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Defining Symptomatic in Prostate Cancer

Panelists:Raoul S. Concepcion, MD, FACS, Urology Associates; Michael S. Cookson, MD, MMHC, University of Oklahoma Health Sciences Center; Daniel P. Petrylak, MD, Yale School of Medicine; Daniel I. Quinn, MBBS, PhD, FRACP, FACP, University of Southern California; Neal D. Shore, MD, FACS, Carolina Urologic Research Center; Charles J. Ryan, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Wednesday, Jun 08, 2016


Transcript:

Raoul S. Concepcion, MD:
For the sake of the discussion, the patient has multiple bone metastases, but he has no pain; he’s clearly not taking a narcotic. This becomes a little bit of a discussion point I think that we talk about all the time: what is the definition of minimally symptomatic, symptomatic? Dan, comment if you will. I think people mistakenly think it’s just about pain.

Daniel P. Petrylak, MD: No, it’s about what you’re taking for the pain at the same time. Narcotic analgesic is what I usually use as the cut point. If somebody is requiring narcotics to control the pain, it’s not minimal pain. If it’s something like a nonsteroidal, that I would consider to be minimal pain. I think it’s a subtle distinction but nonetheless, narcotics is the determining point.

Michael S. Cookson, MD, MMHC: And, I think what he’s saying is exactly right. In fact, when you were looking at the clinical trials, most of them required—with the exception of the immunotherapy—some degree of symptomatology for approval on many levels. And most of that, for entry, the easy way was to require narcotics and fill out pain scores. But, we all know there’s lots of different ways to become symptomatic.

Raoul S. Concepcion, MD: Neal, you’ve looked at this quite a bit. Again, classically we’ve always just talked about pain. But, clearly, there are people—especially men—who are quite stoic. They often times don’t give us the whole answer. Sometimes we have to depend upon their primary caregivers, family members. That seems to also have become more and more important these days.

Neal D. Shore, MD: Yes, I think you’re raising an incredibly important point. I find the concept or the definition of symptomatic is very murky and vague. And more and more I think that we’re changing very significantly, as clinicians, as to what this means. I think you’re alluding to the fact that there are certain generational differences about how we complain about pain. There’s clearly phenotypic differences. Men historically—not everywhere—there’s some concern that to complain is to not be manly, and men don’t cry, that sort of concept. There’s the concept that if a male patient might complain, he might be disappointing his physician for fear of that. There could be a concern that maybe a complaint of any sort of discomfort, whether it’s pain or not—maybe it’s inability to hit a tennis ball, or walk up the stairs, or get in and out of a car—might be perceived as, “My disease is progressing and therefore, my clinician, medical oncologist/urologist/radiation oncologist is going to offer me another therapy. And that scares me because I don’t know what that’s going to be, or I don’t want to burden my family, so I’m not going to tell my wife or my children.”

I think we’ve all had the experience where we ask some of these patients, when we’re sitting knee-to-knee to them in a clinic, are you having any discomfort? Are you having any pain? (We usually say pain. We’re very binary about it.) We probably should be much more interrogative about other signs and symptoms. Are you moving around? Are you playing golf anymore? Do you drive your car? Do you take out the garbage? How are you sleeping? Are you getting up in the middle of the night and taking NSAIDs or COX-2 inhibitors? But, when you ask that question of your patient and he nods his head, “Oh, no, I’m not having any discomfort,” how many of us have had the wife sitting next to him go, “Oh my gosh, he’s miserable.”? And I see this all the time. I think one of the constraints is that we’re all very busy seeing more patients, and we need to take the time to interrogate that of our patients, even culturally. Certain parts of the world, there are certain cultures that just won’t complain and then there are other cultures that are much more aggressive about their complaining. We see that in the United States, different regions of the country.

I think there’s a lot of new data that’s coming out that would help us—not just the physicians, but our nurses who often times spend more time with patients regarding their symptomatology—so that we could do a better job. And this becomes important because, thanks to the work that Mike’s done, and Dave, and Dan, and all the trials that they’ve led, we have these therapeutic options. And if we’re not asking, well then we can’t think about the right therapy to give.

Raoul S. Concepcion, MD: As Mike had alluded to earlier, we have these windows. The fact that for many of these metastatic castration resistant prostate cancer patients—because we know that bone metastasis is so prevalent—there does seem to be this element that symptomatic is defined as the use of opiates. But, like Dan said, it depends upon what they’re using, how much they’re using. Dave, can you help us clarify this because, again, symptomatic isn’t not necessarily just opiates.

