Chapter 28: Prevention and Early Detection of Cancer

Improved understanding of carcinogenesis has allowed cancer prevention and early detection (also known as cancer control) to expand beyond the identification and avoidance of carcinogens. Specific interventions to prevent cancer in those at risk, and effective screening for early detection of cancer, are the goals.

Carcinogenesis is not an event but a process, a continuum of discrete tissue and cellular changes over time resulting in aberrant physiologic processes. Prevention concerns the identification and manipulation of the biologic, environmental, social, and genetic factors in the causal pathway of cancer.

Public education on the avoidance of identified risk factors for cancer and encouraging healthy habits contributes to cancer prevention and control. The clinician is a powerful messenger in this process. The patient-provider encounter provides an opportunity to teach patients about the hazards of smoking, the features of a healthy lifestyle, use of proven cancer screening methods, and avoidance of excessive sun exposure.

SMOKING CESSATION

Tobacco smoking is a strong, modifiable risk factor for cardiovascular disease, pulmonary disease, and cancer. Smokers have an approximately 1 in 3 lifetime risk of dying prematurely from a tobacco-related cancer, cardiovascular, or pulmonary disease. Tobacco use causes more deaths from cardiovascular disease than from cancer. Lung cancer and cancers of the larynx, oropharynx, esophagus, kidney, bladder, pancreas, and stomach are all tobacco-related.

The number of cigarettes smoked per day and the level of inhalation of cigarette smoke are correlated with risk of lung cancer mortality. Light- and low-tar cigarettes are not safer, because smokers tend to inhale them more frequently and deeply.

Those who stop smoking have a 30–50% lower 10-year lung cancer mortality rate compared to those who continue smoking, despite the fact that some carcinogen-induced gene mutations persist for years after smoking cessation. Smoking cessation and avoidance would save more lives than any other public health activity.

The risk of tobacco smoke is not limited to the smoker. Environmental tobacco smoke, known as secondhand or passive smoke, causes lung cancer and other cardiopulmonary diseases in nonsmokers.

Tobacco use prevention is a pediatric issue. More than 80% of adult American smokers began smoking before the age of 18 years. Approximately 20% of Americans in grades 9 through 12 have smoked a cigarette in the past month. Counseling of adolescents and young adults is critical to prevent smoking. A clinician’s simple advice can be of benefit. Providers should query patients on tobacco use and offer smokers assistance in quitting.

Current approaches to smoking cessation recognize smoking as an addiction. The smoker who is quitting goes through identifiable stages that include contemplation of quitting, an action phase in which the smoker quits, and a maintenance phase. Smokers who quit completely are more likely to be successful than those who gradually reduce the number of cigarettes smoked or change to lower-tar or lower-nicotine cigarettes. More than 90% of the Americans who have successfully quit smoking did so on their own, without participation in an organized cessation program, but cessation programs are helpful for some smokers. The Community Intervention Trial for Smoking Cessation (COMMIT) was a 4-year program showing that light smokers (<25 cigarettes per day) were more likely to benefit from simple cessation messages and cessation programs than those who did not receive an intervention. Quit rates were 30.6% in the intervention group and 27.5% in the control group. The COMMIT interventions were unsuccessful in heavy smokers (<25 cigarettes per day). Heavy smokers may need an intensive broad-based cessation program that includes counseling, behavioral strategies, and pharmacologic adjuncts, such as nicotine replacement (gum, patches, sprays, lozenges, and inhalers), bupropion, and/or varenicline.

The health risks of cigars are similar to those of cigarettes. Smoking one or two cigars daily doubles the risk for oral and esophageal cancers; smoking three or four cigars daily increases the risk of oral cancers more than eightfold and esophageal cancer fourfold. The risks of occasional use are unknown.

Smokeless tobacco also represents a substantial health risk. Chewing tobacco is a carcinogen linked to dental caries, gingivitis, oral leukoplakia, and oral cancer. The systemic effects of smokeless tobacco (including snuff) may increase risks for other cancers. Esophageal cancer is linked to carcinogens in tobacco dissolved in saliva and swallowed. The net effects of e-cigarettes on health are poorly studied. Whether they aid in smoking cessation or serve as a “gateway” for nonsmoking children to acquire a smoking habit is debated.

PHYSICAL ACTIVITY

Physical activity is associated with a decreased risk of colon and breast cancer. A variety of mechanisms have been proposed. However, such studies are prone to confounding factors such as recall bias, association of exercise with other health-related practices, and effects of preclinical cancers on exercise habits (reverse causality).

DIET MODIFICATION

International epidemiologic studies suggest that diets high in fat are associated with increased risk for cancers of the breast, colon, prostate, and endometrium. These cancers have their highest incidence and mortalities in Western cultures, where fat composes an average of one-third of the total calories consumed.

Despite correlations, dietary fat has not been proven to cause cancer. Case-control and cohort epidemiologic studies give conflicting results. In addition, diet is a highly complex exposure to many nutrients and chemicals. Low-fat diets are associated with many dietary changes beyond simple subtraction of fat. Other lifestyle changes are also associated with adherence to a low-fat diet.

In observational studies, dietary fiber is associated with a reduced risk of colonic polyps and invasive cancer of the colon. However, cancer-protective effects of increasing fiber and lowering dietary fat have not been proven in the context of a prospective clinical trial. The putative protective mechanisms are complex and speculative. Fiber binds oxidized bile acids and generates soluble fiber products, such as butyrate, that may have differentiating properties. Fiber does not increase bowel transit times. Two large prospective cohort studies of >100,000 health professionals showed no association between fruit and vegetable intake and risk of cancer.

