- Email: [email protected]
Management of High Risk Metastatic Prostate Cancer
Discussion Management of High Risk Metastatic Prostate Cancer static disease, there is at least 1 trial that shows there is no difference in survival. Doctor Thompson: How about the neoadjuvant hormones and prostatectomy? Six separate trials show no difference. Dr. Michael Carducci: There are patients for whom it is just a lead time difference until hormonal refractory disease develops. They sit in that space for a long time. They have all the comorbid effects we talked about earlier and they start dying of other causes. Dr. Charles Ryan: I think the issue is that the rising PSA state is not a monolith. The risk is ascertained within that state by PSA kinetics, for example, and in the Department of Defense Center for Prostate Disease Research retrospective analysis Gleason score has emerged as something that is important. Doctor Small: There are 3 randomized trials that tell us there is a survival advantage when you add hormones after radiation. It is not interaction of the radiation and the hormones. We are saying the same thing. It is not 1 disease and our challenge is to select which patients would benefit and not just give it to everyone. Doctor Thompson: But what you have just done is take evidence from another disease state. So we will do that for hormones but we will not do it for chemotherapy. Doctor Ryan: The issue of androgen deprivation in the rising PSA state is buttressed by randomized trials in the localized disease state on one side and metastatic disease studies on the other side. So the extrapolation is easier than it is to say that chemotherapy works in hormone refractory disease. Therefore, we should give it right after radical prostatectomy. Dr. Daniel Petrylak: The problem with extrapolation is that the duration of androgen blockade has clearly changed from what we had years ago. So if you look at the data from AstraZeneca in the randomized bicalutamide study, low risk patients had a poor outcome if you gave them hormone therapy. I am not really sure what the cause of those findings would be, and it could be cardiovascular risk factors. So when making these extrapolations and leaps of faith, we have to consider the side effects of something that has significant morbidity and in some cases mortality. Dr. James Montie: Doctor Carducci, what is the general philosophy for someone with positive nodes? Doctor Carducci: If a patient has a positive node at surgery, we will put him on hormonal therapy. But again here is a state where we do not have anything to recommend except extrapolation. However, I would rather put a high risk patient in a chemotherapy or hormonal therapy study. Doctor Ryan: In terms of clinical trials, you also have the possibility of studying vaccines and other agents which do not target the hormonal axis at all, but may be most effective in this low disease burden state. The hormonal therapies all modulate PSA and probably modulate the nat-
Dr. Michael Glodé: Doctor Swanson, if you can identify those high risk patients by doubling time and preoperative characteristics, do you really need to radiate everyone in the immediate postoperative period or can you wait? You can give 100% of people the side effects, but you may only benefit 50%. So we have already started off with a situation in which we are operating on too many people, and then we take all of those people who are at high risk and radiate too many people; and it is the over treatment issue. Dr. Gregory Swanson: That is the followup study to Southwest Oncology Group (SWOG) 8794 that is currently in development. We have established what immediate postoperative radiotherapy does; it reduces biochemical relapse about 50%. So the question is, can we wait for that PSA bump before we start the radiation? And that is the next study. Dr. Mack Roach: That might be a tough study to finish because there is a salvage rate of 25% to 50% in some patients. So you know you are going to salvage some of those people when you wait until the PSA is detectable, and we already have those data. Dr. Eric Small: Doctor Swanson, what is the design of that study? Doctor Swanson: Just straight up. We have established in SWOG that immediate radiation reduces biochemical failure in these pathological T3 cases, and so the randomization is now to take those with PSA levels less than 0.2 ng/ml and randomize them by these pathological findings to immediate radiation versus waiting until the PSA goes up to a minimum of 0.4 or 0.5. The conjecture is that by waiting, you are not losing anything, and you can eliminate treatment in the 30% of cases in the observation arm that did not fail. Dr. Ian Thompson: In the observation arm of SWOG 8794 there was no difference in metastasis-free survival, because about a third of the patients had PSA recurrence and then got radiation. So is the reason why there is no survival benefit is because salvage works just as well? We know, because we had a quality of life companion study, that there is substantial toxicity. Doctor Small: Within the CALGB (Cancer and Leukemia Group B) we looked at a similar trial design but the issue was field size, full pelvis or not, and hormones, yes or no. The diversity of opinion, not only within our committee, but in the community— because we went out and asked— was so astonishing that we decided we could not do this study. Doctor Swanson: Are there people in the real world who watch the PSA rise and do not start androgen deprivation until there is metastatic disease? Doctor Thompson: The short answer is almost nobody. Doctor Roach: We have all of these randomized trials to show that people live longer who received immediate adjuvant hormonal therapy. Once they have established meta-
0022-5347/06/1766-0081/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
S81
Vol. 176, S81-S82, December 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.09.015
S82
DISCUSSION
