Recommendations About Screening

Transcription

1 36 Recommendations About Screening Alba DiCenso and Gordon Guyatt The following Editorial Board members also made substantive contributions to this chapter: Susan Marks, Andrea Nelson, and Mark Newman. We gratefully acknowledge the work of Alexandra Barratt, Les Irwig, Paul Glasziou, Robert Cumming, Angela Raffle, Nicholas Hicks, and Muir Gray on the original chapter that appears in the Users Guides to the Medical Literature, edited by Guyatt and Rennie. In This Chapter Finding the Evidence Consequences of Screening Are the Recommendations Valid? Is There Randomized Trial Evidence That Earlier Intervention Works? Were the Data Identified, Selected, and Combined in an Unbiased Fashion? What Are the Recommendations? What Are the Benefits? What Are the Risks? Can I Apply the Recommendations to Patient Care? How Do Benefits and Risks Compare in Different People and With Different Screening Strategies? What Is the Impact of Individuals Values and Preferences? What Is the Impact of Uncertainty Associated With the Evidence? What Is the Cost-effectiveness? 526

2 Recommendations About Screening Chapter Clinical Scenario Should a 47-Year-Old Couple Undergo Colon Cancer Screening? You are a primary care nurse practitioner seeing a 47-year-old woman and her husband of the same age. They are concerned because a friend recently was diagnosed with colon cancer, and she has urged them both to undergo screening with the fecal occult blood test (FOBT). Both of these patients have no family history of colon cancer and no change in bowel habit. They ask whether you agree that they should be screened. You know that trials of FOBT screening have shown that screening can reduce mortality from colorectal cancer, but you also recall that FOBTs can have a high false-positive rate, which then necessitates investigation by colonoscopy. You are unsure whether screening these relatively young, asymptomatic people at average risk of colon cancer is likely to do more good than harm. You decide to check the literature to see whether there are any guidelines or recommendations about screening for colorectal cancer that could help you respond to their question. FINDING THE EVIDENCE Because you know that more than one randomized trial exists on this topic, you first look for a systematic review. You search the Cochrane Database of Systematic Reviews using the terms fecal occult blood test and colon cancer. Your search identifies a systematic review by Towler and colleagues. 1 However, because there may be additional evidence that might influence your decision to recommend screening to this couple (e.g., the false-positive rate of the test, side effects of subsequent investigation and treatment, and associated costs), you also check for a clinical practice guideline. You go to the National Guideline Clearinghouse Web site ( enter the same keywords, and find eight guidelines, the most recent of which is by the American Gastroenterological Association (AGA), Colorectal Cancer Screening and Surveillance: Clinical Guidelines and Rationale Update Based on New Evidence. 2 The guideline is based on the same trials as the systematic review and also provides the additional information you were hoping to find. The full text is provided, so you print a copy to review. CONSEQUENCES OF SCREENING The best way to think about screening is as a therapeutic intervention. This clarifies the methodology required to support a policy of screening: randomized trials examining the effect of screening on patient-important outcomes. 3 6 Screening can be used to identify the presence of disease or the presence of risk factors for disease (e.g., cholesterol screening). Table 36-1 presents the possible consequences of screening. Some people will have true-positive results (a) with clinically significant disease (a 0 ); a proportion of this group

