Description of the Evidence
Randomized Controlled Trials
Case-Control and Cohort Studies
Descriptive Studies
Measures of Risk

The summaries in the cancer prevention section of PDQ address the prevention of specific types of cancer. Prevention is defined as the reduction of cancer mortality via reduction in the incidence of cancer. This can be accomplished by avoiding a carcinogen or altering its metabolism; pursuing lifestyle or dietary practices that modify cancer-causing factors or genetic predispositions; and/or medical intervention (chemoprevention) to successfully treat preneoplastic lesions.

Much of the promise for cancer prevention comes from observational epidemiologic studies that show associations between modifiable life style factors or environmental exposures and specific cancers. Evidence is now emerging from randomized controlled trials designed to test whether interventions suggested by the epidemiologic studies, as well as leads based on laboratory research, result in reduced cancer incidence and mortality.

The most consistent finding, over decades of research, is the strong association between tobacco use and cancers of many sites. Hundreds of epidemiologic studies have confirmed this association. Further support comes from the fact that lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men.

Additional examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption, being physically active, and maintaining recommended body weight, may all contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexual and reproductive practices, the use of exogenous estrogens, exposure to ionizing radiation and ultraviolet radiation, certain occupational and chemical exposures, and infectious agents.

Food and nutrient intake have been examined in relation to many types of cancer. Fruit and vegetable consumption have generally been found in epidemiologic studies to be associated with reduced risk for a number of different cancers; however, it is not currently known which specific components of fruits and vegetables are responsible for the observed associations or if healthy diets are simply associated with other beneficial interventions, e.g., exercise. Contrary to expectation, randomized trials found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality; risk of lung cancer was statistically significantly increased in smokers in the beta-carotene arms of 2 of the trials. Similarly, randomized controlled trials have found no reduction in risk of subsequent adenomatous polyps of the colon in individuals who have had polyps resected taking dietary fiber supplements compared with those receiving much lower amounts of supplemental wheat bran fiber. On the other hand, there is evidence from at least 1 randomized controlled trial that calcium supplementation does modestly reduce risk of adenoma recurrence. Consumption of red meat and inadequate folic acid intake have also been associated with increased risk of colon cancer. A large randomized trial is currently underway to investigate whether men taking daily selenium or vitamin E or both experience a reduced incidence of prostate cancer in comparison to men taking placebo pills.

Daily use of tamoxifen, a selective estrogen receptor modulator, for up to 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. Cis-retinoic acid also has been shown to reduce risk of second primary tumors among patients with primary cancers of the head and neck. Finasteride, an alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer. Other examples of drugs that show promise for chemoprevention include COX-2 inhibitors (which inhibit the cyclooxygenase enzymes involved in the synthesis of proinflammatory prostaglandins).

Considerable research effort is now devoted to the development of vaccines to prevent infection by oncogenic agents, and to potential venues for gene therapy for individuals with genetic mutations or polymorphisms that put them at high risk of cancer. Meanwhile, genetic testing for high-risk individuals, with enhanced surveillance or prophylactic surgery for those who test positive, is already available for certain types of cancer, including breast and colon cancers.

Screening for colon cancer through fecal occult blood testing has been demonstrated to reduce both colon cancer incidence and mortality, presumably through the detection and removal of precancerous polyps. Similarly, cervical cytology testing (using the Pap smear) leads to the identification and excision of precancerous lesions. Over time, such testing has been followed by a dramatic reduction of cervical cancer incidence and mortality.

Varying levels of evidence 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 with cancer-specific mortality as the endpoint. It is, however, not always practical to conduct such a trial to address every question in the field of cancer prevention. For each summary of evidence statement, the associated levels of evidence are listed. In order of strength of evidence, the 5 levels are as follows:

1. Evidence obtained from randomized 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; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention).
2. Evidence obtained from 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; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention).
3. Evidence obtained from cohort or case-control 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; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention).
4. Ecologic (descriptive) studies (e.g., international patterns studies, 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; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention).
5. Opinions of respected authorities based on clinical experience or reports of expert committees (e.g., any of the above study designs using nonvalidated surrogate endpoints).

