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Critical analysis of meta-analysis: Individual patient-level data or literature data?

XVIII Congreso Chileno de Cancerolog ía. Critical analysis of meta-analysis: Individual patient-level data or literature data?. Levels of clinical evidence.  Buyse, Bentzen, Tannock, Therasse EJC Suppl. 1(6), 2003. Meta-analysis: objectives.

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Critical analysis of meta-analysis: Individual patient-level data or literature data?

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  1. XVIII CongresoChileno de Cancerología Critical analysis of meta-analysis:Individual patient-level data or literature data? bentzen@humonc.wisc.edu

  2. Levels of clinical evidence  Buyse, Bentzen, Tannock, Therasse EJC Suppl.1(6), 2003

  3. Meta-analysis: objectives • to improve statistical resolution (sample size) • to provide a systematic review of the available evidence • to examine heterogeneity among/quality of studies SAMPLE SIZE

  4. SD vs FX RT for metastatic bone painPower of RCTs in resolving a 10% decrease in RR

  5. Meta-analysis SD vs FX RT for metastatic bone painPower of RCTs in resolving a 5% decrease in RR

  6. Meta-analysis: Literature v individual patient dataAdvanced ovarian carcinoma: combination vs single agent chemotherapy Stewart & Parmar Lancet 341: 418, 1993.

  7. Publication status vs significance487 research projects approved by the Central Oxford Ethics Committee Easterbrook et al. Lancet 337: 867, 1991

  8. SNP’s and late toxicity after breast RT • Substitution of an alternate base pair at a specific nucleotide location • Prevalence ~ 1:1000 nucleotides • Common SNPs in human genome • 7 million SNPs with MAF > 5% • 4 million SNPs with 5% > MAF > 1% • TGF-1 SNP -509C/T – candidate gene SNP for late RT toxicity  Andreassen R&O (in press)

  9. Ian Tannock –

  10. CHEMO LOCOREGIONAL THERAPY FOR HNSCC  Pignon et al. Lancet 355: 949 (2000)

  11. Postoperative radiotherapy in NSCLCPORT Meta-analysis Trialists Group

  12. Postoperative radiotherapy in NSCLC

  13. p<10-4 Postoperative radiotherapy in NSCLC Weighted regression analysis

  14. Postoperative radiotherapy in NSCLC

  15. Meta-analysis of hypoxic modification “…improved loco-regional control with no change in level of complications…”

  16. Meta-analysis of hypoxic modification Importance of type of modification:

  17. Hyperbaric oxygen in ca. cervix • 327 cases with cancer of the uterine cervix stage IIb and III • 4-arm RCT, 10 or 28 F in air or in HBO • Treated at Groote Schur Hospital in Cape Town, SA • No advantage of HBO in terms of tumor control  Dische et al.R&O53: 93, 1999

  18. Quality instruments • A review for the U.S. Department of Health and Human Services found a total of 1602 publications relating to assessment of study quality or strength of evidence: • 121 systems were reviewed, including scales, checklists or other instruments or guidelines • 20 systems were developed for evaluation of systematic reviews • 49 systems for RCTs • 40 systems for grading the strength of a body of evidence. • West et al. AHRQ Publication No. 02-E016. Rockville, MD, (2002)

  19. The nice thing about standards is that there are so many of them to choose from.Andres S. Tannenbaum

  20. Quality scores • 25 quality scales applied to 17 trials of low molecular weight heparin (LMWH) vs standard heparin in the prevention of post-operative thrombosis. • For each scale, the possible relative advantage of LMWH was estimated separately in two strata: low-quality vs high-quality trials HQ: Positive LQ: No difference Similar effect estimates from HQ and LQ trials HQ: No difference LQ: Positive Juni et al. JAMA282: 1054 (1999)

  21. Large RCTs versus meta-analysis • Material: • 12 large RCT's (1000+ pts) • 19 MA's on same question • Results: • Negative predictive value of MA: 67% • Positive predictive value of MA: 68% LeLorier et al. NEJM337: 536, 1997

  22. Effect of RT in early breast cancer EBCTCG,NEJM 333: 1444, 1995

  23. Postoperative Radiotherapy inHigh-Risk Premenopausal Women with Breast Cancer Who Receive Adjuvant Chemotherapy M. Overgaard et al. NEJM337: 949, 1997

  24. Postoperative Radiotherapy in High-Risk Postmenopausal Women with Breast Cancer Who Receive Adjuvant Tamoxifen M. Overgaard et al. Lancet 353: 1641, 1999.

  25. The effect of radiotherapy in breast cancerTrend with starting year of trial Van deStene et al. R&O 55: 263 (2001)

  26. Multiple meta-analyses of same topic • Acetylcysteine in the prevention of contrast associated nephropathy • 10 systematic reviews published August 2003 – March 2005 • 9 pooled events despite heterogeneity • 5 recommended routine use of acetylcysteine and 5 recommended further research Biondi-Zoccai et al. BMJ, e-pub, 2006

  27. Interpretations of MA? 23 randomized controlled trials (RCT) and review articles on the efficacy of intravenous magnesium in the early post-myocardial infarction period organized chronologically and grouped in packages. Presented to 8 reviewers:  Shrier et al. BMC Med Inform Decision Making8: 19, 2008

  28. REQUIRES AN INFORMED AND CRITICAL READER REQUIRES AN INFORMED AND CRITICAL READER

  29. “To call in the statistician after the experiment is done may be no more than asking him to perform a postmortem examination: he may be able to say what the experiment died of.”Ronald A. Fisher (ca. 1938)

  30. Conclusions • A meta-analysis is never better than its constituent trials • Individual patient level data – updated where possible – is preferable to literature based analysis • Critical narrative reviews may rely in part on meta-analysis but will also involve assigning varying weights to various trials depending on quality

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