SURGICAL PREVENTION OF CANCER

Some organs in some people are at such high risk of developing cancer that surgical removal of the organ at risk is recommended. Women with severe cervical dysplasia are treated with conization and occasionally even hysterectomy. Colectomy is used to prevent colon cancer in people with familial polyposis and those with ulcerative colitis. Based on a study in 139 women with BRCA1 and BRCA2 mutations, many women with a genetic predisposition to breast cancer opt to have bilateral mastectomy rather than close surveillance. Of the 139 women, 76 chose mastectomy and 63 chose surveillance; none of the 76 who underwent mastectomy developed breast cancer, but 8 of the 63 women under careful surveillance developed breast cancer. A randomized study is unlikely to be done, and assessment of the effects of prophylactic mastectomy on mortality is also unlikely to be done.

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 save lives and has clearly been shown to do so in the case of cervical, colon, and probably breast cancer, it is also subject to a number of biases, which can suggest a benefit when actually there is none. Bias 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 end point (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.

Screening examinations, tests, or procedures are usually not diagnostic of cancer but instead indicate that a cancer may be present. The diagnosis is then made following a workup that includes a biopsy and pathologic confirmation.

A number of genes have been identified that predispose for a disease, and many more will be identified in the near future. Testing for these genes can define a high-risk population. 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 will 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 prudent, 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 67-2). Sensitivity 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 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 tell that the disease is not present). The positive predictive value is the proportion of persons who test positive who actually have the disease. Similarly, negative predictive value is the proportion of who test negative and do not have the disease. The sensitivity and specificity of a test are relatively 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 (Table 67-3).

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, as demonstrated in Table 67-3.

Potential Biases of Screening Tests  The common biases of screening are lead time, length, 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 proportion of patients diagnosed at an early stage that improves survival statistics without reducing mortality (i.e., the number of deaths from a given cancer relative to the number of people at risk for the cancer). In such a case, the apparent duration of survival 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 bias occurs when slow-growing, less aggressive cancers are detected during screening. 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 is termed overdiagnosis, the detection of "pseudodisease." 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. The individuals screened may have volunteered because of a particular risk factor not found in the general population, such as a strong family history. In general, volunteers for studies may be 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 test results (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, whether the result is positive or negative, 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 end point provides the strongest support for a screening intervention. In a randomized trial, two like populations are randomly established. One is given the medical 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 the usefulness of a screening test, it is not perfect. Unless the trial is population-based, it does not remove the issue 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. After a randomized controlled clinical trial, in descending order of strength, evidence may be derived from:

The findings of internally controlled trials using intervention allocation methods other than randomization (e.g., allocation determined by birth date, date of clinic visit);
The findings of cohort or case-control analytic observational studies;
The results of multiple time series studies with or without the intervention;
The opinions of respected authorities based on clinical experience, descriptive studies, or consensus reports of experts (the weakest evidence because even experts can be misled by the biases described above).

Screening for Specific Cancers  Widespread screening for cervical, colon, and probably breast cancer is beneficial for certain age groups. 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 been carried out to assess the impact of this practice on mortality in specific high-risk populations. 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 screening guidelines of the U.S. Preventive Services Task Force, the Canadian Task Force on Preventive Health Care, and the American Cancer Society are often quoted and show a range of recommendations (Table 67-4).

BREAST CANCER  Breast self-examination, clinical breast examination by a care giver, and mammography have been advocated as useful screening tools. Only breast self-examination, screening mammography alone, and screening mammography with clinical examination have been evaluated in randomized controlled trials. Magnetic resonance imaging is being assessed and may be more accurate than mammography in women at high risk.

A number of trials have suggested that annual or biennial screening with mammography or mammography plus clinical breast examination in women over the age of 50 saves lives. Each trial has been criticized for design flaws. In most trials, the breast cancer mortality rate is decreased by 20 to 30%. Experts disagree on whether average-risk women aged 40 to 49 should receive regular screening (Table 67-4). The significance of the screening effect in women aged 40 to 49 depends on the statistical test used. An analysis of eight large randomized trials showed no benefit from mammographic screening for women aged 40 to 49 when assessed 5 to 7 years after trial entry. However, a small benefit emerged 10 to 12 years after study entry. What proportion of this benefit is due to screening after these women turned 50 is not known. In randomized screening studies of women aged 50 to 69, the decline in mortality begins about 5 years after initiation of screening. Nearly half of women aged 40 to 49 years screened annually will have false-positive mammograms necessitating further evaluation, often including biopsy. The risk of false-positive testing should be discussed with the patient.

While no study has shown breast self-examination to decrease mortality, it is recommended as prudent by many organizations. A substantial fraction of breast cancers are first detected by patients. Self-examination leads to increased biopsy rate without reducing breast cancer mortality.