Randomized controlled trials are designed to correct for or eliminate selection and other biases when prospectively testing a primary prevention strategy to determine its effect on outcome. The highest level of evidence and greatest benefit is mortality reduction in a randomized controlled trial. For most cancers, such evidence is not, and may never be, available. While theoretically feasible, such studies would require a large sample size and a long follow-up, which cannot be justified for rare cancers or those with low morbidity or mortality. Some randomized trials may be impossible, e.g., to test the effect on cancer mortality of removing an environmental pollutant. Therefore, evidence obtained by other design methods is often used, or intermediate endpoints of intervention effect are employed, but these have recognized shortcomings.

Studies that find a preventive intervention to be associated with a decreased incidence of invasive cancers or of precursor lesions provide evidence that suggests the possibility of cancer mortality reduction. The lesions prevented, however, may not have the same lethal potential as cancers occurring in the absence of preventive intervention and so extrapolating the study results to mortality benefits may not be warranted.

A more detailed description of how the overall body of evidence regarding benefits and harms of prevention interventions is graded by the PDQ Screening and Prevention Editorial Board can be found in the PDQ summary on Levels of Evidence for Cancer Screening and Prevention Studies.

Case-control and cohort studies provide indirect evidence for the effectiveness of primary prevention strategies. Such studies may suggest, but do not prove, a mortality reduction effect. The potential for bias to invalidate inferences from case-control and cohort studies, however, must be recognized.

Descriptive uncontrolled studies based on the experience of individual physicians, hospitals, and nonpopulation-based registries may yield some information on prevention, but unwarranted inferences are often drawn from such studies because of the absence of an appropriate control group.

Several measures of risk are used in cancer research. Absolute risk or absolute rate measures the actual cancer occurrence in a population or subgroup (e.g., US population, or whites or African Americans in the United States). For example, the Surveillance, Epidemiology, and End Results (SEER) Program reports risk, and rate of cancer in specific geographic areas of the United States.

Rates are often adjusted (e.g., age-adjusted rates) to allow a more accurate comparison of rates over time or among groups. The purpose of the adjustment is to make the groups more alike with respect to important characteristics that may affect the conclusions. For example, when the SEER Program compares cancer rates over time in the United States, the rates are adjusted to one age distribution. If this were not done, cancer rates would seem to increase over time simply because the US population is getting older and the risk of cancer is higher in older age groups.

Relative risk (RR) compares the risk of developing cancer among those who have a particular characteristic or exposure with those who do not. RR is expressed as a ratio of risks or rates; it ranges from infinity to the inverse of infinity (i.e., zero). If the RR is greater than 1, the exposure or characteristic is associated with a higher cancer risk; if the RR is 1, the exposure and cancer are not associated with one another; if the RR is less than 1, the exposure is associated with a lower cancer risk (i.e., is protective). RR is often used in clinical trials of cancer prevention and screening to estimate a reduction in cancer risk or risk of death, respectively.

An odds ratio (OR) is often used as an estimate of the RR. It too indicates whether there is an association between an exposure or characteristic and cancer. It compares the odds of an exposure or characteristic among cancer cases with the odds among a comparison group without cancer. For relatively uncommon events/diseases such as cancer diagnosis, it can be interpreted in the same way that a RR is interpreted; however, it becomes a progressively inaccurate estimate of the RR as the underlying absolute risk of an event/disease in the population under study rises above 10%. ORs are typically used in case-control studies to identify potential risk factors or protective factors for cancer.

Risk or rate difference (or excess risk) compares the cancer risk or rate among at least 2 groups of people, based on an important characteristic or exposure, by subtracting the risks or rates from one another (e.g., subtracting lung cancer rates among nonsmokers from that of cigarette smokers estimates the excess risk of lung cancer due to smoking). This can be used in public health to estimate the number of cancer cases that could be avoided if an exposure were reduced or eliminated in the population.

Population-attributable risk measures the proportion of cancers that can be attributed to a particular exposure or characteristic. It combines information about the RR of cancer associated with a particular exposure and the prevalence of that exposure in the population, and estimates the proportion of cancer cases in a population that could be avoided if an exposure were reduced or eliminated.

Number needed to screen, or treat, estimates the number of people that must participate in a screening program, or be treated, for 1 death to be prevented over a defined time interval.

Average life-years saved estimates the number of years that an intervention saves, on average, for an individual who receives the intervention. This reflects mortality reduction as well as life extension (or avoidance of premature deaths).

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