SLIDES & TRANSCRIPTS
Wednesday, February 16, 2000

Why Does Treatment Fail?
Joel Tepper, MD

Dr. MAYER: Our last panel is coming up. I want to ask that all of the chairs of the panels stop by the desk over here on the way out to get a little disk of the panel discussions for editing purposes.

Our last and provocative panel topic is why do we fail, and why does treatment fail, and to address that Joel Tepper from the University of North Carolina has assembled a group.

Dr. TEPPER: Thank you, Bob. When Bob invited me to chair this panel I thanked him for the nicely focused topic. We only have about three days worth of discussion on this, so we will have to get going fairly quickly to cover it.

Clearly there is so much that we could discuss in terms of why treatments fail. I had to go along and try to look at some focused areas, and perhaps some areas that are a little bit unconventional, but I think what would be a good idea to start off just in very, very broad terms, making just a couple of moments of introduction because we have three basic treatment modalities that we use right now in the treatment of colon and rectal cancer. The first and still the primary is surgical management, and it is perhaps easiest to figure out why surgery fails.

Surgery fails because there is inadequate definition of the tumor extent. The surgeon thought the disease was one place, and it was someplace else. He didn't get it out. It can fail because you know where it is but because of technical limitations you cannot get it out and the presence of metastases is kind of the same thing. There is more disease than you realized is there, and I think it is fairly straightforward. It is not always clear what to do about these things, but at least in a very broad sense we understand.

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Chemotherapy which has been the object of most of our discussion yesterday and today can also fail for a number of reasons. We have been talking almost entirely about the issues of chemotherapy, biochemical, genetic resistance that goes on, but in point of fact that may not be the only reason for treatment to fail, and in some situations it may not be the dominant reason that treatment would fail with chemotherapy. There are issues that the chemotherapy, if you are going to give it, has to get to the tumor, and it has to be in the tumor long enough to do something, and so issues of blood flow, drug efflux, various tumor pressures and all may be extremely important issues in terms of why chemotherapy treatment fails as well as issues of just tumor growth and tumor regrowth.

As a radiation oncologist I have always found it interesting that we try to give our treatment very rapidly for a short period of time because we are concerned about tumor cell repopulation and medical oncologists sort of every four weeks they give something, and they say, well, that is going to do it. Tumor cells do regrow and may be very important issues, and then there are issues of once the chemotherapy has gotten there and done something does the tumor have the ability to repair any of the damage that was done.

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Radiation therapy is in some ways a mix of surgery and chemotherapy. It is a local modality, but it is a biologically oriented local modality, and we can fail with radiation therapy because of inadequate definition of where the tumor is and presence of metastases in the same way that surgery might fail as a local modality.

We can also fail analogously to surgery because we cannot give enough dose to the tumor to destroy the tumor because of normal structures very analogous to the surgeon's inability to resect the tumor because it is invading into something else. That is sort of a biologic versus physical injury but nonetheless it is an injury just the same that affects our ability to control. But in contrast to chemotherapy with radiation we usually have a very good sense of whether the agent got there, whether the radiation got to the tumor, and the same type of issues of chemotherapy resistance can relate to radiation resistance.

There can be enhanced repair pathways, radical scavengers and as I mentioned before the tumor cell repopulation, and this is clearly just a very scant overview but just to paint it in some fairly broad brush of the type of issues that may go on.

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In order to address some of these issues, I pulled together a panel which is a little bit different than some of the other panels. First of all, two of the three speakers are really not involved in any significant way that I am aware in GI cancers primarily, but I thought this might be good in terms of getting people from a very different perspective to talk to us rather than have the same people always talking to us, and to discuss a number of these issues that I have discussed from the biochemical, genetic resistance as well as issues of drug penetration and repopulation and the like.

I want to start off and ask Carmen Allegra from the Medicine Branch to give us the first talk.

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