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Impact of Volume of Disease in Prostate Cancer

Panelists:Raoul S. Concepcion, MD, FACS, Urology Associates; Michael D. Fabrizio, MD, FACS, Eastern Virginia Medical School; Jorge A. Garcia, MD, FACP, Taussig Cancer Institute; Judd W. Moul, MD, FACS, Duke University Medical Center; Charles J. Ryan, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Friday, Mar 18, 2016



Transcript:

Judd W. Moul, MD, FACS:
It’s interesting seeing how things have evolved, starting at ASCO 2014 when Sweeny presented CHAARTED. Well, the press release had actually come out 6 months before that from the NCI, around the end of 2013, right at the beginning of 2014.

Jorge A. Garcia, MD, FACP: December 6, yeah.

Judd W. Moul, MD, FACS: Early on, our medical oncology guys were very skeptical about chemotherapy with the low-volume disease, based on CHAARTED and the French study. Then what happened, right after ASCO 2015 or when the STAMPEDE data were leaked and then presented, that seems to all have evaporated. So it seems like at our tumor boards now, if I present a case as a urologist, all the medical oncologists are cool with docetaxel irrespective of high or low-volume. I don’t know if that’s just at our institution or is that what you guys are seeing?

Charles J. Ryan, MD: That’s happening, yeah.

Raoul S. Concepcion, MD, FACS: Mike, is that what you’re seeing?

Michael Fabrizio, MD, FACS: Yes.

Raoul S. Concepcion, MD, FACS: Both high volume and low volume.

Michael Fabrizio, MD, FACS: Yes.

Jorge A. Garcia, MD, FACP: I think that the power of CHAARTED was very simple. This trial was designed to detect the difference between adding chemo or not, period. So the concern that I always have when we are making clinical decisions on a daily basis is that we use subset analysis to make those sort of judgment decisions on a clinical basis. But the reality of it is, the study was not powered to detect that difference in the subset analysis between low volume and high volume. Now, what is more important to me is when we talk about median survival. Some physicians just take into consideration hazard ratio.

Look at the evolution of hazard ratio over the last 10 years in prostate cancer. In fact, since 1999, when mitoxantrone became FDA approved, with no survival benefit but just quality of life and pain improvement, hazard ratio back in the days was around .8 or greater. And since then, when you think TAX 327, when you think about SWOG 9916, hazard ratio is in the .76 range. Now, guess what, the hazard ratio of any therapy that we have right now is in the .6 range. In CHAARTED, for that matter, the hazard ratio of those individuals who got androgen deprivation therapy (ADT) and chemo is 0.61.

These hazard ratios, to me, really mean a lot because that clearly states that we have drastically changed the outcome of these patients. I think that STAMPEDE, to me, should settle that issue in our low volume or high volume. The subset analysis of low volume or high volume using the CHAARTED definition has not been presented yet. So I would argue, and I wonder what you guys think about this. If STAMPEDE comes out and says low-volume patients, using the definition that CHAARTED used, don’t have a median survival improvement, then the question is should we pause and stop using chemotherapy for those patients with low-volume disease until we get a little bit longer follow-up? Or should we still say, you know what, every patient should get chemotherapy. And that is also how you define volume, right?

Michael Fabrizio, MD, FACS: Yeah. We asked that at the very beginning.

Charles J. Ryan, MD: The hazard ratio and the low-volume cohort are still low. It’s just that the medians haven’t been reached. And keep in mind that the study started out as a study for high-volume disease. So the low-volume patients have 2 things going for them. They have low-volume disease, and they were entered into the study late in the life cycle of the study.

Raoul S. Concepcion, MD, FACS: I would also ask the question, in these patients with low-volume disease or oligometastatic disease, what is the role of the management of the primary in those patients? Because now we have some very sophisticated rapid autopsy next-generation sequencing studies looking at the mets. And all mets come from a clone that has actually come from the primary, and you have this re-seeding and seeding phenomena.

