CHAPTER 27: 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 simply an event but a process, a continuum of discrete tissue and cellular changes over time, resulting in more autonomous cellular processes. Prevention concerns the identification and manipulation of the biologic, environmental, and genetic factors in the causal pathway of cancer.

Public education on the avoidance of identified risk factors for cancer and encouraging healthy habits contribute 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 sun avoidance.

SMOKING CESSATION

Tobacco smoking is a strong, modifiable risk factor for cardiovascular disease, pulmonary disease, and cancer. Smokers have an approximately one in three lifetime risk of dying prematurely from a tobacco-related cancer or 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 with those who continue smoking, despite the fact that some carcinogen-induced gene mutations persist for years after smoking cessation. Smoking cessation and avoidance have the potential to 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 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 to not start smoking or to quit smoking can be of benefit. Providers should query patients on tobacco use and offer smokers assistance in quitting.

Current approaches to smoking cessation recognize that smoking is an addiction. A smoker who is quitting goes through a process with 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 not successful 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; 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.

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 an increased risk for cancers of the breast, colon, prostate, and endometrium. These cancers have their highest incidence and mortalities in western cultures, where fat comprises 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. High-fiber diets could lower the risk of breast and prostate cancer by absorbing and inactivating dietary estrogenic and androgenic cancer promoters. However, 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 aged 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 while dietary fat intake was lower in the diet intervention group, invasive breast cancers were not reduced over an 8-year follow-up period compared with 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

The risk of cancer appears to increase as body mass index increases to more than 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 risk of breast cancer. A 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 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 the 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 accurately assess their risk of developing skin cancer have some impact. 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 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 27-1). Influences that cause the initiated cell 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 sometimes arbitrary; 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 pro-apoptotic 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. The introduction of the HPV vaccine might eventually reduce oropharyngeal cancer rates.

Oral leukoplakia, a premalignant lesion commonly found in smokers, has been used as an intermediate marker allowing demonstration 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 proven beneficial 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, ages 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 a 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 as 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 (COX) pathway. Pooled findings from observational cohort studies demonstrate a relative reduction in colorectal cancer incidence of approximately 22% and a relative reduction in colorectal adenoma incidence of about 28% with regular aspirin use; however, in two randomized controlled trials (the Physicians' Health Study and the Women's Health Study), aspirin had no effect on colon cancer or adenoma incidence in persons with no previous history of colonic lesions, at up to 10 years of therapy. The randomized controlled trials did show an approximately 18% relative risk reduction for colonic adenoma incidence in persons with a previous history of adenomas after 1 year's therapy.

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 risk of colorectal cancer compared with 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 one-third. In a randomized placebo-controlled prevention trial involving >13,000 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. Tamoxifen has been approved by the U.S. Food and Drug Administration 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: www.nci.nih.gov/cancertopics/pdq/genetics/breast-and-ovarian/healthprofessional#Section_66).

A trial comparing tamoxifen with another selective estrogen receptor modulator, raloxifene, showed that raloxifene is comparable to tamoxifen in cancer prevention. This trial only included postmenopausal women. Raloxifene was associated with more noninvasive breast cancer than tamoxifen; the drugs are similar in risks of other cancers, fractures, ischemic heart disease, and stroke. Because the aromatase inhibitors are even more effective than tamoxifen in adjuvant breast cancer therapy, it is hoped that they would be more effective in breast cancer prevention. However, no data are yet available on this point.

CHEMOPREVENTION OF PROSTATE CANCER

Finasteride is a 5-α-reductase inhibitor. It inhibits conversion of testosterone to dihydrotestosterone (DHT), a potent stimulator of prostate cell proliferation. The Prostate Cancer Prevention Trial (PCPT) randomly assigned men aged 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) and digital rectal examination (DRE). After 7 years of therapy, the incidence of prostate cancer was 18.4% in the finasteride arm and 24.8% 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%). The clinical significance of this finding, if any, is unknown. The observed increase in high-grade tumors was spurious and likely due to an increased sensitivity of PSA and DRE for high-grade tumors in men receiving finasteride.

Another 5-α-reductase inhibitor, 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 aged 50–60 years and 3–10 ng/mL for men aged 60 years or older) and negative prostate biopsy results on enrollment received 0.5 mg/d of dutasteride or placebo. A preliminary report from this trial noted 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 857 cases, respectively). Unlike the PCPT, no difference was observed in the rates of high-grade prostate cancer. Since all men in both the PCPT and REDUCE trials were being screened and since screening approximately doubles the rate of prostate cancer, it is not known if finasteride or dutasteride decrease 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 5.5 years, no significant difference in the prostate cancer incidence rate was observed for any group. In fact, compared with placebo, a trend toward an increased risk of developing prostate cancer was observed for those men taking vitamin E alone (hazard ratio, 1.13; 95% confidence interval [CI], 0.99–1.29)

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 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. Public health officials are encouraging widespread administration of the hepatitis B vaccine, especially in Asia, where the disease is epidemic.