The Polyp Prevention Trial randomly assigned 2000 elderly persons, who had polyps removed, to a low-fat, high-fiber diet versus routine diet for 4 years. No differences were noted in polyp formation.

The U.S. National Institutes of Health Women’s Health Initiative, launched in 1994, was a long-term clinical trial enrolling >100,000 women age 45–69 years. It placed women in 22 intervention groups. Participants received calcium/vitamin D supplementation; hormone replacement therapy; and counseling to increase exercise, eat a low-fat diet with increased consumption of fruits, vegetables, and fiber, and cease smoking. The study showed that although dietary fat intake was lower in the diet intervention group, invasive breast cancers were not reduced over an 8-year follow-up period compared to the control group. No reduction was seen in the incidence of colorectal cancer in the dietary intervention arm. The difference in dietary fat averaged ~10% between the two groups. Evidence does not currently establish the anticarcinogenic value of vitamin, mineral, or nutritional supplements in amounts greater than those provided by a balanced diet.

ENERGY BALANCE

Risk of cancer appears to increase as body mass index increases beyond 25 kg/m². Obesity is associated with increased risk for cancers of the colon, breast (female postmenopausal), endometrium, kidney (renal cell), and esophagus, although causality has not been established.

In observational studies, relative risks of colon cancer are increased in obesity by 1.5–2 for men and 1.2–1.5 for women. Obese postmenopausal women have a 30–50% increased relative risk of breast cancer. An unproven hypothesis for the association is that adipose tissue serves as a depot for aromatase that facilitates estrogen production.

SUN AVOIDANCE

Nonmelanoma skin cancers (basal cell and squamous cell) are induced by cumulative exposure to ultraviolet (UV) radiation. Intermittent acute sun exposure and sun damage have been linked to melanoma, but the evidence is inconsistent. Sunburns, especially in childhood and adolescence, may be associated with an increased risk of melanoma in adulthood. Reduction of sun exposure through use of protective clothing and changing patterns of outdoor activities can reduce skin cancer risk. Sunscreens decrease the risk of actinic keratoses, the precursor to squamous cell skin cancer, but melanoma risk may not be reduced. Sunscreens prevent burning, but they may encourage more prolonged exposure to the sun and may not filter out wavelengths of energy that cause melanoma.

Educational interventions to help individuals assess their risk of developing skin cancer have some impact. In particular, appearance-focused behavioral interventions in young women can decrease indoor tanning use and other UV exposures. Self-examination for skin pigment characteristics associated with skin cancer, such as freckling, may be useful in identifying people at high risk. Those who recognize themselves as being at risk tend to be more compliant with sun-avoidance recommendations. Risk factors for melanoma include a propensity to sunburn, a large number of benign melanocytic nevi, and atypical nevi.

Chemoprevention involves the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenesis before the development of invasive malignancy.

Cancer develops through an accumulation of tissue abnormalities associated with genetic and epigenetic changes, and growth regulatory pathways that are potential points of intervention to prevent cancer. The initial changes are termed initiation. The alteration can be inherited or acquired through the action of physical, infectious, or chemical carcinogens. Like most human diseases, cancer arises from an interaction between genetics and environmental exposures (Table 28-1). Influences that cause the initiated cell and its surrounding tissue microenvironment to progress through the carcinogenic process and change phenotypically are termed promoters. Promoters include hormones such as androgens, linked to prostate cancer, and estrogen, linked to breast and endometrial cancer. The distinction between an initiator and promoter is indistinct; some components of cigarette smoke are “complete carcinogens,” acting as both initiators and promoters. Cancer can be prevented or controlled through interference with the factors that cause cancer initiation, promotion, or progression. Compounds of interest in chemoprevention often have antimutagenic, hormone modulation, anti-inflammatory, antiproliferative, or proapoptotic activity (or a combination).

CHEMOPREVENTION OF CANCERS OF THE UPPER AERODIGESTIVE TRACT

Smoking causes diffuse epithelial injury in the oral cavity, neck, esophagus, and lung. Patients cured of squamous cell cancers of the lung, esophagus, oral cavity, and neck are at risk (as high as 5% per year) of developing second cancers of the upper aerodigestive tract. Cessation of cigarette smoking does not markedly decrease the cured cancer patient’s risk of second malignancy, even though it does lower the cancer risk in those who have never developed a malignancy. Smoking cessation may halt the early stages of the carcinogenic process (such as metaplasia), but it may have no effect on late stages of carcinogenesis. This “field carcinogenesis” hypothesis for upper aerodigestive tract cancer has made “cured” patients an important population for chemoprevention of second malignancies.

Oral human papilloma virus (HPV) infection, particularly HPV-16, increases the risk for cancers of the oropharynx. This association exists even in the absence of other risk factors such as smoking or alcohol use (although the magnitude of increased risk appears greater than additive when HPV infection and smoking are both present). Oral HPV infection is believed to be largely sexually acquired. Although no direct evidence currently exists to confirm the hypothesis, the introduction of the HPV vaccine may eventually reduce oropharyngeal cancer rates.