Judd W. Moul, MD, FACS: Speaking of oligometastatic disease, my former Fellow, Axel Heidenreich, who is now chair of urology in Cologne, had one of the hot papers looking at surgery for oligometastatic disease. There’s now a series of trials starting to address radical prostatectomy in oligometastatic disease. Where is that going to fit with CHAARTED and STAMPED? Just as a follow-up question for the urologists. Let’s say I have a new M1 stage, hormone-sensitive disease. I see the data. I know the right thing to do is to get that patient to medical oncology for docetaxel, and I want to set the stage of optimism. But is there a group of patients where I don’t want the patient who is not a candidate to be disappointed? Is there a subgroup where you would pause and say, sir, this may not be for you?

Raoul S. Concepcion, MD, FACS: I think obviously if you had a neuroendocrine tumor, you wouldn’t use docetaxel. You would probably go more toward a platinum-based agent, right?

Charles J. Ryan, MD: Yeah.

Jorge A. Garcia, MD, FACP: Yeah.

Charles J. Ryan, MD: So patients who aren’t candidates for upfront docetaxel is the question. I’ve had challenges, as have many of my colleagues with older patients, where the goals of therapy might be a little bit different, but it’s still worth having the conversation. I’ve given docetaxel to men in their 90s, so there’s not an absolute cut-off of when it is or not appropriate, but it has to do with frailty, comorbidities, and all those other things. And so, I would say, I would urge a little bit of caution in recommending and being terrifically optimistic about the benefits of docetaxel in a patient who is, aside from his prostate cancer, frail or sick.

Judd W. Moul, MD, FACS: Is there any kind of simple frailty score?

Charles J. Ryan, MD: Absolutely.

Judd W. Moul, MD, FACS: What should urologists use? Is there a tool that’s the best?

Charles J. Ryan, MD: There are frailty indices. There’s a whole field of geriatrics that studies comorbidity indices and things like that. There have been some retrospective analyses looking at this. Like nomograms, you can come up with scores of this. They are a bit intuitive. I ask questions about what’s your typical day like. If I wanted to go for a walk with you, how far could we go and these types of things. Over time, after talking to many, many patients, you get a sense as to where that’s going to pan out.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity

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Transcript:

Judd W. Moul, MD, FACS:
It’s interesting seeing how things have evolved, starting at ASCO 2014 when Sweeny presented CHAARTED. Well, the press release had actually come out 6 months before that from the NCI, around the end of 2013, right at the beginning of 2014.

Jorge A. Garcia, MD, FACP: December 6, yeah.

Judd W. Moul, MD, FACS: Early on, our medical oncology guys were very skeptical about chemotherapy with the low-volume disease, based on CHAARTED and the French study. Then what happened, right after ASCO 2015 or when the STAMPEDE data were leaked and then presented, that seems to all have evaporated. So it seems like at our tumor boards now, if I present a case as a urologist, all the medical oncologists are cool with docetaxel irrespective of high or low-volume. I don’t know if that’s just at our institution or is that what you guys are seeing?

Charles J. Ryan, MD: That’s happening, yeah.

Raoul S. Concepcion, MD, FACS: Mike, is that what you’re seeing?

Michael Fabrizio, MD, FACS: Yes.

Raoul S. Concepcion, MD, FACS: Both high volume and low volume.

Michael Fabrizio, MD, FACS: Yes.

Jorge A. Garcia, MD, FACP: I think that the power of CHAARTED was very simple. This trial was designed to detect the difference between adding chemo or not, period. So the concern that I always have when we are making clinical decisions on a daily basis is that we use subset analysis to make those sort of judgment decisions on a clinical basis. But the reality of it is, the study was not powered to detect that difference in the subset analysis between low volume and high volume. Now, what is more important to me is when we talk about median survival. Some physicians just take into consideration hazard ratio.

