Hind D, Tappenden P, Tumur I, Eggington S, Sutcliffe P, Ryan A
School of Health and Related Research, University of Sheffield, UK.
Health Technol Assess. 2008 May;12(15):iii-ix, xi-162. doi: 10.3310/hta12150.
To evaluate three technologies for the management of advanced colorectal cancer: (1) first-line irinotecan combination [with 5-fluorouracil (5-FU)] or second-line monotherapy; (2) first- or second-line oxaliplatin combination (again, with 5-FU); and (3) raltitrexed, where 5-FU is inappropriate. To examine the role of irinotecan and oxaliplatin in reducing the extent of incurable disease before curative surgery (downstaging).
Ten electronic bibliographic databases covering the period up to August 2004.
Searches identified existing studies of the effectiveness and economics of the technologies and any studies that evaluated any of the indications outlined above were included. Data were extracted and assessed generic components of methodological quality. Survival outcomes were meta-analysed.
Seventeen trials were found, of varying methodological quality. Compared with 5-FU, first-line irinotecan improved overall survival (OS) by 2-4 months (p=0.0007), progression-free survival (PFS) by 2-3 months (p<0.00001) and response rates (p<0.001). It offered a different toxicity profile and no quality of life (QoL) advantage. However, second-line irinotecan compared with 5-FU improved OS by 2 months (p=0.035) and PFS by 1 month (p=0.03), and provided a better partial response rate, but with more toxicities and no QoL advantage. Compared with second-line best supportive care, irinotecan improved OS by 2 months (p=0.0001), had a different toxicity profile and maintained baseline QoL longer, but with no overall difference. The addition of oxaliplatin to second-line 5-FU is associated with a borderline significant improvement in overall survival (p<0.07); a significantly higher response rate (<0.0001); and more serious toxicities. There is no evidence for a significant difference in QoL. Schedules with treatment breaks may not reduce clinical effectiveness but reduce toxicity. The addition of oxaliplatin to second-line 5-FU also saw no improvement in OS (p<0.07), better PFS (by 2.1 months, p=0.0001), an 8.9% higher response rate (p<0.0001), more toxicities and no QoL advantage. There was no significant difference in OS or PFS between first-line irinotecan and oxaliplatin combinations except when 5-FU was delivered by bolus injection, when oxaliplatin provided better OS (p=0.032) and response rates (p=0.032), but not PFS (p=0.169). The regimens had different toxicity profiles and neither conferred a QoL advantage. When compared to 5-FU, raltitrexed is associated with no significant difference in overall or progression-free survival; no significant difference in response rates; more vomiting and nausea, but less diarrhoea and mucositis; no significant difference in, or worse QoL. Raltitrexed treatment was cut short in two out of four included trials due to excess toxic deaths. 5-FU followed by irinotecan was inferior to any other sequence. First-line irinotecan/5-FU combination improved OS and PFS, although further unplanned therapy exaggerated the OS effect size. Staged combination therapy (combination oxaliplatin followed by combination irinotecan or vice versa) provided the best OS and PFS, although there was no head-to-head comparison against other treatment plans. In the only trial to use three active chemotherapies in any staged combination, median OS was over 20 months. In another study, the longest median OS from a treatment plan using two active agents was 16.2 months. Where irinotecan or oxaliplatin were used with 5-FU to downstage people with unresectable liver metastases, studies consistently showed response rates of around 50%. Resection rates ranged from 9 to 35% with irinotecan and from 7 to 51% with oxaliplatin. In the one study that compared the regimens, oxaliplatin enabled more resections (p=0.02). Five-year OS rates of 5-26% and disease-free survival rates of 3-11% were reported in studies using oxaliplatin. Alone or in combination, 5-FU was more effective and less toxic when delivered by continuous infusion. Existing economic models were weak because of the use of unplanned second-line therapies in their trial data: the survival benefits in patients on such trials cannot be uniquely attributed to the allocated therapy. Consequently, the economic analyses are either limited to the use of PES (at best, a surrogate outcome) or are subject to confounding. Weaknesses in cost components, the absence of direct in-trial utility estimates and the limited use of sensitivity analysis were identified. Improvements to the methodologies used in existing economic studies are presented. Using data from two trials that planned treatment sequences, an independent economic evaluation of six plans compared with first-line 5-FU followed on progression by second-line irinotecan monotherapy (NHS standard treatment) is presented. 5-FU followed on progression by irinotecan combination cost 13,174 pounds per life-year gained (LYG) and 10,338 pounds per quality-adjusted life-year (QALY) gained. Irinotecan combination followed on progression by additional second-line therapies was estimated to cost 12,418 pounds per LYG and 13,630 pounds per QALY gained. 5-FU followed on progression by oxaliplatin combination was estimated to cost 23,786 pounds per LYG and 31,556 pounds per QALY gained. Oxaliplatin combination followed on progression by additional second-line therapies was estimated to cost 43,531 pounds per LYG and 67,662 pounds per QALY gained. Evaluations presented in this paragraph should be interpreted with caution owing to missing information on the costs of salvage therapies in the trial from which data were drawn. Irinotecan combination followed on progression by oxaliplatin combination cost 12,761 pounds per LYG and 16,663 pounds per QALY gained. Oxaliplatin combination followed on progression by irinotecan combination cost 16,776 pounds per LYG and 21,845 pounds per QALY gained. The evaluation suggests that these two sequences have a cost-effectiveness profile that is favourable in comparison to other therapies currently funded by the NHS. However, the differences in OS observed between the two trials from which data were taken may be a result of heterogeneous patient populations, unbalanced protocol-driven intensity biases or other differences between underlying health service delivery systems.