Oral leukoplakia, a premalignant lesion commonly found in smokers, has been used as an intermediate marker of chemopreventive activity in smaller shorter-duration, randomized, placebo-controlled trials. Response was associated with upregulation of retinoic acid receptor-β (RAR-β). Therapy with high, relatively toxic doses of isotretinoin (13-cis-retinoic acid) causes regression of oral leukoplakia. However, the lesions recur when the therapy is withdrawn, suggesting the need for long-term administration. More tolerable doses of isotretinoin have not shown benefit in the prevention of head and neck cancer. Isotretinoin also failed to prevent second malignancies in patients cured of early-stage non-small cell lung cancer; mortality rates were actually increased in current smokers.

Several large-scale trials have assessed agents in the chemoprevention of lung cancer in patients at high risk. In the α-tocopherol/β-carotene (ATBC) Lung Cancer Prevention Trial, participants were male smokers, age 50–69 years at entry. Participants had smoked an average of one pack of cigarettes per day for 35.9 years. Participants received α-tocopherol, β-carotene, and/or placebo in a randomized, two-by-two factorial design. After median follow-up of 6.1 years, lung cancer incidence and mortality were statistically significantly increased in those receiving β-carotene. α-Tocopherol had no effect on lung cancer mortality, and no evidence suggested interaction between the two drugs. Patients receiving α-tocopherol had a higher incidence of hemorrhagic stroke.

The β-Carotene and Retinol Efficacy Trial (CARET) involved 17,000 American smokers and workers with asbestos exposure. Entrants were randomly assigned to one of four arms and received β-carotene, retinol, and/or placebo in a two-by-two factorial design. This trial also demonstrated harm from β-carotene: a lung cancer rate of 5 per 1000 subjects per year for those taking placebo and of 6 per 1000 subjects per year for those taking β-carotene.

The ATBC and CARET results demonstrate the importance of testing chemoprevention hypotheses thoroughly before their widespread implementation because the results contradict a number of observational studies. The Physicians’ Health Trial showed no change in the risk of lung cancer for those taking β-carotene; however, fewer of its participants were smokers than those in the ATBC and CARET studies.

CHEMOPREVENTION OF COLON CANCER

Many colon cancer prevention trials are based on the premise that most colorectal cancers develop from adenomatous polyps. These trials use adenoma recurrence or disappearance as a surrogate endpoint (not yet validated) for colon cancer prevention. Early clinical trial results suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), such as piroxicam, sulindac, and aspirin, may prevent adenoma formation or cause regression of adenomatous polyps. The mechanism of action of NSAIDs is unknown, but they are presumed to work through the cyclooxygenase pathway. Although two randomized controlled trials (the Physicians’ Health Study and the Women’s Health Study) did not show an effect of aspirin on colon cancer or adenoma incidence in persons with no previous history of colonic lesions after 10 years of therapy, these trials did show an approximately 18% relative risk reduction for colonic adenoma incidence in persons with a previous history of adenomas after 1 year. Pooled findings from observational cohort studies do demonstrate a 22% and 28% relative reduction in colorectal cancer and adenoma incidence, respectively, with regular aspirin use, and a well-conducted meta-analysis of four randomized controlled trials (albeit primarily designed to examine aspirin’s effects on cardiovascular events) found that aspirin at doses of at least 75 mg resulted in a 24% relative reduction in colorectal cancer incidence after 20 years, with no clear increase in efficacy at higher doses. Cyclooxygenase-2 (COX-2) inhibitors have also been considered for colorectal cancer and polyp prevention. Trials with COX-2 inhibitors were initiated, but an increased risk of cardiovascular events in those taking the COX-2 inhibitors was noted, suggesting that these agents are not suitable for chemoprevention in the general population.

Epidemiologic studies suggest that diets high in calcium lower colon cancer risk. Calcium binds bile and fatty acids, which cause proliferation of colonic epithelium. It is hypothesized that calcium reduces intraluminal exposure to these compounds. The randomized controlled Calcium Polyp Prevention Study found that calcium supplementation decreased the absolute risk of adenomatous polyp recurrence by 7% at 4 years; extended observational follow-up demonstrated a 12% absolute risk reduction 5 years after cessation of treatment. However, in the Women’s Health Initiative, combined use of calcium carbonate and vitamin D twice daily did not reduce the incidence of invasive colorectal cancer compared with placebo after 7 years.

The Women’s Health Initiative demonstrated that postmenopausal women taking estrogen plus progestin have a 44% lower relative risk of colorectal cancer compared to women taking placebo. Of >16,600 women randomized and followed for a median of 5.6 years, 43 invasive colorectal cancers occurred in the hormone group and 72 in the placebo group. The positive effect on colon cancer is mitigated by the modest increase in cardiovascular and breast cancer risks associated with combined estrogen plus progestin therapy.

A case-control study suggested that statins decrease the incidence of colorectal cancer; however, several subsequent case-control and cohort studies have not demonstrated an association between regular statin use and a reduced risk of colorectal cancer. No randomized controlled trials have addressed this hypothesis. A meta-analysis of statin use showed no protective effect of statins on overall cancer incidence or death.

