Chapter 1

Table of Contents

The concept of preventive health care screening has been developed over the last 30 years through clinical trials of screening maneuvers as well as a theoretical statistical literature.^, These data have helped clinicians to understand the profound value of specific screening interventions, as well as the fact that more screening is not always equivalent to better health care. Screening is used in general medical practice in two ways: we screen for early disease, and we screen for risk factors for disease or injury (such as smoking, hyperlipidemia, or non-use of seatbelts). Both are important, despite the emphasis in what follows on screening for disease. Screening for early disease is most effective the disease meets specific criteria and appropriate tests are available. Four criteria are required to make a disease appropriate for screening:

1) The disease must have a detectable preclinical period, before the disease becomes clinically apparent and during which the disease can be detected by the screening test. Cervical intraepithelial neoplasia can be clinically silent for years, yet easily diagnosed by a screening test.

 

2) The detectable preclinical period must be before the disease escapes from cure. Amyotrophic lateral sclerosis (ALS), for example, is incurable regardless of when it is detected and so does not meet this criterion.

 

3) Treatment must be more effective if given earlier (at the time of screen detection) than later (at the time the disease becomes clinically apparent). Radical prostatectomy for low-grade prostate cancer has not been proven to improve overall survival, for example, which is the main reason routine screening for prostate cancer remains controversial.

 

4) The disease must be sufficiently common in the population, since the prevalence of a disease, together with the sensitivity and specificity of the test, determine the positive and negative predictive values of the test.

For a screening test to be effective, it must be sensitive, specific, have high predictive value, be feasible for broad use, and acceptable in terms of cost, risk and patient tolerability.

The current standard for evaluating screening maneuvers is the randomized clinical trial. The endpoint on which interpretation of these studies rests is reduction in cause-specific mortality rather than in the case-fatality rate. The reason for this is that screening tests may detect a cancer at an earlier stage even in the absence of more effective early treatment. People with screen-detected cancers may, therefore, live longer and have a lower case-fatality rate at any time interval after screen detection, compared to people with cancers detected in other ways. This phenomenon is termed lead-time bias. In addition, screening maneuvers detect a mix of fast-growing aggressive tumors and slow-growing tumors that do well regardless of treatment. The screen-detected mix is a point prevalence sample and therefore overrepresents slow-growing tumors compared to the overall mix among all incident cases. This phenomenon is termed length bias, and can also be avoided by the use of cause-specific mortality (rather than length of life after diagnosis, for example) as an outcome measure. Both lead time and length bias favor screening even in the absence of true benefit unless cause-specific mortality is used as the study endpoint.

As the amount of data from clinical trials of screening tests has increased, recommendations have increasingly been based on evidence. Difficulty translating group findings to individual patients, however, continues to create heated controversies. In many clinical situations, evidence-based practice will require education of patients. In others, evidence may be preliminary or lacking entirely. In all cases, the active solicitation of informed patient preference is essential. In addition, screening recommendations should not be static – they will and should change as newer tests and treatments emerge. As with all patient care, screening must be individualized, but the basis of good practice is understanding current recommendations and the evidence on which they are based.

In 1989, the U.S. Preventive Services Task Force, commissioned by the U.S. Department of Health and Human Services, published the results of its survey of strategies for the prevention of disease. The Guide to Clinical Preventive Services was last updated in 1996. The survey examines interventions involving 80 conditions and is available in print and on the Internet (http://cpmcnet.columbia.edu/texts/gcps). While some of these assessments involve counseling, immunization and chemoprophylaxis, the majority of the report deals with screening. The survey does not analyze the screening procedures themselves; rather it examines the medical literature supporting or refuting the procedures. The Guide to Clinical Preventive Services is a cornerstone of evidence-based medicine and the basis of many of the recommendations in this chapter. It is important to realize, however, that there are multiple published screening guidelines – including those from the National Cancer Institutes, the American Cancer Society, subspecialty organizations, and patient advocacy groups – and that these guidelines do not always agree with the Guide or with each other. Only familiarity with the evidence underlying screening recommendations and the principles of clinical epidemiology stressed above can assist the clinician to balance competing guidelines.