ural history of the disease. But with a vaccine, its ability to modulate PSA may not be reflective of its long-term ability to modulate the disease. So then it becomes an issue of end points. Do we do a rising PSA study where we have, for example, high dose bicalutamide versus some vaccine and do we look at the time of the development of metastatic disease or do we look at changes in PSA kinetics? Dr. Peter Carroll: Using these hypersensitive assays, could some of the rising PSA cases be due to benign disease? At University of California, San Francisco we biopsy around the urethra and negative margins in organ confined cancer cases, and we will not infrequently see benign cells sitting in the striated muscle. We use a cut point nadir of 0.02 ng/ml, which is 2/100ths of a single point. With some of these 0.03 and 0.04 recurrence numbers that we are seeing at 18 and 24 months, there might be benign residual cells, and so we have got to be a little cautious in addressing that. Dr. Anthony Tolcher: Within the cooperative groups, what is the lay of the land on introducing chemotherapy early? Doctor Petrylak: The lay of the land is still the SWOG 9921, and we are totally committed to finishing that trial. The accrual is still good despite a competing trial coming out soon. Doctor Carducci: There are also the 2 industry studies, TAX 3501, which is an adjuvant study, and TAX 3502, the Memorial Sloan-Kettering study, which is the Radiation Therapy Oncology Group 0014 study question again. Doctor Glodé: I think that the 2 or 3 vaccines that show promise, depending on how optimistic you are, would be easy to accrue in an adjuvant setting. The toxicities are generally low compared to, say, chemotherapy and even hormonal therapy. It is premature, although an argument could be made that if you wait for metastatic disease it is the wrong place to look at any immunotherapy. But I do not think the companies have enough money to support the studies, and they are the ones who have to make the vaccines. Doctor Small: It is our catch 22. You want drugs that are really attractive to patients and you cannot otherwise get accrual. But if you are on the industry side, your burn rate is just not going to allow you to do an adjuvant study. Just look at what happened in the industry-led zoledronate and atrasentan studies. So I think those trials are going to have to come from the cooperative groups. I do not think they are going to come from industry because they cannot justify it financially. Doctor Carroll: Doctor Tolcher, these agents you discussed are targeted drugs of relatively limited toxicity. The target can be measured in tissue, so why aren’t you testing these drugs in a neoadjuvant setting before radical prostatectomy? You can test the hypothesis that in fact when you deliver the drug, it gets to the cell. Doctor Tolcher: It is hard to do with a new agent because the paradigm that exists is to start off in the advanced refractory setting, which is problematic, as getting biopsies is difficult in metastatic prostate cancer, and yet the biology is going to be key to deciding which drugs are actually appropriate for a patient population. So I am not dis-
agreeing with you but it does require a paradigm shift where we are willing to take risks. It is not just us taking risks, but it is also pharma taking risks, because that is an area about which they are very hesitant. Doctor Glodé: But assuming you can hit the target in a neoadjuvant study and then come to your phase II question, I think we could accrue patients to such a trial without any problems, if we can have an end point to say that you slowed the rate of a rising PSA. Doctor Roach: I am missing the logic here. We have these studies with neoadjuvant hormone therapy to show that you have dramatic reductions in prostate size with fewer positive margins, and then the therapy still fails at the same rate. So even if you show activity on the prostate, the patients who are dying are dying because they have metastatic disease. Doctor Montie: One is a therapeutic intent, which is a neoadjuvant hormone, and this is a study for a biological intent, and so you are not looking for the therapeutic effect. Doctor Small: I think the neoadjuvant study setting is a really important model. It is not a model that can used for all drugs at all times because of differential expression of the target in local versus metastatic, but even more importantly in hormone sensitive versus hormone refractory. For example, insulin like growth factor-1 receptor does not show up in hormone sensitive disease. It really is a hormone refractory phenomenon. So you are at risk of getting a false-negative signal in that model. Doctor Petrylak: Kim and others looked at the warm autopsy specimens and found a marked heterogeneity in the metastatic patterns, even within the same patient. So for these targeted agent studies, we need a better way of imaging with a whole body technique rather than simply going after 1 lesion, because that may not be indicative of what is going on in the entire tumor. Doctor Tolcher: The number of patients who are eligible for clinical studies progressively decreases as you travel along the natural history of the disease. It is a substantial problem because as long as patients are being referred at the point when all available forms of therapy have failed and the many iterations thereof, it is a real issue for us looking for signals in this disease. The greatest pool still remains patients who do have rising PSA levels, and who are hormone refractory and essentially incurable. I think other people do not disagree with that either. Doctor Carroll: Well, I might because in those cases you frequently do not have any measurable disease, right? And we are treating people so early now that we frequently do not have bi-dimensional disease and are using PSA as the response criteria. Doctor Tolcher: Not so much as response. I think of PSA as a signal of antitumor effect, almost a filter, in that those agents that have no effect on PSA, I discard them relatively quickly because the PSA is rising. You can even use randomized phase II strategies to try to sort that out, when a patient gets a placebo versus the agent, to try to benchmark yourself so that you are not being lead astray by a change in the rate of PSA rise.