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 cancer, and types 6 and 11 cause genital papillomas. For females not previously infected with these HPV strains, the vaccines demonstrate high efficacy in preventing persistent strain-specific HPV infections. Trials that evaluated the vaccines' ability to prevent cervical cancer relied on surrogate outcome measures (cervical intraepithelial neoplasia [CIN] I, II, and III), and no cases of cervical cancer were observed in either the vaccine or control arms. The vaccines do not appear to impact preexisting infections; efficacy was markedly lower for populations that had previously been exposed to vaccine-specific HPV strains. The vaccine is recommended for girls and women ages 9–26 years. Reduction in these HPV types could prevent >70% of cervical cancers worldwide.

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 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 8 in the surveillance group had developed breast cancer. A larger (n = 639) retrospective cohort study reported that 3 patients developed breast cancer after prophylactic mastectomy compared with an expected incidence of 30–53 cases, a 90–94% reduction in breast cancer risk. The effect of the procedure on mortality is unknown.

Prophylactic oophorectomy may also be employed for the prevention of ovarian and breast cancers among high-risk women. A case-control study of women with BRCA1 or BRCA2 mutations found that 6 (2.8%) of 259 women who underwent bilateral prophylactic oophorectomy had stage I ovarian cancer at the time of surgery, and 2 (0.8%) developed papillary serous peritoneal carcinoma over 9 years. By comparison, 58 (19.9%) of 292 women in the matched control group developed ovarian cancer: this corresponds to a 96% relative risk reduction for ovarian cancer with the use of prophylactic surgery. Studies of prophylactic oophorectomy for prevention of breast cancer in women with genetic mutations have shown relative risk reductions of approximately 50%.

At present, 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 control participants, and inadequate information about hormone use. Thus, they may give an overestimate of the magnitude of benefit.

Orchiectomy is an effective method of androgen deprivation in prostate cancer.

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, 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. To be of value, screening must detect disease earlier, and treatment of earlier disease must yield a better outcome than treatment at the onset of symptoms. Cause-specific mortality, rather than survival after diagnosis, is the preferred endpoint (see later discussion).

Because screening is done on asymptomatic, healthy persons, it should offer a 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, the 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 saves lives 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 27-2). 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 and 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 and actually have the disease. Similarly, negative predictive value is the proportion testing negative who 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. To be valuable, the screening test should have a high specificity; sensitivity need not be very high.

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 inflated 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 the date of diagnosis) increases without lives being saved or life expectancy changed.

Lead-time bias occurs when a test does not influence the natural history of the disease; the patient is merely diagnosed at an earlier date. When lead-time bias occurs, survival appears increased, but 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, even if life is extended by treatment. 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, an improved survival, or a stage shift are weaker (and possibly misleading) evidence of benefit. These latter criteria are necessary 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 non-randomized 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 cohort or case-control analytic observational studies, or the results of multiple time series studies with or without the intervention.

Screening for specific cancers

Widespread screening for cervical, colon, and breast cancer is beneficial for certain age groups. 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 27-3); the American College of Physicians (ACP) and the American Academy of Family Practitioners (AAFP) generally follow or endorse the USPSTF recommendations. 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.

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 the breast cancer mortality rate. Each trial has been criticized for design flaws. In most trials, the breast cancer mortality rate is decreased by 15–30%. Experts disagree on whether average-risk women aged 40–49 years should receive regular screening (Table 27-3). The U.K. Age Trial, the only randomized trial of breast cancer screening to specifically evaluate the impact of mammography in women aged 40–49 years, found no statistically significant difference in breast cancer mortality rate for screened women versus controls after about 11 years of follow-up (relative risk [RR], 0.83; 95% CI, 0.66–1.04); however, fewer than 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 (RR, 0.85; 95% CI, 0.75–0.96) from mammography screening for women aged 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 aged 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.

No study of breast self-examination has shown it to decrease the mortality rate. A randomized controlled trial of approximately 266,000 women in China demonstrated no difference in the mortality rate between a group that received intensive breast self-exam instruction and reinforcement and reminders and control participants 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 -2 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 smears decreases cervical cancer mortality rates. The cervical cancer mortality rate has fallen substantially since the widespread use of the Pap smear. Screening guidelines recommend regular Pap testing for all women who have reached the age of 21 years; some organizations advocate beginning earlier depending on sexual history. With the onset of sexual activity comes the risk of sexual transmission of HPV, the most common etiologic factor for cervical cancer. The recommended interval for Pap screening varies from 1 to 3 years. At age 30 years, women who have had three normal test results in a row may get screened every 2–3 years. An upper age limit at which screening ceases to be effective is not known, but women aged 65–70 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 non cancerous reasons.

Although the efficacy of the Papanicolaou smear in reducing cervical cancer mortality rates 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 (when indicated) versus counseling on cervical cancer deaths in women aged 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 control participants.

Colorectal cancer

Fecal occult blood testing (FOBT), DRE rigid and flexible sigmoidoscopy, colonoscopy, and computed tomography (CT) colonography have been considered for colorectal cancer screening. Annual FOBT could reduce colorectal cancer mortality by one-third. The sensitivity for fecal occult blood 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 result. Only 2–10% of those with occult blood in the stool have cancer, and 20–30% have adenomas. 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 appears to have increased sensitivity and comparable specificity to FOBT and could potentially reduce harms associated with follow-up of false-positive test results. The body of evidence on the operating characteristics and effectiveness of fecal DNA tests in reducing colorectal cancer mortality rates is limited.

