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Issue 19 Interview Transcript


Interviewer: Gretchen Cuda: You’re listening to the JNCI Podcast, a production of the Journal of the National Cancer Institute. I’m Gretchen Cuda. Imagine you have breast cancer. It wasn’t caught early, it’s already metastasized and spread throughout your body. You want the most aggressive treatment you can get, right? Wipe those cancer cells off the map with some super toxic drugs! The more chemotherapy, the better! Not so fast. Research indicates that sequential therapy, giving one drug followed by another is just as effective with fewer side effects than giving multiple types of chemotherapy in combination. A commentary in Issue 17 of the Journal lays out some guidelines for the use of combination versus sequential agent chemotherapy in metastatic breast cancer. I spoke with one of the authors, Eric Winer, Director of the Breast Oncology Center at the Dana Farber Cancer Institute in Boston to get more details. One of the things that the paper brings up right in the introduction is how we don’t really have a good handle on how to treat metastatic breast cancer compared to new breast cancer.

Interviewee: Eric Winer, M.D.: Yeah, I don’t know that it’s fair to say that we don’t know “how” to do it. But I think that what we can say is that there’s certainly more flexibility in the approach. You know, when we treat early stage breast cancer, we have a limited number of options, based on large studies that have shown that a given regimen works. In the metastatic setting, we have more options. And the positive aspect of that is that one can feel a little bit more flexible about matching a treatment to the needs of a patient. Where that can be a negative, though, is that there are sometimes so many options that they have a hard time knowing quite how to approach the problem.

Interviewer: Gretchen Cuda: Okay, so one of those options is whether a person should get sequential drugs, one after another. Or whether a person should get a combination of therapies given at the same time. What is the controversy there? Sum it up for me.

Interviewee: Eric Winer, M.D.: So you know, personally, I don’t think there’s such controversy, although I know that others do. In my mind, there are just a few situations where one should routinely think about combination therapy. One, is the patient who is highly symptomatic. Where you know that the best thing you can do for that patient’s quality of life is to make that woman’s cancer better as quickly as possible. And in that situation, combination therapy makes sense.

Interviewer: Gretchen Cuda: So, well, you know, what are the arguments against giving combination therapy that...

Interviewee: Eric Winer, M.D.: The argument given against it is that it’s more toxic. And if you give Drugs A and B together, and the patient’s cancer gets better, you don’t know if it’s Drug A, or if it’s Drug B, or if it’s both of them. And the fact is, that if in fact, it’s only one of those two drugs, you are essentially wasting side effects. You’re giving a patient side effects, but she’s not benefiting from the drug. So it is far easier to be more specific about your treatment, if you give single agent therapy. So I think that, you know, many of us routinely give sequential single agent therapy, with the exception that in the patient who either is very symptomatic and is going to feel better if we get her cancer better, or the patient who may-- where you feel like there’s only going to be one opportunity to try a therapy because she’s so sick. Now that patient is also typically quite symptomatic. Then in those situations, combination therapy makes sense. Now, finally, all of this discussion is becoming a little bit more moot than it was once, only because in the era of biologic therapy, we’re often giving combinations, but frequently, we’re not longer giving combination chemotherapy, we’re giving a biologic agent like Trastuzumab in combination with a chemotherapy agent, like a Taxane.

Interviewer: Gretchen Cuda: Hm, and in those situations, we already have a better idea that the drug will work?

Interviewee: Eric Winer, M.D.: Well, so, in those situations, we already do have a better idea that the agent may work. And in those situations, as well, there’s really very little evidence that giving combinations of chemotherapy with the biologic are better than a single chemotherapy drug with the biologic. So for example, Trastuzumab or Herceptin, has been given with Docetaxel and has been compared to Docetaxel, Carboplatin and Trastuzumab. So two chemotherapy drugs, plus Trastuzumab, versus one plus Trastuzumab, no difference in outcome. You know, in that setting with the biologic, giving some chemotherapy is useful. But what’s not clear is that giving more chemotherapy, and giving more complicated chemotherapy is better.

Interviewer: Gretchen Cuda: Let’s say you gave a patient sequential therapy. And you know, Drug A worked pretty well, and the side effects weren’t too bad. And then Drug B also worked pretty well, and the side effects weren’t too bad there either. Would a physician at some point later down the road consider combining those two therapies?

Interviewee: Eric Winer, M.D.: Probably not. Unlikely that they would.

Interviewer: Gretchen Cuda: Does research need to be done to tease this apart, or can we sort of comfortably say that this is maybe the best way of approaching it?

Interviewee: Eric Winer, M.D.: But look, there are many people who still would argue to give combination therapy because they believe that getting a higher response rate will more commonly make a patient feel better. And I don’t entirely disagree. I would just say that for many patients, single agent therapy is probably the better way to go. And I don’t know that this is a great use of resources in terms of further research. You know, I think that we’re interested in combining biologic therapies with chemotherapy, we’re interested in new biologic therapies, we’re interested in combinations of different biologic therapies with one another. And so simply doing studies where we compare one chemotherapy versus two or three, I think at this point in time would be viewed as somewhat less interesting, and less likely to move the field forward. I guess the other thing to keep in mind is that when we take care of a woman with metastatic breast cancer-- and this isn’t any different from taking care of anybody with any illness-- there are ultimately two things that matter. One is how long you live. And clearly, we want to maximize survival. And the other is how well you live.

