Chapter 30: The Intra-Arterial Therapy Pump
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Description
Dr. Levin explains that there was a void in studying the treatment of advanced GI cancer when he began his career, and he stepped in to fill this need despite (discouraging advice from mentors) and wanted to set up multi-disciplinary teams to treat patients. He then speaks about the problem of managing people with metastatic colon cancer in the liver. The drug available at the time, 5 Fluorouracil, had low response rates. A derivate, FUDR, could be delivered via catheter into the liver: Dr. Levin sketches the disadvantages of the drug and the methods, then goes on to explain that William Ensinger developed the concept of the portable infusion pump that could be inserted under the skin of the abdomen, a technique that aroused the interest of Dr. Levin and his colleagues at the University of Chicago. He narrates the story of going to Ann Arbor, Michigan, so see the pump inserted and coming back to Chicago to use the method. Dr. Levin explains that evidence of toxicity made it necessary to conduct a multi-center study of the device. In 1984 he was awarded an RO1 to administer a large study that would pool the data. He explains the negative attitude at MD Anderson toward randomized studies, making it necessary for him to give up the grant. He explains that there is still controversy over the value of delivering drugs directly into the liver.
Identifier
LevinB_05_20130827_C30
Publication Date
8-27-2013
City
Houston, Texas
Interview Session
Topics Covered
The Interview Subject's Story - The Researcher The Researcher Overview Definitions, Explanations, Translations Professional Practice Understanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient Care Discovery and Success Technology and R&D Healing, Hope, and the Promise of Research Institutional Politics
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
Tacey Ann Rosolowski, PhD:
Would you like to move on now and continue your discussion of the—
Bernard Levin, MD:
Arterial.
Tacey Ann Rosolowski, PhD:
Yeah, and the infusion pump, which is where we concluded our last session together.
Bernard Levin, MD:
So, one of my interests as it evolved over time was not only the understanding of how colon cancer developed, but recognizing that there was a great need for individuals who might be interested in the treatment. Going back to my days at University of Chicago, there were not individuals who were specifically interested in the treatment of gastrointestinal malignancy, so there was a void into which I stepped. Recognizing that I didn’t have broad training in oncology, I thought I would be able to learn enough from others who were oncologists by setting up a multidisciplinary gastrointestinal oncology clinic, which is what I did at the University of Chicago, and would have gastroenterologists such as myself working alongside oncologists, a research nurse, data coordinator, social worker, to provide care and start to do research on the treatment of gastrointestinal cancer, but particularly colon cancer, which was the most common.
Tacey Ann Rosolowski, PhD:
Can I ask you, why did that void exist?
Bernard Levin, MD:
Well, there’s one very important reason, and that was because there was no effective treatment for advanced colon cancer, so no one in their right mind would spend their career working in that area. It was thought to be a dead end.
Tacey Ann Rosolowski, PhD:
I see. Okay.
Bernard Levin, MD:
I, perhaps not realizing that, nevertheless thought it was very important to begin to address it and was counseled by more than one individual that I shouldn’t be wasting my time.
Tacey Ann Rosolowski, PhD:
Oh, really? Wow.
Bernard Levin, MD:
Anyway, my foolishness persisted, and so this kind of work began. So one of the big issues with time was how do you manage people with metastatic colon cancer in the liver, because the liver tolerates large amounts of metastases very poorly, and people die from liver failure. The chemotherapy that was developed at the time was a drug called 5- Fluorouracil, which was first perhaps described in 1958, and for a long time it was the only drug available, and had a predictable low response rate. A derivative of the drug, called FUDR, was developed and was found to be able to be administered intra-arterially into the liver with somewhat better results, but the cumbersome nature of the delivery apparatus, which was a catheter inserted into the groin, directed then into the liver under radiographic control, had to be positioned for up to three days with the individual lying in bed, not moving much, because the catheter was situated in a major artery.
Tacey Ann Rosolowski, PhD:
Sounds like it would be unbelievably painful too.
Bernard Levin, MD:
Yes, uncomfortable and painful. At around that time, an individual whose name is Bill, William Ensminger, E-n-s-m-i-n-g-e-r, who is a pharmacologist at the University of Michigan, working with the Infusaid, I-n-f-u-s-a-i-d, Company—and there may have been a precursor to that company; I’m not sure anymore—developed the concept of a portable infusion pump that could be inserted under the skin of the abdomen, not too deeply but just under the skin, and could also be loaded by a syringe directed into a one-way port that could be accessed through the skin. But—
Tacey Ann Rosolowski, PhD:
I’m sorry. About what year was this, with Dr. Ensminger [unclear]?