The Guide makes its screening recommendations based on the probability that a condition is present in a given population. Populations are identified by age group and by various high-risk groups. Thus, the first step is to determine the population to which your patient belongs. The Guide recommends some screening tests for all adult patients (Table 1) and others for those in specific risk groups (Table 2). Many of the screening procedures in these tables are discussed in other chapters in this syllabus. Others are simple, noncontroversial and should be done routinely in all patients (diet history, sexual history) or in those with the risk factors identified in Table 2; these are not discussed further in this chapter.

New cases of invasive cervical carcinoma occur at an annual rate of approximately 20 per 100,000 in women over the age of 35. The lifetime incidence (in the absence of screening) is about 2,500 per 100,000 women, with about a 1 in 100 chance of dying from the disease. In screened populations, the epidemiology is quite different. While virtually undetected in unscreened populations, the additional annual incidence of carcinoma in situ (CIS) in screened populations is 130 per 100,000 with a lifetime incidence of 2,000 per 100,000. In a screened population where CIS is treated when it is detected, the lifetime incidence of invasive disease drops to about 700 per 100,000. Risk factors include race (blacks, Hispanics and Native Americans have a rate double that of whites and Asians), history of multiple sexual partners (two to three times higher risk), smoking (1.5 times higher risk) and oral contraceptives (1.2 to 2 times higher risk).

The standard screening procedure for cervical cancer is the Papanicolaou (Pap) test. Introduced before the advent of randomized trials, it has many of the characteristics of a good screening test. The test is safe, relatively inexpensive, and has a low false-positive rate (0.2 to 0.4 percent). Unfortunately, it has a fairly high false-negative rate (5 to 50 percent), but given the relatively indolent nature of cervical intraepithelial neoplasia (20 years from initial HPV infection to invasive cancer in women with intact immune systems), the impact of a single false negative is diminished considerably by periodic reexamination.

Despite the lack of a randomized trial, the preponderance of evidence shows that periodic Pap tests significantly reduce mortality from this disease by as much as 90 percent. Current controversies concern which age group to screen and the periodicity with which to do so. While many recommendations in the past have been to perform the test annually in all women from age 20 on, it has become clear that this is unnecessary. First, screening women more frequently than every three years does not appear to increase the survival in those in whom CIS is found, since finding the lesion in its first year confers little additional mortality benefit compared to finding it in its third year. Secondly, more frequent screening will detect a higher proportion of transitory dysplasia. As much as 60 percent of cervical dysplasia will regress spontaneously.

Similarly, while testing women over the age of 65 has been shown in the past to be useful for detecting disease, this strategy does not apply to women who have received regular screening prior to that age. Consensus seems to be developing to screen women who are or have been sexually active beginning at the age of onset of sexual activity and continuing to the age of 65. Screening should be performed at least every three years. In women over the age of 65 who have not been screened, screening should be instituted and continued until at least two high-quality Pap results have been reported negative. For women who have been regularly screened prior to age 65 who have negative smears, there is little evidence to support benefit of continued screening and the cost-effectiveness of continued screening is low.

Although cervical cancer is clearly associated with certain types of human papilloma virus infection (most notably HPV 16 and 18), routine screening for HPV infection itself is not currently recommended. As PCR technology is standardized, however, testing for specific oncogenic strains may be helpful in directing screening periodicity and follow-up.

The recommendations above apply to women in the general population. There are several large subgroups of women, however, to whom these recommendations do not apply. Women with HIV infection have higher rates of cervical cancer and higher risk of invasive cervical cancer. Patients with HIV infection should have annual Pap smears; those with AIDS should have Pap smears every 6 months, and those with AIDS and a history of abnormal Pap smears should have the test performed as often as every three months. Women with a history of total hysterectomy for benign gynecologic disease have a very low probability of abnormal findings when Pap smears are done of the vaginal apex, and do not require further cervical cancer screening.

