NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Picot J, Cooper K, Bryant J, et al. The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Dec. (Health Technology Assessment, No. 15.41.)

Cover of The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation

The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation.

Show details

3Methods

The a priori methods for systematically reviewing the evidence of clinical effectiveness and cost-effectiveness are described in the research protocol (Appendix 1), which was sent to our expert advisory group for comment. None of the comments we received identified specific problems with the methods of the review. The methods outlined in the protocol are briefly summarised below.

Search strategy

The search strategies were developed and tested by an experienced information specialist. The strategies were designed to identify studies reporting clinical effectiveness, cost-effectiveness, HRQoL, resource use and costs, epidemiology and natural history.

The following databases were searched for published studies and ongoing research from 1999 (earliest use of thalidomide for MM37 and earliest description of bortezomib as a potential cancer therapy38) to December 2009: MEDLINE, MEDLINE In-Process, EMBASE, Web Of Science, BIOSIS, Centre for Reviews and Dissemination (CRD) Database of Abstracts of Reviews of Effects (DARE), HTA, NHS Economic Evaluation Database (NHS EED) and Cochrane Central Register of Controlled Trials (CENTRAL). Bibliographies of articles and grey literature sources were also searched. Reference lists within drug manufacturers' submissions (MSs) to NICE were searched for any additional studies that met the inclusion criteria. Our expert advisory group was asked to identify additional published and unpublished references. Searches were restricted to English language. Further details, including an example search strategy, can be found in Appendix 2.

Inclusion and exclusion criteria

Study design

  • For the systematic review of clinical effectiveness, randomised controlled trials (RCTs) were eligible for inclusion. In addition, evidence from good-quality observational studies was also eligible for consideration if the data from available RCTs were incomplete (e.g. absence of data on outcomes of interest).
  • For the systematic review of cost-effectiveness economic evaluations (such as cost-effectiveness studies, cost–utility studies, cost–benefit studies) were eligible for inclusion.
  • Abstracts or conference presentations of studies were eligible for inclusion only if sufficient details were presented to allow an appraisal of the methodology and the assessment of results to be undertaken.
  • Case series, case studies, narrative reviews, editorials and opinions were excluded, as were non-English-language studies. Systematic reviews and clinical guidelines were used only as a source of references.

Intervention(s)

  • Bortezomib in combination with an alkylating agent and a corticosteroid for first-line treatment of MM.
  • Thalidomide in combination with an alkylating agent and a corticosteroid for first-line treatment of MM.
  • Studies of treatment with either bortezomib or thalidomide as a single agent were excluded.

Comparator(s)

Population

  • People with previously untreated MM who are not candidates for HDT with SCT.
  • Studies of MM patients who had received previous treatment(s) were excluded.

Outcomes

Studies were included if they reported on one or more of the following outcomes:

  • overall survival
  • progression-free survival (deaths counted as events)
  • time to progression (deaths are excluded from the calculation of this outcome)
  • response rates
  • health-related quality of life
  • cost-effectiveness [such as incremental cost per quality-adjusted life-year (QALY) gained]
  • adverse events of treatment were reported when available within the trials that met the inclusion criteria.

Response definitions

  • Response to treatment is usually assessed based on changes in serum levels of M-protein and/or urinary light chain excretion. Two different systems for categorising response are included in this report, the European Group for Blood and Marrow Transplantation (EBMT) criteria39 and the Intergroupe Francophone du Myélome (IFM) criteria.23 Where there are differences in the two systems, in general the EBMT criteria require a slightly greater improvement. For example, in the definition of partial response (PR) one of the IFM requirements is more than a 75% reduction in 24-hour urinary light chain excretion, whereas one of the EBMT criteria for PR is a 90% decrease in urinary light chain excretion. The EBMT and IFM criteria for judging response are provided in Appendix 3.

Adverse event definitions

  • Two slightly different National Cancer Institute (NCI) criteria have been used to grade AEs, the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4, and the NCI Common Toxicity Criteria (CTC) version 2. The NCI CTCAE version 4 grades AEs on a five-point scale (1–5) and the NCI CTC version 2 grades AEs on a six-point scale, as 0 is included (0 = no AE or within normal limits). Events of a higher grade are more serious than those at a lower grade, with a grade 1 event described as ‘mild’, grade 2 ‘moderate’, a grade 3 event would be considered ‘severe’, while a grade 4 event could be ‘life threatening’. Grade 5 is reserved for deaths related to an AE.

Inclusion and data extraction process

Studies were selected for inclusion in the systematic reviews of clinical effectiveness and cost-effectiveness through a two-stage process. Literature search results (titles and abstracts) were screened independently by two reviewers to identify all of the citations that might meet the inclusion criteria. Full manuscripts of selected citations were then retrieved and assessed by one reviewer against the inclusion/exclusion criteria and checked independently by a second reviewer. Discrepancies were resolved by discussion, with involvement of a third reviewer when necessary.

Data from included studies were extracted by one reviewer using a standardised data extraction form and each data extraction was checked for accuracy by a second reviewer. Again discrepancies in the extracted data were resolved by discussion, with involvement of a third reviewer when necessary.

Critical appraisal strategy

The quality of included clinical effectiveness studies was assessed using the CRD criteria.40 Quality criteria were applied by one reviewer and checked by a second reviewer with any disagreements resolved by consensus and involvement of a third reviewer where necessary.

Methods of data synthesis

Clinical effectiveness and cost-effectiveness studies were synthesised through a narrative review with tabulation of results of included studies. Results of included RCTs were meta-analysed if appropriate (more than one trial with populations, interventions and outcomes believed to be sufficiently similar) and possible (adequate data reported). For time-to-event analyses (OS and PFS) the log-hazard ratio (HR) and its standard error (SE) for each outcome were used to calculate a summary HR and 95% confidence interval (CI) using the Cochrane Collaboration Review Manager 5.0.23 software. However, as the SEs of the log-HRs were not reported by the RCTs, these had to be estimated using the methods and Microsoft Excel spreadsheet of Tierney and colleagues.41

This report contains reference to confidential information provided as part of the NICE appraisal process. This information has been removed from the report and the results, discussions and conclusions of the report do not include the confidential information. These sections are clearly marked in the report.

© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK97487

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this title (1.5M)

Other titles in this collection

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...