Chapter 25: The Celebrex – Colon Cancer Study
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Description
Dr. Levin next discusses a famous study in which he took part: the study of celecoxib (Celebrex) on polyps and adenomas of the colon. He explains how the study originated when an Israeli colleague approached him in the late 90s to be part of a large-scale, international trail based on original work conducted by MD Anderson scientist, Dr. Ray Dubois. Dr. Levin explains Dr. Dubois’ discovery that aspirin inhibited the overexpression of cyclooxygenase 1 (which can lead to a proliferation of cells). The study in which Dr. Levin took part had over 1500 patients: he organized the studies and quality control. Dr. Levin explains that the study was going very well until a sister study by the NIH linked celecoxib to an increased risk of myocardial infarction. Though celecoxib was shown to reduce adenoma formation by thirty to forty percent, both studies were immediately halted. At the end of this Chapter, Dr. Levin discusses special uses of celecoxib.
Identifier
LevinB_03_20130531_C25
Publication Date
5-31-2013
City
Houston, Texas
Interview Session
Topics Covered
The Interview Subject's Story - The ResearcherThe Researcher Overview Definitions, Explanations, Translations Evolution of Career Professional Practice Discovery and Success The Professional at Work Collaborations Understanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient Care
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
Bernard Levin, MD:
So I became involved—I became interested in the treatment of colon cancer and pancreatic cancer too, so I collaborated with colleagues at MD Anderson and recruited new people and became involved in management and treatment of advanced colonic—colorectal and pancreatic cancer and learned myself how to conduct these trials. But my heart always lay with the prevention of cancer, not the treatment of late cancer, and in the late 90s, a colleague in Israel approached me about becoming the co-principal investigator of a large multinational trial of celecoxib, a selective inhibitor of the enzyme cyclooxygenase-2, which is quite important in the development of colorectal polyps and cancers. And this opportunity to direct and engage in a large-scale trial under the auspices of the Pfizer Corporation was an interesting one because it actually began with a discovery that Dr. Ray DuBois, who subsequently became the provost, had made, while at Vanderbilt University, about COX-2, and Philip Needleman, who was at Searle, who worked for Searle in St. Louis, realized the importance of this observation and helped to develop the drug celecoxib to inhibit this enzyme.
Tacey Ann Rosolowski, PhD:
Could explain a little bit about what COX-2 stands for and exactly what it does?
Bernard Levin, MD:
Cyclooxygenase—there are two enzymes, cyclooxygenase-1 and cyclooxygenase-2, and cyclooxygenase-1 is largely inhibited by aspirin, and that’s why aspirin has profound effects on a number of different parts of the body, including platelets and also on the lining of the stomach, causing it to bleed, and also to some extent has an inhibitory effect on the formation of colon cancer and polyps. It has a relatively small effect on cyclooxygenase-2, which is a sister enzyme which isn’t involved in protection of the stomach against bleeding but is involved in metabolism of certain compounds in the cell. And by virtue of that, when it is over-expressed, when there is too much of it, that can lead to stimulation of other genetic engineering materials in the cell, and thus causing the cells to proliferate and to form polyps or adenomas, and then with further genetic events, to form cancer. So the idea was that if you could inhibit this enzyme, you could prevent polyps from forming and reduce cancer. So this trial required large numbers of patients, over 1,500 actually, and had to be done in many centers throughout the world, so my role became that of helping to organize that and to visit a number of these centers to make sure that the quality of the studies, which were primarily endoscopic, colonoscopic evaluation of the lining of the colon to check on numbers of polyps in patients receiving the drug and those who were receiving a placebo—it was a randomized controlled trial—was being done properly. And these results, or this study, rather, was proceeding very well until a sister study, which was being run by the National Institutes of Health, was found to show an increased risk of heart disease, myocardial infarction, in the treatment group. This was a totally unexpected result. Our study, which was a parallel study, used a slightly different dose of the drug, only a once-a-day dose, and the risk of cardiac disease was less than in the twice-a-day dose regimen. But both studies had to be stopped, and the studies were then completed in a way that one could derive meaningful results, and it was shown in side by side New England Journal of Medicine publications that this drug could reduce adenoma formation over a two- or three-year period in people getting the drug compared to placebo by about thirty or forty percent. But because of the increased risk of heart disease, the drug could not be used routinely, possibly only for people at very high risk. Now, I omitted to say—and I’m sorry, I had a lapse of memory—what had led to this trial in normal risk—in people who had normal risk for forming adenomas was another trial that was done by Gideon Steinbach at MD Anderson and Patrick Lynch and colleagues at St. Mark’s Hospital, London in very high-risk individuals using celecoxib, and they were able to show that in people whose colons were lined by many polyps because of this genetic abnormality called familial adenomatous polyposis that there was a reduction in the number of polyps. Not a complete disappearance, but a substantial reduction, and that knowledge was important in formulating the next question, which was can you apply this in the general population?
Tacey Ann Rosolowski, PhD:
I see.
Bernard Levin, MD:
Now, why the risk for heart disease wasn’t found in the familial polyposis trial was that it was a short-term trial, six months, and the people in it were relatively young, so there was no way to observe this. This phenomenon of heart disease attributable to non-steroidal anti-inflammatory drugs, which is what celecoxib is a member of the class of, was found in other non-steroidal anti-inflammatory drugs almost without exception except for one drug called naproxen, which doesn’t have the heart disease risk but does still have the risk of damage to the lining of the stomach, which can cause bleeding and ulcers. I'm sorry, that’s a little bit convoluted, but I wanted to correct that.
Tacey Ann Rosolowski, PhD:
Oh, that’s no problem at all. No problem at all. Dr. Levin, I'm noticing that our sound levels have been going up and down rather dramatically and increasingly so as we’re on the phone longer. And I’m a little concerned about the continuity of sound quality over the course of the interview, and I'm sorry to suggest this, but I wonder if we could stop for today, and I want to make sure that we check this so that we don’t have a problem. And maybe what I can do is get back to you next week and confirm that we have got a good system here to record, and then we can schedule another time. I'm sorry about this.
Bernard Levin, MD:
It’s okay. It’s okay. I hope this part was coherent.
Tacey Ann Rosolowski, PhD:
I'm sure it was coherent. What I'm concerned about is the fluctuation, and there were a few fluctuations in the early part of the interview, but I noticed that in the last ten minutes or so there were some pretty serious ones, so I want to make sure, because this way I'll know if it’s something that’s only the output end but not in the recorded track. Anyway, it looks like you have an hour and a half extra in your afternoon.
Bernard Levin, MD:
Okay, that’s good. I can always use it.
Tacey Ann Rosolowski, PhD:
All right. Well, let me turn off the recording now. It is 12:35. Let me just do that. (End of Audio One Session Three)
Recommended Citation
Levin, Bernard MD and Rosolowski, Tacey A. PhD, "Chapter 25: The Celebrex – Colon Cancer Study" (2013). Interview Chapters. 1361.
https://openworks.mdanderson.org/mchv_interviewchapters/1361
Conditions Governing Access
Open