David I. Quinn, MBBS, PhD: No, I think it’s not. In the population we’re dealing with, they’re not going to say, “My leg hurts, and I’ve got a metastasis there.” It’s a little more complicated than that. So, I have patients that will not take anything more than Tylenol, and if their dosage has gone up and I know they’ve got bone metastasis, there are usually other indicators like the alkaline-phosphatase that have gone up a bit—maybe not even in the abnormal range. But, I’m thinking that they have an abnormal bone milieu from their prostate cancer, and they’re candidates for bone-targeted agents, specifically radium but, also, I’m getting them on board with a calcium and Vitamin D and maybe giving them an antiresorptive agent. I don’t think they have to be necessarily taking opioids at all to be symptomatic. I think it can be much more subtle than that. This is difficult because it’s an area of clinical judgment where when you’re sequentially seeing the patient, I think that’s almost more valuable than anything. Following the progress of their disease is very important.

Neal D. Shore, MD: Raoul, can I make one small comment just to add on to what Dr. Quinn is saying? What’s interesting to me about radium is we’re talking about pain and opioids, or non-opioids. But I never think about really giving this as a pain-alleviating drug. I give radium for survival prolongation, first, and foremost. About a third or 40% of my patients will get some pain benefit. I don’t give it for pain palliation. I give it for survival benefit, which I think is what you clearly showed in the revised CRPC (Castration-Resistant Prostate Cancer) guidelines, thanks to Mike Cookson. That’s really its primary indication, at least in my mind.

Raoul S. Concepcion, MD: I think that’s right. I think that’s the problem because we’ve clearly used other radiopharmaceuticals in the past as palliative agents. Like we all know, this drug is a therapeutic agent that has a survival benefit. As Dan said, that survival benefit is with 6 injections, and should not be used as a palliative agent. But, again, I think like you said earlier, this is a concept of getting into that window with the use of radium.

Michael S. Cookson, MD, MMHC: One of the things that we all know but it should be pointed out is that it can be used pre-docetaxel or post-docetaxel. We talked earlier, it’s hard to combine those. The older agents that we had pretty much would wipe out the bone marrow, eliminate chemotherapy as an option for many patients. That’s not the case with radium, but I think it can be given pre-docetaxel or post-docetaxel, depending on the situation. And because the marrow toxicity is so much less, it still opens up lots of other opportunities.

Daniel P. Petrylak, MD: And also, from that standpoint, there is no difference in the rates of neutropenic fevers in those patients who receive docetaxel either pre-radium or post-radium. There may be a little bit of a diminution in the neutrophil counts after therapy, but that doesn’t seem to be something that’s significant nor that has an impact on patient care.

Raoul S. Concepcion, MD: Something that you mentioned David is, as urologists, we don’t necessarily measure what their alkaline phosphatase is doing pre-therapy as well as post-therapy often enough.

Transcript Edited for Clarity
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Transcript:

Raoul S. Concepcion, MD:
For the sake of the discussion, the patient has multiple bone metastases, but he has no pain; he’s clearly not taking a narcotic. This becomes a little bit of a discussion point I think that we talk about all the time: what is the definition of minimally symptomatic, symptomatic? Dan, comment if you will. I think people mistakenly think it’s just about pain.

Daniel P. Petrylak, MD: No, it’s about what you’re taking for the pain at the same time. Narcotic analgesic is what I usually use as the cut point. If somebody is requiring narcotics to control the pain, it’s not minimal pain. If it’s something like a nonsteroidal, that I would consider to be minimal pain. I think it’s a subtle distinction but nonetheless, narcotics is the determining point.

Michael S. Cookson, MD, MMHC: And, I think what he’s saying is exactly right. In fact, when you were looking at the clinical trials, most of them required—with the exception of the immunotherapy—some degree of symptomatology for approval on many levels. And most of that, for entry, the easy way was to require narcotics and fill out pain scores. But, we all know there’s lots of different ways to become symptomatic.

Raoul S. Concepcion, MD: Neal, you’ve looked at this quite a bit. Again, classically we’ve always just talked about pain. But, clearly, there are people—especially men—who are quite stoic. They often times don’t give us the whole answer. Sometimes we have to depend upon their primary caregivers, family members. That seems to also have become more and more important these days.

Neal D. Shore, MD: Yes, I think you’re raising an incredibly important point. I find the concept or the definition of symptomatic is very murky and vague. And more and more I think that we’re changing very significantly, as clinicians, as to what this means. I think you’re alluding to the fact that there are certain generational differences about how we complain about pain. There’s clearly phenotypic differences. Men historically—not everywhere—there’s some concern that to complain is to not be manly, and men don’t cry, that sort of concept. There’s the concept that if a male patient might complain, he might be disappointing his physician for fear of that. There could be a concern that maybe a complaint of any sort of discomfort, whether it’s pain or not—maybe it’s inability to hit a tennis ball, or walk up the stairs, or get in and out of a car—might be perceived as, “My disease is progressing and therefore, my clinician, medical oncologist/urologist/radiation oncologist is going to offer me another therapy. And that scares me because I don’t know what that’s going to be, or I don’t want to burden my family, so I’m not going to tell my wife or my children.”

