Colorectal Cancer: Have We Identified an Effective Screening Strategy? GARY D. FRIEDMAN, MD, MS, JOSEPH V. SELBY, MD, MPH Three currently used screening methods are aimed at detecting colorectal cancer when it is asymptomatic a n d curable, and at detecting polyps so that they can be removed before they can progress to cancer. Digital rectal examinations are relatively cheap and easy but can detect only a small f r a c t i o n o f large-bowel cancers. Sigmoidoscopy is more sensitive, but its low acceptability to patients has been only partially mitigated by the introduction o f the 35-cm flexible instrument. Fecal occult blood testing has limited sensitivity because blood f r o m cancers a n d polyps is neither continuously shed n o r uniformly distributed in feces; specificity and positive predictive value are also low because o f other sources o f blood in the s t o o l P r u d e n t judgment suggests that all o f these screening tests may p r e v e n t death f r o m colorectal cancer in some patients. However, none has been p r o v e n effective in general use by well-controlled studies. C a s e - c o n t r o l studies can provide timely a n d valuable new evidence in this regard; the authors" investigations in progress are described. The current lack o f strong evidence in support o f these screening tests should not be interpreted as evidence against their use. Key w o r d s : cancers; neoplasms; colon; rectum; screening. J GEN INTERN MED 1990; 5(suppl):s23-S27. CANCER OF THE LARGE BOWEL is the second m o s t c o m m o n of the potentially fatal cancers in the United States, accounting for 14% of cancer-related deaths in m e n and 15% in w o m e n . The five-year relative survival rate is about 85% in cases w h e r e it is diagnosed w h i l e localized, b u t only 34% of all cases are p i c k e d u p in this favorable stage. Most of these cancers have already spread through or b e y o n d the b o w e l wall w h e n detected, and only 38% of victims survive for five years after diagnosis in these m o r e advanced stages. Altogether, 1 5 1 , 0 0 0 n e w cases of colorectal cancer and 6 1 , 0 0 0 deaths from colorectal cancer are estimated to have o c c u r r e d in 1989. Among m e n the colorectal cancer death rate has changed very little since 1950, whereas a m o n g w o m e n there has b e e n a slow, steady decline. Although the relative five-year survival rate has s h o w n steady i m p r o v e m e n t since 1960, overall it is still only 54% in whites and 49% in blacks, x Given the seriousness of colorectal cancer as a p u b l i c health p r o b l e m and the p o o r prognosis of this disease after it has spread, it is understandable that conReceived from the Division of Research, Kaiser Permanente Medical Care Program, Northern California Region, Oakland, California. Presented at the conference, Frontiers in Disease Prevention, The Johns Hopkins University, June 5 - 6, 1989. Supported by Grants #R01 CA 46569 and R35 CA 49761 from the National Cancer Institute. Address correspondence and reprint requests to Dr. Friedman: 3451 Piedmont Avenue, Oakland, CA 94611.
siderable effort has b e e n directed at early detection. Although evidence is a c c u m u l a t i n g that diet and other lifestyle attributes m a y be related to risk of this disease, w e are not likely to be able to p r e v e n t the vast majority of cases that will o c c u r in the n e x t decade b y any k n o w n or foreseeable method. Some individuals w i t h k n o w n predisposing factors, such as previous cancers or a d e n o m a t o u s polyps, familial polyposis syndromes, ulcerative colitis, or familial history of colorectal cancer d e v e l o p i n g at an early age, deserve close surveillance w i t h a systematic p r o g r a m of screening or even diagnostic tests such as colonoscopy. But, like m a n y other chronic diseases, colorectal cancer usually arises in middle-aged and elderly persons not otherwise k n o w n in advance to b e at increased risk. What screening tests are available for these p e o p l e and h o w effective are they in preventing death from this disease? There are three main screening modalities for colorectal cancer: digital rectal examination, sigmoidoscopy, and fecal occult b l o o d testing. These are listed and discussed in order of increasing portions of the large b o w e l in w h i c h they can detect tumors.
DIGITAL RECTAL EXAMINATION The digital rectal examination can detect p a l p a b l e lesions in the r e c t u m that are within r e a c h of the examining finger, those within a b o u t 7 c m of the anus. It is likely that the early detection of cancers b y application of this test in a s y m p t o m a t i c persons will p r e v e n t s o m e deaths f r o m colorectal cancer. However, there have b e e n no controlled studies demonstrating this to be the case. Additional features of the rectal examination that are often valued are that the prostate gland can b e examined and that the small stool s p e c i m e n that is usually obtained can be tested for occult blood. The rectal examination is t i m e - h o n o r e d and r e s p e c t e d b y the medical profession. This is reflected in the old joke regarding the definition of a c o n s u l t a n t - - the physician w h o is called in and p e r f o r m s the rectal examination. Disadvantages include the discomfort of the examination and the fact that only a small p r o p o r t i o n of all colorectal cancers, p r o b a b l y less than 10%, are within reach of the finger. In his recent review of screening tests, Dr. Paul Frame c o n c l u d e d that the disadvantages o u t w e i g h the advantages, and he r e c o m m e n d e d that the rectal e x a m i n a t i o n not be i n c l u d e d in periodic health c h e c k u p s for a s y m p t o m a t i c adults. 2 $Z3
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SIGMOIDOSCOPY Sigmoidoscopy permits visualization o f the r e c t u m and part of the sigmoid colon. On average, the old 25-cm rigid sigmoidoscopes w e r e inserted to a d e p t h of 20 cm. 3 The n e w e r flexible instruments are longer, usually either 35 c m or 60 cm. The 35-cm flexible sigmoidoscopes generally cause less discomfort and are m o r e a c c e p t a b l e to patients than either the 25-cm rigid or the 6 0 - c m flexible instruments. 3 During sigmoidoscopy, if colorectal p o l y p s are seen, they can be removed. Theoretically, s i g m o i d o s c o p y can p r e v e n t death from colorectal cancer by t w o distinct means. One, as w i t h other screening tests, involves the detection of cancers early e n o u g h that they can b e r e m o v e d before t h e y metastasize. The other involves the removal o f p r e m a l i g n a n t p o l y p s before they progress to cancer. While direct p r o o f is lacking, m u c h circumstantial evid e n c e supports the v i e w that most cancers of the large b o w e l arise in polyps. 