To investigate the long-term survival of multiple myeloma patients treated with alpha-interferon (IFN).

IDIS (via CD-ROM) was searched from January 1985 to May 1977, and MEDLINE (via SilverPlatter) from January 1990 to May 1997, using 'interferon' and myeloma' as index terms. The search was supplemented by consulting experts in the field and searching reviews, textbooks, and the reference lists of the identified studies. The search was limited to articles written in the English language.

Study designs of evaluations included in the review

Randomised trials comparing IFN treatment with placebo or no treatment. Studies were excluded for the following reasons: if the authors did not report a survival curve and only provided the crude rates of survival at the end of the follow-up; if randomisation to IFN was carried out at the beginning of the induction phase and not at the start of IFN treatment; if they calculated survival from the start of the induction therapy and not from the start of IFN treatment; or if they enrolled patients with different pre-treatment histories.

Specific interventions included in the review

Alpha-IFN compared with placebo and no treatment. Treatment with recombinant alpha-IFN comprised 5.1, 6.0, 8.6 or 9.0 MU/m2/week, delivered subcutaneously continuously for one year or until relapse.

Participants included in the review

Multiple myeloma patients, who were in remission after conventional induction chemotherapy treatment, were included. The median age was 62 to 70 years.

Outcomes assessed in the review

The outcome assessed in the review was the mean lifetime survival (years per patient).

How were decisions on the relevance of primary studies made?

The authors do not state how the papers were selected for the review, or how many of the authors performed the selection.

The authors do not state that they assessed validity.

The authors do not state how the data were extracted for the review, or how many of the authors performed the data extraction.

How were the studies combined?

The survival curves published in each of the studies were analysed to determine the mean lifetime survival (MLS) for treated patients and controls, using Gompertz' extrapolation (see Other Publications of Related Interest no.1). The MLS values were then pooled using standard meta-analytic techniques, and the pooled values with 95% confidence intervals (CIs) were compared for IFN-treated patients and controls.

How were differences between studies investigated?

No significant differences were found in the outcome measures between the treatment groups and the control groups. Thus, no assessments of inter-trial heterogeneity and publication bias were carried out.

The review included 6 randomised trials (391 participants treated with alpha-IFN and 421 controls).

The pooled MLS value for the control group was 3.42 years per patient (mean value weighted according to sample size). The pooled MLS value for the IFN-treated patients was 3.87 years per patient (95% CI: 2.88, 4.06) when estimated by the method of Simes (see Other Publications of Related Interest no.2)), or 3.42 years per patient when the mean value was weighted according to the sample size. The difference in survival between the two patient groups was not statistically significant (p=0.095).

A simplified analysis was carried out to calculate the cost-effectiveness ratio (incremental cost divided by the incremental survival) for recombinant alpha-IFN. The numerator of the cost-effectiveness ratio was estimated to be US$42,000 per patient. This value was obtained considering the acquisition cost of IFN and other treatment-related costs, such as the costs for subcutaneous administration of IFN, the physician's time for control and adjustment of medication, and laboratory examinations with biomedical testing of liver function (see Other Publications of Related Interest no.3). The acquisition cost of IFN was estimated as US$7,800 per patient per year, assuming an average dosage of 8.6 MU/m2/week and an acquisition cost of IFN of about US$10 per MU (see Other Publications of Related Interest nos.3-4). Treatment-related costs were quantified in terms of an expenditure of US$3,000 per patient per year. On the basis of these data, the yearly cost of IFN was about US$11,000 per patient (US$7,800 plus US$3,000). Considering the MLS of 3.87 years per patient in the IFN group, the lifetime cost of IFN was estimated as US$42,000 per patient (i.e. 3.87 multiplied by US$11,000).

The incremental survival was calculated to be 0.5 years per patient. Hence, the cost per life-year gained of IFN maintenance in myeloma patients was estimated to be around US$84,000. The authors state that this suggests an unfavourable pharmacoeconomic ranking according to current standards (see Other Publications of Related Interest no.5).

For a full discussion of the economic aspects of this study see NHS EED record number 21997001600.

The survival advantage of maintenance treatment with IFN in myeloma patients, if any, has a small clinical relevance and demonstrates an intermediate or unfavourable pharmacoeconomic ranking.

This was a clearly presented review with well-defined criteria for study inclusion. A thorough attempt was made to identify all the possible sources of evidence (published and unpublished) relevant to this review. However, by limiting the search to English language articles, relevant articles may have been excluded. The authors supplied a list of search terms used to retrieve the articles so their search strategy can easily be reproduced.

The authors failed to explain how decisions to include or exclude the studies were made, and whether they assessed study quality. In addition, the authors carried out a secondary analysis including data from one trial, which only provided crude survival data. This trial did not meet the review's inclusion criteria and was only included in order to make the results comparable with those from another similar review. Despite these shortcomings, the results appear to support the authors' conclusions.

The authors state that the meta-analysis has clearly highlighted the uncertainty regarding IFN maintenance in myeloma patients, and that recommendations should be made only with extreme caution.

1. Messori A. Survival curve fitting using the Gompertz function: a methodology for conducting cost-effectiveness analyses on mortality data. Comput Methods Programs Biomed 1997;52:157-64. 2. Simes RJ. Confronting publication bias: a cohort design for meta-analysis. Stat Med 1987;6:11-29. 3. Messori A, Becagli P, Trippoli S, Tendi E. A retrospective cost-effectiveness analysis of interferon as adjuvant therapy in high-risk resected cutaneous melanoma. Eur J Cancer 1997;33:1373-9. 4. Schofield JR, Robinson WA, Murphy JR. Low doses of interferon-alpha are as effective as higher doses in inducing remissions and prolonging survival of chronic myeloid leukemia. Ann Intern Med 1994;121:736-44. 5. Mark DB, Hlatky MA, Califf RM, Naylor CD, Lee KL, Armstrong PW, et al. Cost effectiveness of thrombolytic therapy with tissue plasminogen activator as compared with streptokinase for acute myocardial infarction. New Engl J Med 1995;332:1418-24.

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.