CHEMOPREVENTION OF BREAST CANCER

Tamoxifen is an antiestrogen with partial estrogen agonistic activity in some tissues, such as endometrium and bone. One of its actions is to upregulate transforming growth factor β, which decreases breast cell proliferation. In randomized placebo-controlled trials to assess tamoxifen as adjuvant therapy for breast cancer, tamoxifen reduced the number of new breast cancers in the opposite breast by more than a third. In a randomized placebo-controlled prevention trial involving >13,000 pre- and postmenopausal women at high risk, tamoxifen decreased the risk of developing breast cancer by 49% (from 43.4 to 22 per 1000 women) after a median follow-up of nearly 6 years. Tamoxifen also reduced bone fractures; a small increase in risk of endometrial cancer, stroke, pulmonary emboli, and deep vein thrombosis was noted. The International Breast Cancer Intervention Study (IBIS-I) and the Italian Randomized Tamoxifen Prevention Trial also demonstrated a reduction in breast cancer incidence with tamoxifen use. A trial comparing tamoxifen with another selective estrogen receptor modulator, raloxifene, in postmenopausal women showed that raloxifene is comparable to tamoxifen in cancer prevention. This trial only included postmenopausal women. Raloxifene was associated with more invasive breast cancers and a trend toward more noninvasive breast cancers, but fewer thromboembolic events than tamoxifen; the drugs are similar in risks of other cancers, fractures, ischemic heart disease, and stroke. Both tamoxifen and raloxifene (the latter for postmenopausal women only) have been approved by the U.S. Food and Drug Administration (FDA) for reduction of breast cancer in women at high risk for the disease (1.66% risk at 5 years based on the Gail risk model: http://www.cancer.gov/bcrisktool/).

Because the aromatase inhibitors are even more effective than tamoxifen in adjuvant breast cancer therapy, it has been hypothesized that they would be more effective in breast cancer prevention. A randomized, placebo-controlled trial of exemestane reported a 65% relative reduction (from 5.5 to 1.9 per 1000 women) in the incidence of invasive breast cancer in women at elevated risk after a median follow-up of about 3 years. Common adverse effects included arthralgias, hot flashes, fatigue, and insomnia. No trial has directly compared aromatase inhibitors with selective estrogen receptor modulators for breast cancer chemoprevention.

CHEMOPREVENTION OF PROSTATE CANCER

Finasteride and dutasteride are 5-α-reductase inhibitors. They inhibit conversion of testosterone to dihydrotestosterone (DHT), a potent stimulator of prostate cell proliferation. The Prostate Cancer Prevention Trial (PCPT) randomly assigned men age 55 years or older at average risk of prostate cancer to finasteride or placebo. All men in the trial were being regularly screened with prostate-specific antigen (PSA) levels and digital rectal examination. After 7 years of therapy, the incidence of prostate cancer was 18.4% in the finasteride arm, compared with 24.4% in the placebo arm, a statistically significant difference. However, the finasteride group had more patients with tumors of Gleason score 7 and higher compared with the placebo arm (6.4 vs 5.1%). Reassuringly, long-term (10–15 years) follow-up did not reveal any statistically significant differences in overall mortality between all men in the finasteride and placebo arms or in men diagnosed with prostate cancer; differences in prostate cancer in favor of finasteride persisted.

Dutasteride has also been evaluated as a preventive agent for prostate cancer. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was a randomized double-blind trial in which approximately 8200 men with an elevated PSA (2.5–10 ng/mL for men age 50–60 years and 3–10 ng/mL for men age 60 years or older) and negative prostate biopsy on enrollment received daily 0.5 mg of dutasteride or placebo. The trial found a statistically significant 23% relative risk reduction in the incidence of biopsy-detected prostate cancer in the dutasteride arm at 4 years of treatment (659 cases vs 858 cases, respectively). Overall, across years 1 through 4, there was no difference between the arms in the number of tumors with a Gleason score of 7 to 10; however, during years 3 and 4, there was a statistically significant difference in tumors with Gleason score of 8 to 10 in the dutasteride arm (12 tumors vs 1 tumor, respectively).

The clinical importance of the apparent increased incidence of higher-grade tumors in the 5-α-reductase inhibitor arms of these trials is controversial. It may likely represent an increased sensitivity of PSA and digital rectal exam for high-grade tumors in men receiving these agents. The FDA has analyzed both trials, and it determined that the use of a 5-α-reductase inhibitor for prostate cancer chemoprevention would result in one additional high-grade (Gleason score 8 to 10) prostate cancer for every three to four lower-grade (Gleason score <6) tumors averted. Although it acknowledged that detection bias may have accounted for the finding, it stated that it could not conclusively dismiss a causative role for 5-α-reductase inhibitors. These agents are therefore not FDA-approved for prostate cancer prevention.

Because all men in both the PCPT and REDUCE trials were being screened and because screening approximately doubles the rate of prostate cancer, it is not known if finasteride or dutasteride decreases the risk of prostate cancer in men who are not being screened.

Several favorable laboratory and observational studies led to the formal evaluation of selenium and α-tocopherol (vitamin E) as potential prostate cancer preventives. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) assigned 35,533 men to receive 200 μg/d selenium, 400 IU/d α-tocopherol, selenium plus vitamin E, or placebo. After a median follow-up of 7 years, a trend toward an increased risk of developing prostate cancer was observed for those men taking vitamin E alone as compared to the placebo arm (hazard ratio 1.17; 95% confidence interval, 1.004–1.36).

VACCINES AND CANCER PREVENTION

A number of infectious agents cause cancer. Hepatitis B and C are linked to liver cancer; some HPV strains are linked to cervical, anal, and head and neck cancer; and Helicobacter pylori is associated with gastric adenocarcinoma and gastric lymphoma. Vaccines to protect against these agents may reduce the risk of their associated cancers.

