C Main, L Bojke, S Griffin, G Norman, M Barbieri, L Mather, D Stark, S Palmer, R Riemsma
Centre for Reviews and Dissemination, University of York, UK.
Health Technol Assess. 2006 Mar;10(9):1-132. iii-iv. doi: 10.3310/hta10090.
To examine the clinical effectiveness and cost-effectiveness of intravenous formulations of topotecan monotherapy, pegylated liposomal doxorubicin hydorocholoride (PLDH) monotherapy and paclitaxel used alone or in combination with a platinum-based compound for the second-line or subsequent treatment of advanced ovarian cancer.
Electronic databases covering publication years 2000-4. Company submissions.
Seventeen databases were searched for randomised controlled trials (RCTs) and systematic reviews for the clinical effectiveness of PLDH, topotecan and paclitaxel and economic evaluations of the cost-effectiveness of PLDH, topotecan and paclitaxel. Selected studies were quality assessed and data extracted, as were the three company submissions. A new model was developed to assess the costs of the alternative treatments, the differential mean survival duration and the impact of health-related quality of life. Monte-Carlo simulation was used to reflect uncertainty in the cost-effectiveness results.
Nine RCTs were identified. In five of these trials, both the comparators were used within their licensed indications. Of these five, three included participants with both platinum-resistant and platinum-sensitive advanced ovarian cancer, and a further two only included participants with platinum-sensitive disease. The comparators that were assessed in the three trials that included both subtypes of participants were PLDH versus topotecan, topotecan versus paclitaxel and PLDH versus paclitaxel. In the further two trials that included participants with the subtype of platinum-sensitive disease, the comparators that were assessed were single-agent paclitaxel versus a combination of cyclophosphamide, doxorubicin and cisplatin (CAP) and paclitaxel plus platinum-based chemotherapy versus conventional platinum-based therapy alone. A further four trials were identified and included in the review in which one of the comparators in the trial was used outside its licensed indication. The comparators assessed in these trials were oxaliplatin versus paclitaxel, paclitaxel given weekly versus every 3 weeks, paclitaxel at two different dose levels and oral versus intravenous topotecan. Four studies met the inclusion criteria for the cost-effectiveness review. The review of the economic evidence from the literature and industry submissions identified a number of significant limitations in existing studies assessing the cost-effectiveness of PLDH, topotecan and paclitaxel. Analysis 1 assessed the cost-effectiveness of PLDH, topotecan and paclitaxel administered as monotherapies. Sensitivity analysis was undertaken to explore the impact of patient heterogeneity (e.g. platinum-sensitive and platinum-resistant/refractory patients), the inclusion of additional trial data and alternative assumptions regarding treatment and monitoring costs. In the base-case results for Analysis 1, paclitaxel monotherapy emerged as the cheapest treatment. When the incremental cost-effectiveness ratios (ICERs) were estimated, topotecan was dominated by PLDH. Hence the options considered in the estimation of the ICERs were paclitaxel and PLDH. The ICER for PLDH compared with paclitaxel was pound 7033 per quality-adjusted life-year (QALY) in the overall patient population (comprising platinum-sensitive, -refractory and -resistant patients). The ICER was more favourable in the platinum-sensitive group ( pound 5777 per QALY) and less favourable in the platinum-refractory/resistant group ( pound 9555 per QALY). The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of the additional trial data resulted in less favourable estimates for the ICER for PLDH versus paclitaxel compared with the base-case results. The ICER of PLDH compared with paclitaxel was pound 20,620 per QALY in the overall patient population, pound 16,183 per QALY in the platinum-sensitive population and pound 26,867 per QALY in the platinum-resistant and -refractory population. The results from Analysis 2 explored the cost-effectiveness of the full range of treatment comparators for platinum-sensitive patients. The treatment options considered in this model comprised PLDH, topotecan, paclitaxel-monotherapy, CAP, paclitaxel/platinum combination therapy and platinum monotherapy. Owing to the less robust approaches that were employed to synthesise the available evidence and the heterogeneity between the different trials, the reliability of these results should be interpreted with some caution. Topotecan, paclitaxel monotherapy and PLDH were all dominated by platinum monotherapy (i.e. higher costs and lower QALYs). After excluding these alternatives, the treatments that remained under consideration were platinum monotherapy, CAP and paclitaxel-platinum combination therapy. Of these three alternatives, platinum monotherapy was the least costly and least effective. The ICER for CAP compared with platinum monotherapy was pound 16,421 per QALY. The ICER for paclitaxel-platinum combination therapy compared with CAP was pound 20,950 per QALY.
