Screening for cancer, 1995: An update

Annals of Oncology 6: 537-541, 1995. © 1995 Kluwer Academic Publishers. Printed in the Netherlands.

Arena Screening for cancer, 1995: An update C. La Vecchia,1'2'3 F. Levi1 & S. Franceschi4 l

Regstre Vaudois des Tumeurs, Institut universitaire de medecine sociale et preventive, CHUV, Lausanne, Switzerland; 2Isrituto di Ricerche Farmacologiche 'Mario Negri'; 3lstituto di Statistica Medica e Biometria, Universitd di Milano, Milan; 'Centro di Riferimento Oncologico, Aviano (Pordenone), Italy

Key words: cancer, screening, secondary prevention, early diagnosis

Screening for cancer has been widely studied and discussed over the last few decades [1-5], but a critical approach is infrequently encountered in the published literature, so that many studies may impart misleading impressions to the clinicians. For instance, the Minnesota Colon Cancer Control Study [6] concluded that annual smears for fecal occult blood decreased the 13-year cumulative mortality from colorectal cancer by 33%. However, biennial screening was not associated with any material reduction in risk, and this observation leaves open any inference or interpretation in terms of real association, bias or chance. The debate over the potential impact of screening on cancer rates and mortality is therefore still open with respect to colorectal cancer, as well as other major cancers at sites such as ovary and prostate. In contrast, screening seems to have a definite role in the control of cervical and breast cancers [3], although also for these neoplasms a closer determination of the protection, a more precise definition of the target population, and a cost-benefit analysis are still needed. This review will therefore address a few currently open issues about cancer screening, with a specific focus on results from studies published in the 1990s. Cancer of the cervix

The effect of Pap smears on cervical cancer risk has never been subjected to a controlled randomized study, but evidence from descriptive epidemiology comparisons (between and within countries) and retrospective studies has accumulated to indicate a major impact of screening on the disease [7,8]. This led a IARC Working Group on Evaluation of Cervical Cancer Screening Programmes [9] to estimate percent reductions in cumulative rates according to different screening intervals. Screening at yearly intervals between the ages of 35 and 64 would lead to a 93% reduction in incidence, smears at 5-year intervals to a

84% reduction, and at 10-year intervals to a 64% reduction in incidence. It is now clear, however, that case identification and ascertainment, particularly for pre-invasive neoplasms, is largely a function of the between-screening interval, and that such a selection bias may produce spurious relative risks on the order of 5 to 7, even in the absence of any real association (P. Sasieni, personal communication). Thus, while the importance of screening on cervical cancer risk remains beyond any reasonable discussion, the quantitative assessment of the protection, and hence the definition of the optimal interval between tests, remain open to discussion. Similarly open is the debate about fixing an upper age limit for screening on a population level, which could increase the number of inadequately screened elderly women. Inspection of incidence and mortality data for cervical cancer, in fact, shows unfavourable or less favourable trends over most recent calendar periods for elderly women (i.e., over age 65) [10, 11], who may consequently be a priority target for future screening programmes. Further issues to be clarified over the next few years are the management of women with mild or moderate cervical dyskaryosis and the role of the detection of Human Papillomavirus (HPV). It is now clear, in fact, that even women with mild dyskaryosis have a risk of developing invasive cervical cancer a few dozen times greater than that of women of the same age in the general population, with annual incidence rates of 140 to 400/100,000 [12]. Thus, cytological or colposcopic surveillance is inadequate in these women, and treatment to restore a normal epithelium is required [13]. With respect to HPV, the availability of methods for viral detection in Pap smears opens the possibility of a relatively cheap detection of asymptomatic (and, often, invisible at Pap smear and colposcopy [8]) viral infection. Although the detection of HPV does not yet allow specific treatment, it may greatly improve the predictive value of cervical cancer screening. This would possibly

538 allow less frequent, although more expensive, screening, with potential gains in the extent of population coverage. Breast cancer

It is now clear that breast cancer screening through mammography reduces mortality from the disease by 20% to 25% at ages 50 to 74 [14,15]. This is an overall estimate, which takes into account the accuracy and variability of mammographic interpretations [16]. The optimal interval for screening is, however, still open for debate, at least in terms of cost-benefits. A yearly interval is almost certainly not justified, while the choice between an interval of 2 or 3 years is mainly linked to the availability of resources on a population level. The issue of screening mammography for women aged 40 to 49 is also still controversial [17]. A metaanalysis of published controlled trials showed a mortality reduction, in this age group, of approximately 10%, which is compatible both with the effect observed at age 50 to 74, and with lack of protection. It is possible that further studies or more prolonged follow-up will clarify the issue. This would, however, hardly modify any cost-effectiveness evaluation, which remains unlikely to be favourable in this age group, at least in women not at high risk for breast cancer. It is also unclear whether screening mammography in women above age 70 or 75 may be of value. There is a priori little reason to assume a lower benefit than for younger women [18, 19], albeit the benefits in terms of years of life gained are going to be smaller in elderly women. Another important issue is whether screening mammography has a relevant impact not only on breast cancer mortality, but also on incidence on a population level [20]. The existence of such influence may explain why breast cancer incidence rates are now systematically higher in North America, whereas mortality rates are higher in Britain and a few other northern European countries [21, 22]. The impact of mammography on breast cancer incidence may reach 30%. Finally, other adverse effects which stem from screening mammography, including anxiety, false reassurance and biopsies for benign conditions, should be better quantified. It is now clear, from studies conducted in the UJC. and Finland, that breast self-examination (BSE) does not have a major impact on subsequent breast cancer mortality [23, 24]. Larger studies are in progress in Russia and China, but, at present, there is no adequate evidence that screening by BSE is of value, and hence there is no rationale for setting up organized screening programs, at least in developed countries.