The hepatitis B vaccine is effective in preventing hepatitis and hepatomas due to chronic hepatitis B infection.

A quadrivalent HPV vaccine (covering HPV strains 6, 11, 16, and 18) and a bivalent vaccine (covering HPV strains 16 and 18) are available for use in the United States. HPV types 16 and 18 cause cervical and anal cancer; reduction in these HPV types could prevent >70% of cervical cancers worldwide. HPV types 6 and 11 cause genital papillomas. For individuals not previously infected with these HPV strains, the vaccines demonstrate high efficacy in preventing persistent strain-specific HPV infections; however, the trials and substudies that evaluated the vaccines’ ability to prevent cervical and anal cancer relied on surrogate outcome measures (cervical or anal intraepithelial neoplasia [CIN/AIN] I, II, and III), and the degree of durability of the immune response beyond 5 years is not currently known. The vaccines do not appear to impact preexisting infections and the efficacy appears to be markedly lower for populations that had previously been exposed to vaccine-specific HPV strains. The vaccine is recommended in the United States for females and males age 9–26 years.

Some organs in some individuals are at such high risk of developing cancer that surgical removal of the organ at risk may be considered. Women with severe cervical dysplasia are treated with laser or loop electrosurgical excision or conization and occasionally even hysterectomy. Colectomy is used to prevent colon cancer in patients with familial polyposis or ulcerative colitis.

Prophylactic bilateral mastectomy may be chosen for breast cancer prevention among women with genetic predisposition to breast cancer. In a prospective series of 139 women with BRCA1 and BRCA2 mutations, 76 chose to undergo prophylactic mastectomy and 63 chose close surveillance. At 3 years, no cases of breast cancer had been diagnosed in those opting for surgery, but eight patients in the surveillance group had developed breast cancer. A larger (n = 639) retrospective cohort study reported that three patients developed breast cancer after prophylactic mastectomy compared with an expected incidence of 30–53 cases: a 90–94% reduction in breast cancer risk. Postmastectomy breast cancer–related deaths were reduced by 81–94% for high-risk women compared with sister controls and by 100% for moderate-risk women when compared with expected rates.

Prophylactic oophorectomy may also be employed for the prevention of ovarian and breast cancers among high-risk women. A prospective cohort study evaluating the outcomes of BRCA mutation carriers demonstrated a statistically significant association between prophylactic oophorectomy and a reduced incidence of ovarian or primary peritoneal cancer (36% relative risk reduction, or a 4.5% absolute difference). Studies of prophylactic oophorectomy for prevention of breast cancer in women with genetic mutations have shown relative risk reductions of approximately 50%; the risk reduction may be greatest for women having the procedure at younger (i.e., <50 years) ages.

All of the evidence concerning the use of prophylactic mastectomy and oophorectomy for prevention of breast and ovarian cancer in high-risk women has been observational in nature; such studies are prone to a variety of biases, including case selection bias, family relationships between patients and controls, and inadequate information about hormone use. Thus, they may give an overestimate of the magnitude of benefit.

CANCER SCREENING

Screening is a means of detecting disease early in asymptomatic individuals, with the goal of decreasing morbidity and mortality. While screening can potentially reduce disease-specific deaths and has been shown to do so in cervical, colon, lung, and breast cancer, it is also subject to a number of biases that can suggest a benefit when actually there is none. Biases can even mask net harm. Early detection does not in itself confer benefit. Cause-specific mortality, rather than survival after diagnosis, is the preferred endpoint (see below).

Because screening is done on asymptomatic, healthy persons, it should offer substantial likelihood of benefit that outweighs harm. Screening tests and their appropriate use should be carefully evaluated before their use is widely encouraged in screening programs, as a matter of public policy.

A large and increasing number of genetic mutations and nucleotide polymorphisms have been associated with an increased risk of cancer. Testing for these genetic mutations could in theory define a high-risk population. However, most of the identified mutations have very low penetrance and individually provide minimal predictive accuracy. The ability to predict the development of a particular cancer may some day present therapeutic options as well as ethical dilemmas. It may eventually allow for early intervention to prevent a cancer or limit its severity. People at high risk may be ideal candidates for chemoprevention and screening; however, efficacy of these interventions in the high-risk population should be investigated. Currently, persons at high risk for a particular cancer can engage in intensive screening. While this course is clinically reasonable, it is not known if it reduces mortality in these populations.

The accuracy of screening

A screening test’s accuracy or ability to discriminate disease is described by four indices: sensitivity, specificity, positive predictive value, and negative predictive value (Table 28-2). Sensitivity, also called the true-positive rate, is the proportion of persons with the disease who test positive in the screen (i.e., the ability of the test to detect disease when it is present). Specificity, or 1 minus the false-positive rate, is the proportion of persons who do not have the disease that test negative in the screening test (i.e., the ability of a test to correctly identify that the disease is not present). The positive predictive value is the proportion of persons who test positive that actually have the disease. Similarly, negative predictive value is the proportion testing negative that do not have the disease. The sensitivity and specificity of a test are independent of the underlying prevalence (or risk) of the disease in the population screened, but the predictive values depend strongly on the prevalence of the disease.

Screening is most beneficial, efficient, and economical when the target disease is common in the population being screened. Specificity is at least as important to the ultimate feasibility and success of a screening test as sensitivity.

