Preventive Care Now Can Reduce or Prevent 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 reverse preneoplastic changes.

Much of the promise for cancer prevention comes from observational epidemiologic studies that show associations between modifiable lifestyle 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.

Infections may also be associated with cancer development. Human papillomavirus (HPV) infection is a necessary event for subsequent cervix cancer, and vaccine-conferred immunity results in a marked decrease in precancerous lesions. Likewise, Epstein-Barr virus has been associated with Burkitt lymphoma and Helicobacter pylori with gastric cancer, although specific anti-infective interventions have not yet proven effective in preventing these cancers.

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 obesity (associated with colon, breast, endometrial, and possibly other cancers). Observational evidence shows associations between alcohol consumption, physical inactivity, and obesity and increased incidence of certain cancers. More research is needed to determine whether these associations are causal and whether avoiding these behaviors would actually reduce cancer incidence. 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. As a general rule, epidemiological studies have suggested associations between diet and cancer development, but prospective observational or interventional studies have not provided strong support. For example, case-control epidemiological studies suggest an association between high fruit and vegetable consumption and reduced risk of various cancers, but prospective cohort studies have not observed such strong protective associations. On the basis of population-based epidemiologic data, high-fiber diets were recommended to prevent colon neoplasms, but a randomized controlled trial of supplemental wheat bran fiber did not reduce the risk of subsequent adenomatous polyps in individuals with previously resected polyps. Ecologic, cohort, and case-control studies found an association between fat and red meat intake and colon cancer risk, but a randomized controlled trial of a low-fat diet in postmenopausal women showed no reduction in colon cancer. The low-fat diet did not affect all cancer mortality, overall mortality, or cardiovascular disease. Multivitamin and mineral supplements have been advocated for cancer prevention, but the evidence is insufficient to support their use. For example, beta carotene was thought to prevent or reverse smoking-related changes leading to lung cancer, but two prospective placebo-controlled trials found that smokers and former smokers had increased lung cancer incidence and mortality. A large randomized trial is currently under way to investigate whether men taking daily selenium or vitamin E or both experience a reduced incidence of prostate cancer in comparison with men taking placebo pills.

Chemoprevention trials have had some positive results. Daily use of selective estrogen receptor modulators (tamoxifen or raloxifene) for up to 5 years reduces the incidence of breast cancer in high-risk women by about 50%. Finasteride (an alpha-reductase inhibitor) lowers the incidence of prostate cancer, although the occurrence of more high-grade cancers in treated men is poorly understood. Other chemoprevention candidates include COX-2 inhibitors (which inhibit the cyclooxygenase enzymes involved in the synthesis of proinflammatory prostaglandins) to prevent colon and breast cancer, although the possibility of increased cardiovascular events may preclude their usefulness. Statins have been proposed as cancer-prevention agents, but on review many retrospective studies show that they probably neither increase nor decrease cancer risk.

Considerable research effort is now devoted 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.

Fecal occult blood testing has been demonstrated to reduce both colon cancer incidence and mortality. Screening for colon cancer by colonoscopy and sigmoidoscopy may 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.

Description of the Evidence

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 randomized controlled trials 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 five levels are as follows:

1. Evidence obtained from randomized controlled trials that have:

a. a cancer endpoint

i. mortality

ii. incidence

b. 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:

a. a cancer endpoint

i. mortality

ii. incidence

b. 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:

a. a cancer endpoint

i. mortality

ii. incidence

b. 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:

a. a cancer endpoint

i. mortality

ii. incidence

b. 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 to 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 that 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

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 absolute rate measures the actual cancer occurrence in a population or subgroup (e.g., U.S. 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 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. 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 two 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 one 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.