Five Fundamental Advances in Colon Cancer

NEW ORLEANS--Five recent discoveries could have a big effect on colorectal cancer prevention, early detection, and treatment, Margaret Tempero, MD, deputy director of the UNMC/Eppley Cancer Center, Omaha, Nebraska, said at a public forum held at the 89th annual meeting of the American Association for Cancer Research.

In 1998, more than 131,000 new cases of colon cancer are expected, with about 55,000 deaths, she said. "But let me hasten to add that that’s the bad news. Everything else is good news." The incidence of colon cancer is going down in both men and women, she said, and survival after diagnosis is increasing in men and women and in blacks and whites.

Dr. Tempero outlined five important research advances in colorectal cancer that she expects will lead to reduced incidence and mortality.

1. Use of chemopreventive agents. The first fundamental advance, she said, is that there may be a major reduction in colorectal cancer mortality in patients who take aspirin or other nonsteroidal anti-inflammatory drugs. The mechanism seems to be that these agents interrupt prostaglandins and hinder inflammation by inhibiting the enzymes cyclooxygenase 1 and 2 (COX1 and COX2). Unfortunately, anti-COX drugs have some side effects.

Currently in trials are newer agents that inhibit only COX2 and should have few side effects. (See article on this page on studies of one such agent, celecoxib.) "So I think it’s entirely possible that in the future we will have a simple chemopre-ventive tool that can be used in the general population," she said.

2. New methods to detect polyps. A second advance has been the documentation that removal of polyps reduces the risk of colon cancer. However, there are problems with the current technique for looking for polyps, colonoscopy; it is invasive, and complications can occur.

3D Colography

Dr. Tempero is encouraged by the new technique under development of three-dimensional (3D) colography (also known as virtual colonoscopy, see illustration below). In this technique, pioneered by Mayo Clinic researchers, computed tomography provides a detailed 3D view of the colon. "So this is a noninvasive method that may in the future replace colonoscopy in the setting of average risk or in the setting of screening for sporadic polyps," she said.

3. Identification of genetic mutations. Third, Dr. Tempero pointed to the recent identification of the genetic defects underlying two heritable colon cancer syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC), also known as the Lynch syndrome.

In FAP, affected family members develop hundreds or even thousands of polyps in the colon. With so many polyps, it is inevitable that at least one will develop into cancer. Researchers have now discovered that the mutation underlying FAP occurs in the APC gene on chromosome 5q.

In HNPCC, patients have no more polyps than usual. But the ones that occur become malignant more rapidly. HNPCC is now known to be caused by any of several different mutations in DNA mismatch repair genes. For both FAP and HNPCC, the discovery of the genetic basis means that genetic testing could identify the people most in need of intensive surveillance.

4. Advances in screening. Dr. Tempero’s fourth great advance is the discovery that screening with two procedures reduces the risk of death for people of average risk. One of these procedures is an annual fecal occult blood test and the other is an internal examination of the colon, either by flexible sigmoidoscopy every 5 years or by colonoscopy every 10 years.

In the future, she expects that labs will be able to test stool or possibly blood directly for mutated cells. And 3D colography may make screening comfortable and noninvasive.

5. Chemotherapy after surgery. Rounding out Dr. Tempero’s list of top five advances is the documentation that chemotherapy after surgery can increase survival of certain patients by about a third. And in rectal cancer, the combination of chemotherapy and radiation can nearly double the 5-year survival rate, she said.

"One of my problems as a clinician is that I have no way of knowing when I treat the patient after surgery whether they really need my treatment. Some may already be cured, and some may not be able to respond," Dr. Tempero said.

She expects that in the future, clinicians will be able to identify which patients will benefit most from chemotherapy and treat them, while avoiding treatment for those unlikely to benefit. For example, tissue expression of the enzyme thymidylate synthase seems to predict response to 5-fluorouracil.