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DESCRIPTION

The PDQ Adult Treatment Editorial Board is beginning to integrate information
on levels of evidence, described below, into the PDQ cancer information
summaries.  The gradual inclusion of this information will take place as part
of ongoing reviews of the cancer treatment information in PDQ.

A variety of end points may be measured and reported from clinical studies in
oncology.  These may include total mortality (or survival from the initiation
of therapy), cause-specific mortality, quality of life, or indirect surrogates
of these three outcomes, such as disease-free survival, progression-free
survival, or tumor response rate.  End points may also be determined within
study designs of varying strength, ranging from the gold standard -- the
randomized double-blinded controlled clinical trial -- to case series
experiences from nonconsecutive patients.  The PDQ editorial boards use a
formal ranking system of levels of evidence to help the reader judge the
strength of evidence linked to the reported results of a therapeutic strategy.
For any given therapy, results can be ranked on each of the following two
scales: (1) strength of the study design and (2) strength of the end points.
Together, the two rankings give an idea of the overall level of evidence.
Depending on perspective, different expert panels, professional organizations,
or individual physicians may use different "cut points" of overall strength of
evidence in formulating therapeutic guidelines or in taking action.  However,
a formal description of the level of evidence provides a uniform framework for
the data, leading to specific recommendations.


Strength of study design (ranked in descending order of strength)

1.  Randomized controlled clinical trial(s)
      i)  Double-blinded
      ii) Nonblinded (allocation schema or treatment delivery)

Comment:  The randomized, double-blinded controlled clinical trial (1i)
is the gold standard of study design.  To achieve this ranking, the study
allocation must be blinded to the physician both before and after
randomization and treatment assignment take place.  This design provides
protection from allocation bias by the investigator and from bias in
assessment of outcomes by both the investigator and the patient.
Unfortunately, most clinical trials in oncology cannot be double-blinded
after treatment allocation because procedures or toxic effects often vary
substantially among study allocations in ways that are obvious to both
the health care professional and the patient.  In most cases, however, it
should be possible to blind the investigator and the patient until the
randomization has been made.  If blinding of the therapy delivered cannot
be accomplished, a rank of 1ii is assigned.

Meta-analyses of randomized studies offer a quantitative synthesis of
previously conducted studies.  The strength of evidence from a
meta-analysis is based on the quality of the conduct of individual
studies.  Moreover, meta-analyses can magnify small systematic errors in
individual studies.  A study comparing the results of single large randomized
trials to those of meta-analyses of smaller trials published earlier on
the same topics showed only fair agreement (kappa statistic=0.35).  Outcomes
of the large randomized controlled trials were not predicted accurately by
the meta-analysis 35% of the time.[1,2]  Meta-analyses performed by different
investigators to address the same clinical issue can reach contradictory
conclusions.[2]  Therefore, meta-analyses of randomized studies are placed in
the same category of strength of evidence as are randomized studies, not a
higher level.

Subset analyses of randomized studies are subject to errors inherent in
multiplicity (i.e., "statistically significant" results to be expected as
a result of random variation of measured effects in multiple subsets).
Therefore, subset analyses do not represent the same strength of evidence
as the overall analysis of a randomized trial as designed unless explicit
prospective hypotheses are made for the analyzed subset.  Otherwise,
subset analyses should be placed in the next lower category of study design
(nonrandomized controlled clinical trials).

2.  Nonrandomized controlled clinical trial(s)

Comment:  This category includes trials in which treatment allocation was
made by birth date, chart number, day of clinic appointment, bed
availability, or any other strategy that would make the allocation known
to the investigator prior to obtaining informed consent from the patient.
It is well established that an imbalance can occur in treatment
allocation under such circumstances.  For reasons given above, subset
analyses within randomized trials often fall into this category of
evidence.

3.  Case series
      i)   Population-based, consecutive series
      ii)  Consecutive cases (not population-based)
      iii) Nonconsecutive cases

Comment:  These clinical experiences are the weakest form of study
design, but they may be the only available or practical information in
support of a therapeutic strategy, especially in the case of rare
diseases or when the evolution of the therapy predates the common use of
randomized study designs in medical practice.  It may also be the only
practical design when treatments in study arms are radically different
(e.g., amputation versus limb-sparing surgery).  Nevertheless, these
experiences do not have internal controls and must therefore look to
outside experiences for comparison.  This always raises the issues of
patient selection and comparability with other populations.  In order of
generalizability to other populations are population-based series,
non-population-based but consecutive series, and nonconsecutive cases.


Strength of end points (ranked in descending order of strength)

A.  Total mortality (or overall survival from a defined point in time)

Comment:  This outcome is arguably the most important one to patients and
is also the most easily defined and least subject to investigator bias.

B.  Cause-specific mortality (or cause-specific mortality from a defined
    point in time)

Comment:  Although this may be of the most biologic importance in a
disease-specific intervention, it is a more subjective end point than
total mortality and more subject to investigator bias in its
determination.  It may also miss important effects of therapy that may
actually shorten overall survival.

C.  Carefully assessed quality of life

Comment:  This is an extremely important end point to patients.  Careful
documentation of this end point within a strong study design is therefore
sufficient for most physicians to incorporate a treatment into their
practices.

D.  Indirect surrogates
      i)    Disease-free survival
      ii)   Progression-free survival
      iii)  Tumor response rate

Comment:  These are all subject to investigator interpretation.  More
importantly,  they do not automatically translate into direct patient benefit,
such as survival or quality of life.  Nevertheless, it is rational in many
circumstances to use a treatment that improves these surrogate end
points while awaiting a more definitive end point to support its use.

Summary:  Since studies or clinical experiences are ranked both by
strength of design and importance of end point, a given study would have
a two-tiered ranking [e.g., 1iiA for a nonblinded randomized study
showing a favorable outcome in overall survival and 3iiiDiii for a
phase II trial of selected patients with response rate as the outcome].
In addition, all recommendations must take into account other issues that
cannot be so easily quantified, such as toxicity, width of confidence
intervals of observations, trial size, quality assurance in the trial,
and cost.  Nevertheless, the PDQ ranking system does provide an ordinal
categorization of strength of evidence as a starting point for
discussions of study results.

References:

1. LeLorier J, Gregoire G, Benhaddad A, et al.: Discrepancies between meta- analyses and subsequent large randomized, controlled trials. New England Journal of Medicine 337(8): 536-542, 1997.
2. Bailar JC: The promise and problems of meta-analysis. New England Journal of Medicine 337(8): 559-561, 1997.

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