Cancer Screening

by National Cancer Institute

Cancer Incidence and Mortality

In 2006, an estimated 1,399,790 people in the United States will be diagnosed with cancer, and 564,830 will die of cancer. Estimates of the premature deaths that could have been avoided through screening vary from 3% to 35%, depending on a variety of assumptions. Beyond the potential for avoiding death, screening may reduce cancer morbidity since treatment for earlier-stage cancers is often less aggressive than that for more advanced-stage cancers.

Several potential harms must be considered against any potential benefit of screening for cancer. Although most cancer screening tests are noninvasive or minimally invasive, some involve small risks of serious complications that may be immediate (e.g., perforation with colonoscopy) or delayed (e.g., potential carcinogenesis from radiation). Another harm is the false-positive test result, which may lead to anxiety and unnecessary invasive diagnostic procedures. A less familiar harm is overdiagnosis, i.e., the diagnosis of a condition that would not have become clinically significant had it not been detected by screening. This harm is becoming more common as screening tests become more sensitive at detecting tiny tumors. Finally, a false-negative screening test may falsely reassure an individual with subsequent clinical signs or symptoms of cancer and thereby actually delay diagnosis and effective treatment.

In developing the cancer screening summaries, the PDQ Screening and Prevention Editorial Board uses the following definitions:

• Screening is a means of detecting disease early in asymptomatic people.

• Positive results of examinations, tests, or procedures used in screening are usually not diagnostic but identify persons at increased risk for the presence of cancer who warrant further evaluation.

• Diagnosis is confirmation of disease by biopsy or tissue examination in the work-up following positive screening tests. (Following a positive screening result, cancer can often be ruled out by procedures other than biopsy or tissue examination.)

The purpose of this summary is to present an explicit evidence-based approach used in the development of the screening summaries. In reaching conclusions, evidence on the balance of risks and benefits is weighed. Cost and cost-effectiveness, however, is not taken into account. Assignment of levels of evidence associated with such screening tests is also discussed.

Summary Development

The cancer screening summaries are based on various levels of published scientific evidence and collective clinical experience. The highest level of evidence is taken as mortality reduction in controlled, randomized clinical trials. The results of clinical studies, case-control studies, cohort studies, and other information are also considered in formulating the summaries. In addition, the incidence of cancer, stage distribution, treatment, and mortality rates are considered. The summaries are subject to modification as new evidence becomes available.

The Scientific Basis

At least 2 requirements must be met for screening to be efficacious:

1. A test or procedure must be available to detect cancers earlier than if the cancer were detected as a result of the development of symptoms.

2. Evidence must be available that treatment initiated earlier as a consequence of screening results in an improved outcome.

These requirements are necessary but not sufficient to prove the efficacy of screening, which requires a decrease in cause-specific mortality. For example, these 2 criteria are met in the case of screening for childhood neuroblastoma by assessment of urinary catecholamine metabolites. On the basis of these criteria, a mass screening program was conducted in Saitama Prefecture, Japan, from 1981 to 1992 for 6-month-old infants. Over that 12-year period, the annual incidence of neuroblastoma in children younger than 1 year increased from about 28 per million to 260 per million but without a significant reduction in incidence in children older than 1 year. Because there also was no reduction in mortality for the disease, this experience provided strong evidence of overdiagnosis-diagnosis of some neuroblastomas detectable by screening, which would not have been clinically diagnosed later. Similar experiences have been reported elsewhere in Japan and in the Quebec Neuroblastoma Screening Project (QNSP) in Canada. The history of screening for neuroblastoma also provides a useful illustration of the benefit of undertaking well-designed evaluations of emerging screening technologies before implementing screening programs. Although such studies are very costly, it has been shown that the QNSP itself averted unnecessary morbidity for thousands of children and did so while returning a yield plausibly estimated at a cost savings 64.5 times the investment in the study.

Detection

Direct or assisted visual observation is the most widely available examination for the detection of cancer. It is useful in identifying suspicious lesions in the skin, retina, lip, mouth, larynx, external genitalia, and cervix.

The second most available detection procedure is palpation to detect lumps, nodules, or tumors in the breast, mouth, salivary glands, thyroid, subcutaneous tissues, anus, rectum, prostate, testes, ovaries, and uterus and enlarged lymph nodes in the neck, axilla, or groin.

Internal cancers require procedures and tests such as endoscopy, x-rays, magnetic resonance imaging, or ultrasound. Laboratory tests, such as the Pap smear or the fecal occult blood test have been employed for detection of specific cancers.

The performance of screening tests is usually measured in terms of sensitivity, specificity, and positive-predictive values (PPV) and negative-predictive values (NPV). Sensitivity is the chance that a person with cancer has a positive test. Specificity is the chance a person without cancer has a negative test. PPV is the chance that a person with a positive test has cancer. NPV is the chance that a person with a negative test does not have cancer. PPV and, to a lesser degree, NPV are affected by the prevalence of disease in the screened population. For a given sensitivity and specificity, the higher the prevalence, the higher the PPV.

High-Risk Populations

The type, periodicity, and commencement of screening in high-risk populations for most cancers reflect the judgment of practitioners rather than evidence from scientifically conducted studies. Some individuals are known to be at high risk for cancer, such as those with a personal history of cancer or a strong family history of cancer (in 2 or more first-degree relatives); increasingly, as genetic mutations and polymorphisms are found to be associated with specific cancers, high-risk individuals will be identified through genetic testing. Physician judgment is needed in such circumstances to determine the most appropriate application of available screening methods. Prudence suggests increased vigilance in the higher-risk populations. At a minimum, this means that the high-risk person is identified, is counseled appropriately, and regularly undergoes those screening procedures that have been shown to be of benefit to the general population.

Improved Outcomes

For nearly all cancers, treatment options and survival are related to stage, which is generally characterized by the anatomic extent of disease. On this basis, it is assumed that early detection of cancer, at an earlier stage, may yield better outcomes. In the 1940s, a generalized staging classification of localized, regional, and distant disease was developed to show long-term trends, and it is still useful. In the more detailed TNM system, which has been periodically modified, the (T)umor size, the status of the lymph (N)odes, and the status of distant (M)etastases are also categorized. These elements are grouped into stages 0-IV according to their association with survival. In general, larger primary malignant tumors have a higher incidence of metastasis to regional lymph nodes and to distant sites. Stage has such a profound effect on outcome that all randomized treatment trials require the comparison of similar stages in evaluating differences in outcome. Shifts in stage may also herald improved survival and decreased mortality, though stage shift alone does not establish benefit.

Biologic cellular characteristics of cancer, such as grade, hormone sensitivity, and gene overexpression are recognized as important predictors of cancer behaviors. For example, high-grade cancer may be fast growing and quick to metastasize regardless of stage at the time of diagnosis. Therefore, detection of these cancers when small may not affect outcome. Randomized controlled trials with survival outcomes are necessary to prove screening benefits.

The Natural Experiment

The Surveillance, Epidemiology, and End Results (SEER) Program 2 of the National Cancer Institute gathers cancer incidence data from 11 geographic areas, covering approximately 14% of the US population. These population-based data of long duration (1973-present) are a unique and important resource in monitoring stage-related survival.

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