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Levels of Evidence for Cancer Genetics Studies (PDQ®)

Use of Levels of Evidence

The PDQ editorial boards use a 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 of prevention and treatment studies can be ranked on each of the following two scales:

  1. Strength of the study design.
  2. Strength of the endpoints.

Together, the two rankings provide a measure of the overall level of evidence. Screening studies are ranked on strength of study design alone. Depending on perspective, different expert panels, professional organizations, or individual physicians may use different cut-off points related to 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.

There are varying levels of evidence related to screening, prevention, and treatment that support a given summary. The summaries are subject to modification as new evidence becomes available. The strongest evidence would be that obtained from a well-designed and well-conducted randomized controlled trial. It is not always practical, however to conduct such a trial to address every question in the fields of cancer screening, prevention, and treatment.

Evidence Related to Screening

The PDQ Cancer Genetics Editorial Board has adopted the following definitions related to screening:

  • Screening is a means of accomplishing early detection of disease in people without symptoms of the disease being sought.
  • Examinations, tests, or procedures used in cancer screening are often not definitive but sort out persons suspected of harboring a clinically occult cancer from those in whom a cancer is not likely to be present.
  • Diagnosis of disease is made after a workup, biopsy, or other tests are completed in pursuing symptoms or following positive detection procedures.

The five requirements that should be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice are as follows:[1,2]

  1. The medical condition being sought must cause a substantial burden of suffering, measured both as mortality and as the frequency and severity of morbidity and loss of function.
  2. A screening test or procedure exists that will detect cancers earlier in their natural history than when diagnosis is prompted by symptoms, and this test must be acceptable to patients and society in terms of convenience, comfort, risk, and cost.
  3. Strong evidence exists that early detection and treatment improve disease outcomes, particularly disease-specific survival.
  4. The harms of screening must be known and acceptable.
  5. Screening must be judged to do more good than harm, considering all benefits and harms it induces in addition to the cost and cost-effectiveness of the screening program.

In descending order of strength of evidence, the levels for screening studies are as follows:

  1. Evidence obtained from at least one well-designed and well-conducted randomized controlled trial.
  2. Evidence obtained from well-designed and well-conducted nonrandomized controlled trials.
  3. Evidence obtained from well-designed and well-conducted cohort or case-control analytic studies, preferably from more than one center or research group.
  4. Evidence obtained from multiple time series, with or without intervention.
  5. Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.

Evidence Related to Cancer Prevention

Prevention is defined as a reduction in the incidence (or the rate) of new cancer, with the goal of reducing cancer-related morbidity and mortality. Examples of prevention strategies include smoking cessation, avoidance of excessive exposure to sunlight (ultraviolet) or ionizing radiation, surgical removal of an at-risk target organ before cancer develops, and use of medications (e.g., tamoxifen for breast cancer risk reduction).

For each prevention-related summary of evidence statement, the associated levels of evidence are listed. In descending order of strength of evidence, the five levels are as follows:

  1. Evidence obtained from at least one well-designed and well-conducted randomized controlled trial that has:
    1. A cancer endpoint.
      1. Mortality.
      2. Incidence.
    2. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention).
  2. Evidence obtained from well-designed and well-conducted nonrandomized controlled trials that have:
    1. A cancer endpoint.
      1. Mortality.
      2. Incidence.
    2. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention).
  3. Evidence obtained from well-designed and well-conducted cohort or case-control studies, preferably from more than one center or research group, that have:
    1. A cancer endpoint.
      1. Mortality.
      2. Incidence.
    2. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention).
  4. Ecologic (descriptive) studies (e.g., international patterns studies and migration studies) that have:
    1. A cancer endpoint.
      1. Mortality.
      2. Incidence.
    2. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention).
  5. Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees (e.g., any of the above study designs using invalidated surrogate endpoints).

In assessing a genetic test (or other method of genetic assessment, including family history), the analytic validity, clinical validity, and clinical utility of the test need to be considered.[3]

Evidence Related to Treatment

For each treatment-related summary of evidence statement, the associated levels of evidence are listed. In descending order of strength of evidence, the five levels are as follows:

  1. Evidence obtained from randomized controlled trials.
  2. Evidence obtained from nonrandomized controlled trials.
  3. Evidence obtained from cohort or case-control studies.
    1. Total mortality (or overall survival from a defined time).
    2. Cause-specific mortality (or cause-specific mortality from a defined time).
    3. Carefully assessed quality of life.
    4. Indirect surrogates.
      1. Disease-free survival.
      2. Progression-free survival.
      3. Tumor response rate.
  4. Evidence from ecological, natural history, or descriptive studies.
  5. Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.

References

  1. Woolf SH: Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. N Engl J Med 333 (21): 1401-5, 1995. [PUBMED Abstract]
  2. Winawer S, Fletcher R, Rex D, et al.: Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 124 (2): 544-60, 2003. [PUBMED Abstract]
  3. Holtzman NA, Watson MS, eds.: Promoting Safe and Effective Genetic Testing in the United States: Final Report of the Task Force on Genetic Testing. Baltimore, Md: Johns Hopkins Press, 1998. Also available online. Last accessed June 18, 2014.
  • Updated: July 25, 2012