3 528 Unit VI Moving From Evidence to Action Table 36-1 Summary of Benefits and Risks of Screening by Underlying Disease State Reference Standard Results Disease or Risk Factor Present Disease or Risk Factor Absent Screening a 0 true positives or a 1 true positives b false positives test (significant disease) (inconsequential positive disease) Screening c 0 false negatives or c 1 false negatives d true negatives test (significant disease) (inconsequential negative disease) a 0, disease or risk factor that will cause symptoms in the future (significant disease); a 1, disease or risk factor asymptomatic until death (inconsequential disease); b, false-positive results; c 0, missed disease that will be significant in the future; c 1, missed disease that will be inconsequential in the future; d, true-negative results. Note: sensitivity = a/(a+c) and specificity = d/b+d. Modified and reproduced with permission of the American Medical Association from Barratt A, Irwig L, Glasziou P, et al. Users guides to the medical literature. XVII. How to use guidelines and recommendations about screening. JAMA. 1999;281: will benefit depending on the effectiveness of treatment and the severity of the detected disease. For example, children found to have phenylketonuria will experience large, long-lasting benefits of screening. Other people will have true-positive results with inconsequential disease (a 1 ); they may experience the consequences of labeling, investigation, and treatment for a disease or risk factor that otherwise never would have affected their lives. Consider, for instance, a man in whom screening reveals low-grade prostate cancer. This man will most likely die of coronary artery disease before his prostate cancer becomes clinically manifest. Thus, he may be advised to undergo unnecessary treatment and experience associated adverse effects. People with false-positive results (b) may be adversely affected by the risks associated with investigation of the screen-detected condition. People with false-negative results of clinically important disease (c 0 ) may experience harm if false reassurance results in delayed presentation or investigation of symptoms; some patients may be angry when they discover they have disease despite having negative screening test results. By contrast, patients with false-negative results with inconsequential disease (c 1 ) are not harmed by their disease being missed because it was never destined to affect them. Patients with true-negative results (d) may experience the benefits associated with an accurate reassurance of being disease free, but they may also experience the inconvenience, cost, and anxiety associated with screening. The longer the gap is between possible detection and clinically important consequences, the greater will be the number of people in the inconsequential disease category (a 1 ). When screening for risk factors, very large numbers of people need to be screened and treated to prevent one adverse event years later. 7 Thus, most people found to have

4 Recommendations About Screening Chapter a risk factor at screening will be treated for inconsequential disease. Table 36-2 summarizes the criteria for evaluating a study about screening. ARE THE RECOMMENDATIONS VALID? Is There Randomized Trial Evidence that Earlier Intervention Works? Guidelines recommending screening are on strong ground if they are based on randomized controlled trials that compare screening with conventional care. In the past, many screening programs, some of them effective (e.g., screening for cervical cancer and for phenylketonuria), were implemented on the basis of observational data. When the benefits are enormous and the disadvantages are minimal, randomized trials are not needed. More often, however, the benefits and risks of screening are balanced more evenly. In these situations, observational studies of screening may be misleading. Survival, as measured from the time of diagnosis, may be increased not because patients live longer, but because screening lengthens the time that they know they have a disease (lead-time bias). Patients whose disease is discovered by screening also may appear to live longer because screening tends to detect slowly progressing disease, yet it often misses rapidly progressive disease that becomes symptomatic between screening rounds (length-time bias). Therefore, unless the evidence of benefit is overwhelming, randomized trial assessment is required. Investigators may choose one of two study designs to test the impact of a screening process. Trials may assess the entire screening process (early detection and early intervention; Figure 36-1A), in which case people are randomized to be screened and treated if early abnormality is detected or not screened (and treated only if symptomatic disease occurs). Trials of mammographic screening have used this design Alternatively, all participants may undergo screening, and those with positive results can be randomized to be treated or not treated (Figure 36-1B). If those who receive treatment do better than those who do not, then one can conclude that early treatment has provided some benefit. Investigators usually Table 36-2 Users Guides for an Article About Screening Are the Recommendations Valid? Is there randomized trial evidence that earlier intervention works? Were the data identified, selected, and combined in an unbiased fashion? What Are the Recommendations? What are the benefits? What are the risks? Can I Apply the Recommendations to Patient Care? How do benefits and risks compare in different people and with different screening strategies? What is the impact of individuals values and preferences? What is the impact of uncertainty associated with the evidence? What is the cost-effectiveness?

5 530 Unit VI Moving From Evidence to Action A Randomize B Screen Screen No screen Early disease or risk factor detected No disease or risk factor detected Treat early disease Randomize Treat at usual time of presentation Treat early disease or risk factor Treat at usual time of presentation Outcome Outcome Outcome Outcome Figure Designs for randomized controlled trials of screening. A, Randomized controlled trial can assess the entire screening process, in which case participants are randomized to be screened (and treated) or not screened. B, Alternatively, everyone can participate in the screening, and those with positive results are randomized to be treated or not treated. (Modified and reproduced with permission of the American Medical Association from Barratt A, Irwig L, Glasziou P, et al. Users guides to the medical literature. XVII. How to use guidelines and recommendations about screening. JAMA. 1999;281: ) use this study design when screening detects factors that increase the risk of disease rather than the disease itself. Tests of screening programs for hypertension and high cholesterol have used this design. 11,12 The principles outlined in this chapter apply to both of these study designs (see Figure 36-1) when used to address screening issues. Regardless of which design is used (see Figure 36-1), a successful outcome of screening depends on optimal, or at least appropriate, application of testing and treatment after a positive screening test. One way that investigators can deal with this issue is to include recommendations for the investigative tests and interventions to be delivered if the target condition is detected. The limitation of this approach is that it may not simulate usual clinical practice and thus may limit the applicability of the results. An alternative is to allow clinicians to manage patients as they ordinarily would and document the investigative tests and interventions they use. Without such monitoring, the clinical community may be unaware that the reason screening failed to improve outcome was because of suboptimal management of patients with positive screening results.