4 The efficacy of s i g m o i d o s c o p y has b e e n studied considerably m o r e than that of the rectal examination. T w o reports, w h i c h w e believe are m e r e l y descriptive, described the follow u p of large groups of p e o p l e w h o received sigmoidoscopy, in studies that w e r e not w e l l controlled. One, f r o m the Strang Cancer Prevention Clinic in N e w York, s u m m a r i z e d the results of 47,091 s i g m o i d o s c o p i c examinations p e r f o r m e d o n 2 6 , 1 9 6 patients, 88.5% of w h o m w e r e asymptomatic, s Some examinations included fecal occult b l o o d testing. The colorectal cancer detection rate was 2.2 p e r 1,000 examinations, with 76.5% of cancers discovered b y sigmoidoscopy. Eighty-one p e r c e n t of the cases w e r e localized (Dukes' stage A or B) and the 15-year survival rate was 88%. Both the stage distribution and the survival rate w e r e m u c h better than those f o u n d in groups of cases d e t e c t e d clinically after s y m p t o m s occurred. Another oft-quoted descriptive study was cond u c t e d at the University of Minnesota's Cancer Detection Center, w h e r e a g r o u p of 2 1 , 1 5 0 persons, aged 45 years and over, each received an initial sigmoidoscopy, and as a g r o u p received 9 2 , 6 5 0 m o r e such p r o c e d u r e s annually.6, 7 After removal of 27 cancers f o u n d b y the initial examinations, only 13 cancers w e r e discovered at the annual follow u p s - - 12 stage A and one stage B. T w o of the 13 patients died, one p e r i o p e r a t i v e l y and one of pancreatic cancer. Besides noting this very favorable stage distribution, the researchers c o m p a r e d the 13 cases w i t h 90 e x p e c t e d in a p o p u l a t i o n of this size based on incidence rates for the state of Minnesota. Although striking, this c o m p a r i s o n is i n a p p r o p r i a t e for at least three reasons: 1) the 27 cancers d e t e c t e d initially w e r e not p r e v e n t e d and should have b e e n included in the incidence figures at the clinic (this was previously p o i n t e d out b y MorrisonS); 2) the authors included only those person-years of follow u p that e n d e d in another s i g m o i d o s c o p y - - i f a cancer w e r e
d e t e c t e d clinically six m o n t h s after a s i g m o i d o s c o p y and the patient d r o p p e d out of the screening program, that cancer w o u l d not be counted; and 3) persons returning for r e p e a t e d sigmoidoscopies w e r e a self-selected g r o u p w h o s e risk of death from colorectal cancer might have been, w i t h o u t sigmoidoscopy, m u c h different from that of the general population. At the Kaiser Permanente Medical Care Program, Northern California Region, w e have c o n d u c t e d a controlled trial of multiphasic screening that has b e e n cited b y authoritative groups as high-grade e v i d e n c e for the efficacy of sigmoidoscopy. 9-11 Although this conclusion is not justified, it is instructive to r e v i e w the evidence and see h o w easily such misinterpretations can arise. The Multiphasic Evaluation Study involved the essentially r a n d o m selection in 1964 of two groups of about 5,000 long-term subscribers to o u r health care plan, aged 3 5 - 5 4 years at entry, and residing in the areas served b y our Oakland and San Francisco facilities. Those in the study g r o u p w e r e urged to receive multiphasic health c h e c k u p s (MHCs) annually t h r o u g h mid-1980, and those in the control g r o u p w e r e not so urged although they c o u l d obtain such c h e c k u p s if they wished. As a result of this urging, the study g r o u p received considerably m o r e MHCs (mean----6.8, median = 6) than did the control g r o u p ( m e a n = 2.8, median = I ) . The two g r o u p s w e r e f o l l o w e d u p in similar fashion for mortality, disability, and o t h e r outcomes. One of the study's striking findings was that deaths from a g r o u p of " p o t e n t i a l l y p o s t p o n a b l e " causes, hypothesized in advance to be affected favorably b y MHCs, w e r e significantly (p = 0 . 0 1 ) f e w e r in the study g r o u p ( c u m u l a t i v e 16-year mortality rate = 1 5 . 0 / 1 , 0 0 0 ) than in the control g r o u p ( 2 1 . 5 / 1 , 0 0 0 ) . T h e " potentially p o s t p o n a b l e " disease making the largest contribution to this difference was colorectal cancer, with 12 study-group and 29 control-group deaths, t 2 The MHC consisted of a visit to an a u t o m a t e d laboratory, w h e r e a variety of screening tests w e r e performed, f o l l o w e d b y a physical examination, almost always by a physician during the study period. In the MHC laboratory, persons aged 40 years and o v e r w e r e advised to make an a p p o i n t m e n t for a screening sigmoidoscopy. Fecal occult b l o o d testing was not inc l u d e d in the MHC until mid- 1979, w h e n it was instituted at the Oakland facility. O t h e r c o m p o n e n t s of the MHC that might have led to the early detection of colorectal cancer w e r e the digital rectal e x a m i n a t i o n inc l u d e d in the physical examination, the h e m a t o l o g y tests that c o u l d detect anemia, and questionnaire items c o n c e r n i n g gastrointestinal symptoms. Given the likely l o w sensitivity and specificity o f these c o m p o n e n t s , it was natural to c o n c l u d e that s i g m o i d o s c o p y was responsible for the lives saved. In our reports 12. 13 w e w e r e conservative and careful not to assert this conclusion, ~4yet it must be admitted that until r e c e n t l y w e did
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not question or a t t e m p t to contradict the prevailing opinion. The turning point c a m e w h e n one of us (JVS) raised some questions a b o u t this conclusion, and w e carried out the additional analyses n e e d e d to answer these questions. 1s The questions were: 1 ) H o w m u c h of the reduction in mortality from colorectal cancer in the study g r o u p was due to a reduction in incidence and h o w m u c h was due to an i m p r o v e m e n t in stage distribution at the time of diagnosis? 2) What w e r e the m o d e s of discovery of all of the colorectal cancers, considering b o t h those within and those not within reach of the sigmoidoscope? and 3) H o w m u c h m o r e sigmoidosc o p y did the study g r o u p receive and c o u l d this difference have b e e n responsible for preventing the n u m b e r of deaths e x p e c t e d in the study group? In brief, w e r e v i e w e d all of the colorectal cancers that w e r e detected in the entire study population. We f o u n d that a higher p r o p o r t i o n of those in the study g r o u p w e r e detected b y s i g m o i d o s c o p y and that the s t u d y - c o n t r o l difference in mortality a p p l i e d chiefly to cancers located within reach of the sigmoidoscope. However, only one-third of the reduction in the study g r o u p ' s mortality was due to a lower case fatality rate. Two-thirds w e r e due to a reduction in incidence, w h i c h c o u l d not reasonably be attributable to p o l y p detection and removal because it o c c u r r e d equally in the two groups. Most striking was the small difference b e t w e e n the n u m b e r s of sigmoidoscopies received b y the two groups. Over a ten-year period, 30% of the study g r o u p and 25% of the control g r o u p had at least one. An excess of 929 MHC-related sigmoidoscopies in the study g r o u p was c o n t r i b u t e d by 279 persons w i t h a m e a n of 3.34 sigmoidoscopies each. Over half of this excess was attributable to only 78 persons w h o had five to ten examinations each. Calculations of the potential lives saved b y these additional sigmoidoscopies using local mortality rates and assuming that s i g m o i d o s c o p i c detection of a cancer always saved a life led to an estimate that only one death c o u l d have b e e n prevented. Most colorectal cancers in the two groups w e r e d e t e c t e d following the o c c u r r e n c e of symptoms. But, interestingly, even these w e r e diagnosed at a m o r e favorable stage, on average, in the study group. We susp e c t that the annual urging and greater n u m b e r of MHCs c o u l d have led the study g r o u p to be m o r e health-conscious or to notice s y m p t o m s earlier and thus c o u l d lead to earlier diagnosis and treatment. 15 It is n o w clear that there is no strong evidence f r o m controlled studies that s i g m o i d o s c o p i c screening prevents death from colorectal cancer. Yet it is quite reasonable to believe that this test does detect cancers in an early, curable form in s o m e a s y m p t o m a t i c persons and that lives are saved as a result. Even w i t h the flexible instrument, however, there is still an acceptability p r o b l e m . Many patients are not willing to undergo the p r o c e d u r e with either type of