While lung cancer has surpassed breast cancer as the leading cause of cancer death in women, breast cancer remains the most commonly occurring non-skin cancer and remains one of the most common causes of death in women ages 35 – 55 years. Risk factors include family history of premenopausal breast cancer in a first degree relative (mother, sister or daughter), previous personal history of breast cancer or benign breast disease, menarche before age 12, first pregnancy after age 30, menopause after age 50, obesity, high socioeconomic status, history of ovarian or endometrial cancer, and presence of abnormalities in the BRCA1 and BRCA2 genes. It is, however, important to remember that 75 percent of women diagnosed with breast cancer have no identifiable risk factors.

Five-year survival is strongly dependent on the stage at which the disease is diagnosed, ranging from 94 percent for localized disease to 18 percent for cases with distant metastases. Some of this difference is attributable to lead time bias, but clinical trials of treatment, as well as randomized trials of mammography, clearly demonstrate a mortality benefit for early detection and treatment.

Screening procedures for breast cancer include breast self-examination, clinical examination by a physician, and mammography. Breast self-examination (BSE) is safe and inexpensive, although ineffective. The usual recommendation is that it be performed monthly, at the onset of menstrual bleeding, while in the shower. Proponents argue that teaching BSE serves an educational purpose about breast cancer risk and is self-empowering. The evidence supporting this recommendation is weak. The sensitivity of BSE is rather low - 26 percent in one study - and the false positive rate is currently unknown. False positives may prompt unnecessary physician visits and, perhaps, unnecessary mammography. A very large randomized trial of BSE in China is underway; interim results were negative at five years. Based on these findings, we view the teaching of BSE as discretionary.

Clinical breast examination (CBE) by a health care provider has a somewhat higher sensitivity. In testing with standardized breast models, an 87 percent detection rate was noted for masses one centimeter in diameter. However, in one large clinical study, the sensitivity was as low as 45 percent. A recent systematic review of the literature on CBE concluded that its sensitivity is 54 percent and specificity is 94 percent. In a large retrospective cohort study, the risk of a false-positive CBE was 13 percent over a ten-year period. While there have been no clinical trials of CBE alone, in randomized studies of breast cancer screening, a small proportion of cancers that were not seen on mammography were detected by clinical examination. Like SBE, CBE is safe, inexpensive and an opportunity to provide patient education about breast cancer screening; we recommend annual clinical breast exam for all adult female patients.

Mammography provides a substantial improvement over manual examination alone. Sensitivities of 50 to 87 percent (depending on patient age) have been noted, with specificities of 94 to 99 percent. It is important to note, however, that the risk of a false-positive mammogram is still relatively high for women who obtain regular mammography. One retrospective cohort study showed that the risk of a false-positive mammogram over a ten-year period approached 24 percent;¹⁴ some authors suggest that this number may approach 50 percent. There have been 11 large clinical trials of mammography, eight of which were randomized, controlled studies. In every trial, periodic screening mammography shows a decrease in age-adjusted mortality from breast cancer of approximately 30 percent, and routine mammography is endorsed by every organization that publishes screening guidelines. Remaining areas of controversy include those not yet examined in clinical trials: when to start screening, how frequently to screen and when to stop screening.

The question of when to initiate screening mammography is complicated by the lack of outcomes data. Only one of the clinical trials of mammography was designed to address the question of at what age screening for breast cancer should begin, and this study (the Canadian National Breast Screening Study) is considered by some to be fatally flawed by design weaknesses. Only one of the trials (Gothenberg) shows a statistically significant difference in mortality between women who began screening at 40 and those who began screening at 50. Meta-analyses that include all clinical trials of screening mammography do not show significant differences in mortality after 10 years between women who began screening at 40 and those who began screening at 50, although a mortality benefit can be shown after 12-14 years. In contrast, meta-analyses which exclude the Canadian trial do show a statistically significant difference.

