|
Table of Contents Introduction
Strength of Study Design
Strength of Endpoints
Summary
Get More Information From NCI
Changes to This Summary (03/13/2008)
More Information
Introduction
A variety of endpoints 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 the four outcomes, such as event-free survival, disease-free survival, progression-free
survival, or tumor response rate. Endpoints 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 endpoints.
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.
The PDQ Adult Treatment Editorial Board 1 and the PDQ Pediatric Treatment Editorial Board 2 add information on levels of evidence,
described below, to the PDQ Adult Cancer Treatment Summaries 3 and the PDQ Pediatric Cancer Treatment Summaries 4 when appropriate.
Strength of Study Design
The various types of study design are described below in descending order of strength:
-
Randomized controlled clinical trials.
-
Double-blinded.
-
Nonblinded treatment delivery.
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
the randomization and the 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 at 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).
-
Nonrandomized controlled clinical trials.
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 before informed consent is obtained from the patient.
An imbalance can occur in treatment
allocation under such circumstances. For the reasons given above, subset
analyses within randomized trials often fall into this category of
evidence.
-
Case series.
-
Population-based, consecutive series.
-
Consecutive cases (not population-based).
-
Nonconsecutive cases.
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. They may also provide the only
practical design when treatments in study arms are radically different
(e.g., amputation vs. 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,
nonpopulation-based but consecutive series, and nonconsecutive cases.
References
-
LeLorier J, Grégoire G, Benhaddad A, et al.: Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 337 (8): 536-42, 1997.
[PUBMED Abstract]
-
Bailar JC 3rd: The promise and problems of meta-analysis. N Engl J Med 337 (8): 559-61, 1997.
[PUBMED Abstract]
Strength of Endpoints
Commonly measured endpoints for adult and pediatric cancer treatment studies are listed below in descending order of strength:
-
Total mortality (or overall survival from a defined time).
This outcome is arguably the most important one to patients and
is also the most easily defined and least subject to investigator bias.
-
Cause-specific mortality (or cause-specific mortality from a defined time).
Although this may be of the most biologic importance in a
disease-specific intervention, it is a more subjective endpoint than
total mortality and more subject to investigator bias in its
determination. This endpoint may also miss important effects of therapy that may
actually shorten overall survival.
-
Carefully assessed quality of life.
This is an extremely important endpoint to patients. Careful
documentation of this endpoint within a strong study design is therefore
sufficient for most physicians to incorporate a treatment into their
practices.
-
Indirect surrogates.
-
Event-free survival.
-
Disease-free survival.
-
Progression-free survival.
-
Tumor response rate.
These endpoints may be subject to investigator interpretation. More
importantly, they may, but 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 endpoints while awaiting a more definitive endpoint to support its use.
Summary
Because studies or clinical experiences are ranked both by
strength of design and importance of endpoint, 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 3iiiDiv 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 provides an ordinal
categorization of strength of evidence as a starting point for
discussions of study results. Get More Information From NCI
Call 1-800-4-CANCER
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.
Chat online
The NCI's LiveHelp® 5 online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
- NCI Public Inquiries Office
- Suite 3036A
- 6116 Executive Boulevard, MSC8322
- Bethesda, MD 20892-8322
Search the NCI Web site
The NCI Web site 6 provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
Find Publications
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator 7. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615. Changes to This Summary (03/13/2008)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was renamed from Levels of Evidence for Adult Cancer Treatment Studies.
Introduction 8
Added text 9 to include event-free survival as an indirect surrogate endpoint. More Information
About PDQ
Additional PDQ Summaries
Important:
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). |
