Thursday, February 23, 2012

Obvious or Not

In Science in 1991 Vogelstein et al published one of their many results on colon cancer and its related genes and a Science writer presented the above picture in a summary article. The above paradigm has become common place amongst a wide class of cancers. Namely we see a set of well defined genetic changes that lead to intermediate steps in a cell and eventually to a cancer.

In this weeks NEJM the authors have concluded that colonoscopies with the removal of adenomas actually improves survival.

The authors state:

We previously found that polypectomy reduced the incidence of colorectal cancer in the NPS cohort.The present study suggests that adenoma removal significantly reduced the risk of death from colorectal cancer, as compared with that in the general population, and in the first 10 years after polypectomy, reduced the risk to a level similar to that in an internal concurrent control group of patients with no adenomas.

Our comparison of observed deaths in the adenoma cohort with expected deaths in the general population, based on SEER data that were specific for age, sex, race, and calendar year, may have underestimated the reduction in mortality that may be achieved with colonoscopic polypectomy in screening populations. Because all the patients in the adenoma cohort had adenomas, including 57.3% with advanced adenomas, they represented a higher-risk group than the general population

 Now this is no surprise, namely that survival is better. However what is a surprise is that there should be any deaths at all for those being closely watched with polyp removal. Namely if colon cancer, adenoma type, are following the Vogelstein paradigm, then careful colonoscopies would in almost all cases catch and remove a polyp before going to a final stage, especially one of metastatic potential. Thus one should have assumed that zero mortality was expected and anything but would and should be questioned.
 The authors state:

This prospective study has some limitations. First, a small number of trained endoscopists performed the colonoscopies according to a study protocol that required examination to the cecum, adequate preparation, careful inspection of the colon, and removal of all identified polyps, features that are consistent with reports of high-quality performance. Consequently, the NPS observations may not be generalizable to present community practice, for which reported incidence rates of colorectal cancer after polypectomy are higher than those reported in the NPS

Indeed there are concerns, for why were there any mortalities if the colonoscopies were done as we would expect.

You see, if we believe Vogelstein, and after 21 years the belief is fact, that when we remove an adenoma we are removing the pre-malignant cells, that is those cells which will eventually become the cancer stem cell, and their progeny, then we remove any future malignancy from that source.  Thus what then is the source for the cancer which consumes the patient.

Perhaps looking at the data may provide some evidence but then again perhaps not. The paper qua report does not offer that detail. Thus one wonders if the Vogelstein model is in error or that there may be some secondary but highly significant issues in the patient pool.

One should have concluded total removal of any colon cancer, not a 50% reduction in death from that cause. This should in my opinion be the conclusion of this report, instead the press seems to laud the reduction in death rate by 50%, not the fact that it really should be 100%! Was the adenoma the cause, where else did the cell come from, had it metastasized already, where was the resulting stem cell hiding, is the Vogelstein model wrong, does this effect happen elsewhere, such as in melanoma in situ? What of the presence and then absence of HGPIN, was that a removal of a CSC?

This result raises many questions from the aspect of a systems model for cancer. Unfortunately few seem to be considering them. Hopefully it will instigate a few.