In the current study, we found no demonstrable difference in crude survival after colon cancer in path_MMR carriers who had had their last colonoscopy 3 years before the diagnosis of colon cancer, compared to those with shorter times between last colonoscopy and diagnosed colon cancer. Considered together with our previous reports, in which we found no decrease in the incidence of CRC with advanced stages of CRCs where the interval since last colonoscopy was less than 3 years before cancer diagnosis, our findings may be considered to be in conflict with the view underlying the current recommendations on the follow up of path_MMR carriers with colonoscopy more often than every 3 years.
In a previous report, we discussed the possibility that not only microsatellite unstable non-invasive lesions, but also infiltrating cancers in LS, may be removed by the host immune system . Aysel Ahadova et al. suggested that although some CRCs in LS may develop from MMR-proficient adenomas after secondary inactivation of the MMR system, a larger portion of LS CRCs appear to develop from MMR deficient crypt foci, either through an adenomatous phase or as non-polyp lesions with immediate invasive growth that may not have colonoscopically visible precursor lesions [11, 12]. Our current report does not aim to provide a full discussion of the biological models that may explain our results: the few we mention are provided to illustrate the wide range of possible explanations that require further investigation.
Our study included only path_MLH1 and path_MSH2 carriers, except for two path_MSH6 carriers, and any conclusions based on this report should be applied to path_MLH1 and path_MSH2 carriers only. Besides, it has already been described that path_PMS2 carriers have almost no incident cancer risk under surveillance.
Clinical guidelines should be based on observed outcomes of interventions. Whatever the reasons for the results presented herein, we report our observed prospective empirical outcomes of clinical guidelines that aim to prevent colon cancer in path_MMR carriers. Our data may therefore be useful in formulating future revisions to clinical guidelines for LS.
In our study, the survival analyses included only colon and not rectal cancers. There were several reasons for this, including differences in the treatment, classification and time from diagnosis to surgical resection of rectal cancers (e.g. this can vary from immediate to delays of several months due to neoadjuvant therapy). In addition, wide variation in the treatment choices across different regions/countries have been described . Since these differences may be confounders to our chosen endpoint, survival by stage, we decided to perform survival analysis only in colon cancers. It is, however, of utmost importance to also report these measures for rectal cancer separately. To achieve this, we will need to collate data for more rectal cancer cases than are currently reported to the PLSD.
There are several limitations to the current study. Numbers included are limited. All centres previously having contributed to the PLSD reports were invited to participate, but not all provided data to this report. We present no information on survival after a second colon cancer subsequent to a first colon cancer. It is possible that some existing lesions were missed during earlier colonoscopies that preceded the diagnosis of colon cancers. We have not excluded that colonoscopy with new techniques and better knowledge on what to look for may prevent cancer and improve survival, but even if so it still remains to be demonstrated that such is possible to implement in a broader health care setting: what we report is the observed outcome of health care so far, not what putatively might have been obtained otherwise. However, if colonoscopy quality did play a significant role related to survival, the impact might be expected to be greatest for the lesions missed with a three-yearly strategy, and survival would be expected to be worse in that group. Because we have recently shown that there is no significant difference between AJCC stages of cancers diagnosed when colonoscopies are done yearly or three-yearly, and as annual colonoscopy has been implemented more recently, there is no reason to assume that colonoscopies with short intervals were of lower quality. We restricted our analysis to the core subset of 96 carriers described to provide a robust crude survival analysis for colon cancer in path_MMR carriers with as few confounders as possible, and we found the same results when also including cases with prior or prevalent cancers in other organs.
While we report the largest prospective analysis undertaken so far of colon cancer survival in LS patients according to time since last colonoscopy, we do not, based on the current and our previous reports, advocate any revision of current clinical guidelines, and the PLSD will ask more contributors to provide data to repeat this study in an independent data set. More detailed studies are needed to understand why there are still some carriers dying from colon cancer, and how this may be prevented. Health economic studies are indicated to establish whether colonoscopy more frequently than every 3 years is justified from a resource perspective. These studies require data on the costs from all aspects, including unwanted (side-) effects, borne by health care systems and patients. The PLSD is presenting some of the many pieces of evidence that need consideration in discussions to revise current clinical guidelines for LS surveillance.