Dr. Michael Glodé: Doctor Swanson, if you can identify those high risk patients by doubling time and preoperative characteristics, do you really need to radiate everyone in the immediate postoperative period or can you wait? You can give 100% of people the side effects, but you may only benefit 50%. So we have already started off with a situation in which we are operating on too many people, and then we take all of those people who are at high risk and radiate too many people; and it is the over treatment issue. Dr. Gregory Swanson: That is the followup study to Southwest Oncology Group (SWOG) 8794 that is currently in development. We have established what immediate postoperative radiotherapy does; it reduces biochemical relapse about 50%. So the question is, can we wait for that PSA bump before we start the radiation? And that is the next study. Dr. Mack Roach: That might be a tough study to finish because there is a salvage rate of 25% to 50% in some patients. So you know you are going to salvage some of those people when you wait until the PSA is detectable, and we already have those data. Dr. Eric Small: Doctor Swanson, what is the design of that study? Doctor Swanson: Just straight up. We have established in SWOG that immediate radiation reduces biochemical failure in these pathological T3 cases, and so the randomization is now to take those with PSA levels less than 0.2 ng/ml and randomize them by these pathological findings to immediate radiation versus waiting until the PSA goes up to a minimum of 0.4 or 0.5. The conjecture is that by waiting, you are not losing anything, and you can eliminate treatment in the 30% of cases in the observation arm that did not fail. Dr. Ian Thompson: In the observation arm of SWOG 8794 there was no difference in metastasis-free survival, because about a third of the patients had PSA recurrence and then got radiation. So is the reason why there is no survival benefit is because salvage works just as well? We know, because we had a quality of life companion study, that there is substantial toxicity. Doctor Small: Within the CALGB (Cancer and Leukemia Group B) we looked at a similar trial design but the issue was field size, full pelvis or not, and hormones, yes or no. The diversity of opinion, not only within our committee, but in the community— because we went out and asked— was so astonishing that we decided we could not do this study. Doctor Swanson: Are there people in the real world who watch the PSA rise and do not start androgen deprivation until there is metastatic disease? Doctor Thompson: The short answer is almost nobody. Doctor Roach: We have all of these randomized trials to show that people live longer who received immediate adjuvant hormonal therapy. Once they have established meta-
0022-5347/06/1766-0081/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
S81
Vol. 176, S81-S82, December 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.09.015
S82
DISCUSSION
ural history of the disease. But with a vaccine, its ability to modulate PSA may not be reflective of its long-term ability to modulate the disease. So then it becomes an issue of end points. Do we do a rising PSA study where we have, for example, high dose bicalutamide versus some vaccine and do we look at the time of the development of metastatic disease or do we look at changes in PSA kinetics? Dr. Peter Carroll: Using these hypersensitive assays, could some of the rising PSA cases be due to benign disease? At University of California, San Francisco we biopsy around the urethra and negative margins in organ confined cancer cases, and we will not infrequently see benign cells sitting in the striated muscle. We use a cut point nadir of 0.02 ng/ml, which is 2/100ths of a single point. With some of these 0.03 and 0.04 recurrence numbers that we are seeing at 18 and 24 months, there might be benign residual cells, and so we have got to be a little cautious in addressing that. Dr. Anthony Tolcher: Within the cooperative groups, what is the lay of the land on introducing chemotherapy early? Doctor Petrylak: The lay of the land is still the SWOG 9921, and we are totally committed to finishing that trial. The accrual is still good despite a competing trial coming out soon. Doctor Carducci: There are also the 2 industry studies, TAX 3501, which is an adjuvant study, and TAX 3502, the Memorial Sloan-Kettering study, which is the Radiation Therapy Oncology Group 0014 study question again. Doctor Glodé: I think that the 2 or 3 vaccines that show promise, depending on how optimistic you are, would be easy to accrue in an adjuvant setting. The toxicities are generally low