I think we’ve all had the experience where we ask some of these patients, when we’re sitting knee-to-knee to them in a clinic, are you having any discomfort? Are you having any pain? (We usually say pain. We’re very binary about it.) We probably should be much more interrogative about other signs and symptoms. Are you moving around? Are you playing golf anymore? Do you drive your car? Do you take out the garbage? How are you sleeping? Are you getting up in the middle of the night and taking NSAIDs or COX-2 inhibitors? But, when you ask that question of your patient and he nods his head, “Oh, no, I’m not having any discomfort,” how many of us have had the wife sitting next to him go, “Oh my gosh, he’s miserable.”? And I see this all the time. I think one of the constraints is that we’re all very busy seeing more patients, and we need to take the time to interrogate that of our patients, even culturally. Certain parts of the world, there are certain cultures that just won’t complain and then there are other cultures that are much more aggressive about their complaining. We see that in the United States, different regions of the country.

I think there’s a lot of new data that’s coming out that would help us—not just the physicians, but our nurses who often times spend more time with patients regarding their symptomatology—so that we could do a better job. And this becomes important because, thanks to the work that Mike’s done, and Dave, and Dan, and all the trials that they’ve led, we have these therapeutic options. And if we’re not asking, well then we can’t think about the right therapy to give.

Raoul S. Concepcion, MD: As Mike had alluded to earlier, we have these windows. The fact that for many of these metastatic castration resistant prostate cancer patients—because we know that bone metastasis is so prevalent—there does seem to be this element that symptomatic is defined as the use of opiates. But, like Dan said, it depends upon what they’re using, how much they’re using. Dave, can you help us clarify this because, again, symptomatic isn’t not necessarily just opiates.

David I. Quinn, MBBS, PhD: No, I think it’s not. In the population we’re dealing with, they’re not going to say, “My leg hurts, and I’ve got a metastasis there.” It’s a little more complicated than that. So, I have patients that will not take anything more than Tylenol, and if their dosage has gone up and I know they’ve got bone metastasis, there are usually other indicators like the alkaline-phosphatase that have gone up a bit—maybe not even in the abnormal range. But, I’m thinking that they have an abnormal bone milieu from their prostate cancer, and they’re candidates for bone-targeted agents, specifically radium but, also, I’m getting them on board with a calcium and Vitamin D and maybe giving them an antiresorptive agent. I don’t think they have to be necessarily taking opioids at all to be symptomatic. I think it can be much more subtle than that. This is difficult because it’s an area of clinical judgment where when you’re sequentially seeing the patient, I think that’s almost more valuable than anything. Following the progress of their disease is very important.

Neal D. Shore, MD: Raoul, can I make one small comment just to add on to what Dr. Quinn is saying? What’s interesting to me about radium is we’re talking about pain and opioids, or non-opioids. But I never think about really giving this as a pain-alleviating drug. I give radium for survival prolongation, first, and foremost. About a third or 40% of my patients will get some pain benefit. I don’t give it for pain palliation. I give it for survival benefit, which I think is what you clearly showed in the revised CRPC (Castration-Resistant Prostate Cancer) guidelines, thanks to Mike Cookson. That’s really its primary indication, at least in my mind.

Raoul S. Concepcion, MD: I think that’s right. I think that’s the problem because we’ve clearly used other radiopharmaceuticals in the past as palliative agents. Like we all know, this drug is a therapeutic agent that has a survival benefit. As Dan said, that survival benefit is with 6 injections, and should not be used as a palliative agent. But, again, I think like you said earlier, this is a concept of getting into that window with the use of radium.

Michael S. Cookson, MD, MMHC: One of the things that we all know but it should be pointed out is that it can be used pre-docetaxel or post-docetaxel. We talked earlier, it’s hard to combine those. The older agents that we had pretty much would wipe out the bone marrow, eliminate chemotherapy as an option for many patients. That’s not the case with radium, but I think it can be given pre-docetaxel or post-docetaxel, depending on the situation. And because the marrow toxicity is so much less, it still opens up lots of other opportunities.

Daniel P. Petrylak, MD: And also, from that standpoint, there is no difference in the rates of neutropenic fevers in those patients who receive docetaxel either pre-radium or post-radium. There may be a little bit of a diminution in the neutrophil counts after therapy, but that doesn’t seem to be something that’s significant nor that has an impact on patient care.

Raoul S. Concepcion, MD: Something that you mentioned David is, as urologists, we don’t necessarily measure what their alkaline phosphatase is doing pre-therapy as well as post-therapy often enough.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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