Forbes C, Shirran L, Bagnall A M, Duffy S, ter Riet G
NHS Centre for Reviews and Dissemination, University of York, UK.
Health Technol Assess. 2001;5(28):1-110. doi: 10.3310/hta5280.
Ovarian cancer is the most common gynaecological cancer with an annual incidence of 21.6 per 100,000 in England and Wales. Due to the often asymptomatic nature of the early stages of the disease, most cases are not detected until the advanced stages. Consequently, the prognosis after diagnosis is poor and the 5-year survival rate in the UK is only about 30%. Current recommendations suggest that first-line chemotherapy for ovarian cancer should involve paclitaxel and platinum (Pt)-based therapy (cisplatin/ carboplatin), however, most patients develop resistant or refractory disease and require second-line therapy. Patients may respond to re-challenge with Pt-agents if the treatment-free interval is > 6 months, but an alternative is often required. Topotecan is one of six drugs currently licensed in the UK for second-line therapy, and recent reviews suggest that it has modest efficacy in the treatment of advanced disease and performs favourably against paclitaxel. However, these reviews are based on a limited number of reports mainly consisting of non-randomised Phase I and II studies.
To examine the clinical effectiveness and cost-effectiveness of oral and intravenous topotecan (Hycamtin, SmithKline Beecham, UK) for the treatment of all stages of ovarian cancer.
Sixteen electronic databases from inception to September 2000 and Internet resources were searched, in addition to the bibliographies of retrieved articles and submissions from pharmaceutical companies.
Two reviewers independently screened all titles/abstracts and included/excluded studies based on full copies of manuscripts. Any disagreements were resolved through discussion. Only randomised controlled trials (RCTs) and full economic evaluations comparing topotecan to non-topotecan regimens were included. All stages of therapy and disease were considered, and the outcomes included were survival, response, symptom relief, quality of life, adverse effects and costs.
DATA EXTRACTION STRATEGY: Data were extracted into an Access database by one reviewer and checked by a second. Any disagreements were resolved through discussion.
QUALITY ASSESSMENT STRATEGY: Two reviewers, using specified criteria, independently assessed the quality of the clinical effectiveness studies and the economic evaluations. Any disagreements were resolved through discussion.
ANALYSIS STRATEGY: Due to the limited number of studies included in the review and the fact that they compared topotecan with different comparators, the out-come data could not be pooled statistically. Clinical effectiveness data are discussed separately under the different outcome subheadings. For time-to-event data, hazard ratios with 95% confidence intervals are presented where available, and for the remaining outcomes, relative risks are reported or calculated where sufficient data were available. Relative risk data are also presented in the form of Forest plots without pooled estimates. Economic data are presented in the form of a summary and critique of the evidence, and a grading (A-I) assigned to each study indicating the direction and magnitude of the cost-effectiveness data.
A total of 568 titles/abstracts were identified and screened for relevance. Full copies of 72 papers were assessed and seven published manuscripts reporting details of two studies of clinical effectiveness and one economic evaluation were included. Further details of the two clinical effectiveness studies and two new economic evaluations were identified from confidential company submissions. Overall, two international multicentre RCTs of effectiveness comparing topotecan with paclitaxel (trial 039) and topotecan with caelyx (trial 30-49) were included in the review. The three economic evaluations included in the review comprised one cost-minimisation analysis (CMA) comparing topotecan with caelyx, one cost-consequences analysis (CCA) comparing topotecan with paclitaxel, etoposide and altretamine and one cost-effectiveness analysis (CEA) comparing topotecan with paclitaxel.
QUALITY OF CLINICAL EFFECTIVENESS DATA: Both clinical effectiveness studies (trial 30-49 and 039) were of reasonable quality, although it was unclear whether either performed valid intention-to-treat analyses. In addition, trial 30-49 failed to state whether the outcome assessors were blinded to treatment allocation. RESULTS --QUALITY OF ECONOMIC EVALUATIONS: The CCA (comparing topotecan with three comparators) was of poor quality and of little relevance to the UK NHS. The CMA and CEA were of reasonable quality overall and relevant to the UK NHS. However, both, in particular the CEA, suffered from methodological problems, and thus their findings should be interpreted with caution.
ASSESSMENT OF CLINICAL EFFECTIVENESS: The assessment of clinical effectiveness was based on limited data. Only two trials with a total of 709 participants were identified. In general, with a few minor exceptions, there were no statistically significant differences between topotecan and paclitaxel, or topotecan and caelyx in survival, response rate, median time to response, median duration of response and quality of life. Significant differences that were reported were mainly identified in subgroup analyses (Pt-sensitive disease and disease without ascites) of questionable validity and their relevance to a general advanced ovarian cancer patient population undergoing second-line chemotherapy is unclear. However, statistically significant differences were observed in the incidence of adverse effects. Topotecan was associated with increased incidences of haematological toxicities (including neutropenia, leukopenia, anaemia and thrombocytopenia), alopecia, nausea and vomiting. Caelyx-treated patients suffered from significantly increased incidences of Palmar-Plantar erythrodysesthesia, stomatitis, mucous membrane disorders and skin rashes. Paclitaxel was associated with significant increases in alopecia, arthralgia, myalgia, neuropathy, paraesthesiae, skeletal pain and flushing.