Potential biases of screening tests

Common biases of screening are lead time, length-biased sampling, and selection. These biases can make a screening test seem beneficial when actually it is not (or even causes net harm). Whether beneficial or not, screening can create the false impression of an epidemic by increasing the number of cancers diagnosed. It can also produce a shift in the proportion of patients diagnosed at an early stage and inflate survival statistics without reducing mortality (i.e., the number of deaths from a given cancer relative to the number of those at risk for the cancer). In such a case, the apparent duration of survival (measured from date of diagnosis) increases without lives being saved or life expectancy changed.

Lead-time bias occurs whether or not a test influences the natural history of the disease; the patient is merely diagnosed at an earlier date. Survival appears increased even if life is not really prolonged. The screening test only prolongs the time the subject is aware of the disease and spends as a patient.

Length-biased sampling occurs because screening tests generally can more easily detect slow-growing, less aggressive cancers than fast-growing cancers. Cancers diagnosed due to the onset of symptoms between scheduled screenings are on average more aggressive, and treatment outcomes are not as favorable. An extreme form of length bias sampling is termed overdiagnosis, the detection of “pseudo disease.” The reservoir of some undetected slow-growing tumors is large. Many of these tumors fulfill the histologic criteria of cancer but will never become clinically significant or cause death. This problem is compounded by the fact that the most common cancers appear most frequently at ages when competing causes of death are more frequent.

Selection bias must be considered in assessing the results of any screening effort. The population most likely to seek screening may differ from the general population to which the screening test might be applied. In general, volunteers for studies are more health conscious and likely to have a better prognosis or lower mortality rate, irrespective of the screening result. This is termed the healthy volunteer effect.

Potential drawbacks of screening

Risks associated with screening include harm caused by the screening intervention itself, harm due to the further investigation of persons with positive tests (both true and false positives), and harm from the treatment of persons with a true-positive result, whether or not life is extended by treatment (e.g., even if a screening test reduces relative cause-specific mortality by 20–30%, 70–80% of those diagnosed still go on to die of the target cancer). The diagnosis and treatment of cancers that would never have caused medical problems can lead to the harm of unnecessary treatment and give patients the anxiety of a cancer diagnosis. The psychosocial impact of cancer screening can also be substantial when applied to the entire population.

Assessment of screening tests

Good clinical trial design can offset some biases of screening and demonstrate the relative risks and benefits of a screening test. A randomized controlled screening trial with cause-specific mortality as the endpoint provides the strongest support for a screening intervention. Overall mortality should also be reported to detect an adverse effect of screening and treatment on other disease outcomes (e.g., cardiovascular disease). In a randomized trial, two like populations are randomly established. One is given the usual standard of care (which may be no screening at all) and the other receives the screening intervention being assessed. The two populations are compared over time. Efficacy for the population studied is established when the group receiving the screening test has a better cause-specific mortality rate than the control group. Studies showing a reduction in the incidence of advanced-stage disease, improved survival, or a stage shift are weaker (and possibly misleading) evidence of benefit. These latter criteria are early indicators but not sufficient to establish the value of a screening test.

Although a randomized, controlled screening trial provides the strongest evidence to support a screening test, it is not perfect. Unless the trial is population-based, it does not remove the question of generalizability to the target population. Screening trials generally involve thousands of persons and last for years. Less definitive study designs are therefore often used to estimate the effectiveness of screening practices. However, every nonrandomized study design is subject to strong confounders. In descending order of strength, evidence may also be derived from the findings of internally controlled trials using intervention allocation methods other than randomization (e.g., allocation by birth date, date of clinic visit); the findings of analytic observational studies; or the results of multiple time series studies with or without the intervention.

Screening for specific cancers

Screening for cervical, colon, and breast cancer is beneficial for certain age groups. Depending on age and smoking history, lung cancer screening can also be beneficial in specific settings. Special surveillance of those at high risk for a specific cancer because of a family history or a genetic risk factor may be prudent, but few studies have assessed the influence on mortality. A number of organizations have considered whether or not to endorse routine use of certain screening tests. Because these groups have not used the same criteria to judge whether a screening test should be endorsed, they have arrived at different recommendations. The American Cancer Society (ACS) and the U.S. Preventive Services Task Force (USPSTF) publish screening guidelines (Table 28-3); the American Academy of Family Practitioners (AAFP) generally follow/endorse the USPSTF recommendations; and the American College of Physicians (ACP) develops recommendations based on structured reviews of other organizations’ guidelines.

Breast cancer

Breast self-examination, clinical breast examination by a caregiver, mammography, and magnetic resonance imaging (MRI) have all been variably advocated as useful screening tools.

A number of trials have suggested that annual or biennial screening with mammography or mammography plus clinical breast examination in normal-risk women older than age 50 years decreases breast cancer mortality. Each trial has been criticized for design flaws. In most trials, breast cancer mortality rate is decreased by 15–30%. Experts disagree on whether average-risk women age 40–49 years should receive regular screening (Table 28-3). The U.K. Age Trial, the only randomized trial of breast cancer screening to specifically evaluate the impact of mammography in women age 40–49 years, found no statistically significant difference in breast cancer mortality for screened women versus controls after about 11 years of follow-up (relative risk 0.83; 95% confidence interval 0.66–1.04); however, <70% of women received screening in the intervention arm, potentially diluting the observed effect. A meta-analysis of eight large randomized trials showed a 15% relative reduction in mortality (relative risk 0.85; 95% confidence interval 0.75–0.96) from mammography screening for women age 39–49 years after 11–20 years of follow-up. This is equivalent to a number needed to invite to screening of 1904 over 10 years to prevent one breast cancer death. At the same time, nearly half of women age 40–49 years screened annually will have false-positive mammograms necessitating further evaluation, often including biopsy. Estimates of overdiagnosis range from 10 to 40% of diagnosed invasive cancers. In the United States, widespread screening over the last several decades has not been accompanied by a reduction in incidence of metastatic breast cancer despite a large increase in early-stage disease, suggesting a substantial amount of overdiagnosis at the population level.