6 Recommendations About Screening Chapter Were the Data Identified, Selected, and Combined in an Unbiased Fashion? As is true for all systematic reviews and guidelines, developers must specify the inclusion and exclusion criteria for the studies they choose to consider, conduct a comprehensive search, and assess the methodological quality of the studies they include. Using the Guide In their systematic review, Towler and colleagues 1 identified four randomized controlled trials that evaluated the effectiveness of screening with the FOBT Hemoccult Three trials randomly allocated individuals or households identified from general practitioner records or population registers to invitation to screening with Hemoccult or control groups, and one trial 13 allocated volunteers to screening or control groups. Meta-analysis of the results of the four randomized controlled trials showed that those allocated to screening had a 16% reduction in the relative risk of dying of colorectal cancer (relative risk, 0.84; 95% confidence interval, 0.77 to 0.93). The AGA guideline 2 states that three randomized controlled trials (all included in the systematic review) showed that testing of two samples from each of three consecutive stools for the presence of occult blood using a guaiac-impregnated slide test reduced the risk of death from colorectal cancer. One of the trials included in the systematic review 16 was not cited in the AGA guideline, possibly because the authors had not yet published mortality data but had provided these data for the meta-analysis via personal communication. After completion of the systematic review, investigators of one of the trials 13 reported an 18-year follow-up of study participants in which they found that FOBT screening every other year reduced colorectal cancer mortality by 21%. 17 Towler and colleagues 1 searched for published and unpublished trials and assessed the quality of individual trials using criteria recommended by the Cochrane Collaboration. 18 The investigators abstracted data from the trials and combined them in a meta-analysis on an intention-to-screen basis. For the AGA guideline, 2 panel members updated the original guideline 19 by conducting literature searches, preparing evidence tables to summarize scientifically strong studies that were relevant to colorectal cancer screening and surveillance, and circulating the tables to the entire panel for comments. The panel then met to critique the new evidence and used a consensus process to draft guidelines. WHAT ARE THE RECOMMENDATIONS? A good guideline should summarize the trial evidence about the benefits and risks of a screening program, for example, in a balance sheet. 20 The guideline should also provide information about how the benefits and risks might vary in population subgroups and with different screening strategies.

7 532 Unit VI Moving From Evidence to Action What Are the Benefits? Which outcomes need to be measured to estimate the benefits of a screening program? Some of the people who test positive will experience a reduction in mortality or an increase in quality of life. The benefit can be estimated as an absolute risk reduction (ARR) or a relative risk reduction (RRR) in adverse outcomes such as mortality (or an absolute benefit increase [ABI] or a relative benefit increase [RBI] in positive outcomes such as improved quality of life) (see Chapter 27, Measures of Association). Briefly, the ARR depends on the baseline risk of disease and thus presents a more realistic estimate of the size of the mortality benefit. By contrast, the RRR is independent of baseline risk and may provide a misleading impression of benefit (Table 36-3). The number of people needed to screen to prevent an adverse outcome is another way of representing the benefit of screening (see Chapter 27, Measures of Association, and Chapter 32, Number Needed to Treat). When the benefit is a reduction in mortality, we would like to see a reduction in both disease-specific mortality and total mortality. However, because the target condition is typically only one of many causes of death, even important reductions in disease-specific mortality are unlikely to result in statistically significant reductions in total mortality (i.e., mortality from any and all possible causes). In some conditions with high mortality rates, it may be reasonable to expect reductions in both total and disease-specific mortality. An example is screening and treatment for high cholesterol in people who already have symptomatic heart disease. In this instance, the risk of death from heart disease is high and is the most likely cause of death. Meta-analyses have shown significant effects of screening and treatment on both disease-specific and total mortality. 21 For the most part, we will have to be satisfied with demonstrated reductions in disease-specific mortality, although it is reassuring if data show no increase in total mortality. In addition to prevention of adverse outcomes, people may also regard knowledge of the presence of an abnormality as a benefit, as in antenatal screening for Down syndrome. Another potential benefit of screening comes from the reassurance afforded by Table 36-3 Comparison of Data Presented as Relative and Absolute Risk Reductions and Number Needed to Screen With Varying Baseline Risks of Disease and Constant Relative Risk Baseline Risk (Risk in Risk in Unscreened Screened Relative Risk Absolute Risk Number Needed Group) Group Reduction Reduction to Screen 4% 2% 50% 2% 50 2% 1% 50% 1% 100 1% 0.5% 50% 0.5% % 0.05% 50% 0.05% 2000 Modified and reproduced with permission of the American Medical Association from Barratt A, Irwig L, Glasziou P, et al. Users guides to the medical literature. XVII. How to use guidelines and recommendations about screening. JAMA. 1999;281:

