Executive Summary of HTA journal title
Health Technol Assess 2008;12(15):1–182
The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation
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D Hind,* P Tappenden, I Tumur, S Eggington, P Sutcliffe and A Ryan
School of Health and Related Research (ScHARR), University of Sheffield, UK
* Corresponding author
The objective of this study were 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. The study also examined the role of irinotecan and oxaliplatin in reducing the extent of incurable disease before curative surgery (downstaging).
Searches in ten electronic bibliographic databases identified existing studies of the effectiveness and economics of the technologies. Studies that evaluated any of the indications outlined above were included. Two reviewers independently extracted data and assessed generic components of methodological quality. Survival outcomes were meta-analysed.
Seventeen trials were found, of varying methodological quality.
Caveat: over half of first-line trial participants across all studies, except for two, were treated with unplanned second-line therapies (a confounding factor); estimates of overall survival (OS) should be read with caution. Trial data are based on atypically young populations, but available evidence suggests no difference in the efficacy or toxicity of combination therapy in older people.
Compared with 5-FU, first-line irinotecan improved 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.
Compared with 5-FU, second-line irinotecan 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 quality of life longer, but with no overall difference.
The addition of oxaliplatin to first-line 5-FU was associated with no difference in OS (see caveat), improved PFS (p < 0.00001), higher response rates (p < 0.0001), more gastrointestinal and haematological toxicities, and no QoL advantage. Schedules with treatment breaks may not reduce clinical effectiveness but reduce toxicity.
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.
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 irinotecanmonotherapy (NHS standard treatment) is presented.
5-FU followed on progression by irinotecan combination cost £13,174 per life-year gained (LYG) and £10,338 per quality-adjusted life-year (QALY) gained. Irinotecan combination followed on progression by additional second-line therapies was estimated to cost £12,418 per LYG and £13,630 per QALY gained. 5-FU followed on progression by oxaliplatin combination was estimated to cost £23,786 per LYG and £31,556 per QALY gained. Oxaliplatin combination followed on progression by additional second-line therapies was estimated to cost £43,531 per LYG and £67,662 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 per LYG and £16,663 per QALY gained. Oxaliplatin combination followed on progression by irinotecan combination cost £16,776 per LYG and £21,845 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.
Recommendations for research
The collection of routine data from within the NHS would help to validate the downstaging of people with liver metastasis. A meta-analysis using individual patient-level data is also suggested to validate the optimal treatment sequence and to provide a baseline against which future treatment sequences could be compared.
PublicationHind D, Tappenden P, Tumur I, Eggington E, Sutcliffe P, Ryan A. The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation. Health Technol Assess 2008;12(15).
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The Health Technology Assessment (HTA) Programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.
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The research reported in this issue of the journal was commissioned and funded by the HTA Programme on behalf of NICE as project number 04/12/01. The protocol was agreed in August 2004. The assessment report began editorial review in May 2005 and was accepted for publication in October 2005. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
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