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 BRCA mutations, possibly because such cancers occur in younger women, in whom mammography is known to be less sensitive.

CERVICAL CANCER  Screening with Papanicolaou smears decreases cervical cancer mortality. The cervical cancer mortality rate has fallen substantially since the widespread use of the Pap smear, although this trend actually began earlier. Most screening guidelines recommend regular Pap testing for all women who are or have been sexually active for 3 years or have reached the age of 21. With the onset of sexual activity comes the risk of sexual transmission of HPV3, the most common etiologic factor for cervical cancer. The recommended interval for Pap screening varies from 1 to 3 years. At age 30, women who have had three normal test results in a row may get screened every 2 to 3 years. An upper age limit at which screening ceases to be effective is not known, but women age =70 years who have had no abnormal results in the previous 10 years may choose to stop screening.

COLORECTAL CANCER  Fecal occult blood testing, digital rectal examination, rigid and flexible sigmoidoscopy, radiographic barium contrast studies, and colonoscopy have been considered for colorectal cancer screening. Annual fecal occult blood testing using hydrated specimens could reduce colorectal cancer mortality by a 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 fecal occult blood testing is high; 1 to 5% of persons tested have a positive result. About 2 to 10% of those with occult blood in the stool have cancer, and 20 to 30% have adenomas. The high false-positive rate of fecal occult blood testing dramatically increases the number of colonoscopies performed.

Two case-control studies suggest that regular screening of people over 50 with sigmoidoscopy decreases mortality. These types of studies are prone to selection biases. A quarter to a 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 polyposis by sigmoidoscopy should lead to evaluation of the entire colon with colonoscopy and/or barium enema. The most efficient interval for screening sigmoidoscopy is unknown. Case-control studies suggest that testing at intervals of up to 15 years may confer benefit.

One-time colonoscopy detects about 25% more advanced lesions (polyps > 10 mm, villous adenomas, polyps with high-grade dysplasia, invasive cancer) than does one-time fecal occult blood testing with sigmoidoscopy. Colonoscopy is well suited to screening subjects at high risk, such as those with ulcerative colitis or family predisposition. Perforation rates are 3/1000 for colonoscopy and 1/1000 for sigmoidoscopy. Debate continues on whether full colonoscopy is too expensive and invasive for widespread use as a screening tool in standard-risk populations. Data are not available on digital rectal examination or barium enema as colon cancer screening tools, but both are insensitive.

LUNG CANCER  Chest radiographs and sputum cytology have been evaluated as methods for lung cancer screening. No reduction in lung cancer mortality has been found in these studies, although all the controlled trials performed have had low statistical power. Even screening of high-risk subjects (smokers) has not been proved to be beneficial. Spiral computed tomography (CT) can diagnose lung cancers at early stages; however, false-positive rates are high. Spiral CT screening increases the number of lesions detected and increases the number of diagnostic and therapeutic procedures. However, its capacity to save lives is being tested.

OVARIAN CANCER  Adnexal palpation, transvaginal ultrasound, and serum CA-125 determination have been considered for ovarian cancer screening. Adnexal palpation is too insensitive to detect ovarian cancer at an early enough stage to affect mortality substantially. Neither transvaginal ultrasound nor CA-125 screening has been tested in a completed randomized prospective trial. Ovarian cancer screening can lead to an invasive diagnostic workup, which may include laparotomy. In a clinical study, 0.6% of 900 adult women had a serum CA-125 level >35 U/mL. Thus, if 100,000 adult women were screened, 600 would be identified as having a high CA-125 level. The prevalence of ovarian cancer in the female adult population is ~20 per 100,000. Thus, the screening test would identify 600 women who would undergo further evaluation to identify 20 cases of ovarian cancer. Some of these 600 would only be inconvenienced by an ultrasound examination. Others would undergo an exploratory laparotomy. A large proportion of the 20 women identified as having ovarian cancer would have advanced, incurable disease and thus not benefit from screening. A National Institutes of Health consensus conference in 1994 concluded that routine screening for ovarian cancer was not indicated for standard-risk women or those with a single affected family member, but that it might be worthwhile in families with genetic ovarian cancer syndromes.

PROSTATE CANCER  The most common prostate cancer screening modalities are digital rectal examination and assays for serum prostate-specific antigen (PSA). Newer serum tests, such as measurement of the ratio 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. Screening for this disease is very prone to lead-time bias, length bias, and overdiagnosis, and substantial debate rages among experts on whether it is effective. Some experts are concerned that prostate cancer screening, more than screening for other cancers, may cause net harm. 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 over age 50 have a very high prevalence of indolent, clinically insignificant prostate cancers. No well-designed trial has demonstrated the benefit of prostate cancer screening and treatment. BR>
The placebo arm of the Prostate Cancer Prevention Trial showed that rigorous screening of low-risk men for 7 years leads to the diagnosis of prostate cancer in >12% of patients. However, >12% of patients with normal annual DREs and PSAs4 biopsied after 7 years were found to have cancer. Thus, prostate cancer screening had moderate success in early detection, but screening missed half the prostate cancers.

