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Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer |
Thirion P, Piedbois P, Buyse M, O'Dwyer P J, Cunningham D, Man A, Greco F A, Colucci G, Kohne C H, Di Costanzo F, Piga A, Palmeri S, Dufour P, Cassano A, Pajkos G, Pensel R, Aykan N F, Marsh J, Seymour M T |
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Authors' objectives To investigate the impact of alpha-interferon (alpha-IFN) in advanced colorectal cancer, through a meta-analytic approach based on individual patient data (IPD).
Searching The search for relevant trials was initiated in October 1996. The trials were identified by searching MEDLINE, PDQ, and the proceedings of major conferences since 1989, and by contacting principal investigators. A secretariat and collaborative group of trial investigators (Meta-Analysis Group in Cancer) was established to identify trials and undertake the meta-analysis.
Study selection Study designs of evaluations included in the reviewOnly properly randomised controlled trials (RCTs) were eligible for inclusion in the review. The review included the IPD from these trials.
Specific interventions included in the reviewAlpha-IFN consisting of alpha-2a-IFN or alpha-2b-IFN. Alpha-IFN, either as monotherapy or in combination with 5-fluorouracil (5-FU) with or without folinic acid, was compared with 5-FU with or without folinic acid.
Participants included in the reviewPatients with advanced colorectal cancer who had been included in the trials before July 1996.
Outcomes assessed in the reviewThe outcome measures were complete response and partial response using the criteria adopted in individual trials (World Health Organization recommendations; see Other Publications of Related Interest). Minimal response, stable disease or progressive disease were classified as 'no response' for the purposes of this meta-analysis.
How were decisions on the relevance of primary studies made?The principal investigators were contacted.
Assessment of study quality The validity of the data for each individual trial was checked. The authors do not state how the papers were assessed for validity, or how many of the reviewers performed the validity assessment. All IPD were included on an intention to treat basis. One trial that had not used the same regimen of 5-FU in both treatment arms was excluded. Patients with unmeasurable disease were removed.
Data extraction The IPD were provided by the principal investigators of each identified study. The following information was requested for each randomised patient: the date of randomisation; tumour measurability; treatment assigned by randomisation; age; gender; performance status; primary tumour site; prior adjuvant chemotherapy; prior chemotherapy for metastatic disease; site of metastases; overall response status with first assigned treatment; date of response or progression with first allocated treatment; crossover to another treatment arm; date of death or last visit; survival status; and cause of death if applicable.
Methods of synthesis How were the studies combined?Two meta-analyses were conducted. One compared 5-FU with or without folinic acid with the combination of alpha-IFN and 5-FU with or without folinic acid. The second compared 5-FU and folinic acid with 5-FU and alpha-IFN. The statistical methods used were those for meta-analyses based on IPD. The tumour responses were compared through relative risks in the individual trials and overall. The prognostic factors for response were identified through a logistic regression model. The survival times were compared through hazard ratios (HRs) in the individual trials and overall. The prognostic factors for survival were identified through a proportional hazards regression model. All p-values were two-sided.
How were differences between studies investigated?Heterogeneity was investigated using the chi-squared test.
Results of the review Seventeen trials (n=3,254) were included in the review. A further three trials were identified but could not be included due to a lack of information or data.
5-FU with or without folinic acid versus 5-FU with or without folinic acid and alpha-IFN (n=1,683). The overall tumour response rate was 25% for 5-FU with folinic acid and 24% for 5-FU with folinic acid and alpha-IFN. This gave a relative risk of 1.02 (95% confidence interval, CI: 0.87, 1.2, p=0.8; heterogeneity chi-squared 15.79, p=0.15), showing no advantage of alpha-IFN administration. There was no statistically-significant difference in survival with the addition of alpha-IFN to 5-FU or to 5-FU plus folinic acid. The overall survival HR for the comparison was 0.95 (95% CI: 0.86, 1.05, p=0.33). The median survivals were 11.5 and 11.4 months for patients treated with and without alpha-IFN, respectively.
5-FU with folinic acid versus 5-FU with alpha-IFN (n=1,305).
The overall tumour response rate was 23% for 5-FU with folinic acid and 18% for 5-FU with alpha-IFN. This gave a relative risk of 1.26 (95% CI: 1.01, 1.59, p=0.04), showing a benefit of 5-FU with folinic acid over 5-FU with alpha-IFN. The heterogeneity was, however, important (p=0.001). An analysis stratified by the type of 5-FU administration found that the advantage of 5-FU with folinic acid was limited to those trials using the same 5-FU schedules in both treatment arms (relative risk 1.80, 95% CI: 1.29, 2.51, p=0.0005). A survival analysis showed a small, non statistically-significant trend in favour of 5-FU with folinic acid (HR 1.11, 95% CI: 0.99, 1.24, p=0.066). The median survivals were 11.7 and 11.3 months for patients allocated to 5-FU with folinic acid and 5-FU with alpha-IFN, respectively. The survival difference reached statistical significance in those trials where the same 5-FU schedules were used in both treatment arms.
Authors' conclusions Alpha-IFN did not increase the efficacy of 5-FU in advanced colorectal cancer, and should not be offered in routine clinical practice.
CRD commentary This review addressed an appropriate question with well-defined inclusion and exclusion criteria. It was not completely clear from the review whether the search for studies was comprehensive; for example, further details of the research groups contacted would have been useful. The report did not clarify what criteria were used to exclude studies or patients from the analyses. In addition, it did not explore the effect of the three studies excluded due to a lack of information.
The authors' conclusions are supported by the findings of the meta-analyses as presented, but the limitations highlighted should be borne in mind.
Implications of the review for practice and research Practice: The authors state that 'Alpha-IFN does not increase the efficacy of 5-FU in advanced colorectal cancer and should not be offered in routine clinical practice'.
Research: The authors did not state any implications for further research.
Funding European Association for Research in Oncology (AERO), France; Roche Laboratories.
Bibliographic details Thirion P, Piedbois P, Buyse M, O'Dwyer P J, Cunningham D, Man A, Greco F A, Colucci G, Kohne C H, Di Costanzo F, Piga A, Palmeri S, Dufour P, Cassano A, Pajkos G, Pensel R, Aykan N F, Marsh J, Seymour M T. Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer. British Journal of Cancer 2001; 84(5): 611-618 Other publications of related interest Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-14.
Indexing Status Subject indexing assigned by NLM MeSH Antineoplastic Combined Chemotherapy Protocols /therapeutic use; Colorectal Neoplasms /drug therapy /mortality; Fluorouracil /therapeutic use; Humans; Interferon-alpha /therapeutic use; Leucovorin /therapeutic use; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Survival Analysis AccessionNumber 12001000868 Date bibliographic record published 31/07/2002 Date abstract record published 31/07/2002 Record Status 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. |
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