Cancer of the colorectum

Colorectal cancer is the most common cancer site in non-smokers of both sexes combined in developed countries [22]. Any effective screening program would, hence, have a major public health impact. Unfortunately, although already widely practiced, possible screening strategies must be considered as still at an experimental level, and thus cannot be recommended outside controlled clinical trials. Besides digital rectal examination, which can detect only the small proportion of rectal tumours within the range of the examiner's finger, there are essentially two main possible screening procedures: fecal occult blood test (FOBT), and sigmoidoscopy [25]. The fecal occult blood test as a screening procedure is relatively easy and cheap to perform, but has low sensitivity. More important, there is as yet no convincing evidence of a favourable impact of FOBT on colorectal cancer mortality. So far, only one randomized study, the Minnesota Colon Cancer Control Study, has shown a mortality reduction [6]. The follow-up time of this study had to be extended from 10 to 13 years, due to a particularly strong 'healthy volunteer effecf. Eventually, the colorectal cancer mortality rate in the annually screened group was 5.88/1000, significantly lower than the rate of 8.43/1000 in the control group. However, the biennially screened group had a mortality rate (8.33/1000) superimposable upon that of the control group. This may be due to some underlying bias, random variation or chance selection of subjects for colonoscopy examination following fecal occult bleeding, whose rate was higher in the group with annual screening [26]. Likewise, a case-control study from the Kaiser Permanente Medical Care Program of North Carolina [27] found an odds ratio of 0.69 for exposure to at least one screening FOBT during the previous five years, but the confidence interval around the estimate was wide, and there was no convincing trend in risk with time since the last test. Three European studies of FOBT are also ongoing, in England, Denmark and Sweden. They have shown shifts to earlier-stage diagnosis, but no mortality benefit. The Danish and English studies, however, did not rehydrate fecal specimens, at variance with the Minnesota investigation. Rehydration is reported to increase FOBT sensitivity, but at the expense of an already unsatisfactory specificity [28]. Screening sigmoidoscopy appears to have two distinct advantages over FOBT: it is highly sensitive for lesions as small as 5 mm, and allows the immediate endoscopical removal of premalignant adenomas and is thus a therapeutical as well as diagnostic procedure [25]. Evidence of a mortality benefit is, however, still limited. A case-control study conducted within the Kaiser Permanente Medical Care Program [29] found a relative risk (RR) for mortality from colorectal cancer of 0.4 (with 95% confidence interval (CI) 0.3 to 0.7) for

539 subjects who had undergone screening sigmoidoscopy as compared to those who had not. The protection lasted for at least 10 years following sigmoidoscopy. A similar case-control study in the Greater Marshfield Community Health Plan [30] found an RR of 0.21 (95% CI: 0.08-0.52) among individuals who had undergone a single sigmoidoscopy examination. The protection was greater for cancers of the rectum and distal colon. No protection was afforded by FOBT or digital rectal examination. A potential interpretation of such a strong protection is that cancer of the colon (including the proximal colon) appears to be related to the extent and size of adenomas and villous changes in adenomas in the rectosigmoid colon, which could therefore represent a reliable indication of subsequent colorectal cancer risk [31, 32]. On the basis of these findings, and following this line of reasoning, Atkin et al. [32, 33] proposed a randomized study based on a single flexible sigmoidoscopy examination at age 55 to 60, with subsequent colonoscopic surveillance for the 3% to 5% of subjects found to have high-risk adenomas. Such a trial would have to be large, with an accrual of over 100,000 participants, and based on a long-term follow-up. Issues of compliance, sensitivity, specificity and predictive value on a population scale for such a study remain to be clarified. Finally, a combination of FOBT and sigmoidoscopy has been proposed [34], but evidence for its advantage over sigmoidoscopy alone is still unclear. It is thus likely that it will be several more years before we can give definitive and reliable information about colorectal cancer screening on a population level.

