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Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy

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Part 3. Imatinib for Chronic Myeloid Leukemia (CML) (continued)


Methods

Search Strategy

The search strategy was constructed by combining three concepts:

  1. The intervention imatinib.
  2. The disease chronic myeloid leukemia.
  3. Prospective clinical trials.

To identify the intervention concept, since these new drugs lack a specific term in the MeSH lexicon, we used text word searching for the following text strings: imatinib or gleevec or glivec or STI571. The disease concept was implemented using the MeSH headings Leukemia, Chronic, Myeloid and Leukemia, Chronic, Philadelphia-Positive as well as text word searching for CML or adjacent text strings for chronic within two words of myeol$ adjacent to (leukemia$ or leukaemia). This is designed to detect various spellings such as chronic myelogenous leukemia or chronic myeloid leukemia or chronic myeloid leukaemia, etc. A published strategy, validated for finding randomized controlled trials (RCTs), was used to identify prospective clinical trials.57 This strategy is designed to find all prospective clinical trials (maximize sensitivity), rather than to eliminate non-randomized trials (maximize specificity), and so is appropriate for this study's goal of finding phase II and III prospective clinical trials. Finally, the three concepts were combined (Boolean "or"). The strategy was executed in MEDLINE® (1966 through September 2004, updated July 2005) and limited to articles published in the English language. The exact text of the OVID MEDLINE® versions of the search strategy is provided in Appendix A.

Supplemental searches were conducted in International Pharmaceutical Abstracts, The Cochrane Library (Central Register of Controlled Trials [CENTRAL] and Health Technology Assessment [HTA] database), American Society of Hematology 2004 annual meeting abstracts database, the American Society of Clinical Oncology 2004 and 2005 annual meeting abstracts databases. References lists of identified studies and relevant systematic reviews and meta-analyses were hand-checked. Additional articles not indexed in the major bibliographies by July 2005 were identified through ongoing searches and discussions with field experts and monitoring new sources.

Selection Criteria

Each citation identified from the search strategies was evaluated according to the following selection criteria. Evaluations were performed by the authors.

Inclusion criteria were as follows:

Selection Criteria
Patients Patients with CML—any phase
Interventions Imatinib (Gleevec™ or Glivec™ or [STI571])
Comparators Any

Study designs:

  • For efficacy questions: Prospective clinical trials; may be phase II uncontrolled, or phase III randomized controlled trials.
  • For studies of adverse effects: May be retrospective or prospective case series, cohort studies, or clinical trials provided the number of patients treated (at risk for adverse effects) as well as the number with adverse effects can be ascertained.
  • For studies of predictors of response: May be retrospective or prospective case series, cohort studies, case-control studies, or clinical trials provided the response can be ascertained for patients with and without the predictor.

Outcomes:

  • For efficacy questions: Survival, disease-free survival, tumor response, and quality of life (QOL). Tumor response was defined according to Figure 4.
  • For studies of adverse effects: Adverse effects, tolerability, and compliance with treatment.
  • For studies of predictors of response: Predictive value of patient or tumor characteristics that are associated with clinically important differences in treatment response that are:
    1. Related to the mechanism of action of the drug (i.e., molecular target).
    2. Candidates for diagnostic testing (even if not commercially or clinically available currently [e.g., RT-PCR]).

Data Abstraction

The following data were abstracted from included studies: study design, population characteristics (including sex, age, and diagnosis), eligibility and exclusion criteria, interventions (dose and duration), outcomes assessed and results for each outcome.

We developed data collection forms in Excel® (Microsoft®; Redmond, WA) and summarized the data in evidence tables. Predictors of disease response to imatinib were usually presented as results from univariate or mulitvariate statistics. When multivariate results were available these were presented, delineated by the presentation of an odd ratio (OR), relative risk (RR) or hazard ratio (HR). Otherwise results reflect univariate analyses.

Quality Assessment

We assessed the quality of included studies by evaluating elements of internal validity (e.g., randomization and allocation concealment; similarity of compared groups at baseline; specification of eligibility criteria; blinding of assessors, care providers, and patients) and external validity (e.g., description of the patient population, similarity to the target population of the report, use of highly selective criteria). Importantly, quality assessment reflected the quality of reporting of the study in a clinical research context (internal and external validity); quality of the the basic science research or its reporting were not assessed as they were outside of the scope of this review.

We used as a framework the quality assessment criteria from the National Institute for Clinical Excellence (NICE).58 These are displayed in Appendix B. They provide specific criteria for the range of study designs used in this report including experimental studies, cohort studies, case-control studies, and case series.

Point scores were allocated by assigning one point for each quality category. There were a total of six possible categories. Quality ratings of "yes" to a quality criteria were assigned one point; no and unknown were both assigned zero points. The last category, adequate description of subseries, was not applicable to all studies. Hence, the total possible quality points were five or six depending upon the applicability of the subseries category. We defined high quality studies as those with > 3/5 or 4/6 points. Abstract quality was not scored.

Data Synthesis

In addition to the data abstraction and quality analysis, a narrative description of study findings was prepared. Further quantitative analyses were considered, but the available data were not adequate to support these.

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