In this paper, we combined data from a unique nationwide colonoscopy registry and from population‐based cancer registries from Germany to project age and sex specific risk of CRC development among carriers of advanced colorectal adenomas. Any direct estimation of this parameter from cohorts of adenoma carriers would be unethical, as advanced adenomas have to be removed once they are detected, and pertinent data from the pre‐colonoscopy era are very sparse. Our analysis shows that the risk of advanced adenoma–CRC transition is comparable among women and men, but strongly increases with age.
Our projections of advanced adenoma progression to CRC in the older age groups are in line with previous estimates based on much smaller samples, which have been used for all age groups in previous analyses of cost effectiveness of CRC screening. For example, the cost effectiveness analyses of colorectal cancer screening by Frazier et al11
and O'Leary et al16
assumed a base‐case value of 5% for the annual transition rate from high‐risk polyps to localised cancer regardless of age, citing the 1987 report of Stryker et al
from the Mayo clinic case series as pertinent reference.9
The same estimate was used, again for all age groups and both sexes, in the recent cost‐effectiveness analysis by Ladabaum and Song.17
Furthermore, polyp dwell time, which is closely related to the adenoma–CRC transition rate, has been found to be an important influential parameter in pertinent sensitivity analyses in a number of cost effectiveness studies.10,13,16,18
Therefore, the finding of a strongly age‐dependent transition rate may be of high relevance for the optimal design of CRC screening programmes.
In our analysis, we implicitly made the assumption that all CRCs arising from adenomas were arising from advanced adenomas—that is, advanced adenomas represent a necessary interim stage in the adenoma–CRC sequence. A similar assumption (eg large adenomas or high risk polyps being necessary intermediate stages in the development of CRC from small adenomas or from low risk polyps, respectively) has been implicitly or explicitly made by other authors, and it appears plausible on biological grounds.11,16,17
In the interpretation of our results, specific strengths and limitations of this study require careful consideration. Strengths include the large population‐based data sources, especially a unique nationwide registry with more than 840 000 records from screening colonoscopies. The latter allowed estimating age and sex‐specific prevalences of advanced adenomas in an unselected screening population with very small random error. Unfortunately, no data for age group 50–54 years could be provided, as colonoscopy screening in Germany is offered from 55 years on only. Given the lack of information on adenoma location in the national colonoscopy database, it was not possible to further assess potential differences in transition rates of proximal and distal advanced adenomas. The latter might be of interest when (cost‐) effectiveness of screening colonoscopy and screening sigmoidoscopy are compared. Furthermore, although high levels of qualification and experience are a prerequisite for conducting screening colonoscopies and for certification of pathology labs in Germany, and all screening colonoscopies have to be documented on a standardised form, the degree of standardisation of information given on colonoscopy reports is likely to be less perfect in such a nationwide database than it could be achieved in a trial conducted by a few specialised centres with centralised review of all adenomas. However, our results might be more relevant for judging the risk that advanced adenomas detected in routine practice will progress to cancer. Furthermore, potentially less than perfect classification of adenomas provided on colonoscopy reports would be expected to apply to all ages. The resulting potential misclassification would therefore be expected to be “non‐differential” with respect to age, which, according to epidemiological theory, implies that differences in age‐specific transition rates would tend to be underestimated rather than overestimated.24
Potentially less than perfect classification of histopathological findings would thus not explain the major differences in estimates of CRC transition rates between age groups.
A possible concern could be that adenoma prevalences among screening participants might not be representative for adenoma prevalences among the general population. On the one hand, prevalences could be somewhat lower among screening participants, assuming that they are more health conscious than non‐participants. However, in contrast to other cancers, no major variation of CRC risk by factors related to health consciousness, such as indicators of education or socioeconomic status, has been found. However, adenoma prevalences among screening participants might even be somewhat higher than in the general population, assuming that people at higher risk of CRC, such as people with a family history of CRC, might be more likely to undergo screening. Overall, the estimates of advanced adenoma prevalences from the German national screening registry were in line with25,26,27
or somewhat lower than28
previous, less detailed, estimates from much smaller colonoscopy studies conducted in the USA. Although selection patterns could have led to some underestimation or overestimation of advanced adenoma prevalences overall, it is unlikely that they could account for the strong age gradient in advanced adenoma progression estimates found in our study.
National estimates of CRC incidence in Germany referred to the year 2002—the year immediately preceding introduction of screening colonoscopy to avoid “contamination” by detection of asymptomatic CRC by screening colonoscopy. As described in the Methods section, CRC onset rates were derived from CRC incidence rates in our calculations. Therefore, major changes in CRC incidence in the years preceding 2003 and 2004 could, in theory, have influenced our results. However, incidence rates of colorectal cancer have been very stable in Germany since the middle of the 1990s,20
and it appears particularly unlikely that the strong age gradient, which is a universal finding in CRC incidence,29
should have markedly changed in recent years.
Like other studies, we had to rely on external sources for estimates of the proportion of CRC arising from adenomas, but uncertainty with respect to this parameter was taken care of in sensitivity analyses. The same applies to estimates of the duration from CRC onset to CRC detection. The main finding of our study, the strong age dependency of adenoma–CRC transition rates, was not affected by variation of overall levels of these parameters. However, we cannot rule out that potential variation of these parameters between age groups might affect the projections of age‐specific CRC transition rates to some extent.
Despite its limitations, our analysis provides information on age and sex‐specific advanced adenoma transition rates, which could be helpful in the design of endoscopy based screening programmes and their optimisation regarding effectiveness and cost effectiveness. Our finding that advanced adenoma transition rates are strongly age‐dependent could have important clinical implications, possibly including a higher age at first screening or differential endoscopy intervals according to age. However, additional risk factors, such as family history of CRC, also have to be taken into account. To further differentiate estimates of the natural history of colorectal adenomas—for example, by various types and by location—large studies with more detailed information about colonoscopic findings are needed.