So we want to maximize quality of life. And any other measure of the effect of a treatment, so response rate; time to progression, that is, time to when the cancer gets worse. All of those other endpoints are only important if they correlate with either survival or quality of life. Because in the end, it’s how long and how well you live that matter.

Interviewer: Gretchen Cuda: Hm, so it sounds that maybe like our endpoints really should be maybe a combination of both overall survival, as they point out in the paper; and also, quality of life.

Interviewee: Eric Winer, M.D.: Well, and but the pro-- and the problem with quality of life is that in spite of now probably three decades of research, looking at measuring quality of life in patients with cancer, it is still widely viewed as problematic getting accurate assessments of quality of life. And even when you compare different treatments, it’s often very hard to demonstrate differences in quality of life. So that, you know, we’re often forced to use other measures like time to progression, as ways that we can get a sense of what someone’s quality of life may be like.

Interviewer: Gretchen Cuda: Hm. So in the absence of a good measure, what’s a clinician supposed to do?

Interviewee: Eric Winer, M.D.: I think that you can’t overstate the importance of listening to patients, paying attention to the patient’s quality of life, even though we don’t necessarily have an easy way of measuring it. But you know, getting as accurate a sense as you can as a clinician in terms of a patient’s quality of life. And then really trying to match a therapy, both to the cancer, when possible. So for example, you know, Trastuzumab or Herceptin is used in HER-2 positive breast cancer, and isn’t used in other settings. But then also to match the therapy to the kinds of side effects that a patient will find most easy to tolerate. So for example, there are women with metastatic breast cancer, who care tremendously about losing their hair. They know that ultimately metastatic breast cancer is something that may threaten their lives, and in that setting, they simply just don’t-- they simply don’t want to go around wearing a wig, or going without hair. There are others who say, “Hair loss? It’s no big deal. I’ve lost my hair before. I’ll lose it again.” You know, don’t think about it for a second. And as clinicians we have to listen to those different points of view from patients and we have to respect them.

Interviewer: Gretchen Cuda: Well, let me ask you this, too, I mean, we’ve been treating breast cancer for years now, how come we still don’t know the answer to some of these questions about whether or not combination therapy or sequential therapy has-- is the best way to go?

Interviewee: Eric Winer, M.D.: So I’d actually argued that to a large extent we do know. And we know that there’s a substantial difference in survival. And that we also know that there isn’t a substantial difference in quality of life. And so it turns out to be more of a philosophical issue, and a clinical judgment issue, than a right or a wrong. And I think that there are many areas in medicine where we don’t have a right or wrong-- we just have different treatment approaches, and people can debate what they think may be best, but in the end, it probably is not critical exactly how you do it.

Interviewer: Gretchen Cuda: I just have one final question, and it’s that whenever our last podcast dealt with the increasing cost of cancer drugs, particularly in biologics, and I was wondering is there any cost argument here in terms of giving sequential therapy versus combination therapy?

Interviewee: Eric Winer, M.D.: You know, I haven’t seen any analysis of that. I would assume that giving sequential therapy ultimately is less costly, because the total amount of drug used is probably less, and there are fewer complications. But I don’t think that’s the major driver here. And you know, the other issue, of course, with cost, is that while we can consider cost when we think about approaches to treatment, in general, the one thing I think we don’t want to see happen is for clinicians to walk in the room and feel that they have to, in some way, ration treatment, based on cost.

Interviewer: Gretchen Cuda: Right.

Interviewee: Eric Winer, M.D.: It’s not, you know, dealing with cost isn’t something that necessarily should be done by the bedside. It’s something that needs to be done outside of the patient room, and as a matter of policy.

Interviewer: Gretchen Cuda: Well, I thank you so much for your time.

Interviewee: Eric Winer, M.D.: Oh, sure!

Interviewer: Gretchen Cuda: I appreciate that you had a few minutes here to talk to me about this. It’s an important topic, I think.

Interviewee: Eric Winer, M.D.: Oh, anytime!

Interviewer: Gretchen Cuda: Bye-bye.

Interviewee: Eric Winer, M.D.: Bye.

Interviewer: Gretchen Cuda: Dr. Eric Winer is Director of the Breast Oncology Center at the Dana Farber Cancer Institute in Boston, Massachusetts. That’s it for this edition of the the JNCI Podcast. If you like what you hear, let us know. Send an email to podcasts@jnci.org. And don’t forget to check back in two weeks for our next update. In the meantime, you can listen to this, or any of our other podcasts online at jnci.oxfordjournals.org. That’s also where you’ll find additional information on today’s topic, and other fascinating articles on the latest cancer research from the print journal as well. I’m Gretchen Cuda. Come listen to us again soon.