Two case-control studies suggest that regular screening of those older than age 50 years with sigmoidoscopy decreases mortality rates. This type of study is prone to selection biases. One-quarter to one-third of polyps can be discovered with the rigid sigmoidoscope; half are found with a 35-cm flexible scope, and two-thirds to three-quarters are found with a 60-cm scope. 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 5 years is often recommended. Case-control studies suggest that intervals of up to 15 years may confer benefit.

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. Perforation rates are about 3/1000 for colonoscopy and 1/1000 for sigmoidoscopy. Debate continues on whether colonoscopy is too expensive and invasive for widespread use as a screening tool in standard-risk populations. Two observational studies suggest that efficacy of colonoscopy to decrease colorectal cancer mortality rates is restricted 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 radiography and sputum cytology have been evaluated in randomized lung cancer screening trials. No reduction in lung cancer mortality has been seen, although all controlled trials have had low statistical power. Preliminary (unpublished) findings from the National Lung Screening Trial, a randomized controlled trial of screening for lung cancer in ~53,000 persons aged 55-74 years with a 30+ pack-year smoking history, have shown a statistically significant 20% reduction in lung cancer mortality in the spiral CT arm (354 deaths) compared with the chest radiography arm (442 deaths). However, the mortality benefits must be weighed against the disadvantages of spiral CT for a given population. These 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 test results can lead to invasive diagnostic procedures associated with anxiety, expense, and complications (e.g., pneumo- or hemothorax after lung biopsy).

Ovarian cancer

Adnexal palpation, transvaginal ultrasound, and serum CA-125 assay have been considered for ovarian cancer screening. These tests alone and in combination do not have sufficiently high sensitivity or specificity to be recommended for routine screening of ovarian cancer. The risks and costs associated with the high number of false-positive results is an impediment to routine use of these modalities for screening. A large randomized controlled trial has shown that of female participants receiving at least one false-positive serum CA-125 test result, 14% underwent a major surgical procedure (e.g., laparotomy with oophorectomy) for benign disease. For transvaginal ultrasound, the rate was close to 40%.

Prostate cancer

The most common prostate cancer screening modalities are DRE and serum PSA assay. Newer serum tests, such as measurement of bound to free serum PSA, have yet to be fully evaluated. An emphasis on PSA screening has caused prostate cancer to become the most common non-skin cancer diagnosed in American males. This disease is prone to lead-time bias, length bias, and overdiagnosis, and substantial debate rages among experts as to whether it is effective. 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. Men older than age 50 years have a high prevalence of indolent, clinically insignificant prostate cancers.

Two randomized controlled trials of the impact of PSA screening on prostate cancer mortality have been published. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was a multicenter U.S. trial that randomized almost 77,000 men ages 55–74 years to receive annual PSA testing for 6 years or usual care. At 7 years of follow-up, no statistically significant difference in the number of prostate cancer deaths was noted between the arms (rate ratio, 1.13; 95% CI, 0.75–1.90). The data at 10 years (67% complete) showed similar results. Approximately 44% of men in the control arm received at least one PSA test during the trial, which may have potentially diluted an observed effect.

The European Randomized Study of Screening for Prostate Cancer (ERSPC) was a multinational study that randomized approximately 162,000 men between ages 50 and 74 years (with a predefined "core" screening group of men ages 55–69 years) to receive PSA testing every 4 years or no screening. Recruitment and randomization procedures and actual frequency of PSA testing varied by country. After a median follow-up of 9 years, a 20% relative reduction in the risk of prostate cancer death in the screened arm was noted in the "core" screening group (no difference in mortality was observed in the overall study population). The trial also found that 1140 men would need to be screened and 48 additional cases treated to avert 1 death from prostate cancer.

The effectiveness of treatments for low-stage prostate cancer is under study. However, both surgery and radiation therapy may cause significant morbidity, such as impotence and urinary incontinence. Comparison of radical prostatectomy with "watchful waiting" in clinically diagnosed (not screen-detected) prostate cancers showed a small decrease in prostate cancer death rate in the surgery arm, but no statistically significant decrease in overall mortality was seen after 11 years of follow-up. Benefits were restricted to men younger than age 65 years. Urinary incontinence and sexual impotence were more common in the surgery arm. A man should have a life expectancy of at least 10 years to be eligible for screening. The USPSTF has found insufficient evidence to recommend prostate cancer screening for men younger than age 75 years; it recommends against screening for prostate cancer in men age 75 years or older ("D" recommendation) (Table 27-3).

Endometrial cancer

Transvaginal ultrasound and endometrial sampling have been advocated as screening tests for endometrial cancer. Benefit from routine screening has not been shown. Transvaginal ultrasound and endometrial sampling are indicated for workup of vaginal bleeding in postmenopausal women but are not considered as screening tests in symptomatic women.

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.