Because the prevalence of breast cancer among young women is lower, and because higher breast density (such as that seen in younger women) decreases the sensitivity of mammograms, the positive predictive value of an abnormal mammogram is lower in a 40-year old than in a 50-year old. In addition, starting to screen at the age of 40 means that each woman may have as many as 35 mammograms in her lifetime. The topic is a controversial one; the National Cancer Institute and the American Cancer Society now recommend mammography for all women 40 and older while the U.S. Preventive Services Task Force Guide does not.

At present, it is fair to say that initiating screening mammography at 40 instead of at 50 may make a difference in mortality from breast cancer. As Drs. Shea and Antman point out in a recent article, age, risk of breast cancer and cost-effectiveness of mammography are all continua – there is no abrupt change at the age of 50. Given this uncertainty (described as a "toss-up" by some authors), it is reasonable to leave this decision to the discretion of patient and provider. Women with higher risk (such as family history) may choose to be screened earlier, although there are no studies of this screening strategy. As noted above, there is no substitute for informed patient participation in this sort of decision-making.

No clinical trial has been designed to answer the question of how often women should undergo screening mammography, and there is some controversy over the optimal schedule. Enthusiasm for annual mammography is tempered by the fact that since the prior probability of new disease is between 0.02 percent and 0.18 percent (depending on age), the positive predictive value (depending on test performance) is only one to 13 percent. In contrast, many oncologists point to the data from studies such as the Gothenburg trial in which subgroup analyses suggest that the shorter the interval between mammograms, the larger the mortality benefit.¹⁷ Current recommendations from the ACS, NCI and the Division of Oncology at New York Presbyterian Hospital are to screen with annual mammography after the age of 50.

Clinical trials have not demonstrated a mortality benefit from breast cancer screening in women over the age of 75. There have been very few women in this age group in the clinical trials of breast cancer screening, however, and the usefulness of mammography in women over the age of 74 who have previously been screened is unclear. Many practitioners use functional status rather than age as an indication to stop screening; if a patient has a limited life expectancy or comorbid conditions that would preclude lumpectomy and tamoxifen, few would recommend continuing screening mammography. In contrast, an active 85 year-old willing and able to undergo surgery and radiation therapy if breast cancer is detected might be a good candidate for continued screening.

Risk factors for colorectal cancer include family history, diet (high saturated fat, low fiber), alcohol use and sedentary life style. Like breast cancer, five-year survival is strongly dependent on the stage at which the disease is diagnosed, ranging from 90 percent for localized disease (Duke’s A) to 6 percent for cases with distant metastases (Duke’s D). Only one third of cases are detected while still in the localized stage, suggesting that increased screening could result in improved overall mortality.

Screening procedures include digital rectal exam (DRE), fecal occult blood testing (FOBT) usually with Hemoccult cards, flexible sigmoidoscopy (FOS), colonoscopy and biologic markers such as carcinoembryonic antigen (CEA). DRE is a useful method for conducting FOBT; however as a primary method for palpating colorectal lesions it is inadequate, since over 85 percent of lesions are beyond reach. Colonoscopy has not been extensively evaluated as a screening strategy, primarily because of expense, risk and tolerability. The overall complication rate of colonoscopy is 1-2 percent and the risk of colonic perforation has been estimated to be 0.1 percent. Biologic markers, such as CEA, while useful for monitoring disease relapse, are generally considered to be of inadequate sensitivity and specificity for use as a screening tool.

