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Overall and subgroup analysis by 5WOkfS65

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									  Overall and subgroup analysis
• If the OVERALL results show highly
  significant evidence of a worthwhile effect of
  treatment, but a few subgroups of the
  overview unexpectedly indicate no benefit
  (which could well happen by chance), then
  the appropriate question is whether there is
  good evidence that this life-saving treatment
  should be denied to these patients.
• REVERSAL of the usual demand that there
  should be proof of worthwhile benefit.
                         Courtesy of Dr. K. Wheatley
   Meta-analysis vs. randomized controlled
  trials: internal validity vs. generalizibility
• Have complimentary roles
  – RCT, large adequately powered
     • If our desire is to assess the efficacy of treatment
       (i.e. understand a measure of benefit of the
       treatment under ideal conditions of a clinical trial
       using narrow defined eligibility criteria)
  – Meta-analysis (of totality of evidence)
     • If our goal is to obtain reliable estimate about the
       treatment effectiveness (i.e. understand the extent
       to which a given treatment can produce a
       beneficial effect under variety of circumstances
       and eligibility criteria)
Meta-analysis vs. randomized controlled trials
   Small CTs            To study mechanisms

Meta-analyses          To generate hypotheses for
                       more reliable RCTs
of small RCTs
                    To obtain reliable overall
Large RCts          answers under specific
                    conditions of a trial

                     To obtain a typical and
Meta-analyses
                     unbiased and generalizible
of large RCTs        estimate of treatment effect
                     and to explore interactions
                     among subgroups
   Literature-based vs. individual
    patient data meta-analysis?

   • IPD MA gold-standard
   • LMA may be misleading
      – Data extraction, patient exclusion,
        length of follow-up, method analysis
        may be less accurate in LMA


Lancet 1993;341:418-22; Stat Med 1998;14:2057-2079
IV Ethical obligations to account
    of what’s already known
• To avoid unnecessary trials if reliable
  knowledge already exists
• Conversely, to determine if there is true
  uncertainty about relative values of
  competing treatment alternatives
  – A new trial should be conducted if there is a
    substantial uncertainty which of the trial
    treatments would benefit the patient better
     • Requirement that equipoise
       (uncertainty principle) is met
     Ethical obligation of building
systematically on what is already known
 • Clinical trials should be preceded by a
   systematic review and should be reported
   with a discussion of assessing the trial’s
   results in the context what is already known
   – Ethical requirement for updating systematic
     reviews
 • UK, Denmark, Holland now mandates search
   or conduct of SR before a new clinical trial is
   done

       JAMA 1998;280:280-282;Lancet 2001:358:1648
V Knowledge resources
          Archie Cochrane




“It is surely a great criticism of our profession
that we have not organised a critical summary,
by specialty or subspecialty, adapted
periodically, of all relevant randomised
controlled trials.”
   Cochrane Database of Systematic
             Reviews -
   The Cochrane Collaboration - an international
   network of individuals and institutions
   committed to preparing, maintaining, and
   promoting the accessibility of systematic reviews
   of the effects of health care interventions.

Cochrane Systematic Reviews (2,796) (January 2003)
Database of Abstracts of Reviews of Effectiveness (3,875)
Registry of Randomized Controlled Trials (353,809)
 How many systematic reviews are
needed to “cover” whole medicine?


• 10,000 systematic reviews to provide
  broad coverage of most health care topics




           Clarke M, personal communication
                     Cochrane Centres
                       Canadian
                                   Nordic
San Francisco                       German
                        UK
                      Dutch
                     French
                  Iberoamerican   Italian
 San                                                Chinese
Antonio
      New
     England



      Brazilian
                       South         Australasian
                       African
Cochrane Systematic reviews

• Cochrane reviews have been shown to
  be methodologically superior to non-
  Cochrane systematic reviews




    BMJ 2000;320:537-40, JAMA 1998;280:278-80
                      The Cancer Library


                                 Cochrane Cancer Network
                                 with Update Software Ltd
Courtesy of Dr. Chris Williams
Meta-analyses in radiation oncology

• 100 meta-analyses in the Cochrane
  Database of Systematic Reviews
  – 22 Cochrane Reviews
  – 78 DARE reviews
• MEDLINE (Clinical Queries) search
  – 616 systematic reviews
    Meta-analyses in radiation oncology: an
   example of reliable review with long-term
              (20 years) follow-up

  • Favourable and unfavourable effects on
    long-term survival of radiotherapy for
    early breast cancer: an overview of the
    randomised trials

Early Breast Cancer Trialists' Collaborative Group*
                           Lancet 2000; 355: 1757-70
                           (20 May 2000 )
Proportional effects on all-cause mortality
       in 40 trials of radiotherapy
L
a
n
c
e
t

2
0
0
0
;

3
5
Absolute effects of radiotherapy
   on cause-specific survival
Absolute benefits and hazards
          Part VI
Evidence and decision-making
  Clinical Decision Making
     Patient circumstances




Evidence                Preferences,
from                    values and
research                rights

                  Courtesy of Dr. G. Lyman
  Reporting data on benefits and
             harms

• If evidence on benefits and harms are not
  reported or is of poor quality, one has to
  wonder how physicians make decisions
  and recommendations for their patients



               Eddy D. JAMA 1990;264:1737-39
Reporting data on benefits and harms:
         RCTs in myeloma
   • Survival outcomes
   111/136 (82%)
   • Survival beyond 5 years
   15/111 (14%)
   • Treatment-related mortality
     33/136 (24%)
   • Non-fatal adverse events
    91/136 (67%)

              Annals Oncol 2001;12:1611-1617
                              Reporting harms in RTOG
                                  randomized trials
                        100                                91.5%
Porcentage of studies




                                      86.4%
                         90
                         80                                                    74.6%
                         70
                         60
                         50
                         40
                         30
                         20          N= 51               N = 54              N = 44
                         10
                              Overall survival    Toxicity reported    treatment-related
                                                                            mortality
                                                      Outcomes
                                              Total number of studies: 59
 HOW TO INTEGRATE BENEFITS
  AND RISKS OF AVAILABLE
   THERAPEUTIC OPTIONS
• Should we always use the option with the
  best benefit/risk ratio?

Efficacy=80%    Toxicity=10%    E/R=8

Efficacy=20%    Toxicity=1%     E/R=20
   Decision-making at the bedside
• Minimal conditions for treatment benefit at
  which therapy is worth considering is met
  when
  – Absolute benefits>absolute harms
    (adjusted for the probability of bad event,
    e.g. relapse)
• Never administer treatment or order
  diagnostic test if treatment harm is greater
  than its efficacy
  Integrating benefits and harms of
  radiation therapy of breast cancer
  • Threshold for administering radiation
    therapy (RT):
        probability of breast cancer recurrence
        (without RT)>
      Deaths due to (RT) (%)
Deaths due to breast cancer without RT- deaths due to breast cancer on RT


       4.3%
    51.4-46.6 (=4.8%)              = 89.6%        (actual relapse=30.1%)

								
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