ASSESSMENT OF COST-EFFECTIVENESS: The assessment of cost-effectiveness was also based on limited data, with three evaluations identified, one of which was not relevant. The two remaining studies, comparing topotecan with paclitaxel (CEA) and topotecan with caelyx (CMA), both used effectiveness data from multicentre RCTs and based their costs on 1999/2000 UK sources. The evaluations were conducted from a UK NHS perspective and findings presented in GB pounds/Euros. Topotecan for the second-line treatment of advanced ovarian cancer was shown to be more cost-effective than paclitaxel (32,513 GB pounds versus 46,186 GB pounds per person in terms of any response (complete or partial), incremental cost-effectiveness = 3065 GB pounds) in all respects except cost per time without toxicity or symptoms, but less cost-effective than caelyx (14,023 GB pounds versus 9979 GB pounds per person regardless of whether the patient responded). However, direct comparisons of the cost findings between the two studies is difficult because they used different designs, different time horizons for the cost analyses and the findings were presented as costs per person for only patients who responded in one study (topotecan versus paclitaxel) and costs per person regardless of whether they responded in the other study (topotecan versus caelyx).
This review indicates that there is little evidence in the form of RCTs on which to base an assessment of the effectiveness of topotecan as second-line therapy for advanced ovarian cancer. The evidence suggests there were no statistically significant differences overall between topotecan and paclitaxel, or topotecan and caelyx in clinical outcomes. However, statistically significant differences were observed in the incidence of adverse effects. The clinical significance of the findings is not discussed. Overall, the effects of topotecan could at best be described as modest, but the alternative agents offer no real advantages except fewer side-effects and possibly improved cost-effectiveness. Both of the clinical effectiveness studies on which this evidence is based had methodological flaws, the most serious being the lack of a blinded assessor in the topotecan versus caelyx trial, which is important for unbiased assessment of response outcomes. The economic evaluations also suffered from a number of potential problems.
RECOMMENDATIONS FOR RESEARCH: Further good quality RCTs and CEAs are required comparing topotecan with other licensed and potentially useful (soon to be licensed) second-line treatments for ovarian cancer. At present, it is difficult to make any decisions about topotecan and other drugs for second-line therapy without good quality direct comparisons. In view of the ongoing studies identified, an update of the current review should be considered in approximately 18 months (Summer 2002) or possibly sooner if the recently commissioned National Institute for Clinical Excellence review of caelyx for ovarian cancer identifies additional data relevant to topotecan.