8 Recommendations About Screening Chapter a negative test, particularly in people who feel anxious because a family member or friend has developed the target condition or because of discussion in the popular media. However, a person s self-perception of being at risk can be enhanced rather than reduced by testing. When people experience anxiety as a result of publicity surrounding the screening program itself, we would not view anxiety reduction as a benefit. For example, assume that women are not anxious about breast cancer. However, extensive publicity about a new screening program for breast cancer causes them to become anxious. The screening program should not be credited with achieving a benefit if women s anxiety generated by the publicity of the screening test decreases after negative screening test results. Testing for fecal occult blood can be done using guaiac-based or immunochemical tests, both of which can detect blood in the stool. The sensitivity of guaiac-based tests is increased if the test slide is rehydrated with a few drops of water before adding the hydrogen peroxide reagent. However, although rehydration increases sensitivity, the readability of the test is unpredictable, and rehydration substantially increases the false-positive rate. Because elements of an ordinary diet can cause false-positive reactions of guaiac-based tests, the person being tested may be asked to restrict intake of red meat and certain vegetables. The AGA guideline 2 reports that offering yearly FOBT with rehydration reduced colorectal cancer deaths by 33% after 13 years; biennial testing reduced colorectal cancer deaths by 15% and 18% after 7.8 and 10 years, respectively, without rehydration 14,15 and 21% at 18 years with rehydration. 17 The guideline recommends against the use of rehydration for the reasons cited earlier. An estimate of the uncertainty associated with these RRRs (e.g., the 95% confidence interval around a pooled RRR) would help readers to appreciate the range within which the true RRR plausibly lies. Based on a computer simulation using data from the original AGA guideline for annual screening with FOBT, 19 and assuming 100% participation, screening of 100,000 people beginning at age 50 years and continuing until age 85 or death would result in a reduction of 1330 deaths (13.3 per 1000) from colon cancer (Table 36-4). 22 What Are the Risks? Among those who test positive, adverse consequences may include the following: 1. Complications arising from investigation 2. Side effects of treatment 3. Unnecessary treatment of persons with true-positive results but inconsequential disease 4. Adverse effects of labeling or early diagnosis 5. Anxiety generated by investigations and treatment 6. Costs and inconvenience incurred during investigations and treatment The AGA guideline 2 reports that most people who test positive do not have colorectal neoplasia (i.e., have false-positive test results) and thus undergo the discomfort, cost, and risk of colonoscopy without benefit. In the trials, only 2% to 6% of those who tested positive actually had colon cancer. Thus, for every 100 participants who have a positive test result, only 2 to 6 will have cancer, but all 100 will be exposed to colonoscopy and its attendant risks (see Table 36-4). Although colonoscopies will reveal few cancers, they will show many polyps (25% of people aged 50 years or older have polyps, some of which will be judged to need removal, depending on their size). Part of the benefit of screening will come from removal of the small proportion of polyps that would have

