05)。白蛋白紫杉醇组的胃肠道反应、骨髓抑制发生率显著低于紫杉醇注射液组(P <0.05)。结论与紫杉醇注射液联合卡铂相比,白蛋白紫杉醇联合卡铂治疗宫颈癌的安全性更为理想。     

Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer

OBJECTIVE: In vitro and animal studies suggest that antitumor effect of chemotherapeutic agents may be enhanced by antioxidants. Therefore, we initiated a clinical study to test the efficacy of high-dose multiple antioxidants (vitamins C, E and beta carotene) as an adjunct to chemotherapy (paclitaxel and carboplatin) in non-small-cell lung cancer. METHODS: 136 patients of stage IIIb and stage IV NSCLC were randomized to receive chemotherapy (paclitaxel and carboplatin) alone (chemotherapy arm, n = 72) or chemotherapy in combination with ascorbic acid 6100 mg/day, dl-alpha-tocopherol (vitamin E) 1050 mg/day and beta-carotene 60 mg/day (combination arm, n = 64). Survival were calculated by the Kaplan-Meier method and compared using the log-rank test. RESULTS: An overall response rate (RR) of 33% was observed in chemotherapy arm with 24 patients showing a partial response (PR) and none showing a complete response (CR). In combination arm the overall RR was 37% with 24 patients showing PR and two showing CR. The median survival times in chemotherapy arm and combination arm were nine and 11 months respectively. The overall survival (OS) rates in chemotherapy arm and combination arm at one year were 32.9% and 39.1%, and at two years, 11.1% and 15.6% respectively. None of these differences were statistically significant (p = 0.20). Toxicity profiles were similar in both arms. CONCLUSIONS: These results do not support the concern that antioxidants might protect cancer cells from the free radical damage induced by chemotherapy. Larger trials are needed to demonstrate whether high-dose multiple antioxidants in conjunction with chemotherapy increase the response rates and/or survival time in advanced lung cancer.     

培美曲塞联合卡铂治疗晚期非小细胞肺癌的近期疗效观察

目的观察培美曲塞联合卡铂治疗晚期非小细胞肺癌的近期疗效及毒副作用。方法晚期非小细胞肺癌患者共45例,培美曲塞500mg／m^2,第1天,卡铂300mg／m^2第1天静脉滴注,21d为一周期,每例患者至少接受2个周期的治疗。结果45例患者均可评价疗效,无完全缓解（CR）,19例获部分缓解（PR）,12例稳定（SD）,14例疾病进展（PD）,总有效率为42．2％,其中位疾病进展时间为5．2个月,中位生存时间为10．3个月,1年生存率为55．6％。毒副作用主要有骨髓抑制、恶心、呕吐和腹泻以及白细胞下降导致的发热等,但患者多为Ⅰ、Ⅱ度反应,耐受性良好。结论培美曲塞联合卡铂是一种对晚期非小细胞肺癌有效的化疗方法,不良反应发生率低,耐受性良好。     

Novel antiangiogenic therapies in ovarian cancer

Epithelial ovarian cancer is the leading cause of death in the developed world for women with gynecologic carcinomas. Despite the effectiveness of platinum salts and taxanes as primary treatments, approximately 80% of women will recur and for them prognosis with available treatments is poor. Of the novel mechanisms under active investigation, there is ample evidence to indicate that angiogenesis is important to the development, progression and poor prognosis of ovarian cancer. Novel treatments are therefore required. A number of agents are undergoing evaluation, including vascular disrupting agents, angiogenesis inhibitors, tyrosine kinase inhibitors and agents targeting the folate receptor. At present, Phase III data are only available for the VEGF-targeted monoclonal antibody, bevacizumab, and that has demonstrated a progression-free survival benefit when used in combination with first-line paclitaxel/carboplatin and continued as maintenance therapy. The strategy of inhibiting angiogenesis in ovarian cancer remains promising. However, other agents in development may point to other important targets in ovarian cancer.     