No study of breast self-examination has shown it to decrease mortality. A randomized controlled trial of approximately 266,000 women in China demonstrated no difference in breast cancer mortality between a group that received intensive breast self-exam instruction and reinforcement/reminders and controls at 10 years of follow-up. However, more benign breast lesions were discovered and more breast biopsies were performed in the self-examination arm.

Genetic screening for BRCA1 and BRCA2 mutations and other markers of breast cancer risk has identified a group of women at high risk for breast cancer. Unfortunately, when to begin and the optimal frequency of screening have not been defined. Mammography is less sensitive at detecting breast cancers in women carrying BRCA1 and BRCA2 mutations, possibly because such cancers occur in younger women, in whom mammography is known to be less sensitive. MRI screening may be more sensitive than mammography in women at high risk due to genetic predisposition or in women with very dense breast tissue, but specificity may be lower. An increase in overdiagnosis may accompany the higher sensitivity. The impact of MRI on breast cancer mortality with or without concomitant use of mammography has not been evaluated in a randomized controlled trial.

Cervical cancer

Screening with Papanicolaou (Pap) smears decreases cervical cancer mortality. The cervical cancer mortality rate has fallen substantially since the widespread use of the Pap smear. With the onset of sexual activity comes the risk of sexual transmission of HPV, the fundamental etiologic factor for cervical cancer. Screening guidelines recommend regular Pap testing for all women who have reached the age of 21 (prior to this age, even in individuals that have begun sexual activity, screening may cause more harm than benefit). The recommended interval for Pap screening is 3 years. Screening more frequently adds little benefit but leads to important harms, including unnecessary procedures and overtreatment of transient lesions. Beginning at age 30, guidelines also offer the alternative of combined Pap smear and HPV testing for women. The screening interval for women who test normal using this approach may be lengthened to 5 years.

An upper age limit at which screening ceases to be effective is not known, but women age 65 years with no abnormal results in the previous 10 years may choose to stop screening. Screening should be discontinued in women who have undergone a hysterectomy for noncancerous reasons.

Although the efficacy of the Pap smear in reducing cervical cancer mortality has never been directly confirmed in a randomized, controlled setting, a clustered randomized trial in India evaluated the impact of one-time cervical visual inspection and immediate colposcopy, biopsy, and/or cryotherapy (where indicated) versus counseling on cervical cancer deaths in women age 30–59 years. After 7 years of follow-up, the age-standardized rate of death due to cervical cancer was 39.6 per 100,000 person-years in the intervention group versus 56.7 per 100,000 person-years in controls.

Colorectal cancer

Fecal occult blood testing (FOBT), digital rectal examination (DRE), rigid and flexible sigmoidoscopy, colonoscopy, and computed tomography (CT) colonography have been considered for colorectal cancer screening. A meta-analysis of four randomized controlled trials demonstrated a 15% relative reduction in colorectal cancer mortality with FOBT. The sensitivity for FOBT is increased if specimens are rehydrated before testing, but at the cost of lower specificity. The false-positive rate for rehydrated FOBT is high; 1–5% of persons tested have a positive test. Only 2–10% of those with occult blood in the stool have cancer. The high false-positive rate of FOBT dramatically increases the number of colonoscopies performed.

Fecal immunochemical tests appear to have higher sensitivity for colorectal cancer than nonrehydrated FOBT tests. Fecal DNA testing is an emerging testing modality; it may have increased sensitivity and comparable specificity to FOBT and could potentially reduce harms associated with follow-up of false-positive tests. The body of evidence on the operating characteristics and effectiveness of fecal DNA tests in reducing colorectal cancer mortality is limited.

Two meta-analyses of five randomized controlled trials of sigmoidoscopy (i.e., the NORCCAP, SCORE, PLCO, Telemark, and U.K. trials) found an 18% relative reduction in colorectal cancer incidence and a 28% relative reduction in colorectal cancer mortality. Participant ages ranged from 50 to 74 years, with follow-up ranging from 6 to 13 years. Diagnosis of adenomatous polyps by sigmoidoscopy should lead to evaluation of the entire colon with colonoscopy. The most efficient interval for screening sigmoidoscopy is unknown, but an interval of 5 years is often recommended. Case-control studies suggest that intervals of up to 15 years may confer benefit; the U.K. trial demonstrated benefit with one-time screening.

One-time colonoscopy detects ~25% more advanced lesions (polyps >10 mm, villous adenomas, adenomatous polyps with high-grade dysplasia, invasive cancer) than one-time FOBT with sigmoidoscopy; comparative programmatic performance of the two modalities over time is not known. Perforation rates are about 3/1000 for colonoscopy and 1/1000 for sigmoidoscopy. Debate continues on whether colonoscopy is too expensive and invasive and whether sufficient provider capacity exists to be recommended as the preferred screening tool in standard-risk populations. Some observational studies suggest that efficacy of colonoscopy to decrease colorectal cancer mortality is primarily limited to the left side of the colon.