Bernard Levin, MD:
This would have been in about 1980, ’79, ’80. And this technology became of interest to us at the University of Chicago, and the surgeon who was primarily involved, Richard Karl, K-a-r-l, who subsequently became the Director of the Moffitt Cancer Center in Tampa, Florida, and Professor and Chair of Surgery at University of South Florida, was the surgeon who was most involved. And we went to Ann Arbor with a team of individuals that included Dr Richard Pazdur, who is now the Director of the Office of Oncology Drug Products at the FDA, ,and who was then a young oncology fellow at the University of Chicago. We went to see how Bill Ensminger and his colleagues inserted this pump and managed patients. The surgeon involved at that time at the University of Michigan was John Niederhuber who subsequently became director of the University of Wisconsin Cancer Center and then the Director of the National Cancer Institute. So it was an interesting, interesting time, and we learned from Bill Ensminger and John Niederhuber how this pump worked. Our research nurse at the time was Mary Hagle, RN, and she learned how to load this pump through the skin. So we went back to U. of Chicago and started inserting this pump into patients and learned a lot about its tricks and also some of the toxicities associated with intra-arterial infusion. As might be expected, the arteries which received the high dose of chemotherapy sometimes reacted poorly, became inflamed, and the liver itself also sustained liver injury and bile duct injury. So although the treatment seemed to be working and seemed to produce a better response in some patients, it wasn’t certainly a universal panacea. Some people didn’t respond, others responded only for a short while, and others had significant toxicity.
Tacey Ann Rosolowski, PhD:
Can I ask you about the pump itself and where you got the pumps that you were inserting into patients? Was it still experimental at this phase? What was the status of the device itself?
Bernard Levin, MD:
] At some point it became a commercially available device, available to certain teams of investigators. I forget when it became commercially available. But one of the issues which relates to that is the very next subject, which is that because of these various results and different levels of enthusiasm, it became necessary to pose the idea of a study, a multi-center study, to really evaluate the importance or value of this kind of device. So a variety of teams met, and it was decided that there would be a multi-center investigation in which there would be a principal investigator who would be awarded an RO1, but all data would be pooled. So it was an unusual mechanism, but the NCI thought it was worthwhile. So I applied and became the investigator, but because I was then in 1984 about to move to MD Anderson, I informed the NCI and, of course, University of Chicago that I was on my way out to MD Anderson. Also by that time, our surgeon, Richard Karl, had moved, so there wasn’t as much interest at the University of Chicago anyway in continuing this work. So I knew that there was a lot of interest in intra-arterial therapy at MD Anderson. Some very pioneering work had been done by Dr. Yehuda Patt, P-a-t-t, and Dr. Giora Mavligit, M-a-v-l-i-g-i-t, and some of their colleagues. But so what I didn’t anticipate was that there would actually be substantial obstacles to instituting a randomized study at MD Anderson. So when I came, I tried to get IRB approval for the study, but I was told that it was unethical, that we already knew the value of intra-arterial therapy and it wasn’t feasible to do a study like this. This very unscientific approach by several of my new colleagues was a real disappointment to me. So I eventually had to give up the RO1 and return the funds to the National Cancer Institute. It just wasn’t possible to do the study.
Tacey Ann Rosolowski, PhD:
Wow. That must have been really difficult, I have to say.
Bernard Levin, MD:
Yeah, it was. In fact, the study, I don’t think was ever done, never completed by other centers, and to this day there is—perhaps almost thirty years later, there’s some controversy. I think most people believe that with new drugs available now, that were not even dreamed of in those days, that the concept of giving treatment directly into the liver is probably unnecessary and isn’t done much outside of perhaps one center in the world.
Tacey Ann Rosolowski, PhD:
Huh. What’s your sense of that?
Bernard Levin, MD:
I think that’s true. I think that combination therapy, using powerful drugs administered orally or intravenously that can reach the liver and metastases in adequate concentrations are more effective than delivering a drug under high concentration into the liver and causing a lot of bystander damage.
Recommended Citation
Levin, Bernard MD and Rosolowski, Tacey A. PhD, "Chapter 30: The Intra-Arterial Therapy Pump" (2013). Interview Chapters. 1366.
https://openworks.mdanderson.org/mchv_interviewchapters/1366
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