compared to, say, chemotherapy and even hormonal therapy. It is premature, although an argument could be made that if you wait for metastatic disease it is the wrong place to look at any immunotherapy. But I do not think the companies have enough money to support the studies, and they are the ones who have to make the vaccines. Doctor Small: It is our catch 22. You want drugs that are really attractive to patients and you cannot otherwise get accrual. But if you are on the industry side, your burn rate is just not going to allow you to do an adjuvant study. Just look at what happened in the industry-led zoledronate and atrasentan studies. So I think those trials are going to have to come from the cooperative groups. I do not think they are going to come from industry because they cannot justify it financially. Doctor Carroll: Doctor Tolcher, these agents you discussed are targeted drugs of relatively limited toxicity. The target can be measured in tissue, so why aren’t you testing these drugs in a neoadjuvant setting before radical prostatectomy? You can test the hypothesis that in fact when you deliver the drug, it gets to the cell. Doctor Tolcher: It is hard to do with a new agent because the paradigm that exists is to start off in the advanced refractory setting, which is problematic, as getting biopsies is difficult in metastatic prostate cancer, and yet the biology is going to be key to deciding which drugs are actually appropriate for a patient population. So I am not dis-
agreeing with you but it does require a paradigm shift where we are willing to take risks. It is not just us taking risks, but it is also pharma taking risks, because that is an area about which they are very hesitant. Doctor Glodé: But assuming you can hit the target in a neoadjuvant study and then come to your phase II question, I think we could accrue patients to such a trial without any problems, if we can have an end point to say that you slowed the rate of a rising PSA. Doctor Roach: I am missing the logic here. We have these studies with neoadjuvant hormone therapy to show that you have dramatic reductions in prostate size with fewer positive margins, and then the therapy still fails at the same rate. So even if you show activity on the prostate, the patients who are dying are dying because they have metastatic disease. Doctor Montie: One is a therapeutic intent, which is a neoadjuvant hormone, and this is a study for a biological intent, and so you are not looking for the therapeutic effect. Doctor Small: I think the neoadjuvant study setting is a really important model. It is not a model that can used for all drugs at all times because of differential expression of the target in local versus metastatic, but even more importantly in hormone sensitive versus hormone refractory. For example, insulin like growth factor-1 receptor does not show up in hormone sensitive disease. It really is a hormone refractory phenomenon. So you are at risk of getting a false-negative signal in that model. Doctor Petrylak: Kim and others looked at the warm autopsy specimens and found a marked heterogeneity in the metastatic patterns, even within the same patient. So for these targeted agent studies, we need a better way of imaging with a whole body technique rather than simply going after 1 lesion, because that may not be indicative of what is going on in the entire tumor. Doctor Tolcher: The number of patients who are eligible for clinical studies progressively decreases as you travel along the natural history of the disease. It is a substantial problem because as long as patients are being referred at the point when all available forms of therapy have failed and the many iterations thereof, it is a real issue for us looking for signals in this disease. The greatest pool still remains patients who do have rising PSA levels, and who are hormone refractory and essentially incurable. I think other people do not disagree with that either. Doctor Carroll: Well, I might because in those cases you frequently do not have any measurable disease, right? And we are treating people so early now that we frequently do not have bi-dimensional disease and are using PSA as the response criteria. Doctor Tolcher: Not so much as response. I think of PSA as a signal of antitumor effect, almost a filter, in that those agents that have no effect on PSA, I discard them relatively quickly because the PSA is rising. You can even use randomized phase II strategies to try to sort that out, when a patient gets a placebo versus the agent, to try to benchmark yourself so that you are not being lead astray by a change in the rate of PSA rise.