The effectiveness of radical prostatectomy, radiation therapy, and other treatments for low-stage prostate cancer is also under study in randomized trials. Definitive treatment of cancers detected by screening may cause morbidity for some men, such as impotence and urinary incontinence, and carries a low but finite risk of death. Comparison of radical prostatectomy to "watchful waiting" in clinically diagnosed (not screening PSA4-detected) prostate cancers showed a decreased rate of death from prostate cancer for those undergoing surgery, but overall mortality was not different in the two arms. Patients undergoing surgery had a higher rate of impotence and urinary incontinence.

Ongoing randomized trials are comparing usual care to prostate screening and comparing definitive therapy to "watchful waiting." The American Cancer Society and the American Urologic Association recommend that men be offered screening after being informed of the potential risks and benefits. A man should have a life expectancy of at least 10 years to be eligible for screening. The U.S. Preventive Services Task Force finds insufficient evidence to recommend prostate cancer screening (Table 67-4).

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. Observational epidemiologic evidence from Scotland and Australia suggests that screening programs have caused a stage shift in melanomas diagnosed. Screening may reinforce sun avoidance and other skin cancer prevention behaviors.

FURTHER READING

THE CANADIAN TASKFORCE ON PREVENTIVE HEALTH CARE: www.ctfphc.org/

HUMPHREY LL et al: Breast cancer screening: A summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 137:347, 2002

KIM ES et al: Chemoprevention of aerodigestive tract cancers. Annu Rev Med 53:223, 2002

THE NATIONAL CANCER INSTITUTE CANCERNET: cancernet.nci.nih.gov/

NATIONAL INSTITUTES OF HEALTH CONSENSUS DEVELOPMENT PANEL: Breast cancer screening for women ages 40-49. J Natl Cancer Inst 89:1015, 1997

SCREENING FOR PROSTATE CANCER: Recommendation and rationale. Ann Intern Med 137:915, 2002

SMITH RA et al: American Cancer Society guidelines for the early detection of cancer, 2003. CA Cancer J Clin 53:27, 2003

STOUTJESDIJK M : Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer. J Natl Cancer Inst 93:1095, 2001

BIBLIOGRAPHY

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FISHER B et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90:1371, 1998

FLETCHER SW et al: Report of the International Workshop on Screening for Breast Cancer. J Natl Cancer Inst 85:1644, 1993

GREENWALD P et al: Cancer Prevention and Control. New York, Marcel Dekker, 1995

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HENSCHKE CI et al: Early Lung Cancer Action Project: Overall design and findings from baseline screening. Lancet 354:99, 1999

SOX HC : Preventive health services in adults. N Engl J Med 330:1589, 1995

THE CANADIAN TASK FORCE ON PREVENTIVE HEALTH CARE: The Canadian Guide to Clinical Preventive Health Care. London, Ontario, Canada. Minister of Supply and Services Canada, 1994

THE ALPHA-TOCOPHEROL, BETA CAROTENE CANCER PREVENTION STUDY GROUP: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330:1029, 1994

THE COMMIT RESEARCH GROUP: Community intervention trial for smoking cessation (COMMIT): I. Cohort results from a four-year community intervention. Am J Public Health 85:183, 1995

THE COMMIT RESEARCH GROUP: Community intervention trial for smoking cessation (COMMIT): II. Changes in adult cigarette smoking prevalence. Am J Public Health 85:193, 1995

THOMAS DB et al: Randomized trial of breast self-examination in Shanghai: Methodology and preliminary results. J Natl Cancer Inst 89:355, 1997

WOOLF SH : Screening for prostate cancer with prostate-specific antigen. N Engl J Med 333:1401, 1995

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1Alpha-Tocopherol/Beta-Carotene (ATBC)

2Beta-Carotene and Retinol Efficacy Trial (CARET)

3Human papilloma virus (HPV)

4prostate-specific antigen (PSA)

 

Location In Book:

 

HARRISON'S PRINCIPLES OF INTERNAL MEDICINE - 16th Ed. (2005)
   PART FIVE - ONCOLOGY AND HEMATOLOGY
      Section 1 - Neoplastic Disorders
          67. PREVENTION AND EARLY DETECTION OF CANCER - Otis W. Brawley, Barnett S. Kramer
            INTRODUCTION