FOBT can detect the presence of a wide variety of conditions, including colorectal cancer, premalignant adenomata, benign adenomata, gastric carcinoma and peptic ulcer. It can also detect blood produced from gastric irritation due to nonsteroidal anti-inflammatory agents and it can produce false positives due to the ingestion of a variety of medications. Nevertheless, in an asymptomatic population over the age of 50, FOBT has a positive predictive value of 5 to 10 percent for cancer and 30 percent for adenomata. The sensitivity of FOBT has been as high as 92 percent in some studies of patients with known malignancy, but is probably much lower in asymptomatic populations (hence lowering the negative predictive value). One study of 248 patients with guaiac-positive stool but without iron deficiency or active GI bleeding showed that upper gastrointestinal lesions were found more frequently than colonic lesions (21.8 percent vs. 28.6 percent).

The best and largest randomized trial conducted in men and women 50 to 80 years of age compared the outcomes of three strategies: annual screening (three rehydrated Hemoccult cards), biannual screening, and control (no screening). Patients in the first two groups with at least one positive Hemoccult test were evaluated with colonoscopy. The incidence of cancer was comparable in the three groups. Mortality from colorectal cancer was 33 percent lower in the annually-screened group when compared to the other two groups after 13 years (each group had approximately 15,500 patients with 82, 117 and 121 colorectal cancer deaths respectively). Other large trials have replicated these results and support the conclusion that annual FOBT screening is superior to biannual screening. We recommend annual use of the protocol followed in this study. Patients should be instructed to avoid red meat and NSAIDS for several days prior to testing and to collect the samples on three consecutive days. Compliance with this strategy may be lower in our setting than in the study population.

FOS is extremely sensitive for the area visualized; however its actual performance is limited by the amount of colon it can reach. Longer scopes can visualize just under half of the colon and, not surprisingly, sensitivity of sigmoidoscopy is approximately 45 percent that of colonoscopy. Specificity of the test depends on what is being sought. Detection of benign polyps is frequent and is often considered a false positive result. At the time of discovery, of course, there is no way to know the malignant potential and all polyps must be removed. Removing adenomas appears to decrease the incidence of later malignant transformation.

There are no randomized clinical trials of screening sigmoidoscopy, although case-control studies have produced suggestive results. One case-control study showed that endoscopic procedures of the large bowel (including sigmoidoscopy and colonoscopy) were associated with a 50 percent reduction in the risk of developing colorectal cancer. Another case-control study compared patients who had had a rigid sigmoidoscopy with those who had not; the former had an odds ratio for distal colorectal cancer of 0.41 (0.25-0.69). There was no difference in the rate of proximal colorectal cancer – i.e. cancer diagnoses dropped significantly only for the area of the colon visualized by the sigmoidoscope. The American Cancer Society recommends flexible sigmoidoscopy at age 50 for patients with no risk factors.

There are no trials of screening colonoscopy. Although clearly more sensitive than sigmoidoscopy, even colonoscopy is not 100 percent sensitive. A 1997 study of 183 patients undergoing two colonoscopies on the same day showed miss rates of 6 percent for adenomas > 1 cm, 13 percent for adenomas 6-9 mm and 27 percent for adenomas smaller than 5 mm. Given the risk and expense of the procedure, colonoscopy does not meet the criteria of a good screening test outlined above and we do not recommend this screening strategy in the absence of supportive data. We await the results of a Veterans’ Administration randomized controlled trial of a single colonoscopy at the age of 60, as well as further developments in advanced imaging studies of the colon.

Prostate cancer is the leading cause of non-skin cancer in American men, and the second leading cause of cancer death. It meets almost all of the criteria for a "screenable" disease – it is prevalent, serious, and treatable and has a preclinical detectable period. In addition, mortality from prostate cancer has fallen seven percent since 1992, which some attribute to the introduction of PSA screening. Why, then, is there so much controversy about the utility of prostate cancer screening? The two answers are closely related – first, a mortality benefit from early treatment of asymptomatic low-grade disease has not been proven, and second, there have not been randomized controlled studies that convincingly demonstrate the efficacy of prostate cancer screening. A single randomized trial has been published, and suggests a mortality benefit – its critics await further studies. Such trials are underway, however, and recommendations about screening may change over the next few years, as interim data become available. The two largest screening trials – the National Cancer Institute’s prostate, lung, colorectal and ovarian (PLCO) trial and the European Randomized Study of Screening for Prostate Cancer (ERSSPC) – include 37,000 and 135,000 men, respectively and final data are expected starting in 2006. An intervention trial, the U.S. Prostate Cancer Intervention Versus Observation Trial (PIVOT) has enrolled over half of its target 1,050 patients.