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instrument. Note that in o u r study group, although 84% had at least one MHC (with f e w of these not receiving an MHC at age 40 or above), only 25% had an MHC-related (rigid) s i g m o i d o s c o p y and only 30% had any sigmoidoscopy. This affects not only the usefulness of sigm o i d o s c o p y as a screening test, but also our ability to evaluate it by a r a n d o m i z e d controlled trial. Poor compliance and, in absolute terms, the relatively l o w incidence of and mortality from colorectal cancers within reach of the s i g m o i d o s c o p e make it necessary to think in terms of several tens of thousands of subjects for such a trial. FECAL OCCULT BLOOD T E S T I N G Testing stool s p e c i m e n s for occult b l o o d is m u c h s i m p l e r and c h e a p e r than e n d o s c o p i c p r o c e d u r e s such as s i g m o i d o s c o p y and it holds the p r o m i s e of detecting cancers and polyps anywhere in the large bowel. Today guaiac-impregnated p a p e r slides are the most comm o n l y used version of the test. The patient is usually asked to a p p l y two samples each from stools passed on three consecutive occasions and these are later tested in the laboratory. Screening by fecal occult b l o o d testing has b e e n t h o r o u g h l y r e v i e w e d recently by Knight, Fielding, and Battista. a6 Their article is the source of m u c h of the information given below. The sensitivity of fecal occult b l o o d testing is limited by the fact that not all large b o w e l cancers and polyps b l e e d continuously, and b y the n o n u n i f o r m distribution of b l o o d in the feces. A normal person loses about 0.5 to 2.0 ml of b l o o d p e r day via the gastrointestinal tract. The H e m o c c u l t II test, n o w one of the most c o m m o n l y used, consistently yields positive results w i t h 20 ml of b l e e d i n g p e r day. The sensitivity to k n o w n cancers is r e p o r t e d to be 50% to 87%, whereas only a b o u t 25% of a d e n o m a s are detected: only those over 2 c m in diameter. The specificity and positive predictive value of fecal occult b l o o d testing are limited b y the fact that other conditions and certain medications can p r o d u c e gastrointestinal bleeding, and certain foods can produce false-positive reactions. Positive predictive value is about 10% or less for cancers and 30% or less for a d e n o m a t o u s polyps. Naturally, positive predictive value is increased w h e n screening is p e r f o r m e d in persons with a high p r e v a l e n c e of these conditions, such as the elderly. W h e n fecal occult b l o o d tests are positive, a costly and u n c o m f o r t a b l e w o r k u p is d e e m e d necessary. This usually includes a b a r i u m e n e m a (often w i t h air contrast), sigmoidoscopy, a n d / o r colonoscopy. But the l o w positive predictive value reflects the fact that most of these w o r k u p s do not reveal any cancers or polyps. Thus, undertaking this form of screening entails costs in terms of money, professional time, and patient time and discomfort, and rare b u t serious complications of the diagnostic tests (such as b o w e l p e r f o r a t i o n ) - - c o s t s considerably greater than those of the fecal o c c u l t
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b l o o d tests alone. There is also a c o m p l i a n c e p r o b l e m , but it is not nearly as great as that for sigmoidoscopy. Thus, screening b y this m e t h o d is still controversial. It holds the p r o m i s e of saving lives b y early detection, but this has yet to be d e m o n s t r a t e d in well-controlled studies. Five such studies are n o w u n d e r way, two in the United States and one each in Denmark, Great Britain, and Sweden. T e c h n o l o g i c advances m a y also i m p r o v e the effectiveness of fecal occult b l o o d testing. Quantitative rather than yes-or-no qualitative results can c o m e f r o m i m m u n o c h e m i c a l techniques, w h i c h have the advantage of being specific for h u m a n blood, and f r o m the H e m o Q u a n t test. Screening w i t h these m e t h o d s has not yet b e e n p u t into routine practice. O u r overall assessment of screening b y fecal occult b l o o d testing is similar to that for s i g m o i d o s c o p y D likely to save lives but as yet u n p r o v e n to do so.
A NEW CASE-CONTROL STUDY OF THESE SCREENING TESTS Although r a n d o m i z e d controlled trials p r o v i d e the most c o m p e l l i n g evidence of efficacT of screening tests, none directed at colorectal cancer screening has b e e n c o m p l e t e d , and the only ones in progress n o w c o n c e r n fecal occult b l o o d testing. As n o t e d above, rand o m i z e d controlled trials of s i g m o i d o s c o p y w o u l d entail formidable effort and cost. Properly c o n d u c t e d observational studies, either cohort or c a s e - c o n t r o l in design, can also provide useful data on efficacy. We have just b e g u n a c a s e - control study of the efficacy of e a c h of the three screening modalities in p r e v e n t i n g death from colorectal cancer. This is being c o n d u c t e d in the setting of the Kaiser Permanente Medical Care Program, Northern California Region, a health maintenance organization that has p r o v i d e d c o m p r e h e n s i v e inpatient and outpatient medical care, usually on a long-term basis, to a subscriber p o p u l a t i o n that n o w e x c e e d s 2.2 million. The organization's medical records p r o v i d e objective d o c u m e n t a t i o n of the r e c e i p t of these screening tests and the o c c u r r e n c e of cancer. In a c a s e - c o n t r o l study of a screening test, one identifies cases w i t h the stages or o u t c o m e s of the disease that the screening test is s u p p o s e d to prevent, and controls are representative of the underlying p o p u l a tion in w h i c h the cases occur. The controls n e e d not b e free of the disease, but the disease should not have r e a c h e d the m o r e undesirable stage or o u t c o m e that defines the case. Receipt of the screening tests b y the cases and controls is then ascertained. If the screening test has preventive efficacy, then it will have b e e n received by f e w e r of the cases than the controls. In other words, the cases will have had a deficit of these screening tests relative to c o m p a r a b l e persons in the general population. The main p r o b l e m in interpreting these c a s e -