CT colonography, if done at expert centers, appears to have a sensitivity for polyps ≥6 mm comparable to colonoscopy. However, the rate of extracolonic findings of abnormalities of uncertain significance that must nevertheless be worked up is high (~15–30%); the long-term cumulative radiation risk of repeated colonography screenings is also a concern.

Lung cancer

Chest x-ray and sputum cytology have been evaluated in several randomized lung cancer screening trials. The most recent and largest (n = 154,901) of these, one substudy of the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial, found that, compared with usual care, annual chest x-ray did not reduce the risk of dying from lung cancer (relative risk 0.99; 95% confidence interval 0.87–1.22) after 13 years. Low-dose CT has also been evaluated in several randomized trials. The largest and longest of these, the National Lung Screening Trial (NLST), was a randomized controlled trial of screening for lung cancer in approximately 53,000 persons age 55–74 years with a 30+ pack-year smoking history. It demonstrated a statistically significant relative reduction of about 15–20% in lung cancer mortality in the CT arm compared to the chest x-ray arm (or about 3 fewer deaths per 1000 people screened with CT). However, the harms include the potential radiation risks associated with multiple scans, the discovery of incidental findings of unclear significance, and a high rate of false-positive test results. Both incidental findings and false-positive tests can lead to invasive diagnostic procedures associated with anxiety, expense, and complications (e.g., pneumo- or hemothorax after lung biopsy). The NLST was performed at experienced screening centers, and the balance of benefits and harms may differ in the community setting at less experienced centers.

Ovarian cancer

Adnexal palpation, transvaginal ultrasound (TVUS), and serum CA-125 assay have been considered for ovarian cancer screening. A large randomized controlled trial has shown that an annual screening program of TVUS and CA-125 in average-risk women does not reduce deaths from ovarian cancer (relative risk 1.21; 95% confidence interval 0.99–1.48). Adnexal palpation was dropped early in the study because it did not detect any ovarian cancers that were not detected by either TVUS or CA-125. The risks and costs associated with the high number of false-positive results are impediments to routine use of these modalities for screening. In the PLCO trial, 10% of participants had a false-positive result from TVUS or CA-125, and one-third of these women underwent a major surgical procedure; the ratio of surgeries to screen-detected ovarian cancer was approximately 20:1.

Prostate cancer

The most common prostate cancer screening modalities are DRE and serum PSA assay. An emphasis on PSA screening has caused prostate cancer to become the most common nonskin cancer diagnosed in American males. This disease is prone to lead-time bias, length bias, and overdiagnosis, and substantial debate continues among experts as to whether screening should be offered unless the patient specifically asks to be screened. Virtually all organizations stress the importance of informing men about the uncertainty regarding screening efficacy and the harms associated with screening. Prostate cancer screening clearly detects many asymptomatic cancers, but the ability to distinguish tumors that are lethal but still curable from those that pose little or no threat to health is limited, and randomized trials indicate that the effect of PSA screening on prostate cancer mortality across a population is, at best, small. Men older than age 50 years have a high prevalence of indolent, clinically insignificant prostate cancers (about 30–50% of men, increasing further as men age).

Two major randomized controlled trials of the impact of PSA screening on prostate cancer mortality have been published. The PLCO Cancer Screening Trial was a multicenter U.S. trial that randomized almost 77,000 men age 55–74 years to receive either annual PSA testing for 6 years or usual care. At 13 years of follow-up, no statistically significant difference in the number of prostate cancer deaths were noted between the arms (rate ratio 1.09; 95% confidence interval 0.87–1.36). Approximately 50% of men in the control arm received at least one PSA test during the trial, which may have potentially diluted a small effect.

The European Randomized Study of Screening for Prostate Cancer (ERSPC) was a multinational study that randomized approximately 182,000 men between age 50 and 74 years (with a predefined “core” screening group of men age 55–69 years) to receive PSA testing or no screening. Recruitment and randomization procedures, as well as actual frequency of PSA testing, varied by country. After a median follow-up of 11 years, a 20% relative reduction in the risk of prostate cancer death in the screened arm was noted in the “core” screening group. The trial found that 1055 men would need to be invited to screening, and 37 cases of prostate cancer detected, to avert 1 death from prostate cancer. Of the seven countries included in the mortality analysis, two demonstrated statistically significant reductions in prostate cancer deaths, whereas five did not. There was also an imbalance in treatment between the two study arms, with a higher proportion of men with clinically localized cancer receiving radical prostatectomy in the screening arm and receiving it at experienced referral centers.

Treatments for low-stage prostate cancer, such as surgery and radiation therapy, can cause significant morbidity, including impotence and urinary incontinence. In a trial conducted in the United States after the initiation of widespread PSA testing, random assignment to radical prostatectomy compared with “watchful waiting” did not result in a statistically significant decrease in prostate cancer deaths (absolute risk reduction 2.7%; 95% confidence interval–1.3 to 6.2%).

Skin cancer

Visual examination of all skin surfaces by the patient or by a health care provider is used in screening for basal and squamous cell cancers and melanoma. No prospective randomized study has been performed to look for a mortality decrease. Unfortunately, screening is associated with a substantial rate of overdiagnosis.