Until these data are available, clinicians must decide what to tell patients about prostate cancer screening. Because indolent disease is extremely common and the treatment of advanced disease is rarely curative, the utility of screening for this disease has been challenged. As Whitmore has asked, "When cure is possible, is it necessary? When cure is necessary, is it possible?" Screening for prostate cancer has been complicated by the inability of screening tests to distinguish between three clinical settings: detection of an asymptomatic cancer that would never have caused illness, detection of an asymptomatic cancer that has already escaped from cure, and detection of an asymptomatic cancer which can be cured with therapy. It is clear that the majority of cancers identified by prostate cancer screening fall into one of the first two groups and equally clear that the goal of screening should be to detect those in the third – those with clinically significant and still-treatable disease.

The Guide to Clinical Preventive Services summarizes studies of the effectiveness of digital rectal exam, transrectal ultrasonography and serum tumor markers (such as prostate specific antigen) for detection of and reducing mortality from prostate cancer. The sensitivity and specificity of these tests is variable, and there was no evidence to support the hypothesis that early detection and aggressive treatment of prostate cancer leads to improved mortality (after taking into account lead time and length bias). The Task Force concluded that there was no evidence to support screening for prostate cancer and, in fact, recommended against screening.

Since the Guide’s most recent edition, in 1996, there have been additional studies of prostate cancer screening, and the controversy surrounding this intervention continues to grow.^,, PSA testing, always extremely sensitive, has become somewhat more specific with the addition of PSA isoenzyme testing,^, PSA density corrections, age-specific and race-specific PSA cutoffs and PSA velocity observations. Treatment of screen-detected prostate cancer has advanced, with some data suggesting a mortality benefit for selected patients. We recognize that there is significant controversy about prostate cancer screening and that the American Urological Association and the American Cancer Society advocate screening at this time, however, we do not recommend routine screening of all asymptomatic men. We endorse the guideline of the American College of Physicians, which suggest that "as a matter of routine, physicians should describe the potential benefits and known harms of screening, diagnosis, and treatment; listen to the patient’s concerns; and then individualize the decision to screen."

Even when physicians agree that patients should have preventive health care screening, such screening is often underused. Physicians do not refer patients for screening tests as often as they should, and when they do, the tests are often not completed. In addition, physicians significantly overestimate their own performance of screening tests. In spite of wide consensus about the utility of mammograms, for example, fewer than 25 percent of women in the general population have completed annual mammography. Low income, Hispanic and African-American ethnicity, low educational attainment and age over 65 are associated with underuse of mammography. Similarly, there are marked racial differences in mortality from cervical cancer – African American women are twice as likely to be diagnosed and two to three times as likely to die of the disease as are white women – suggesting differences in access to screening as well as to treatment.

There are multiple studies of interventions aimed at improving the utilization of screening tests. A trial of multiple outreach programs in public housing projects increased screening mammography among Hispanic women in Los Angeles from 12 to 27 percent. The use of lay health advisers and a nurse practitioner increased screening mammography and Pap smears in a clinic serving low-income women. Computerized reminder systems for providers increases rates of screening tests, as do reminders by nurses or other trained personnel; even the use of screening flow sheets in charts has been shown to improve provider adherence to screening recommendations.

It is an auditable standard of care to offer preventive services to appropriate patients, to document the counseling provided and the actions taken, and to follow up with results of screening tests.

We thank Dr. Karen Antman for helpful comments and suggestions.

Table of Contents

<