control studies lies in the possibility of self-selection bias. Persons w h o later d e v e l o p or die f r o m the disease m a y have a different p r o p e n s i t y to be screened, quite i n d e p e n d e n t of w h e t h e r the screening does any good. For example, l o w e r s o c i o e c o n o m i c status is associated w i t h a higher incidence of cervical cancer and relatively less interest in obtaining health c h e c k u p s and Pap smears. Thus, a c a s e - c o n t r o l study of invasive or fatal cervical cancer m i g h t find f e w e r Pap smears a m o n g the cases even if Pap smears had no value in preventing invasive or fatal disease. On the o t h e r hand, one m i g h t suspect that persons with a family history of colorectal c a n c e r w h o are at h e i g h t e n e d risk might b e m o r e apt to u n d e r g o screening sigmoidoscopy. In this instance the o p p o s i t e bias c o u l d occur, w h e r e i n cases w o u l d have a relative excess of screening tests or at least sufficient additional screenings to mask a deficit reflecting efficacy. In these c a s e - control studies it is t e m p t i n g to select, as controls, persons w i t h the disease diagnosed at an early stage. The question to be answered m a y be stated as: "Let's see w h e t h e r p e o p l e w i t h the disease diagnosed early, and thus w i t h a better prognosis, have b e e n getting m o r e of the screening tests." This app r o a c h is almost guaranteed to p r o d u c e a favorable-appearing result. We can grant f r o m the start that the screening test picks u p the disease early, and this is all that such a c a s e - c o n t r o l c o m p a r i s o n can show. What w e w a n t to find out, however, is w h e t h e r the screening prevents or delays death or s o m e other o u t c o m e . This can be d e t e r m i n e d only b y c o m p a r i n g cases w h o have the o u t c o m e w i t h a representative g r o u p of controls w i t h o u t the o u t c o m e . C a s e - c o n t r o l studies of screening are complicated b y other subtle biases. One is the "healthyscreenee effect," first described b y Morrison. s This can c o m e into play if certain aspects of screening such as the f r e q u e n c y of the test or the r e c e n c y of the last test, w h i c h reflects frequency, are evaluated. People w h o screen negative one or m o r e times are b y this very process selected to b e at l o w risk for b e c o m i n g a case, because they are p r o v e n to be free of detectable preclinical disease. This differs from self-selection bias m e n t i o n e d above, as it is a result of the p r i o r screenings, not a predisposition to have them. It is m o r e akin to the " h e a l t h y - w o r k e r effect," in w h i c h the process of hiring and retaining e m p l o y e e s w e e d s out the less healthy. The theoretical aspects and pitfalls of c a s e control studies of screening have b e e n discussed by Morrison,S. 17 Weiss,iS Rhoads and Mills, 19 and Sasco, Day, and Walter. 2° O u r study is threefold. Rectal examinations have b e e n w i d e l y p e r f o r m e d in o u r program, so that w e are selecting subjects from the entire region. Cases will have had fatal rectal cancer located within 7 c m of the anus (estimated n u m b e r , 4 5 0 ) and one control p e r case
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w i l l b e c h o s e n . S c r e e n i n g s i g m o i d o s c o p y has b e e n regu l a r l y p e r f o r m e d at t h r e e o f o u r facilities (Hayward, O a k l a n d , a n d San F r a n c i s c o ) . Thus, cases w i l l have fatal c a n c e r s l o c a t e d w i t h i n 20 c m of t h e a n u s d i a g n o s e d at a n y of t h e t h r e e facilities ( e s t i m a t e d n u m b e r , 2 7 5 ) . Controls will be selected from among persons living in t h e r e s i d e n t i a l areas s e r v e d b y t h e s e facilities, f o u r p e r case. Fecal o c c u l t b l o o d t e s t i n g has b e e n u s e d w i d e l y i n our region but only since about 1979. Therefore, we w i l l c h o o s e as cases p e r s o n s w i t h fatal c a n c e r s diagn o s e d i n 1981 or later a n d l o c a t e d a n y w h e r e i n t h e large b o w e l ( e s t i m a t e d n u m b e r , 9 7 5 ) . C o n t r o l s w i l l b e s e l e c t e d f r o m t h e e n t i r e m e m b e r s h i p , o n e p e r case. M e d i c a l r e c o r d s w i l l b e r e v i e w e d to o b t a i n data o n t h e a d m i n i s t r a t i o n o f t h e s c r e e n i n g test o f i n t e r e s t u p to t e n years b e f o r e d i a g n o s i s of the c a n c e r , w i t h corres p o n d i n g t i m e i n t e r v a l s i n t h e c o n t r o l s . W e e x p e c t this s t u d y to b e c o m p l e t e d b y m i d - 1 9 9 1 .
CONCLUSION U n f o r t u n a t e l y , w e d o n o t yet k n o w w h e t h e r t h e r e is a n effective s c r e e n i n g strategy for c o l o r e c t a l c a n c e r . T h e r e are t h r e e basic s c r e e n i n g m e t h o d s , a n d p r u d e n t j u d g m e n t suggests that e a c h o f t h e s e c a n p r e v e n t s o m e deaths f r o m c o l o r e c t a l c a n c e r . Yet b y t h e u s u a l scientific standards, w e c a n n o t c l a i m that s u c h efficacy has been objectively demonstrated. T h e r e is a d a n g e r that i n t h e s e c o s t - c u t t i n g times, this lack o f e v i d e n c e w i l l b e t a k e n as e v i d e n c e against, o r as r e a s o n to stop or d e n y . That is w h y i n o u r r e v i e w o f s i g m o i d o s c o p y w e stated e x p l i c i t l y , " t h e r e are n o g r o u n d s for d i s c o u r a g i n g or d i s c o n t i n u i n g this f o r m o f s c r e e n i n g i n t h e office s e t t i n g or for w i t h h o l d i n g it f r o m p e r s o n s w h o r e q u e s t it."3 W e h o p e that w i t h i n t h e n e x t f e w years, s o m e g o o d e v i d e n c e o n e w a y or t h e o t h e r w i l l b e c o m e available. I n the m e a n t i m e , t h e a d v i c e o f K n i g h t et al. ~6 is w e l l taken. " P a t i e n t s s h o u l d b e i n f o r m e d o f the u n c e r t a i n t i e s i n v o l v e d i n r e c o m m e n d i n g s c r e e n i n g a n d all o w e d to p a r t i c i p a t e i n t h e d e c i s i o n . T h e c u r r e n t
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k n o w l e d g e base, i n c l u d i n g o p e n q u e s t i o n s of efficacy, can support a range of r e c o m m e n d a t i o n s . "
REFERENCES 1. Silverberg E, Lubera JA. Cancer statistics, 1989. CA. 1989;39:3-20. 2. Frame PS. A critical review of adult health maintenance. Part 3: Prevention of cancer. J Faro Pract. 1986;22:511-20. 3. Selby.lV, Friedman GD. Sigmoidoscopy in the periodic health examinationof asymptomatic adults. JAMA. 1989;261:595-601. 4. Fleischer DE, Goldberg SB, Browning TH, et al. Detection and surveillance of colorectal cancer. JAMA. 1989;261:580-5. 5. Hertz REL,Deddish MR, Day E. Value of periodic examinations in detecting cancer of the colon and rectum. Postgrad Med. 1960;27:290-4. 6. GilbertsenVA. Proctosigmoidoscopy and polypectomy in reducing the incidence of rectal cancer. Cancer. 1974;34:936-9. 7. Gilbertsen VA, Nelms JM. The prevention of invasive cancer of the rectum. Cancer. 1978;41 : 1137-9. 8. Morrison AS. Screening in chronic disease. New York: Oxford University Press, 1985. 9. Fletche~ SW, Dauphinee WD. Should colorectal carcinoma be sought in periodic health examinations? An approach to the evidence. Clin Invest Med. 1981 ;4:23-31. 10. Eddy D. Guidelines for the cancer-related checkup: recommendations and rationale. CA. 1980;30:194-240. 11. Crespi M, Weissman GS, Gilbertsen VA,Winawer SJ, Sherlock P. The role of proctosigmoidoscopy in screening for colorectal neoplasia. CA. 1984;34:158-65. 12. Friedman GD, Collen MF, Fireman BH. Multiphasic health checkup evaluation: a 16-year follow-up. J Chronic Dis. 1986;39:453-63. 13. Dales LG, Friedman GD, Collen MF. Evaluating periodic multiphasic health checkups: a controlled trial. J Chronic Dis. 1979;32:385-404. 14. FrankJW. Causationrevisited.JClinEpidemiol.1988;41:425-6. 15. SelbyJV,Friedman GD, Collen MF. Sigmoidoscopy and mortality from colorectal cancer: the Kaiser Permanente Multiphasic Evaluation Study. J Clin Epidemiol. 1988;41:427-34. 16. Knight KK, FieldingJE, Battista RN. Occult blood screening for colorectal cancer. JAMA. 1989;261:587-93. 17. Morrison AS. Case definition in case-control studies of the efficacy of screening. AmJ Epidemiol. 1982; 115:6-8. 18. Weiss NS. Control definition in case-control studies of the efficacy of screening and diagnostic testing. Am J Epidemiol. 1983;118:457-60. 19. Rhoads GG, MillsJL.The role of case- control studies in evaluating health interventions. Am J Epidemiol. 1984; 120:803-8. 20. SascoAJ, Day NE, Walter SD. Case- control studies for the evaluation of screening. J Chronic Dis. 1986;39:399-405.
