Discussion

Management of High Risk Metastatic Prostate Cancer

Dr. Michael Glodé: Doctor Swanson, if you can identifythose high risk patients by doubling time and preoperativecharacteristics, do you really need to radiate everyone in theimmediate postoperative period or can you wait? You cangive 100% of people the side effects, but you may only benefit50%. So we have already started off with a situation inwhich we are operating on too many people, and then wetake all of those people who are at high risk and radiate toomany people; and it is the over treatment issue.

Dr. Gregory Swanson: That is the followup study toSouthwest Oncology Group (SWOG) 8794 that is currentlyin development. We have established what immediate post-operative radiotherapy does; it reduces biochemical relapseabout 50%. So the question is, can we wait for that PSAbump before we start the radiation? And that is the nextstudy.

Dr. Mack Roach: That might be a tough study to finishbecause there is a salvage rate of 25% to 50% in somepatients. So you know you are going to salvage some of thosepeople when you wait until the PSA is detectable, and wealready have those data.

Dr. Eric Small: Doctor Swanson, what is the design ofthat study?

Doctor Swanson: Just straight up. We have establishedin SWOG that immediate radiation reduces biochemical fail-ure in these pathological T3 cases, and so the randomizationis now to take those with PSA levels less than 0.2 ng/ml andrandomize them by these pathological findings to immediateradiation versus waiting until the PSA goes up to a mini-mum of 0.4 or 0.5. The conjecture is that by waiting, you arenot losing anything, and you can eliminate treatment in the30% of cases in the observation arm that did not fail.

Dr. Ian Thompson: In the observation arm of SWOG8794 there was no difference in metastasis-free survival,because about a third of the patients had PSA recurrenceand then got radiation. So is the reason why there is nosurvival benefit is because salvage works just as well? Weknow, because we had a quality of life companion study, thatthere is substantial toxicity.

Doctor Small: Within the CALGB (Cancer and Leuke-mia Group B) we looked at a similar trial design but theissue was field size, full pelvis or not, and hormones, yes orno. 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 thisstudy.

Doctor Swanson: Are there people in the real world whowatch the PSA rise and do not start androgen deprivationuntil 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 adju-

vant hormonal therapy. Once they have established meta-

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static disease, there is at least 1 trial that shows there is nodifference in survival.

Doctor Thompson: How about the neoadjuvant hor-mones and prostatectomy? Six separate trials show no dif-ference.

Dr. Michael Carducci: There are patients for whom it isjust a lead time difference until hormonal refractory diseasedevelops. They sit in that space for a long time. They have allthe comorbid effects we talked about earlier and they startdying of other causes.

Dr. Charles Ryan: I think the issue is that the risingPSA state is not a monolith. The risk is ascertained withinthat state by PSA kinetics, for example, and in the Depart-ment of Defense Center for Prostate Disease Research ret-rospective analysis Gleason score has emerged as somethingthat is important.

Doctor Small: There are 3 randomized trials that tell usthere is a survival advantage when you add hormones afterradiation. It is not interaction of the radiation and the hor-mones. We are saying the same thing. It is not 1 disease andour challenge is to select which patients would benefit andnot just give it to everyone.

Doctor Thompson: But what you have just done is takeevidence from another disease state. So we will do that forhormones but we will not do it for chemotherapy.

Doctor Ryan: The issue of androgen deprivation in therising PSA state is buttressed by randomized trials in thelocalized disease state on one side and metastatic diseasestudies on the other side. So the extrapolation is easier thanit is to say that chemotherapy works in hormone refractorydisease. Therefore, we should give it right after radical pros-tatectomy.

Dr. Daniel Petrylak: The problem with extrapolation isthat the duration of androgen blockade has clearly changedfrom what we had years ago. So if you look at the data fromAstraZeneca in the randomized bicalutamide study, low riskpatients had a poor outcome if you gave them hormonetherapy. I am not really sure what the cause of those find-ings would be, and it could be cardiovascular risk factors. Sowhen making these extrapolations and leaps of faith, wehave to consider the side effects of something that has sig-nificant morbidity and in some cases mortality.

Dr. James Montie: Doctor Carducci, what is the generalphilosophy for someone with positive nodes?

Doctor Carducci: If a patient has a positive node atsurgery, we will put him on hormonal therapy. But againhere is a state where we do not have anything to recommendexcept extrapolation. However, I would rather put a highrisk patient in a chemotherapy or hormonal therapy study.

Doctor Ryan: In terms of clinical trials, you also havethe possibility of studying vaccines and other agents whichdo not target the hormonal axis at all, but may be mosteffective in this low disease burden state. The hormonal

therapies all modulate PSA and probably modulate the nat-

Vol. 176, S81-S82, December 2006Printed in U.S.A.

