Cancer Prevention

The summaries in this section of the 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 successfully treating 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, actually result in reduced cancer incidence and mortality.

The most consistent finding, over what is now 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.

Additional examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, 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. 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 has been examined in relation to many types of cancer. Fruit and vegetable consumption has 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 they are partially or wholly the result of confounding factors. Contrary to expectation, randomized trials found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality; in fact, 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 adenomatous polyps of the colon for high-risk individuals taking fiber supplements compared to those receiving much lower doses 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, 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. 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) to reduce the risk of colon cancer and finasteride (an alpha-reductase inhibitor that reduces testosterone) to lower the risk of prostate cancer.

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 (FOBT) 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.

Levels of Evidence

There are varying levels of evidence 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 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 at least one well-designed and 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; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention)
2. Evidence obtained from well-designed and 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; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention)
3. Evidence obtained from well-designed and 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; 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

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.

Case-Control and Cohort 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 Studies

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.

Measures of Risk

Several measures of risk are used in cancer research. Absolute risk or rate measures the actual cancer risk or rate in a population or subgroup (e.g., U.S. population, or Caucasians or African Americans in the United States). This shows how common a condition is. 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 better compare 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 increase over time simply because the U.S. 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. Relative risk is expressed as a ratio of risks or rates; it ranges from infinity to the inverse of infinity. If the relative risk is greater than 1, the exposure or characteristic is associated with a higher cancer risk; if the relative risk is 1, the exposure and cancer are not associated with one another; if the relative risk is less than 1, the exposure is associated with a lower cancer risk. Relative risk 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 relative risk. 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 relative risk is interpreted. Odds ratios 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 actual 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 relative risk 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 estimates the number of people that must participate in a screening program 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).