siderable effort has b e e n directed at early detection. Although evidence is a c c u m u l a t i n g that diet and other lifestyle attributes m a y be related to risk of this disease, w e are not likely to be able to p r e v e n t the vast majority of cases that will o c c u r in the n e x t decade b y any k n o w n or foreseeable method. Some individuals w i t h k n o w n predisposing factors, such as previous cancers or a d e n o m a t o u s polyps, familial polyposis syndromes, ulcerative colitis, or familial history of colorectal cancer d e v e l o p i n g at an early age, deserve close surveillance w i t h a systematic p r o g r a m of screening or even diagnostic tests such as colonoscopy. But, like m a n y other chronic diseases, colorectal cancer usually arises in middle-aged and elderly persons not otherwise k n o w n in advance to b e at increased risk. What screening tests are available for these p e o p l e and h o w effective are they in preventing death from this disease? There are three main screening modalities for colorectal cancer: digital rectal examination, sigmoidoscopy, and fecal occult b l o o d testing. These are listed and discussed in order of increasing portions of the large b o w e l in w h i c h they can detect tumors.
DIGITAL RECTAL EXAMINATION The digital rectal examination can detect p a l p a b l e lesions in the r e c t u m that are within r e a c h of the examining finger, those within a b o u t 7 c m of the anus. It is likely that the early detection of cancers b y application of this test in a s y m p t o m a t i c persons will p r e v e n t s o m e deaths f r o m colorectal cancer. However, there have b e e n no controlled studies demonstrating this to be the case. Additional features of the rectal examination that are often valued are that the prostate gland can b e examined and that the small stool s p e c i m e n that is usually obtained can be tested for occult blood. The rectal examination is t i m e - h o n o r e d and r e s p e c t e d b y the medical profession. This is reflected in the old joke regarding the definition of a c o n s u l t a n t - - the physician w h o is called in and p e r f o r m s the rectal examination. Disadvantages include the discomfort of the examination and the fact that only a small p r o p o r t i o n of all colorectal cancers, p r o b a b l y less than 10%, are within reach of the finger. In his recent review of screening tests, Dr. Paul Frame c o n c l u d e d that the disadvantages o u t w e i g h the advantages, and he r e c o m m e n d e d that the rectal e x a m i n a t i o n not be i n c l u d e d in periodic health c h e c k u p s for a s y m p t o m a t i c adults. 2 $Z3
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SIGMOIDOSCOPY Sigmoidoscopy permits visualization o f the r e c t u m and part of the sigmoid colon. On average, the old 25-cm rigid sigmoidoscopes w e r e inserted to a d e p t h of 20 cm. 3 The n e w e r flexible instruments are longer, usually either 35 c m or 60 cm. The 35-cm flexible sigmoidoscopes generally cause less discomfort and are m o r e a c c e p t a b l e to patients than either the 25-cm rigid or the 6 0 - c m flexible instruments. 3 During sigmoidoscopy, if colorectal p o l y p s are seen, they can be removed. Theoretically, s i g m o i d o s c o p y can p r e v e n t death from colorectal cancer by t w o distinct means. One, as w i t h other screening tests, involves the detection of cancers early e n o u g h that they can b e r e m o v e d before t h e y metastasize. The other involves the removal o f p r e m a l i g n a n t p o l y p s before they progress to cancer. While direct p r o o f is lacking, m u c h circumstantial evid e n c e supports the v i e w that most cancers of the large b o w e l arise in polyps. 4 The efficacy of s i g m o i d o s c o p y has b e e n studied considerably m o r e than that of the rectal examination. T w o reports, w h i c h w e believe are m e r e l y descriptive, described the follow u p of large groups of p e o p l e w h o received sigmoidoscopy, in studies that w e r e not w e l l controlled. One, f r o m the Strang Cancer Prevention Clinic in N e w York, s u m m a r i z e d the results of 47,091 s i g m o i d o s c o p i c examinations p e r f o r m e d o n 2 6 , 1 9 6 patients, 88.5% of w h o m w e r e asymptomatic, s Some examinations included fecal occult b l o o d testing. The colorectal cancer detection rate was 2.2 p e r 1,000 examinations, with 76.5% of cancers discovered b y sigmoidoscopy. Eighty-one p e r c e n t of the cases w e r e localized (Dukes' stage A or B) and the 15-year survival rate was 88%. Both the stage distribution and the survival rate w e r e m u c h better than those f o u n d in groups of cases d e t e c t e d clinically after s y m p t o m s occurred. Another oft-quoted descriptive study was cond u c t e d at the University of Minnesota's Cancer Detection Center, w h e r e a g r o u p of 2 1 , 1 5 0 persons, aged 45 years and over, each received an initial sigmoidoscopy, and as a g r o u p received 9 2 , 6 5 0 m o r e such p r o c e d u r e s annually.6, 7 After removal of 27 cancers f o u n d b y the initial examinations, only 13 cancers w e r e discovered at the annual follow u p s - - 12 stage A and one stage B. T w o of the 13 patients died, one p e r i o p e r a t i v e l y and one of pancreatic cancer. Besides noting this very favorable stage distribution, the researchers c o m p a r e d the 13 cases w i t h 90 e x p e c t e d in a p o p u l a t i o n of this size based on incidence rates for the state of Minnesota. Although striking, this c o m p a r i s o n is i n a p p r o p r i a t e for at least three reasons: 1) the 27 cancers d e t e c t e d initially w e r e not p r e v e n t e d and should have b e e n included in the incidence figures at the clinic (this was previously p o i n t e d out b y MorrisonS); 2) the authors included only those person-years of follow u p that e n d e d in another s i g m o i d o s c o p y - - i f a cancer w e r e