ed that the increase in life expectancy for men aged 50 to 70 undergoing DRE and PSA was negligible (around 1 day). It is therefore clear that, also from the ethical standpoint, screening for prostatic cancer cannot be implemented or recommended on a population level [40]. Even randomized controlled trials [41] on the issue should have a substantial chance of offering a mortality benefit, and thereby meet the usual ethical requirements before being designed and implemented [40]. Ovarian and endometrial cancers Screening for ovarian cancer can be based on pelvic examination, ultrasonography (possibly with fineneedle aspiration) and the CA125 radioimmunoassay [42-44]. Unfortunately, there is no evidence that any of these methods, nor their combination, has sufficient sensitivity, specificity and positive predictive value to justify implementation of screening on a population level or even in high-risk groups [45], except, perhaps, for women with familial ovarian cancer histories including two or more first-degree relatives with ovarian cancer [46,47]. Screening for endometrial cancer can also be based on ultrasound and CA125, with limitations similar to those for ovarian cancer. Endometrial sampling, by contrast, has satisfactory sensitivity, but the invasive nature of the test severely hampers adoption of its use in the absence of clinical symptoms [48-50]. This should therefore be considered as an instrument for early diagnosis rather than a screening approach on a population level.

Other neoplasms Cancer of the prostate Cancer of the prostate is a common disease in elderly men, and will therefore become a greater public health problem in the future, as a function of the increased number and proportion of the elderly in the population. Several screening techniques have been proposed, including digital rectal examination (DRE), transrectal ultrasound and prostate-specific antigen (PSA) [3537]. Unfortunately, none of these has satisfactory sensitivity or specificity and positive predictive value. It is unclear whether the screening performance could be improved by the combination of various tests, and whether any such combination would have a cost-effective practical application. More important, there is as yet no evidence that any of these tests can materially modify mortality from prostate cancer on a population level, mainly because of the indolent nature and slow progression of most prostatic neoplasms [38]. A decision-analysis view, using a stochastic model to predict the outcome of screening by PSA [39], estimat-

Regular and systematic screening may have favourable impact on mortality from skin melanoma, and other neoplasms at sites where inspection is possible, such as other skin neoplasms, oral cavity, larynx or the vulva [49,51-53]. In these tumours, however, the exact screening test schedule and target population are still poorly defined. In most instances, educational campaigns, as opposed to population-based screening, were undertaken, which contributed unsatisfactory data for use in assessment of benefit. Conclusions Over the last few years, further quantitative evidence has accumulated of the role of cervical screening in reducing cervical cancer incidence and mortality, the importance of extending screening to elderly women and of appropriately treating pre-neoplastic cervical lesions. Likewise, an approximately 25% reduction in

540 breast cancer mortality for women aged 50 to 74 undergoing regular mammography screening has now been defined, whereas the role of mammography for younger women remains open to debate. With reference to colorectal cancer, while the role of the faecal occult blood test remains unconvincing, there is now a rationale for planning a randomized study of a once-alife time sigmoidoscopy at age 55 to 60 for the reduction of colorectal cancer mortality. In contrast, it is still unclear whether any trial on prostate cancer screening would have a reasonable rationale, and hence would be ethically acceptable. Similarly, there is no promising approach for ovarian or endometrial cancer screening. It is difficult to say what the shape of cancer screening will be in coming years. From the beginning population-based screening represented the optimal target from the standpoint of effectiveness and social equality in medical expenditure. These concepts are presently under threat by several practical difficulties. The inadequacies, for instance, of population registers and methods for obtaining high compliance are even too clear [54]. The search for an effective screening test which could be performed only a few times, if not once in a lifetime, may constitute an important way to improve population compliance and coverage. Furthermore, the future mix of new technologies, cost pressures, and sophisticated consumers will certainly have a marked, albeit not precisely predictable, effect on screening strategies [55]. Acknowledgement The contribution of the Swiss League against Cancer is gratefully acknowledged. References 1. Wilson JMJ, Jungner G. Principles and practice of screening for disease. WHO Public Health Paper 1968; 34. 2. U.S. Department of Health and Human Services. Cancer Control Objectives for the Nation: 1985-2000. NCI Monographs, Bethesda, MD Public Health Service, National Institute of Health 1986; Number 2. 3. Miller AB, Chamberlain J, Day NE. Report on a Workshop of the UICC Project on evaluation of screening for cancer. Int J Cancer 1990; 46: 761-9. 4. La Vecchia C, Levi F, Franceschi S, Boyle P. Assessment of screening for cancer. Int J Technol Assess Health Care 1991; 7: 275-85. 5. del Moral Aldaz A, Aupee M, Batal-Steil S et al. Cancer screening in the European Union. Eur J Cancer 1994; 30: 860-72. 6. Mandel JS, Bond JH, Church TR et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993; 328:1365-71. 7. La Vecchia C, Decarli A, Gallus G. Epidemiological data on cervical carcinoma relevant to cytopathology. Applied Pathol 1987; 5: 25-32. 8. Austoker J. Screening for cervical cancer. Br Med J 1994; 309: 241-8.

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