Response to the letter to the editor by Hassan et al.: The diminutive lesion versus the advanced adenoma: Which is the real target of CT colonography screening?

Dear Sir, We thank Dr. Hassan and colleagues for their interest and their careful reading of our article. In their letter to the editor, Dr. Hassan et al. express their concern with our result that optical colonoscopy (OC) every 10 years was more clinically effective than CT colonography (CTC) every 5 years with a 6 mm cut-off for post-CTC polypectomy. Before responding to their suggestions for possible explanations, we would first like to stress that although 10-yearly OC was indeed more effective, the difference with 5-yearly CTC was negligible (0.002 life-years, less than 2% of life-years gained). Based on the only slightly lower test characteristics of CTC compared with OC, Dr. Hassan et al. expected superior effectiveness of 5-yearly CTC compared with that of 10-yearly OC because of superior cumulative sensitivity of 2 independent CTC examinations. Two subsequent CTC examinations indeed have superior sensitivity over 1 OC examination. However, when these 2 CTC examinations are 5 years apart, some of the advanced lesions missed at the first examination will have already progressed to clinical colorectal cancer (CRC) before the repeat CTC, making CTC no longer superior. Dr. Hassan and colleagues suggest that the superiority of 10-yearly OC in the MISCAN model is due to the relative importance of polyps 5 mm in the MISCAN modeling of the adenoma-carcinoma sequence. Although the MISCAN model does have a relatively short duration of the development from adenoma to cancer in comparison with other models, we do not believe that this explains the lack of superiority of 5-yearly CTC. In a comparative cost-effectiveness analysis of CTC screening for the Centers for Medicaid and Medicare Services (CMS), 2 other models (SimCRC and CRC-SPIN) with considerably longer durations of the adenoma-carcinoma sequence also found that 10-yearly OC was more clinically effective than 5-yearly CTC. These models are comparable in their duration assumptions to the model of Dr. Hassan, so there has to be a different explanation for the discrepancy in result between the MISCAN model and Dr. Hassan’s model. Dr. Hassan et al. also suggest that the MISCAN modeling results are not consistent with a very low rate of advanced features detected in diminutive lesions ( 5 mm) in clinical studies (0.09%). However, the MISCAN results are consistent with these observed results. The MISCAN model incorporates the growth of adenomas, whereas these prevalence studies do not. Growth of adenomas increases their malignant potential, so not accounting for the growth will underestimate the true malignant potential of small adenomas over time. Furthermore, the MISCAN model allows for heterogeneity of adenoma growth and increasing malignant potential with increasing age. In the MISCAN model, 16% of new small adenomas occurring at younger ages become cancerous within 16 years. However, by age 65 the percent of new adenomas that become cancer increases, such that by age 100, 96% of new adenomas become cancer. At old age, many of these fast-growing adenomas still do not make it to cancer because of competing death from other causes. But even in the hypothetical situation without death from other causes, the situation is not that 96% of all small adenomas at age 100 actually make it to cancer within 16 years, or that 10–64% of adenomas make it to cancer within 10 years as stated by Dr. Hassan et al. Small adenomas that are present at age 100 but started earlier in life have a much smaller potential of becoming cancer, it is only the newly arising adenomas that have higher malignant potential. This heterogeneity in growth between adenomas causes the relatively short duration of the adenoma-carcinoma sequence in the MISCAN model, while the model is still in line with clinical studies such as the one suggested by Dr. Hassan et al. Furthermore, the average duration from adenoma to carcinoma of 20 years is in line with the beliefs of experts in the field of CRC. The current data are insufficient to rule out heterogeneity in growth of adenomas. Longitudinal data from large prospective endoscopy studies such as PLCO, the UK flexible sigmoidoscopy trial and the SCORE trial are required to answer the dwell time heterogeneity question. The title of the letter by Dr. Hassan et al. ‘‘The diminutive lesion versus the advanced adenoma: Which is the real target of CT colonography screening?’’ suggests that our results favor follow-up and treatment of diminutive lesions. However, our analysis finds superior cost-effectiveness of CTC when diminutive lesions are ignored compared with CTC with follow-up