9 534 Unit VI Moving From Evidence to Action Table 36-4 Clinical Consequences for 1000 People Entering a Program of Annual Fecal Occult Blood Test Screening for Colorectal Cancer at Age 50 Years and Remaining in it Until Age 85 or Death Number of Events Clinical Consequences in 1000 People Risks Screening tests 27,030 Diagnostic evaluations (by colonoscopy) 2263 False-positive screening tests 2158 Deaths from colonoscopy complications 0.5 Bowel perforations from colonoscopy 3 Major bleeding episodes from colonoscopy 7.4 Minor complications from colonoscopy 7.7 Benefits Deaths averted 13.3 Years of life saved Years of life gained per person whose cancer 9.3 death was prevented (Data from Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale update based on new evidence.gastroenterology. 2003;124: ) (Modified and reproduced with permission of the American Medical Association from Barratt A, Irwig L, Glasziou P, et al. Users guides to the medical literature. XVII. How to use guidelines and recommendations about screening. JAMA. 1999;281: ) progressed to invasive cancer. Part of the risk of screening will come from regular colonoscopies that are recommended for people who have had benign or inconsequential polyps removed. The AGA guideline 2 includes certain recommendations to reduce the false-positive rate, including avoiding rehydration when examining stools and restricting diet for the more sensitive guaiac-based tests. Among those who test negative, adverse consequences may include the following: 1. Anxiety generated by the screening test (waiting for result) 2. False reassurance (and delayed presentation of symptomatic disease later) 3. Costs and inconvenience incurred during the screening test According to the AGA guideline, 2 the sensitivity of a single FOBT is low, ranging from 30% to 50%. Patients who present with symptoms after a false-negative result may experience a sense of anger and betrayal that they would not suffer in the absence of a screening program. Using computer simulation, the original AGA guideline 19 presents data on the frequency of some of these risks. Table 36-4 summarizes data for 1000 people, 50 to 85 years of age, who participate in annual screening by FOBT. The model assumes that those who test positive undergo colonoscopy. We now know the magnitude of both benefits and risks (as presented in Table 36-4). This balance sheet tells us that screening 1000 people annually with FOBT from age

10 Recommendations About Screening Chapter ,030 annual FOBT screens in 1000 people aged 50 years until age 85 years 2263 colonoscopies 2158 no cancer 18.6 complications 0.5 death 3.0 perforations 7.4 major hemorrhages 7.7 minor hemorrhages 105 cancers 28.7 deaths 63.0 usual survivors* 13.3 extra survivors Figure Clinical consequences for 1000 people in a program of annual fecal occult blood test screening for colorectal cancer. FOBT, Fecal occult blood test *Usual survivors are those who would have survived with or without screening Extra survivors are those in whom the earlier detection of cancer averts death. (Data from Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale update based on new evidence. Gastroenterology. 2003;124: Modified and reproduced with permission of the American Medical Association from Barratt A, Irwig L, Glasziou P, et al. Users guides to the medical literature. XVII. How to use guidelines and recommendations about screening. Evidence-Based Medicine Working Group. JAMA. 1999;281: ) 50 years will prevent 13.3 deaths from colorectal cancer but will cause 0.5 deaths from complications of investigation and surgery. There will also be 10.4 major complications (perforations and major bleeding episodes) and 7.7 minor complications. The authors provide no data on anxiety, but we can assume that some people will feel anxious before colonoscopy. Figure presents these data as a flow diagram.