Treatment with three active therapies appears most clinically effective and cost-effective. NHS routine data could be used to validate downstaging findings and a meta-analysis using individual patient-level data is suggested to validate the optimal treatment sequence.
评估三种晚期结直肠癌的治疗技术：（1）一线伊立替康联合[5-氟尿嘧啶（5-FU）]或二线单药治疗；（2）一线或二线奥沙利铂联合（同样与5-FU联合）；（3）雷替曲塞，用于不适合使用5-FU的情况。研究伊立替康和奥沙利铂在根治性手术前减少不可治愈疾病范围（降期）中的作用。
涵盖截至2004年8月的十个电子文献数据库。
检索确定了关于这些技术有效性和经济学的现有研究，纳入任何评估上述任何适应证的研究。提取数据并评估方法学质量的一般组成部分。对生存结果进行荟萃分析。
共找到17项试验，方法学质量各异。与5-FU相比，一线伊立替康使总生存期（OS）延长2 - 4个月（p = 0.0007），无进展生存期（PFS）延长2 - 3个月（p < 0.00001），缓解率提高（p < 0.001）。它具有不同的毒性特征，且无生活质量（QoL）优势。然而，二线伊立替康与5-FU相比，使OS延长2个月（p = 0.035），PFS延长1个月（p = 0.03），部分缓解率更高，但毒性更大且无QoL优势。与二线最佳支持治疗相比，伊立替康使OS延长2个月（p = 0.0001），毒性特征不同，维持基线QoL的时间更长，但总体无差异。二线5-FU联合奥沙利铂与总生存期的改善接近显著相关（p < 0.07）；缓解率显著更高（< 0.0001）；毒性更严重。在QoL方面无显著差异的证据。有治疗间歇的方案可能不会降低临床疗效，但可降低毒性。二线5-FU联合奥沙利铂在OS方面也无改善（p < 0.07），PFS更好（延长2.1个月，p = 0.0001），缓解率高8.9%（p < 0.0001），毒性更大且无QoL优势。一线伊立替康和奥沙利铂联合方案在OS或PFS方面无显著差异，除非5-FU采用推注给药，此时奥沙利铂的OS更好（p = 0.032），缓解率更高（p = 0.032），但PFS无差异（p = 0.169）。这些方案具有不同的毒性特征，均未带来QoL优势。与5-FU相比，雷替曲塞在总生存期或无进展生存期方面无显著差异；缓解率无显著差异；呕吐和恶心更多，但腹泻和黏膜炎更少；QoL无显著差异或更差。在纳入的四项试验中有两项因毒性死亡过多而提前终止雷替曲塞治疗。5-FU后接伊立替康劣于任何其他顺序。一线伊立替康/5-FU联合方案改善了OS和PFS，尽管进一步的非计划治疗夸大了OS效应大小。分期联合治疗（奥沙利铂联合后接伊立替康联合或反之）提供了最佳的OS和PFS，尽管未与其他治疗方案进行直接对比。在唯一一项使用任何分期联合的三种活性化疗药物的试验中，中位OS超过20个月。在另一项研究中，使用两种活性药物的治疗方案的最长中位OS为16.2个月。在使用伊立替康或奥沙利铂与5-FU使不可切除肝转移患者降期的研究中，一致显示缓解率约为50%。伊立替康的切除率为9%至35%，奥沙利铂为7%至51%。在一项比较这些方案的研究中，奥沙利铂能实现更多切除（p = 0.02）。使用奥沙利铂的研究报告的5年OS率为5%至26%，无病生存率为3%至11%。单独或联合使用时，5-FU持续输注更有效且毒性更小。现有的经济模型存在缺陷，因为其试验数据中使用了非计划的二线治疗：此类试验中患者的生存获益不能唯一归因于分配的治疗。因此，经济分析要么限于使用PES（充其量是替代结局），要么存在混杂因素。确定了成本组成部分的弱点、试验中缺乏直接的效用估计以及敏感性分析的有限使用。提出了对现有经济研究中使用的方法的改进。使用两项计划治疗顺序的试验数据，对六个方案与一线5-FU进展后二线伊立替康单药治疗（NHS标准治疗）进行了独立的经济评估。5-FU进展后接伊立替康联合方案每获得一个生命年（LYG）成本为13,174英镑，每获得一个质量调整生命年（QALY）成本为10,338英镑。伊立替康联合方案进展后接额外的二线治疗估计每LYG成本为12,418英镑，每QALY成本为13,630英镑。5-FU进展后接奥沙利铂联合方案估计每LYG成本为23,786英镑，每QALY成本为31,556英镑。奥沙利铂联合方案进展后接额外的二线治疗估计每LYG成本为43,531英镑，每QALY成本为67,662英镑。由于所提取数据的试验中关于挽救治疗成本的信息缺失，本段中的评估应谨慎解释。伊立替康联合方案进展后接奥沙利铂联合方案每LYG成本为12,761英镑，每QALY成本为16,663英镑。奥沙利铂联合方案进展后接伊立替康联合方案每LYG成本为16,776英镑，每QALY成本为21,845英镑。评估表明，与目前由NHS资助的其他疗法相比，这两个顺序具有有利的成本效益特征。然而，所采用数据的两项试验之间观察到的OS差异可能是由于患者群体异质性、方案驱动的强度偏差不平衡或基础医疗服务提供系统之间的其他差异所致。
三种活性疗法的治疗似乎在临床效果和成本效益方面最佳。NHS常规数据可用于验证降期结果，建议使用个体患者水平数据进行荟萃分析以验证最佳治疗顺序。
