Chapter 24: Assessment of Response to Therapy

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Chapter 24: Assessment of Response to Therapy

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Description

Dr. Benjamin talks about his focus on assessing responses to therapy. He explains why this is a complex process, giving examples of confusing results that a clinician might confront. For example, GIST tumors only reduce slightly in size with treatment, but change structure. He describes a study in which patients responded well to Imatinib, but there was no way to document their improvement with the current guidelines. Dr. Benjamin says he collaborated with Dr. Choi in studying GIST tumors, work leading to the creation of the Choi Criteria for assessing therapy. These criteria, he says, have had some impact, then talks about the challenges of getting the model out and accepted. Dr. Benjamin explains what is needed for the model to be improved and expanded.

Identifier

BenjaminR_02_20150116_C24

Publication Date

1-16-2015

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Overview; Definitions, Explanations, Translations; Discovery and Success

Transcript

Tacey Ann Rosolowski, PhD:

What are some other areas of study that have been really significant for you?

Robert Benjamin, MD:

So I think the other area that’s been a longstanding interest and has sort of cut across the different tumors and different therapeutic approaches I deal with is the assessment of the response to therapy, which sounds like it ought to be very simple, and it isn’t. It’s very clear. When oncology first started, the patients with leukemia would have bone-marrow aspirations done, and you would count the number of leukemia cells before and after the treatment, and you had a very good quantitative measure of what were the effects of treatment. When solid-tumor oncology started, people tried to come up with quantitative measures of the effects of treatment, and so they measured the size of the mass that they could feel and tried to equate what happened to that mass as to how much tumor was destroyed. I mean, it’s pretty intuitive that if the mass gets smaller, the tumor is probably getting better, and if the mass continues to grow, the tumor is probably getting worse. And the first is true and the second is not necessarily true, because the size of the mass doesn’t necessarily reflect the number of tumor cells present.So in bone tumors, since we started doing chemotherapy before surgery, but surgery was always part of the treatment, we could measure the effects of the chemotherapy by having the pathologist take out the bone and cut through the bone and see how much was dead and how much was alive. And it was very clear, because of peculiarities of osteosarcoma, osteosarcoma when it heals sometimes forms a rim of bone around the tumor, and if there’s a rim of bone around it, it can’t shrink, but everything in the middle may be dead or everything in the middle may be totally alive. And so the only way we really knew was to ask the pathologist, and we found that, okay, if a rim of bone formed, that was almost always associated with a good response, so that was evidence of response to therapy.So we knew from treating osteosarcoma, probably by the 1980s, that just measuring tumor size was not necessarily the right answer. And we knew from treating patients with liver metastases with tumor embolization, blocking off the blood supply, that often we could get a profound effect on the growth of the tumor, but the CT scan would still have a hole in it. We knew from treating giant cell tumors of bone that there could still be a major abnormality in the residual bone that was embolized, but the patient could live without any progressive disease for decades.But when we started treating gastrointestinal stromal tumors with Gleevec, we found that tumors sometimes got smaller, they usually got smaller, but they didn’t usually get a lot smaller, they just got a little bit smaller, but their imaging characteristics changed markedly. So they went from being hyper-vascular, intensely enhancing lesions to basically being holes within the liver, but they were still there.

Tacey Ann Rosolowski, PhD:

And I will assume that the patients were getting better.

Robert Benjamin, MD:

The patients were getting better. And if you did a PET scan in the setting of the gastrointestinal stromal tumor, the PET scan could go from very, very hot, showing active metabolic tumor, to very, very cold showing no residual tumor, but the size of the hole in the liver could remain the same.So when we started the work with Imatinib, Gleevec, for treating GIST, it was very apparent that the vast majority of the patients were getting better, but only a minority of the patients qualified as having responded to therapy under the arbitrary rules that had been set up. So we decided—and, I mean, I think everybody else probably saw that as well, but, I don’t know, they didn’t comment on it. So we describe for the first time here that these patients could have either minor shrinkage or no shrinkage at all, even tumor growth, but have change in the imaging characteristics such that you could very easily call them responders to therapy and that the responders by those criteria did just as well as responders by the traditional standard criteria.

Tacey Ann Rosolowski, PhD:

Wow.

Robert Benjamin, MD:

So a lot of the work that we did in with gastrointestinal tumors was done in collaboration with Dr. Choi in Radiology, so we put forward new criteria and called them Choi Criteria to look at alternative strategies for determining the effectiveness of treatment, because if you think about the clinical experiment, if you do your clinical experiment to determine how many patients respond to your new treatment, and you haven’t defined response correctly, you get the wrong answer.

