February 24, 2012 1 Comment
Two papers in the February 23, 2012, New England Journal of Medicine reported important findings in the fight against colon cancer. The first paper (Zuber, AG et al; Colonoscopic Polypectomy and Long-Term Prevention of Colorectal Cancer Deaths) conducted by American investigators establishes the benefit of polyp removal in the prevention of death from colorectal cancer. The study conducted upon 2,602 patients who had adenomas removed reveals a 53 percent reduction in mortality from colon cancer compared with the expected death rate from the disease in this population.
To put this into perspective – virtually no intervention in the advanced disease setting provides a survival advantage. The best we can usually do once the disease is established is an improvement in time to progression. When we do observe a true survival advantage it is usually in the range of a few percentage points and never of this magnitude. How might we explain this astonishingly positive result?
One way to view this finding is to reexamine the biology of cancer. One of the leading experts in the field, Bert Vogelstein, MD, from Johns Hopkins, explained colon carcinogenesis as a pattern of gene perturbations starting at atypia, progressing to carcinoma in situ and ending with invasive, metastatic disease. According to Dr. Vogelstein, the average colon cancer found in a patient at the time of colonoscopy has been present in that person’s colon for 27 years. From there it is only a hop, skip and a jump from one-centimeter adenomatous polyp to metastatic (lethal) disease, all playing out over the last three years in the natural history of the disease. Thus, cancer truly is a disease that doesn’t grow too much, but dies too little and interrupting this process while it is still slumbering can, it would seem, lead to cures.
What I find surprising is the success of the strategy. Since it is now well established that cancer can metastasize when it has achieved the rather diminutive proportions of 0.125 cubic centimeters or less and the average polyp can only be detected at one or more cubic centimeters, it is our good fortune that so many cancers chose not to (or could not) metastasize prior to detection. Reading between the lines, those 12 patients who died of colon cancer as opposed to the expected 25.4 are presumably those with early metastasizing disease. The next frontier will be the detection of these cancers when they are teenagers and not 20-somethings. It may be that proteomic analyses will provide an avenue for earlier detection in the future.
The second article is a European study (Quintero, E et al; Colonoscopy versus Fecal Immunohistochemical Testing in Colorectal-Cancer Screening) that compared colonoscopy with fecal blood testing in a large cohort of patients. While the rates of detection for colorectal cancer were similar, the rates of detecting both advanced and early adenomas, favored colonoscopy (p < .001). This study represents an interesting adjunct to the American study described above. Specifically, if the early detection (and removal) of adenomas can confer a survival advantage then it could be argued that colonoscopy by its virtue of it’s higher detection rate of these precancerous adenomas, is the preferred “screening” modality. With over 50,000 deaths attributed to colorectal cancer in the U.S. each year, the public health benefit of colonoscopies becomes an intersecting point of discussion. Until now, fecal occult blood testing yearly or sigmoidoscopies every several years has been considered equivalent to colonoscopies every 10 years starting at age 50. Do we need to move colonoscopies to the front of the line?
What is most interesting about both these reports is the low-tech nature of the study modalities – and the astonishing efficacy of their application. Colonoscopies have been conducted for decades. They are comparatively simple, do not require affymetrix chips, and yet provide demonstrable benefit that appears to exceed anything offered, to date, by the “genomic revolution.” Perhaps we should all keep an open mind about other comparatively low-tech methodologies that can provide survival advantages.