11 536 Unit VI Moving From Evidence to Action These data assume that the screening programs will deliver the same magnitude of benefits and risks as found in randomized controlled trials, but this will be true only if the programs are delivered to the same standard of quality as those in the trials. Otherwise, the benefits will be smaller, and the risks will be greater. CAN I APPLY THE RECOMMENDATIONS TO PATIENT CARE? How Do Benefits and Risks Compare in Different People and With Different Screening Strategies? The AGA guideline 2 recommends that clinicians offer screening for colorectal cancer to men and women at average risk beginning at age 50 years. The authors of the guideline recommend any one of several screening strategies, including FOBT, sigmoidoscopy, combined FOBT and flexible sigmoidoscopy, colonoscopy, and double-contrast barium enema, because no single test is unequivocally superior and giving patients a choice allows them to apply personal preferences. In relation to FOBT, the authors of the guideline recommend annual screening. The magnitude of benefits and adverse consequences will vary in different patients and with different screening strategies, as the following discussion reveals. Risk for Disease Assuming that the RRR is constant over a broad range of disease risk, benefits will be greater for people at higher risk for disease. For example, mortality from colorectal cancer increases with age, and the mortality benefit achieved by screening increases accordingly (Figure 36-3, top). 22 However, life-years lost to colorectal cancer are related to both the age at which mortality is highest and the length of life still available. Thus, the number of life-years that can be saved by colorectal cancer screening increases with age to about 75 years and then decreases again as life expectancy declines (Figure 36-3, bottom). 22 The number of deaths averted by screening over 10 years for those aged 40, 50, and 60 years at first screening (0.2, 1.0, and 2.4 per 1000 people, respectively 1 ) reflects these differences. Because of greater benefits, it may be rational for a person aged 60 years to decide that screening is worthwhile, whereas a person aged 40 years (or 80 years) with smaller potential benefits could decide that it is not worthwhile. Risk for disease and therefore the benefits of screening may be increased by other factors, such as family history of disease. The AGA guideline 2 reports that people with a first-degree relative (parent, sibling, or child) or two second-degree relatives (grandparents, aunts, and uncles) with colorectal cancer should be advised to begin having colonoscopies at age 40 years. This recommendation is based on their estimate that the incidence of colorectal cancer in people aged 40 years who have a first-degree relative with colorectal cancer is comparable to that of people aged 50 years who do not have a family history of disease. Screening Interval As the screening interval is shortened, the effectiveness of a screening program will tend to improve, although there is a limit to the amount of improvement that is possible. For example, screening twice as often could theoretically double the relative mortality reduction obtained by screening, but in practice, the effect is usually much less. Cervical

12 Recommendations About Screening Chapter Mortality per 1000 per year Age, years 25 Life-years lost per Age, years Figure Mortality from colorectal cancer and years of life lost due to colorectal cancer with and without screening. Top, Mortality from colorectal cancer. Bottom, Life-years lost due to colorectal cancer. Broken lines indicate with screening, solid lines without screening. (Data from Towler BP, Irwig L, Glasziou P, Weller D, Kewenter J. Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev. 2000;(2):CD ) (Modified and reproduced with permission of the American Medical Association from Barratt A, Irwig L, Glasziou P, et al. Users guides to the medical literature. XVII. How to use guidelines and recommendations about screening. JAMA. 1999;281: )

13 538 Unit VI Moving From Evidence to Action cancer screening, for instance, may reduce the incidence of invasive cervical cancer by 64%, 84%, and 94% if screening is conducted at 10-year, 5-year, and 1-year intervals, respectively. 23 The frequency of risks also will increase with more frequent screening, potentially in direct proportion to the frequency of screening. Thus, we will see diminishing marginal return as the screening interval is shortened. Ultimately, the marginal risks will outweigh the marginal benefits of further reductions in the screening interval. The AGA guideline recommends yearly screening with FOBT using a guaiac-based test with dietary restriction or an immunochemical test without dietary restriction. Test Characteristics If the sensitivity of a new test is greater than that of the test used in the trials and if it detects significant disease earlier, the benefit of screening will increase. However, it may be that the new, apparently more sensitive, test is detecting more cases of inconsequential disease (e.g., more low-grade prostate cancers or more low-grade cervical epithelial abnormalities 24 ), which will increase the potential for risk. Conversely, if specificity is improved and testing produces fewer false-positive results, net benefit will increase, and the new test may be useful in groups in which the old test was not as useful. Ideally, clinicians should look to randomized trials of the new test compared with the old test (see Chapter 6, Diagnosis). However, new tests often appear in profusion, and randomized trials are expensive and often require long follow-up periods. Being pragmatic, we accept that if trials have shown that earlier detection reduces the risk of adverse effects, a comparison of a new and an old test only needs to examine test characteristics. In the case of colorectal cancer screening, randomized trials have shown reduced mortality after early detection by FOBT, and thus, we may assume that early detection works in principle. It seems reasonable to assume that early detection using other methods, such as flexible sigmoidoscopy, will also reduce mortality from colorectal cancer even though there are no published reports of randomized trials of the effects of screening with flexible sigmoidoscopy on mortality. This theoretical approach is supported by the available observational data, which indicate benefits from other methods of screening for colorectal cancer. 2 What Is the Impact of Individuals Values and Preferences? The ways and extent to which people value the benefits and risk of screening can vary. For example, pregnant women who are considering fetal screening for Down syndrome may make different choices depending on the value they place on having a child with Down syndrome, as opposed to the risk of iatrogenic abortion from amniocentesis. 25 Perception plays a large role. Persons who choose to participate in screening programs are benefiting (in their view) from screening, and others are benefiting (in their view) from not participating. Individuals can make the right choice for themselves only if they have access to high-quality information about the benefits and risks of screening and if they are able to weigh that information. This probably will require better educational and decision-support materials than traditionally have been provided, although some examples of such materials are already available. 26,27