For participants with platinum-resistant disease there was a low probability of response to treatment with PLDH, topotecan or paclitaxel. Furthermore, there was little difference between the three comparators in relation to overall survival. The comparators did, however, differ considerably in their toxicity profiles. Given the low survival times and response rates, it appears that the maintenance of quality of life and the control of symptoms and toxicity are paramount in this patient group. As the three comparators differed significantly in terms of their toxicity profiles, patient and physician choice is also an important element that should be addressed when decisions are made regarding second-line therapy. It can also be suggested that this group of patients may benefit from being included in further clinical trials of new drugs. For participants with platinum-sensitive disease there was a considerable range of median survival times observed across the trials. The most favourable survival times and response rates were observed for paclitaxel and platinum combination therapy. This suggests that treatment with combination therapy may be more beneficial than treatment with a single-agent chemotherapeutic regimen. In terms of single-agent compounds, the evidence suggests that PLDH is more effective than topotecan. Evidence from a further trial that compared PLDH and paclitaxel suggests that there is no significant difference between these two comparators in this trial. The three comparators did, however, differ significantly in terms of their toxicity profiles across the trials. Although treatment with PLDH may therefore be more beneficial than that with topotecan, patient and physician choice as to the potential toxicities associated with each of the comparators and the patient's ability and willingness to tolerate these are of importance. Assuming the NHS is willing to pay up to pound 20,000-40,000 per additional QALY, PLDH appears to be cost-effective compared with topotecan and paclitaxel monotherapy, in terms of the overall patient population and the main subgroups considered. The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of additional trial data gave less favourable estimates for the ICER for PLDH versus paclitaxel monotherapy, compared with the base-case results. Although the ICER of PLDH compared with paclitaxel monotherapy was less favourable, PLDH was still cost-effective compared with topotecan and paclitaxel monotherapy. For platinum-sensitive patients, the combination of paclitaxel and platinum appears to be cost-effective. On the strength of the evidence reviewed