Look at the evolution of hazard ratio over the last 10 years in prostate cancer. In fact, since 1999, when mitoxantrone became FDA approved, with no survival benefit but just quality of life and pain improvement, hazard ratio back in the days was around .8 or greater. And since then, when you think TAX 327, when you think about SWOG 9916, hazard ratio is in the .76 range. Now, guess what, the hazard ratio of any therapy that we have right now is in the .6 range. In CHAARTED, for that matter, the hazard ratio of those individuals who got androgen deprivation therapy (ADT) and chemo is 0.61.

These hazard ratios, to me, really mean a lot because that clearly states that we have drastically changed the outcome of these patients. I think that STAMPEDE, to me, should settle that issue in our low volume or high volume. The subset analysis of low volume or high volume using the CHAARTED definition has not been presented yet. So I would argue, and I wonder what you guys think about this. If STAMPEDE comes out and says low-volume patients, using the definition that CHAARTED used, don’t have a median survival improvement, then the question is should we pause and stop using chemotherapy for those patients with low-volume disease until we get a little bit longer follow-up? Or should we still say, you know what, every patient should get chemotherapy. And that is also how you define volume, right?

Michael Fabrizio, MD, FACS: Yeah. We asked that at the very beginning.

Charles J. Ryan, MD: The hazard ratio and the low-volume cohort are still low. It’s just that the medians haven’t been reached. And keep in mind that the study started out as a study for high-volume disease. So the low-volume patients have 2 things going for them. They have low-volume disease, and they were entered into the study late in the life cycle of the study.

Raoul S. Concepcion, MD, FACS: I would also ask the question, in these patients with low-volume disease or oligometastatic disease, what is the role of the management of the primary in those patients? Because now we have some very sophisticated rapid autopsy next-generation sequencing studies looking at the mets. And all mets come from a clone that has actually come from the primary, and you have this re-seeding and seeding phenomena.

Judd W. Moul, MD, FACS: Speaking of oligometastatic disease, my former Fellow, Axel Heidenreich, who is now chair of urology in Cologne, had one of the hot papers looking at surgery for oligometastatic disease. There’s now a series of trials starting to address radical prostatectomy in oligometastatic disease. Where is that going to fit with CHAARTED and STAMPED? Just as a follow-up question for the urologists. Let’s say I have a new M1 stage, hormone-sensitive disease. I see the data. I know the right thing to do is to get that patient to medical oncology for docetaxel, and I want to set the stage of optimism. But is there a group of patients where I don’t want the patient who is not a candidate to be disappointed? Is there a subgroup where you would pause and say, sir, this may not be for you?

Raoul S. Concepcion, MD, FACS: I think obviously if you had a neuroendocrine tumor, you wouldn’t use docetaxel. You would probably go more toward a platinum-based agent, right?

Charles J. Ryan, MD: Yeah.

Jorge A. Garcia, MD, FACP: Yeah.

Charles J. Ryan, MD: So patients who aren’t candidates for upfront docetaxel is the question. I’ve had challenges, as have many of my colleagues with older patients, where the goals of therapy might be a little bit different, but it’s still worth having the conversation. I’ve given docetaxel to men in their 90s, so there’s not an absolute cut-off of when it is or not appropriate, but it has to do with frailty, comorbidities, and all those other things. And so, I would say, I would urge a little bit of caution in recommending and being terrifically optimistic about the benefits of docetaxel in a patient who is, aside from his prostate cancer, frail or sick.

Judd W. Moul, MD, FACS: Is there any kind of simple frailty score?

Charles J. Ryan, MD: Absolutely.

Judd W. Moul, MD, FACS: What should urologists use? Is there a tool that’s the best?

Charles J. Ryan, MD: There are frailty indices. There’s a whole field of geriatrics that studies comorbidity indices and things like that. There have been some retrospective analyses looking at this. Like nomograms, you can come up with scores of this. They are a bit intuitive. I ask questions about what’s your typical day like. If I wanted to go for a walk with you, how far could we go and these types of things. Over time, after talking to many, many patients, you get a sense as to where that’s going to pan out.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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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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