|Clinical effectiveness and cost-effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastiatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: a systematic review and economic evaluation
|Hislop J, Quayyum Z, Elders A, Fraser C, Jenkinson D, Mowatt G, Sharma P, Vale L, Petty R
The authors concluded that around one third of patients with unresectable and/or metastatic gastrointestinal stromal tumour who failed on 400mg per day of imatinib may show response or stable disease with escalated doses. The evidence base was limited, and potentially biased by non-randomised data. The conclusion reflects the limited evidence and seems reliable.
To evaluate the effects of imatinib (600mg or 800mg per day) in patients with unresectable and/or metastatic gastrointestinal stromal tumours, where the disease had progressed on treatment at 400mg per day.
Ten databases were searched (including MEDLINE, EMBASE, CINAHL, The Cochrane Library and the Health Technology Assessment database). Search dates covered 1966 to 2009. Ongoing and recently completed trials were searched via several sources. Conference proceedings and manufacturer's websites were also scanned for additional studies. Search strategies were reported.
Eligible for inclusion were randomised controlled trials (RCTs), non-randomised comparative studies and case series of imatinib at escalated doses (600mg or 800mg per day) administered with best supportive care to patients with tyrosine kinase (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumour, where disease had progressed with treatment at 400mg per day. Eligible comparators were sunitinib (27mg to 75mg) with or without best supportive care, and best supportive care only. best supportive care was defined in the report. Outcomes of interest were: overall response and survival; disease- and progression-free survival; time to treatment failure; health-related quality of life (HRQoL); and discontinuations due to adverse events.
There were no RCTs or non-randomised comparative studies for the direct comparison of escalated imatinib with sunitinib or best supportive care, and there were no studies at all that compared with best supportive care only. None of the included studies were designed to assess patients whose disease had progressed from drug treatment at 400mg per day. Included studies provided observational data after requests to the study authors for any information that could be used in relation to the population of interest. Four studies assessed imatinib (400mg to 800mg per day) and one study assessed sunitinib (50mg per day for four weeks, followed by two weeks without treatment), and were conducted worldwide (one included the UK as a location). A larger proportion of men than women were included, with average age ranging from 52 years to 61.9 years (range 18 to 92 years).
Two reviewers independently selected studies for inclusion. Disagreements were resolved by consensus, or with the involvement of a third reviewer.
Assessment of study quality
Randomised controlled trials (RCTs) were assessed with the Cochrane risk of bias tool. Non-randomised comparative studies and case series were assessed with an adapted checklist, which included the sequence generation and allocation concealment elements of the Cochrane tool. Only full text papers were assessed.
Two reviewers independently carried out the quality assessment. Disagreements were resolved by consensus, or with the involvement of a third reviewer.
Planned data extraction was to enable the calculation of relative risks (RR), mean differences (MDs), ratios of median survival or hazard ratios (HR), along with 95% confidence intervals (CI).
One reviewer extracted the data, and this was checked by a second reviewer. Disagreements were resolved by consensus, or with the involvement of a third reviewer.
Methods of synthesis
Meta-analyses using appropriate methods were planned. However, due to the available evidence being observational (comprising mainly reports of patient subgroups in RCTs), a narrative synthesis was provided.
Results of the review
Four full-text studies (based on three RCTs with crossover data, and one non-randomised retrospective study) and one abstract (total 669 participants) provided non-comparative observational data for the review. Follow up ranged from eight months to 63 months. The four full-text studies generally scored well on quality items relating to sample definition and selection (although representativeness was unclear, and none of the studies had consecutive sample selection). Interventions were clearly described, valid and reliable outcome measures were used, and follow-up was sufficient for outcome measurement. Other criteria were unclear or not met.
Imatinib at 600mg per day resulted in between 26% and 42% of patients demonstrating either a partial response or stable disease. The median time to progression was 1.7 months (range 0.7 to 24.9 months).
At 800mg per day, imatinib resulted in 29% to 33% of patients demonstrating either a partial response or stable disease. Median overall survival was 19 months (95% CI; 13 to 23 months). Average progression-free survival was 81 days to five months (95% CI; two to 10 months). Median duration of response was 153 days (range 37 to 574 days). Treatment progression showed that 88% of patients discontinued treatment. Dose reduction was required in 16% to 31% of patients, and 23% required a dose delay. Fatigue and anaemia were significantly increased as a result of dose escalation.
For sunitinib, median overall survival was 90 weeks (95% CI; 73 to 106 weeks).
Best supportive care only was cost-effective when cost per quality-adjusted-life-year (QALY) was below £25,000. Imatinib at 600mg per day was most likely to be cost-effective at a threshold between £25,000 and £45,000 per QALY. Imatinib at 600mg per day followed by further escalation followed by sunitinib was most likely to be cost-effective at a threshold above £45,000.
Around one-third of patients with unresectable and/or metastatic gastrointestinal stromal tumour who fail on 400mg per day of imatinib may show response or stable disease with escalated doses. The evidence base was limited and potentially biased by non-randomised data.
The review question was clear, and inclusion criteria were sufficiently reproducible. However, the absence of studies that met the inclusion criteria led the authors to focus on observational data which did not allow for analyses as planned. A wide range of data sources were selected and attempts were made to minimise publication bias. The review process was conducted with adequate effort to minimise error and bias. Study details were sufficiently detailed and quality assessment criteria were appropriate to enable interpretation of the strength of the review findings. Whilst the review findings were based largely on subgroups of patients and did not fully address the review question, the authors' conclusion reflects the limited evidence and seems reliable.
Implications of the review for practice and research
Practice: The authors stated that there was not enough evidence to demonstrate that dose escalation of imatinib from 400mg per day for patients with unresectable and/or metastatic gastrointestinal stromal tumour was an effective strategy for the NHS.
Research: The authors stated that, where feasible, a future RCT was needed to compare alternative combinations of dose escalation with imatinib and use of sunitinib in patients who progress on 400mg per day with imatinib. This should include an economic evaluation and measurement of health state utilities. Reporting of outcomes for subgroups of patients with specific tyrosine kinase mutations was also recommended.
The National Institute of Health Research Health Technology Assessment Programme.
Hislop J, Quayyum Z, Elders A, Fraser C, Jenkinson D, Mowatt G, Sharma P, Vale L, Petty R. Clinical effectiveness and cost-effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastiatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: a systematic review and economic evaluation. Health Technology Assessment 2011; 15(25): 1-171
Subject indexing assigned by NLM
Antineoplastic Agents /administration & dosage /economics /therapeutic use; Confidence Intervals; Cost-Benefit Analysis; Disease Progression; Gastrointestinal Stromal Tumors /drug therapy /economics /pathology; Humans; Incidence; Models, Economic; Piperazines /administration & dosage /economics /therapeutic use; Pyrimidines /administration & dosage /economics /therapeutic use; Quality-Adjusted Life Years; Survival Analysis; Time Factors; Treatment Outcome; Uncertainty; United States
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.