14 Recommendations About Screening Chapter What Is the Impact of Uncertainty Associated With the Evidence? Uncertainty about the benefits and risks of screening will always exist. The 95% confidence intervals around the estimates of each benefit and adverse consequence provide an indication of the amount of uncertainty for each estimate. Studies with small sample sizes will have wider confidence intervals, and nurses should explain to potential screening participants that the magnitude of benefits or risks could be considerably smaller or greater than the point estimate. What Is the Cost-effectiveness? Although clinicians will be most interested in the balance of benefits and risks for individual patients, policy makers must consider issues of cost-effectiveness and local resources in their decisions (see Chapter 18, Economic Evaluation). The AGA guideline 2 reports that cost-effectiveness analyses have shown that each of the screening strategies recommended (FOBT, flexible sigmoidoscopy, colonoscopy, and double-contrast barium enema) costs less than US$25,000 per year of life saved This cost per year of life saved is within the range of what is currently paid in some countries for the benefits of other screening programs, such as mammographic screening for women aged 50 to 69 years (estimated at US$21,400 per life-year saved 32 ), ultrasound screening for patients with carotid stenosis (estimated incremental cost per quality-adjusted life-year gained of US$39, ), and ultrasound screening for abdominal aortic aneurysm in men aged 60 to 80 years (estimated US$41,550 per life-year gained 34 ). Costs increase out of proportion to benefits with shorter intervals between screening examinations. Clinical Resolution A clinical practice guideline should quantify the benefits of screening according to age so that accurate information can be provided to individual patients about the potential benefits of screening. The AGA guideline does not provide age-specific mortality reductions attributable to screening, and therefore, you cannot easily quantify the benefits for the couple in your practice. Based on the AGA guideline, you can say with confidence that screening a group of 1000 people with FOBT beginning at age 50 years and continuing annually to age 85 will avert about 13 deaths from colorectal cancer. We know from the systematic review by Towler and colleagues 1 that the mortality benefit for people 40 to 50 years of age is about 0.2 to 1.0 deaths averted over 10 years per 1000 people screened. The AGA guideline cites a study of screening colonoscopy 35 in people 40 to 49 years of age that confirms that colorectal cancers are uncommon in this age group and estimates that at least 250 persons, and perhaps 1000 or more, would need to be screened to detect a single case of cancer in this age group. Based on these data and given the couple s age, negative family history, and lack of symptoms, you explain that the absolute benefit of screening with FOBT at their age is extremely small. Next, you outline the potential risks of screening. According to the computer simulation based on the original AGA guideline, 19 for every 1000 people screened annually with FOBT, there will be 0.5 deaths, 3.0 bowel perforations, 7.4 major bleeding episodes, and 7.7 minor complications related to colonoscopy. In addition, issues of cost, inconvenience, and anxiety should be considered. Continued