卵巢癌是最常见的妇科癌症，在英格兰和威尔士，其年发病率为每10万人中有21.6例。由于该病早期通常无症状，多数病例直到晚期才被发现。因此，确诊后的预后较差，英国的5年生存率仅约为30%。目前的建议表明，卵巢癌一线化疗应采用紫杉醇和铂类（Pt）疗法（顺铂/卡铂），然而，大多数患者会出现耐药或难治性疾病，需要二线治疗。如果无治疗间隔大于6个月，患者可能对再次使用铂类药物治疗有反应，但通常需要其他替代方案。拓扑替康是英国目前获批用于二线治疗的六种药物之一，最近的综述表明，它在治疗晚期疾病方面疗效一般，与紫杉醇相比表现良好。然而，这些综述基于数量有限的报告，主要包括非随机的I期和II期研究。
考察口服和静脉注射拓扑替康（Hycamtin，英国史克必成公司）治疗各期卵巢癌的临床有效性和成本效益。
检索了从建库至2000年9月的16个电子数据库和互联网资源，此外还检索了检索文章的参考文献以及制药公司提供的资料。
两名评审员独立筛选所有标题/摘要，并根据手稿全文纳入/排除研究。如有分歧，通过讨论解决。仅纳入比较拓扑替康与非拓扑替康方案的随机对照试验（RCT）和全面经济评估。考虑了所有治疗阶段和疾病阶段，纳入的结局包括生存、缓解、症状缓解、生活质量、不良反应和成本。
数据提取策略：由一名评审员将数据提取到Access数据库中，另一名评审员进行核对。如有分歧，通过讨论解决。
质量评估策略：两名评审员使用特定标准独立评估临床有效性研究和经济评估的质量。如有分歧，通过讨论解决。
分析策略：由于纳入综述的研究数量有限，且它们将拓扑替康与不同对照进行比较，因此结局数据无法进行统计学合并。临床有效性数据在不同结局小标题下分别讨论。对于事件发生时间数据，如有可用数据，则呈现95%置信区间的风险比；对于其余结局，如有足够数据，则报告或计算相对风险。相对风险数据也以森林图的形式呈现，无合并估计值。经济数据以证据总结和评论的形式呈现，并为每项研究分配一个等级（A - I），表明成本效益数据的方向和大小。
共识别并筛选了568个标题/摘要的相关性。评估了72篇论文的全文，纳入了7篇已发表的手稿，报告了两项临床有效性研究和一项经济评估的详细信息。从公司保密提交材料中确定了两项临床有效性研究和两项新经济评估的更多详细信息。总体而言，综述纳入了两项比较拓扑替康与紫杉醇（试验039）以及拓扑替康与凯素（试验30 - 49）的国际多中心有效性RCT。综述纳入的三项经济评估包括一项比较拓扑替康与凯素的成本最小化分析（CMA）、一项比较拓扑替康与紫杉醇、依托泊苷和六甲蜜胺的成本后果分析（CCA）以及一项比较拓扑替康与紫杉醇的成本效益分析（CEA）。
临床有效性数据质量：两项临床有效性研究（试验30 - 49和039）质量尚可，不过尚不清楚是否进行了有效的意向性分析。此外，试验30 - 49未说明结局评估者是否对治疗分配不知情。
结果 - 经济评估质量：CCA（比较拓扑替康与三种对照）质量较差，与英国国家医疗服务体系（NHS）相关性不大。CMA和CEA总体质量尚可，与英国NHS相关。然而，两者尤其是CEA存在方法学问题，因此其结果应谨慎解读。
临床有效性评估：临床有效性评估基于有限的数据。仅识别出两项试验，共709名参与者。总体而言，除少数小例外，拓扑替康与紫杉醇或拓扑替康与凯素在生存、缓解率、中位缓解时间、中位缓解持续时间和生活质量方面无统计学显著差异。报告的显著差异主要在亚组分析（铂敏感疾病和无腹水疾病）中发现，其有效性存疑，且与接受二线化疗的一般晚期卵巢癌患者群体的相关性尚不清楚。然而，在不良反应发生率方面观察到统计学显著差异。拓扑替康与血液学毒性（包括中性粒细胞减少、白细胞减少、贫血和血小板减少）、脱发、恶心和呕吐的发生率增加相关。接受凯素治疗的患者手足红斑性感觉异常、口腔炎、黏膜疾病和皮疹的发生率显著增加。紫杉醇与脱发、关节痛、肌痛、神经病变、感觉异常、骨骼疼痛和潮红的显著增加相关。
成本效益评估：成本效益评估也基于有限的数据，确定了三项评估，其中一项不相关。其余两项研究，比较拓扑替康与紫杉醇（CEA）以及拓扑替康与凯素（CMA），均使用多中心RCT的有效性数据，并以1999/2000年英国数据为基础计算成本。评估从英国NHS角度进行，结果以英镑/欧元呈现。对于晚期卵巢癌二线治疗，拓扑替康在除无毒性或症状的每次治疗成本外的所有方面均比紫杉醇更具成本效益（就任何缓解（完全或部分）而言，每人32,513英镑对46,186英镑，增量成本效益 = 3065英镑），但比凯素成本效益低（无论患者是否缓解，每人14,023英镑对9979英镑）。然而，两项研究的成本结果难以直接比较，因为它们采用了不同的设计、不同的成本分析时间范围，且一项研究（拓扑替康与紫杉醇）的结果以仅缓解患者的人均成本呈现，另一项研究（拓扑替康与凯素）的结果以无论是否缓解的人均成本呈现。
本综述表明，几乎没有RCT形式的证据可用于评估拓扑替康作为晚期卵巢癌二线治疗的有效性。证据表明，拓扑替康与紫杉醇或拓扑替康与凯素在临床结局方面总体无统计学显著差异。然而，在不良反应发生率方面观察到统计学显著差异。未讨论这些发现的临床意义。总体而言，拓扑替康的效果充其量只能说是一般，但替代药物除副作用较少和可能成本效益有所改善外，并无实际优势。本证据所基于的两项临床有效性研究均存在方法学缺陷，最严重的是拓扑替康与凯素试验中缺乏盲法评估者，这对于无偏倚评估缓解结局很重要。经济评估也存在一些潜在问题。
研究建议：需要进一步开展高质量的RCT和CEA，比较拓扑替康与其他获批的以及可能有用的（即将获批的）卵巢癌二线治疗药物。目前，在没有高质量直接比较的情况下，很难就拓扑替康和其他二线治疗药物做出任何决策。鉴于已识别的正在进行的研究，应考虑在大约18个月后（2002年夏季）更新本综述，如果最近委托国家临床优化研究所对凯素用于卵巢癌的综述发现与拓扑替康相关的其他数据，则可能更早更新。
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