Treatment of epithelial ovarian cancer

Epithelial ovarian cancer is the most lethal gynecological cancer among women. The median age at diagnosis is 63 years. The vast majority of patients present with advanced disease and require a combination of cytoreductive surgery and adjuvant chemotherapy. Important features that determine the outcome of treatment include the stage of disease, hystological type, grade and the size of the residual tumour after initial surgery. Current guidelines recommend that standard first-line chemotherapy should include a platinum-based regimen with paclitaxel. Despite the combined therapy, over 50% of all the patients has relapse. Relapsed ovarian cancer is incurable, however chemotherapy can improve quality of life and survival. Currently, there is no worldwide accepted standard treatment for patients with platinum-refractory ovarian cancer. Docetaxel, topotecan, gemcitabine, pegylated liposomal doxorubicin, etoposide and tamoxifen can be used in this group. However response duration rarely exceeds 12 months. Intraperitoneal chemotherapy, gene therapy, immunotherapy, signal transduction inhibitors (trastuzumab) and angiogenesis inhibitors (bevacizumab) are all potential future therapies, and are being investigated in ongoing clinical research. In this publication authors review the literature of current treatment options in epithelial ovarian carcinoma.     

BMP-2在卵巢癌中的表达及对卵巢癌患者预后的影响

目的:检测BMP-2及其受体BMPRⅠA、BMPRⅠB和BMPRⅡ在上皮性卵巢癌中的表达并分析其对卵巢癌患者预后的影响。方法:应用免疫组化方法检测BMP-2及其受体BMPRⅠA、BMPRⅠB和BMPRⅡ在100例上皮性卵巢癌组织中的表达水平并通过病例随访分析其对卵巢癌患者术后5年存活率和生存时间的影响。结果:①BMP-2及其受体BMPRⅠA、BM-PRⅠB、BMPRⅡ的蛋白阳性染色主要集中在卵巢癌细胞胞浆中。②BMP-2、BMPRⅠB、BMPRⅡ阳性表达的上皮性卵巢癌患者术后5年存活率明显高于阴性表达者,且其术后平均存活时间明显长于阴性表达者。而BMPRⅠA与卵巢癌患者的术后5年存活率和平均生存时间无关。结论:BMP-2、BMPRⅠB和BMPRⅡ在上皮性卵巢癌组织中表达减弱或缺失可能预示着卵巢癌患者预后较差。     

Radiosensitizing effect of carboplatin and paclitaxel to carbon-ion beam irradiation in the non-small-cell lung cancer cell line H460

The present study investigated the ability of carboplatin and paclitaxel to sensitize human non-small-cell lung cancer (NSCLC) cells to carbon-ion beam irradiation. NSCLC H460 cells treated with carboplatin or paclitaxel were irradiated with X-rays or carbon-ion beams, and radiosensitivity was evaluated by clonogenic survival assay. Cell proliferation was determined by counting the number of viable cells using Trypan blue. Apoptosis and senescence were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and senescence-associated β-galactosidase (SA-β-gal) staining, respectively. The expression of cleaved caspase-3, Bax, p53 and p21 was analyzed by western blotting. Clonogenic survival assays demonstrated a synergistic radiosensitizing effect of carboplatin and paclitaxel with carbon-ion beams; the sensitizer enhancement ratios (SERs) at the dose giving a 10% survival fraction (D₁₀) were 1.21 and 1.22, respectively. Similarly, carboplatin and paclitaxel showed a radiosensitizing effect with X-rays; the SERs were 1.41 and 1.29, respectively. Cell proliferation assays validated the radiosensitizing effect of carboplatin and paclitaxel with both carbon-ion beam and X-ray irradiation. Carboplatin and paclitaxel treatment combined with carbon-ion beams increased TUNEL-positive cells and the expression of cleaved caspase-3 and Bax, indicating the enhancement of apoptosis. The combined treatment also increased SA-β-gal-positive cells and the expression of p53 and p21, indicating the enhancement of senescence. In summary, carboplatin and paclitaxel radiosensitized H460 cells to carbon-ion beam irradiation by enhancing irradiation-induced apoptosis and senescence.     

The implications of age and comorbidity on survival following epithelial ovarian cancer: summary and results from a centers for disease control and prevention study