15 540 Unit VI Moving From Evidence to Action Clinical Resolution cont d The couple must determine whether the benefit of reduced risk of death from colorectal cancer is worth the potential adverse consequences such as the inconvenience and potential complications of colonoscopy, the adverse effects of early treatment for colon cancer, side effects of treatment, and the anxiety generated by the investigations and treatment. If the couple feels that they are unable to weigh the benefits and risks, you could help them to clarify their values about the possible outcomes. For example, if they are not bothered by the prospect of colonoscopy, they would probably choose to be screened. However, if either of them places a high value on avoiding colonoscopy now, he or she may prefer to reconsider screening in a few years, when the benefits will be greater than they are at the present time. REFERENCES 1. Towler BP, Irwig L, Glasziou P, Weller D, Kewenter J. Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev. 2000;(2):CD Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale update based on new evidence. Gastroenterology. 2003;124: Wilson JMG, Jungner G. Principles and Practice of Screening for Disease. Geneva: World Health Organization; Gray JA. Evidence-Based Healthcare. London: Churchill Livingstone; Sackett DL, Haynes RB, Tugwell P. Clinical Epidemiology: A Basic Science for Clinical Medicine. 2nd ed. Boston: Little, Brown; Welch HG, Black WC. Evaluating randomized trials of screening. J Gen Intern Med. 1997;12: Khaw KT, Rose G. Cholesterol screening programmes: how much potential benefit? BMJ. 1989;299: Andersson I, Aspegren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: the Malmo mammographic screening trial. BMJ. 1988;297: Tabar L, Fagerberg G, Duffy SW, Day NE. The Swedish two county trial of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Community Health. 1989;43: Roberts MM, Alexander FE, Anderson TJ, et al. Edinburgh trial of screening for breast cancer: mortality at seven years. Lancet. 1990;335: Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial: risk factor changes and mortality results. JAMA. 1982;248: Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317: Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med. 1993;328: Hardcastle JD, Chamberlain JO, Robinson MHE, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet. 1996;348: Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet. 1996;348: Kewenter J, Brevinge H, Engaras B, Haglind E, Ahren C. Results of screening, rescreening, and follow-up in a prospective randomized study for detection of colorectal cancer by fecal occult blood testing. Results for 68,308 subjects. Scand J Gastroenterol. 1994;29: Mandel JS, Church TR, Ederer F, Bond JH. Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood. J Natl Cancer Inst. 1999;91:

16 Recommendations About Screening Chapter Mulrow CD, Oxman AD, eds. Critical Appraisal of Studies. Cochrane Collaboration Handbook (updated September 1997); section 4. In: The Cochrane Library (database on disk and CD-ROM). Cochrane Collaboration. Oxford: Update Software; 1997, issue Winawer SJ, Fletcher RH, Millar L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology. 1997;112: Eddy DM. Comparing benefits and harms: the balance sheet. JAMA. 1990;263:2493, 2498, Barratt A, Irwig L. Is cholesterol testing/treatment really beneficial? Med J Aust. 1993;159: Barratt A, Irwig L, Glasziou P, et al. Users guides to the medical literature. XVII. How to use guidelines and recommendations about screening. JAMA. 1999;281: IARC Working Group on Evaluation of Cervical Cancer Screening Programmes. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. Br Med J Clin Res Ed. 1986;293: Raffle AE. New tests in cervical screening. Lancet. 1998;351: Fletcher J, Hicks NR, Kay JD, Boyd PA. Using decision analysis to compare policies for antenatal screening for Down s syndrome. BMJ. 1995;311: Wolf AM, Nasser JF, Wolf AM, Schorling JB. The impact of informed consent on patient interest in prostate-specific antigen screening. Arch Intern Med. 1996;156: Flood AB, Wennberg JE, Nease RF Jr, Fowler FJ Jr, Ding J, Hynes LM, for the Prostate Patient Outcomes Research Team. The importance of patient preference in the decision to screen for prostate cancer. J Gen Intern Med. 1996;11: Wagner JL, Tunis S, Brown M, Ching A, Almeida R. Cost-effectiveness of colorectal cancer screening in average-risk adults. In: Young G, Rozen P, Levin B, eds. Prevention and Early Detection of Colorectal Cancer. London: WB Saunders; 1996: Frazier AL, Colditz GA, Fuchs CS, Kuntz KM. Cost-effectiveness of screening for colorectal cancer in the general population. JAMA. 2000;284: Loeve F, Brown ML, Boer R, van Ballegooijen M, van Oortmarssen GJ, Habbema JD. Endoscopic colorectal cancer screening: a cost-saving analysis. J Natl Cancer Inst. 2000;92: Sonnenberg A, Delco F, Inadomi JM. Cost-effectiveness of colonoscopy in screening for colorectal cancer. Ann Intern Med. 2000;133: Salzmann P, Kerlikowske K, Phillips K. Cost-effectiveness of extending screening mammography guidelines to include women 40 to 49 years of age. Ann Intern Med. 1997;127: Yin D, Carpenter JP. Cost-effectiveness of screening for asymptomatic carotid stenosis. J Vasc Surg. 1998;27: Frame PS, Fryback DG, Patterson C. Screening for abdominal aortic aneurysm in men ages 60 to 80 years: a cost-effectiveness analysis. Ann Intern Med. 1993;119: Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF. Results of screening colonoscopy among persons 40 to 49 years of age. N Engl J Med. 2002;346: