Chapter 17: Studies of Adriamycin and Cardiac Toxicity

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Chapter 17: Studies of Adriamycin and Cardiac Toxicity

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In this chapter, Dr. Benjamin talks about his clinical studies aimed at reducing the cardiac toxicity of Adriamycin. He explains how his work was based on pathology studies conducted at Stanford University. He talks about how he adapted the protocols and discovered how to modify the administration of the drug. He talks about the results that were published, noting in particular those achieved when the drug was administered by continuous infusion. He notes that this protocol has been used at MD Anderson since the 1970s, though it is now being supplanted by a cardio-protective drug.

Identifier

BenjaminR_02_20150116_C17

Publication Date

1-16-2015

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Discovery and Success; Patients, Treatment, Survivors

Transcript

Tacey Ann Rosolowski, PhD:

So tell me about some of those first projects, the patient-directed projects.

Robert Benjamin, MD:

Hard to remember. So I guess the first thing, again, challenge from Dr. Freireich, was the studies on Adriamycin cardiac toxicity.

Tacey Ann Rosolowski, PhD:

We talked a bit about that last time.

Robert Benjamin, MD:

Yeah. So that I understood the pharmacology of Adriamycin pretty well, probably better than just about anybody else, having been involved in the actual initial studies. So Freireich said one day, “Isn’t there something we can do about cardiac toxicity? Why don’t you go and study that.”And around that time, I’d heard a presentation from one of the pathologists at Stanford, Margaret Billingham, who had done some studies on the pathology of Adriamycin cardiac toxicity using cardiac biopsies, and they had used cardiac biopsies at Stanford in assessing rejection from cardiac transplants, so they’d developed the techniques for how to do it pretty easily, and I realized that if we could do these cardiac biopsies early on with patients getting Adriamycin, we’d have a much better idea of what was actually happening to the heart and, therefore, have a better way of figuring out which manipulations would modify it.So we developed a series of protocols looking at different strategies of modifying Adriamycin cardiac toxicity. We looked at weekly administration, because some people had said that that’s less cardiac-toxic than standard every-three-week administration, and we saw a little bit of difference, not a major one, but enough to make us think that, okay, what are the differences between weekly Adriamycin and standard every-three-week Adriamycin. And the major difference was the peak level of the drug and how long that peak was present. So the basic principle of pharmacology is if you want to reduce a peak, you just give the drug over a longer period of time. So we said why not give the drug over several days by continuous infusion rather than giving it all at one, and we were lucky that that coincided with the time when we developed—or when others had developed the use of silicone central venous catheters. So we started implanting central venous catheters in patients and giving continuous infusion Adriamycin, and we were able to do that on an outpatient basis, because there were portable infusion pumps that could be used, so we didn’t have to keep people in the hospital and do it.

Tacey Ann Rosolowski, PhD:

Wow. It sounds like a win-win.

Robert Benjamin, MD:

Yeah. But so we were able to look at what happens when you get continuous infusion Adriamycin.

Tacey Ann Rosolowski, PhD:

What year was this? Just approximately. Was it into the eighties or was it still late seventies?

Robert Benjamin, MD:

Seventies, late seventies. I’d have to go back and look at the data on the first problem.

Tacey Ann Rosolowski, PhD:

Sure, no problem. So what were the results? I mean, it’s sounding like it’s really promising.

Robert Benjamin, MD:

Yeah. So we found that we could actually markedly reduce the incidents of cardiac toxicity by continuous infusion, so we published those results and then had developed, based on that, a series of other studies using the continuous infusion of Adriamycin. So that’s been used here since the seventies and only now is getting supplanted by—there’s a cardioprotective drug that can be given that also has a marked effect, possibly even more marked than the continuous infusion. But that was my major area of research, drug-related research during my early years.

Tacey Ann Rosolowski, PhD:

Were there any special lessons that you learned from doing that study that you kind of carried to other studies? (Benjamin sighs.) Oh-oh. (laughs)

Robert Benjamin, MD:

I don’t think so. I think the way we approached the study is just based on sound research training in terms of what’s the goal of the study. So what we did was we measured the Adriamycin levels and showed that as predicted the peak would go down, and it did that. We used the cardiac biopsy endpoint as a way of getting early information as to what was happening to the heart before the heart failed. Cardiac functional measurements were just developing at that time, and they were okay but really not very precise, and you only saw the functional changes after too much damage had been done to the heart, and so it wasn’t safe. Now we have better functional tools, so I think we’re a little bit better prepared to do that.

Tacey Ann Rosolowski, PhD:

I mean, in case you were wondering, I didn’t have any agenda in asking that question. It was more that, you know, you were saying this kind of represented a new, slightly new area of activity, so I wondered if there were any kind of light-bulb, eureka moments there.

Robert Benjamin, MD:

So we did studies with some of the other anthracyclines similar to Adriamycin, to sort of assess the cardiac toxicity using the same strategy, and the biopsies were things—so at Stanford, these were done by the cardiologists. Well, here, the cardiology department had no interventional cardiologists. They did only echocardiograms until Dr. Ewer came, and he had at least been trained in interventional cardiology, so he knew how to do cardiac catheterizations, and he was interested in participating in these studies as well, so he got involved.

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