Tacey Ann Rosolowski, PhD:

Right. Well, then there’s also the administrative in patient care. You can’t document there’s been a change, there’s no reason to change standard of care, and to bill for it, you know. It just keeps cascading down the line.

Robert Benjamin, MD:

Right. So we figured out new ways of looking, and those apply probably at least—they’re applied to a large fraction of the patients with soft-tissue sarcomas that we treat with various forms of chemotherapy as well. So I’ve been interested in trying to figure out better ways to evaluate who’s getting better and who’s not.

Tacey Ann Rosolowski, PhD:

So these Choi Criteria are kind of one formal way the institution has found—

Robert Benjamin, MD:

It’s one formal way. It’s something which is used by some but not all, some but probably not most people working with GI stromal tumors. But it’s being used by more and more people in more and more areas or at least being investigated by them. So I think we’ve at least—and the Choi Criteria were never designed to be the final say on what was there. It’s just the major point being that the criteria that we’ve always accepted as written in stone don’t always work and therefore shouldn’t necessarily be applied.

Tacey Ann Rosolowski, PhD:

Is there a—I mean, I don’t know quite how to contextualize this. So you’re developing these new observations, new way of systematizing how a patient is assessed for response and improvement, and is the obstacle, or however you want to use the word, to having other people acknowledge that, is it just ignorance or is it controversial? Like what’s going on there with getting this system out and disseminating and either having it discussed or accepted?

Robert Benjamin, MD:

I wish I knew the answer to that question. (Rosolowski laughs.) The simple answer is that sometimes it takes a little more work, and, as I said, it’s far from perfect, so I think those are the key things. But I think it’s clearly an area that needs to be addressed in continuing fashion and appropriately modified for each of the situations that people deal with, because I don’t think that what happens in a gastrointestinal tumor treated with Gleevec necessarily applies to what happens in a colon cancer treated with whatever regimen they now use. I just know that the old criteria that had been applied don’t necessarily work.So basically, at least with sarcomas, I know that the tumors never got the opportunity to read the book, as in terms of what they were supposed to do when they responded. The initial observations, you treat the tumor, it gets smaller, that’s good, come from the initial tumors that responded to the first generation of chemotherapeutic drugs that were out there. And those tumors did read the book, or maybe those tumors wrote the book, but they only wrote the book for themselves. It’s a leap of faith to say that other tumors treated in other ways necessarily will behave the same way.And my bottom line is looking at the pathology and looking at the bone tumors, because if there’s a big mass present and you take that whole mass out and you can’t find any tumor cells in it, that means the treatment worked. So the fact that the mass didn’t know to disappear is a different problem, but the efficacy of the therapy is based on going back to the leukemia model and counting how many tumor cells there are after you treat. And it’s clearly a leap of faith that the number of tumor cells is necessarily proportional to the size of the mass. So we see tumors that become scarred, we see tumors that fill up with fluid, and it’s tricky to figure out what to do. Part of what makes the medicine fun, it’s figuring out are you really helping or are you not helping, and realizing that how the reports are written and how the tumor measurements come out may or may not be representative of what’s really happening.

Tacey Ann Rosolowski, PhD:

Well, it’s reflective, too, of an entirely new state of knowledge. I mean, as you were going through all of the situations that are really counterintuitive based on the old model, I’m thinking, wow, I mean, the depth of experience with tumors and the numbers of patients that represents is staggering. And that comes from institutions that have long experience, have done many, many, many studies with many, many, many patients. Of course you’re going to have a more nuanced view of the entire terrain of cancer after going through that.

Robert Benjamin, MD:

Oh, yeah, yeah.

Tacey Ann Rosolowski, PhD:

Yeah, so you’re changing knowledge base at that point, and rightly so. That’s really fascinating. No wonder you think it’s fun. (laughs)

Robert Benjamin, MD:

Yeah. It is.

Tacey Ann Rosolowski, PhD:

Well, Dr. Benjamin, we’re actually at ten after four, and I know I’ve sort of abused your time here, but thank you for going over—

Robert Benjamin, MD:

No problem.

Tacey Ann Rosolowski, PhD:

I hope we can talk about having another session, because we haven’t talked about certain questions that I’d like to ask you.

Robert Benjamin, MD:

Okay, sure.

Tacey Ann Rosolowski, PhD:

We can talk about that tomorrow.

Robert Benjamin, MD:

No problem. I’m happy to help out.

Tacey Ann Rosolowski, PhD:

Well, great. Well, let me just close off. So I’m turning off the interview at about twelve minutes after four. Thank you very much for your time today.

Robert Benjamin, MD:

Sounds good. Good. You’re welcome. (end of audio session two)

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Chapter 24: Assessment of Response to Therapy

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