Abstract Background: Advances in treatment have improved ovarian cancer survival for most women, although less for the elderly. We report on this disparity and add further evidence about the relationship among age, comorbidity, and survival after ovarian cancer. Methods: To examine age and comorbidity, Centers for Disease Control and Prevention (CDC)-funded cancer registries examined 2367 women residing in New York and Northern California diagnosed with epithelial ovarian cancer (1998-2000). Subjects were identified through tumor registries, treatment data were supplemented with physician survey, and comorbidity was identified through hospital discharge database linkages. Proportional hazards modeling was used to estimate the risk of death by age and comorbidity, adjusting for clinical and sociodemographic factors. Results: Crude survival at 1 year and 3 years was 71.9% and 50.1%, respectively. Within stage, age-specific survival rates were lower in the oldest groups, particularly for those with advanced disease. For age 75+, 3-year survival was 13% vs. 50% in those <35 (stage IV). For all stages, women without comorbidity had higher survival rates than those with comorbidity. Older age and comorbidity were both associated with advanced stage and less aggressive treatment. The adjusted risk of death was 40%, and it was 80% higher for the 65-74 and 75+ groups, respectively, compared to women 35-64 (p<0.00). Comorbidity increased the risk of death by 40% (p<0.00). Conclusions: This study confirmed the independent adverse effects of age and comorbidity on survival following ovarian cancer. As the population ages, the co-occurrence of ovarian cancer and comorbidity will increase. Further work identifying critical conditions that impact survival could potentially inform complex treatment decisions.     

铂类耐药性卵巢上皮癌患者卵巢上皮中VEGF-C表达的研究

目的:探讨铂类耐药性卵巢上皮癌患者卵巢上皮癌组织中VEGF-C蛋白的表达。方法:应用免疫组织化学染色法检测43例卵巢上皮癌组织中VEGF-C蛋白的表达,同时检测其在中-高分化的卵巢癌组织中的单层、复层及癌巢的表达情况。结果:VEGF-C蛋白在中-高分化的卵巢癌组织中的单层、复层及癌巢的表达无显著性差异(P>0.05)。在耐药复发组和为复发组的癌组织中VEGF-C蛋白表达有显著性差异(P<0.05)。耐药复发组中单层上皮、癌巢中存在VEGF-C过表达。结论:VEGF-C蛋白在卵巢癌组织中的表达与组织学分级不具有明显相关性。VEGF-C蛋白在耐药组卵巢组织存在过表达,VEGF-C蛋白的检测对提示可能出现铂类耐药有重要价值。     

An audit of surgical treatment of ovarian cancer in a metropolitan health region. Association of Obstetricians and Gynaecologists of the North East Thames Region.

The varied application of surgery to the initial treatment of 908 cases of primary ovarian cancer is analysed. In patients with advanced disease (FIGO Stages IIb, III and IV) 256 (46%) of 555 women achieved minimal residual disease status by primary surgery and this proportion fell to 24% when only stages III and IV were considered; of these cases 7% underwent adjunctive intestinal resection or urinary tract surgery. Although not in a clinical trial situation the women achieving minimal residual disease status before chemotherapy survived better in the short term, although long-term survival remained disappointing. In early disease 3% of young women have been subjected to hysterectomy and removal of both ovaries. By contrast, in 16% of women over the age of 40 years with early ovarian cancer bilateral oophorectomy was not carried out.     

Survivin在上皮性卵巢癌中的表达及意义

目的:检测survivin在上皮性卵巢癌组织中的表达,探讨survivin的表达与上皮性卵巢癌临床病理特征的关系。方法:应用免疫组织化学链霉亲和素-生物素-过氧化物霉复合物(SABC)方法,检测40例上皮性卵巢癌组织,20例良性上皮性卵巢肿瘤组织,20例正常卵巢组织中survivin的表达情况。结果:上皮性卵巢癌组织中survivin的阳性表达率为77.5%,高于良性上皮性卵巢肿瘤组织及正常卵巢组织的10%～0%(P<0.05),与组织学类型无相关性(P>0.05),与临床分期、组织学分级及淋巴结转移有关(P<0.05)。结论:survivin在上皮性卵巢癌组织中皆呈高表达,提示survivin可能与上皮性卵巢癌的浸润、转移有关。     

Activin在上皮性卵巢癌中的表达及意义

目的:检测activin在上皮性卵巢癌组织中的表达,探讨activin的表达与上皮性卵巢癌临床病理特征的关系。方法:应用免疫组织化学链霉亲和素-生物素-过氧化物霉复合物(SABC)方法,检测40例上皮性卵巢癌组织,20例良性上皮性卵巢肿瘤组织,20例正常卵巢组织中activin的表达情况。结果:上皮性卵巢癌组织中activin的阳性表达率为67.5%,高于良性上皮性卵巢肿瘤组织及正常卵巢组织的25%及10%(P<0.05),与组织学类型、临床分期无相关性(P>0.05),与组织学分级及淋巴结转移有关(P<0.05)。结论:Activin在上皮性卵巢癌组织中皆呈高表达,提示activin可能与上皮性卵巢癌的浸润、转移有关。