d e t e c t e d clinically six m o n t h s after a s i g m o i d o s c o p y and the patient d r o p p e d out of the screening program, that cancer w o u l d not be counted; and 3) persons returning for r e p e a t e d sigmoidoscopies w e r e a self-selected g r o u p w h o s e risk of death from colorectal cancer might have been, w i t h o u t sigmoidoscopy, m u c h different from that of the general population. At the Kaiser Permanente Medical Care Program, Northern California Region, w e have c o n d u c t e d a controlled trial of multiphasic screening that has b e e n cited b y authoritative groups as high-grade e v i d e n c e for the efficacy of sigmoidoscopy. 9-11 Although this conclusion is not justified, it is instructive to r e v i e w the evidence and see h o w easily such misinterpretations can arise. The Multiphasic Evaluation Study involved the essentially r a n d o m selection in 1964 of two groups of about 5,000 long-term subscribers to o u r health care plan, aged 3 5 - 5 4 years at entry, and residing in the areas served b y our Oakland and San Francisco facilities. Those in the study g r o u p w e r e urged to receive multiphasic health c h e c k u p s (MHCs) annually t h r o u g h mid-1980, and those in the control g r o u p w e r e not so urged although they c o u l d obtain such c h e c k u p s if they wished. As a result of this urging, the study g r o u p received considerably m o r e MHCs (mean----6.8, median = 6) than did the control g r o u p ( m e a n = 2.8, median = I ) . The two g r o u p s w e r e f o l l o w e d u p in similar fashion for mortality, disability, and o t h e r outcomes. One of the study's striking findings was that deaths from a g r o u p of " p o t e n t i a l l y p o s t p o n a b l e " causes, hypothesized in advance to be affected favorably b y MHCs, w e r e significantly (p = 0 . 0 1 ) f e w e r in the study g r o u p ( c u m u l a t i v e 16-year mortality rate = 1 5 . 0 / 1 , 0 0 0 ) than in the control g r o u p ( 2 1 . 5 / 1 , 0 0 0 ) . T h e " potentially p o s t p o n a b l e " disease making the largest contribution to this difference was colorectal cancer, with 12 study-group and 29 control-group deaths, t 2 The MHC consisted of a visit to an a u t o m a t e d laboratory, w h e r e a variety of screening tests w e r e performed, f o l l o w e d b y a physical examination, almost always by a physician during the study period. In the MHC laboratory, persons aged 40 years and o v e r w e r e advised to make an a p p o i n t m e n t for a screening sigmoidoscopy. Fecal occult b l o o d testing was not inc l u d e d in the MHC until mid- 1979, w h e n it was instituted at the Oakland facility. O t h e r c o m p o n e n t s of the MHC that might have led to the early detection of colorectal cancer w e r e the digital rectal e x a m i n a t i o n inc l u d e d in the physical examination, the h e m a t o l o g y tests that c o u l d detect anemia, and questionnaire items c o n c e r n i n g gastrointestinal symptoms. Given the likely l o w sensitivity and specificity o f these c o m p o n e n t s , it was natural to c o n c l u d e that s i g m o i d o s c o p y was responsible for the lives saved. In our reports 12. 13 w e w e r e conservative and careful not to assert this conclusion, ~4yet it must be admitted that until r e c e n t l y w e did
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not question or a t t e m p t to contradict the prevailing opinion. The turning point c a m e w h e n one of us (JVS) raised some questions a b o u t this conclusion, and w e carried out the additional analyses n e e d e d to answer these questions. 1s The questions were: 1 ) H o w m u c h of the reduction in mortality from colorectal cancer in the study g r o u p was due to a reduction in incidence and h o w m u c h was due to an i m p r o v e m e n t in stage distribution at the time of diagnosis? 2) What w e r e the m o d e s of discovery of all of the colorectal cancers, considering b o t h those within and those not within reach of the sigmoidoscope? and 3) H o w m u c h m o r e sigmoidosc o p y did the study g r o u p receive and c o u l d this difference have b e e n responsible for preventing the n u m b e r of deaths e x p e c t e d in the study group? In brief, w e r e v i e w e d all of the colorectal cancers that w e r e detected in the entire study population. We f o u n d that a higher p r o p o r t i o n of those in the study g r o u p w e r e detected b y s i g m o i d o s c o p y and that the s t u d y - c o n t r o l difference in mortality a p p l i e d chiefly to cancers located within reach of the sigmoidoscope. However, only one-third of the reduction in the study g r o u p ' s mortality was due to a lower case fatality rate. Two-thirds w e r e due to a reduction in incidence, w h i c h c o u l d not reasonably be attributable to p o l y p detection and removal because it o c c u r r e d equally in the two groups. Most striking was the small difference b e t w e e n the n u m b e r s of sigmoidoscopies received b y the two groups. Over a ten-year period, 30% of the study g r o u p and 25% of the control g r o u p had at least one. An excess of 929 MHC-related sigmoidoscopies in the study g r o u p was c o n t r i b u t e d by 279 persons w i t h a m e a n of 3.34 sigmoidoscopies each. Over half of this excess was attributable to only 78 persons w h o had five to ten examinations each. Calculations of the potential lives saved b y these additional sigmoidoscopies using local mortality rates and assuming that s i g m o i d o s c o p i c detection of a cancer always saved a life led to an estimate that only one death c o u l d have b e e n prevented. Most colorectal cancers in the two groups w e r e d e t e c t e d following the o c c u r r e n c e of symptoms. But, interestingly, even these w e r e diagnosed at a m o r e favorable stage, on average, in the study group. We susp e c t that the annual urging and greater n u m b e r of MHCs c o u l d have led the study g r o u p to be m o r e health-conscious or to notice s y m p t o m s earlier and thus c o u l d lead to earlier diagnosis and treatment. 15 It is n o w clear that there is no strong evidence f r o m controlled studies that s i g m o i d o s c o p i c screening prevents death from colorectal cancer. Yet it is quite reasonable to believe that this test does detect cancers in an early, curable form in s o m e a s y m p t o m a t i c persons and that lives are saved as a result. Even w i t h the flexible instrument, however, there is still an acceptability p r o b l e m . Many patients are not willing to undergo the p r o c e d u r e with either type of
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instrument. Note that in o u r study group, although 84% had at least one MHC (with f e w of these not receiving an MHC at age 40 or above), only 25% had an MHC-related (rigid) s i g m o i d o s c o p y and only 30% had any sigmoidoscopy. This affects not only the usefulness of sigm o i d o s c o p y as a screening test, but also our ability to evaluate it by a r a n d o m i z e d controlled trial. Poor compliance and, in absolute terms, the relatively l o w incidence of and mortality from colorectal cancers within reach of the s i g m o i d o s c o p e make it necessary to think in terms of several tens of thousands of subjects for such a trial. FECAL OCCULT BLOOD T E S T I N G Testing stool s p e c i m e n s for occult b l o o d is m u c h s i m p l e r and c h e a p e r than e n d o s c o p i c p r o c e d u r e s such as s i g m o i d o s c o p y and it holds the p r o m i s e of detecting cancers and polyps anywhere in the large bowel. Today guaiac-impregnated p a p e r slides are the most comm o n l y used version of the test. The patient is usually asked to a p p l y two samples each from stools passed on three consecutive occasions and these are later tested in the laboratory. Screening by fecal occult b l o o d testing has b e e n t h o r o u g h l y r e v i e w e d recently by Knight, Fielding, and