here, it can be suggested that participants with platinum-resistant disease may benefit from being included in further clinical trials of new drugs. To assess the effectiveness of combination therapy against a single-agent non-platinum-based compound, it can be suggested that a trial that compared paclitaxel in combination with a platinum-based therapy versus single-agent PLDH would be a reasonable option.
研究拓扑替康单药静脉制剂、聚乙二醇脂质体阿霉素（PLDH）单药以及紫杉醇单药或联合铂类化合物用于晚期卵巢癌二线或后续治疗的临床有效性和成本效益。
涵盖2000 - 2004年发表年份的电子数据库。公司提交资料。
检索17个数据库以查找随机对照试验（RCT）以及关于PLDH、拓扑替康和紫杉醇临床有效性的系统评价，以及关于PLDH、拓扑替康和紫杉醇成本效益的经济学评价。对所选研究以及三份公司提交资料进行质量评估并提取数据。开发了一个新模型来评估替代治疗的成本、平均生存时间差异以及对健康相关生活质量的影响。采用蒙特卡罗模拟来反映成本效益结果的不确定性。
共识别出9项RCT。其中5项试验中，两种对照药物均在其获批适应症范围内使用。在这5项试验中，3项纳入了铂耐药和铂敏感的晚期卵巢癌患者，另外2项仅纳入了铂敏感疾病患者。在纳入两种亚型患者的3项试验中评估的对照药物为PLDH与拓扑替康、拓扑替康与紫杉醇以及PLDH与紫杉醇。在另外2项纳入铂敏感疾病亚型患者的试验中，评估的对照药物为单药紫杉醇与环磷酰胺、阿霉素和顺铂联合方案（CAP），以及紫杉醇加铂类化疗与单纯传统铂类疗法。另外识别出4项试验并纳入综述，其中试验中的一种对照药物在其获批适应症范围外使用。这些试验中评估的对照药物为奥沙利铂与紫杉醇、每周给药的紫杉醇与每3周给药的紫杉醇、两种不同剂量水平的紫杉醇以及口服与静脉注射拓扑替康。4项研究符合成本效益综述的纳入标准。对来自文献和行业提交资料的经济学证据进行综述发现，现有评估PLDH、拓扑替康和紫杉醇成本效益的研究存在一些重大局限性。分析1评估了PLDH、拓扑替康和紫杉醇作为单药治疗的成本效益。进行敏感性分析以探讨患者异质性（如铂敏感和铂耐药/难治患者）、纳入额外试验数据以及关于治疗和监测成本的替代假设的影响。在分析1的基础病例结果中，紫杉醇单药治疗是最便宜的治疗方法。当估计增量成本效益比（ICER）时，拓扑替康被PLDH所主导。因此，在估计ICER时考虑的选项为紫杉醇和PLDH。在总体患者人群（包括铂敏感、难治和耐药患者）中，PLDH与紫杉醇相比的ICER为每质量调整生命年（QALY）7033英镑。在铂敏感组中ICER更有利（每QALY 5777英镑），在铂难治/耐药组中则较不利（每QALY 9555英镑）。基础病例分析的成本效益结果对纳入额外试验数据敏感。纳入额外试验数据的结果导致与基础病例结果相比，PLDH与紫杉醇相比的ICER估计值更不利。在总体患者人群中，PLDH与紫杉醇相比的ICER为每QALY 20,620英镑，在铂敏感人群中为每QALY 16,183英镑，在铂耐药和难治人群中为每QALY 26,867英镑。分析2的结果探讨了铂敏感患者所有治疗对照药物的成本效益。该模型中考虑的治疗选项包括PLDH、拓扑替康、紫杉醇单药治疗、CAP、紫杉醇/铂联合治疗和铂单药治疗。由于用于综合现有证据的方法不够稳健以及不同试验之间的异质性，这些结果的可靠性应谨慎解释。拓扑替康、紫杉醇单药治疗和PLDH均被铂单药治疗所主导（即成本更高且QALY更低）。排除这些替代方案后，仍在考虑的治疗方法为铂单药治疗、CAP和紫杉醇 - 铂联合治疗。在这三种替代方案中，铂单药治疗成本最低且效果最差。CAP与铂单药治疗相比的ICER为每QALY 16,421英镑。紫杉醇 - 铂联合治疗与CAP相比的ICER为每QALY 20,950英镑。
对于铂耐药疾病患者，使用PLDH、拓扑替康或紫杉醇治疗的缓解可能性较低。此外，这三种对照药物在总生存期方面差异不大。然而，这三种对照药物在毒性特征方面差异很大。鉴于生存时间和缓解率较低，对于该患者群体而言，维持生活质量以及控制症状和毒性似乎至关重要。由于这三种对照药物在毒性特征方面差异显著，患者和医生的选择也是二线治疗决策时应考虑的重要因素。还可以建议，这组患者可能会从参与新药的进一步临床试验中受益。对于铂敏感疾病患者，各试验观察到的中位生存时间范围相当大。紫杉醇和铂联合治疗观察到最有利的生存时间和缓解率。这表明联合治疗可能比单药化疗方案更有益。就单药化合物而言，证据表明PLDH比拓扑替康更有效。另一项比较PLDH和紫杉醇的试验证据表明，在该试验中这两种对照药物之间没有显著差异。然而，在各项试验中，这三种对照药物在毒性特征方面差异显著。因此，尽管使用PLDH治疗可能比使用拓扑替康更有益，但患者和医生对于每种对照药物相关潜在毒性的选择以及患者耐受这些毒性的能力和意愿很重要。假设英国国家医疗服务体系（NHS）愿意为每增加一个QALY支付高达20,000 - 40,000英镑，就总体患者人群和所考虑的主要亚组而言，PLDH与拓扑替康和紫杉醇单药治疗相比似乎具有成本效益。基础病例分析的成本效益结果对纳入额外试验数据敏感。与基础病例结果相比，纳入额外试验数据后，PLDH与紫杉醇单药治疗相比的ICER估计值更不利。尽管PLDH与紫杉醇单药治疗相比的ICER较不利，但与拓扑替康和紫杉醇单药治疗相比，PLDH仍具有成本效益。对于铂敏感患者，紫杉醇和铂的联合治疗似乎具有成本效益。基于此处综述的证据，可以建议铂耐药疾病患者可能会从参与新药的进一步临床试验中受益。为了评估联合治疗相对于单药非铂类化合物的有效性，可以建议进行一项比较紫杉醇联合铂类疗法与单药PLDH的试验是一个合理的选择。