Battista. a6 Their article is the source of m u c h of the information given below. The sensitivity of fecal occult b l o o d testing is limited by the fact that not all large b o w e l cancers and polyps b l e e d continuously, and b y the n o n u n i f o r m distribution of b l o o d in the feces. A normal person loses about 0.5 to 2.0 ml of b l o o d p e r day via the gastrointestinal tract. The H e m o c c u l t II test, n o w one of the most c o m m o n l y used, consistently yields positive results w i t h 20 ml of b l e e d i n g p e r day. The sensitivity to k n o w n cancers is r e p o r t e d to be 50% to 87%, whereas only a b o u t 25% of a d e n o m a s are detected: only those over 2 c m in diameter. The specificity and positive predictive value of fecal occult b l o o d testing are limited b y the fact that other conditions and certain medications can p r o d u c e gastrointestinal bleeding, and certain foods can produce false-positive reactions. Positive predictive value is about 10% or less for cancers and 30% or less for a d e n o m a t o u s polyps. Naturally, positive predictive value is increased w h e n screening is p e r f o r m e d in persons with a high p r e v a l e n c e of these conditions, such as the elderly. W h e n fecal occult b l o o d tests are positive, a costly and u n c o m f o r t a b l e w o r k u p is d e e m e d necessary. This usually includes a b a r i u m e n e m a (often w i t h air contrast), sigmoidoscopy, a n d / o r colonoscopy. But the l o w positive predictive value reflects the fact that most of these w o r k u p s do not reveal any cancers or polyps. Thus, undertaking this form of screening entails costs in terms of money, professional time, and patient time and discomfort, and rare b u t serious complications of the diagnostic tests (such as b o w e l p e r f o r a t i o n ) - - c o s t s considerably greater than those of the fecal o c c u l t
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b l o o d tests alone. There is also a c o m p l i a n c e p r o b l e m , but it is not nearly as great as that for sigmoidoscopy. Thus, screening b y this m e t h o d is still controversial. It holds the p r o m i s e of saving lives b y early detection, but this has yet to be d e m o n s t r a t e d in well-controlled studies. Five such studies are n o w u n d e r way, two in the United States and one each in Denmark, Great Britain, and Sweden. T e c h n o l o g i c advances m a y also i m p r o v e the effectiveness of fecal occult b l o o d testing. Quantitative rather than yes-or-no qualitative results can c o m e f r o m i m m u n o c h e m i c a l techniques, w h i c h have the advantage of being specific for h u m a n blood, and f r o m the H e m o Q u a n t test. Screening w i t h these m e t h o d s has not yet b e e n p u t into routine practice. O u r overall assessment of screening b y fecal occult b l o o d testing is similar to that for s i g m o i d o s c o p y D likely to save lives but as yet u n p r o v e n to do so.
A NEW CASE-CONTROL STUDY OF THESE SCREENING TESTS Although r a n d o m i z e d controlled trials p r o v i d e the most c o m p e l l i n g evidence of efficacT of screening tests, none directed at colorectal cancer screening has b e e n c o m p l e t e d , and the only ones in progress n o w c o n c e r n fecal occult b l o o d testing. As n o t e d above, rand o m i z e d controlled trials of s i g m o i d o s c o p y w o u l d entail formidable effort and cost. Properly c o n d u c t e d observational studies, either cohort or c a s e - c o n t r o l in design, can also provide useful data on efficacy. We have just b e g u n a c a s e - control study of the efficacy of e a c h of the three screening modalities in p r e v e n t i n g death from colorectal cancer. This is being c o n d u c t e d in the setting of the Kaiser Permanente Medical Care Program, Northern California Region, a health maintenance organization that has p r o v i d e d c o m p r e h e n s i v e inpatient and outpatient medical care, usually on a long-term basis, to a subscriber p o p u l a t i o n that n o w e x c e e d s 2.2 million. The organization's medical records p r o v i d e objective d o c u m e n t a t i o n of the r e c e i p t of these screening tests and the o c c u r r e n c e of cancer. In a c a s e - c o n t r o l study of a screening test, one identifies cases w i t h the stages or o u t c o m e s of the disease that the screening test is s u p p o s e d to prevent, and controls are representative of the underlying p o p u l a tion in w h i c h the cases occur. The controls n e e d not b e free of the disease, but the disease should not have r e a c h e d the m o r e undesirable stage or o u t c o m e that defines the case. Receipt of the screening tests b y the cases and controls is then ascertained. If the screening test has preventive efficacy, then it will have b e e n received by f e w e r of the cases than the controls. In other words, the cases will have had a deficit of these screening tests relative to c o m p a r a b l e persons in the general population. The main p r o b l e m in interpreting these c a s e -
control studies lies in the possibility of self-selection bias. Persons w h o later d e v e l o p or die f r o m the disease m a y have a different p r o p e n s i t y to be screened, quite i n d e p e n d e n t of w h e t h e r the screening does any good. For example, l o w e r s o c i o e c o n o m i c status is associated w i t h a higher incidence of cervical cancer and relatively less interest in obtaining health c h e c k u p s and Pap smears. Thus, a c a s e - c o n t r o l study of invasive or fatal cervical cancer m i g h t find f e w e r Pap smears a m o n g the cases even if Pap smears had no value in preventing invasive or fatal disease. On the o t h e r hand, one m i g h t suspect that persons with a family history of colorectal c a n c e r w h o are at h e i g h t e n e d risk might b e m o r e apt to u n d e r g o screening sigmoidoscopy. In this instance the o p p o s i t e bias c o u l d occur, w h e r e i n cases w o u l d have a relative excess of screening tests or at least sufficient additional screenings to mask a deficit reflecting efficacy. In these c a s e - control studies it is t e m p t i n g to select, as controls, persons w i t h the disease diagnosed at an early stage. The question to be answered m a y be stated as: "Let's see w h e t h e r p e o p l e w i t h the disease diagnosed early, and thus w i t h a better prognosis, have b e e n getting m o r e of the screening tests." This app r o a c h is almost guaranteed to p r o d u c e a favorable-appearing result. We can grant f r o m the start that the screening test picks u p the disease early, and this is all that such a c a s e - c o n t r o l c o m p a r i s o n can show. What w e w a n t to find out, however, is w h e t h e r the screening prevents or delays death or s o m e other o u t c o m e . This can be d e t e r m i n e d only b y c o m p a r i n g cases w h o have the o u t c o m e w i t h a representative g r o u p of controls w i t h o u t the o u t c o m e . C a s e - c o n t r o l studies of screening are complicated b y other subtle biases. One is the "healthyscreenee effect," first described b y Morrison. s This can c o m e into play if certain aspects of screening such as the f r e q u e n c y of the test or the r e c e n c y of the last test, w h i c h reflects frequency, are evaluated. People w h o screen negative one or m o r e times are b y this very process selected to b e at l o w risk for b e c o m i n g a case, because they are p r o v e n to be free of detectable preclinical disease. This differs from self-selection bias m e n t i o n e d above, as it is a result of the p r i o r screenings, not a predisposition to have them. It is m o r e akin to the " h e a l t h y - w o r k e r effect," in w h i c h the process of hiring and retaining e m p l o y e e s w e e d s out the less healthy. The theoretical aspects and pitfalls of c a s e control studies of screening have b e e n discussed by Morrison,S. 17 Weiss,iS Rhoads and Mills, 19 and Sasco, Day, and Walter. 2° O u r study is threefold. Rectal examinations have b e e n w i d e l y p e r f o r m e d in o u r program, so that w e are selecting subjects from the entire region. Cases will have had fatal rectal cancer located within 7 c m of the anus (estimated n u m b e r , 4 5 0 ) and one control p e r case
JOURNALOF GENERALINTERNALMEDICINE, Volume S (September/October Supplement), 1990
w i l l b e c h o s e n . S c r e e n i n g s i g m o i d o s c o p y has b e e n regu l a r l y p e r f o r m e d at t h r e e o f o u r facilities (Hayward, O a k l a n d , a n d San F r a n c i s c o ) . Thus, cases w i l l have fatal c a n c e r s l o c a t e d w i t h i n 20 c m of t h e a n u s d i a g n o s e d at a n y of t h e t h r e e facilities ( e s t i m a t e d n u m b e r , 2 7 5 ) . Controls will be selected from among persons living in t h e r e s i d e n t i a l areas s e r v e d b y t h e s e facilities, f o u r p e r case. Fecal o c c u l t b l o o d t e s t i n g has b e e n u s e d w i d e l y i n our region but only since about 1979. Therefore, we w i l l c h o o s e as cases p e r s o n s w i t h fatal c a n c e r s diagn o s e d i n 1981 or later a n d l o c a t e d a n y w h e r e i n t h e large b o w e l ( e s t i m a t e d n u m b e r , 9 7 5 ) . C o n t r o l s w i l l b e s e l e c t e d f r o m t h e e n t i r e m e m b e r s h i p , o n e p e r case. M e d i c a l r e c o r d s w i l l b e r e v i e w e d to o b t a i n data o n t h e a d m i n i s t r a t i o n o f t h e s c r e e n i n g test o f i n t e r e s t u p to t e n years b e f o r e d i a g n o s i s of the c a n c e r , w i t h corres p o n d i n g t i m e i n t e r v a l s i n t h e c o n t r o l s . W e e x p e c t this s t u d y to b e c o m p l e t e d b y m i d - 1 9 9 1 .
CONCLUSION U n f o r t u n a t e l y , w e d o n o t yet k n o w w h e t h e r t h e r e is a n effective s c r e e n i n g strategy for c o l o r e c t a l c a n c e r . T h e r e are t h r e e basic s c r e e n i n g m e t h o d s , a n d p r u d e n t j u d g m e n t suggests that e a c h o f t h e s e c a n p r e v e n t s o m e deaths f r o m c o l o r e c t a l c a n c e r . Yet b y t h e u s u a l scientific standards, w e c a n n o t c l a i m that s u c h efficacy has been objectively demonstrated. T h e r e is a d a n g e r that i n t h e s e c o s t - c u t t i n g times, this lack o f e v i d e n c e w i l l b e t a k e n as e v i d e n c e against, o r as r e a s o n to stop or d e n y . That is w h y i n o u r r e v i e w o f s i g m o i d o s c o p y w e stated e x p l i c i t l y , " t h e r e are n o g r o u n d s for d i s c o u r a g i n g or d i s c o n t i n u i n g this f o r m o f s c r e e n i n g i n t h e office s e t t i n g or for w i t h h o l d i n g it f r o m p e r s o n s w h o r e q u e s t it."3 W e h o p e that w i t h i n t h e n e x t f e w years, s o m e g o o d e v i d e n c e o n e w a y or t h e o t h e r w i l l b e c o m e available. I n the m e a n t i m e , t h e a d v i c e o f K n i g h t et al. ~6 is w e l l taken. " P a t i e n t s s h o u l d b e i n f o r m e d o f the u n c e r t a i n t i e s i n v o l v e d i n r e c o m m e n d i n g s c r e e n i n g a n d all o w e d to p a r t i c i p a t e i n t h e d e c i s i o n . T h e c u r r e n t
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k n o w l e d g e base, i n c l u d i n g o p e n q u e s t i o n s of efficacy, can support a range of r e c o m m e n d a t i o n s . "
REFERENCES 1. Silverberg E, Lubera JA. Cancer statistics, 1989. CA. 1989;39:3-20. 2. Frame PS. A critical review of adult health maintenance. Part 3: Prevention of cancer. J Faro Pract. 1986;22:511-20. 3. Selby.lV, Friedman GD. Sigmoidoscopy in the periodic health examinationof asymptomatic adults. JAMA. 1989;261:595-601. 4. Fleischer DE, Goldberg SB, Browning TH, et al. Detection and surveillance of colorectal cancer. JAMA. 1989;261:580-5. 5. Hertz REL,Deddish MR, Day E. Value of periodic examinations in detecting cancer of the colon and rectum. Postgrad Med. 1960;27:290-4. 6. GilbertsenVA. Proctosigmoidoscopy and polypectomy in reducing the incidence of rectal cancer. Cancer. 1974;34:936-9. 7. Gilbertsen VA, Nelms JM. The prevention of invasive cancer of the rectum. Cancer. 1978;41 : 1137-9. 8. Morrison AS. Screening in chronic disease. New York: Oxford University Press, 1985. 9. Fletche~ SW, Dauphinee WD. Should colorectal carcinoma be sought in periodic health examinations? An approach to the evidence. Clin Invest Med. 1981 ;4:23-31. 10. Eddy D. Guidelines for the cancer-related checkup: recommendations and rationale. CA. 1980;30:194-240. 11. Crespi M, Weissman GS, Gilbertsen VA,Winawer SJ, Sherlock P. The role of proctosigmoidoscopy in screening for colorectal neoplasia. CA. 1984;34:158-65. 12. Friedman GD, Collen MF, Fireman BH. Multiphasic health checkup evaluation: a 16-year follow-up. J Chronic Dis. 1986;39:453-63. 13. Dales LG, Friedman GD, Collen MF. Evaluating periodic multiphasic health checkups: a controlled trial. J Chronic Dis. 1979;32:385-404. 14. FrankJW. Causationrevisited.JClinEpidemiol.1988;41:425-6. 15. SelbyJV,Friedman GD, Collen MF. Sigmoidoscopy and mortality from colorectal cancer: the Kaiser Permanente Multiphasic Evaluation Study. J Clin Epidemiol. 1988;41:427-34. 16. Knight KK, FieldingJE, Battista RN. Occult blood screening for colorectal cancer. JAMA. 1989;261:587-93. 17. Morrison AS. Case definition in case-control studies of the efficacy of screening. AmJ Epidemiol. 1982; 115:6-8. 18. Weiss NS. Control definition in case-control studies of the efficacy of screening and diagnostic testing. Am J Epidemiol. 1983;118:457-60. 19. Rhoads GG, MillsJL.The role of case- control studies in evaluating health interventions. Am J Epidemiol. 1984; 120:803-8. 20. SascoAJ, Day NE, Walter SD. Case- control studies for the evaluation of screening. J Chronic Dis. 1986;39:399-405.