DOI:10.1016/j.juro.2006.09.015

DISCUSSIONS82

ural history of the disease. But with a vaccine, its ability tomodulate PSA may not be reflective of its long-term abilityto modulate the disease. So then it becomes an issue of endpoints. Do we do a rising PSA study where we have, forexample, high dose bicalutamide versus some vaccine and dowe look at the time of the development of metastatic diseaseor 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 aroundthe urethra and negative margins in organ confined cancercases, and we will not infrequently see benign cells sitting inthe 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 0.03and 0.04 recurrence numbers that we are seeing at 18 and24 months, there might be benign residual cells, and so wehave 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 chemotherapyearly?

Doctor Petrylak: The lay of the land is still the SWOG9921, and we are totally committed to finishing that trial.The accrual is still good despite a competing trial coming outsoon.

Doctor Carducci: There are also the 2 industry studies,TAX 3501, which is an adjuvant study, and TAX 3502, theMemorial Sloan-Kettering study, which is the RadiationTherapy Oncology Group 0014 study question again.

Doctor Glodé: I think that the 2 or 3 vaccines that showpromise, depending on how optimistic you are, would be easyto accrue in an adjuvant setting. The toxicities are generallylow compared to, say, chemotherapy and even hormonaltherapy. It is premature, although an argument could bemade that if you wait for metastatic disease it is the wrongplace to look at any immunotherapy. But I do not think thecompanies have enough money to support the studies, andthey are the ones who have to make the vaccines.

Doctor Small: It is our catch 22. You want drugs thatare really attractive to patients and you cannot otherwiseget accrual. But if you are on the industry side, your burnrate is just not going to allow you to do an adjuvant study.Just look at what happened in the industry-led zoledronateand atrasentan studies. So I think those trials are going tohave to come from the cooperative groups. I do not thinkthey are going to come from industry because they cannotjustify it financially.

Doctor Carroll: Doctor Tolcher, these agents you dis-cussed are targeted drugs of relatively limited toxicity. Thetarget can be measured in tissue, so why aren’t you testingthese drugs in a neoadjuvant setting before radical prosta-tectomy? You can test the hypothesis that in fact when youdeliver the drug, it gets to the cell.

Doctor Tolcher: It is hard to do with a new agentbecause the paradigm that exists is to start off in the ad-vanced refractory setting, which is problematic, as gettingbiopsies is difficult in metastatic prostate cancer, and yet thebiology is going to be key to deciding which drugs are actu-

ally appropriate for a patient population. So I am not dis-

agreeing with you but it does require a paradigm shift wherewe are willing to take risks. It is not just us taking risks, butit is also pharma taking risks, because that is an area aboutwhich they are very hesitant.

Doctor Glodé: But assuming you can hit the target in aneoadjuvant study and then come to your phase II question,I think we could accrue patients to such a trial without anyproblems, if we can have an end point to say that you slowedthe rate of a rising PSA.

Doctor Roach: I am missing the logic here. We havethese studies with neoadjuvant hormone therapy to showthat you have dramatic reductions in prostate size withfewer positive margins, and then the therapy still fails at thesame rate. So even if you show activity on the prostate, thepatients who are dying are dying because they have meta-static disease.

Doctor Montie: One is a therapeutic intent, which is aneoadjuvant hormone, and this is a study for a biologicalintent, and so you are not looking for the therapeutic effect.

Doctor Small: I think the neoadjuvant study setting is areally important model. It is not a model that can used for alldrugs at all times because of differential expression of thetarget in local versus metastatic, but even more importantlyin hormone sensitive versus hormone refractory. For exam-ple, insulin like growth factor-1 receptor does not show up inhormone sensitive disease. It really is a hormone refractoryphenomenon. So you are at risk of getting a false-negativesignal in that model.

Doctor Petrylak: Kim and others looked at the warmautopsy specimens and found a marked heterogeneity in themetastatic patterns, even within the same patient. So forthese targeted agent studies, we need a better way of imag-ing with a whole body technique rather than simply goingafter 1 lesion, because that may not be indicative of what isgoing on in the entire tumor.

Doctor Tolcher: The number of patients who are eligi-ble for clinical studies progressively decreases as you travelalong the natural history of the disease. It is a substantialproblem because as long as patients are being referred at thepoint when all available forms of therapy have failed and themany iterations thereof, it is a real issue for us looking forsignals in this disease. The greatest pool still remains pa-tients who do have rising PSA levels, and who are hormonerefractory and essentially incurable. I think other people donot disagree with that either.

Doctor Carroll: Well, I might because in those cases youfrequently do not have any measurable disease, right? Andwe are treating people so early now that we frequently donot have bi-dimensional disease and are using PSA as theresponse criteria.

Doctor Tolcher: Not so much as response. I think ofPSA as a signal of antitumor effect, almost a filter, in thatthose agents that have no effect on PSA, I discard themrelatively quickly because the PSA is rising. You can evenuse randomized phase II strategies to try to sort that out,when a patient gets a placebo versus the agent, to try tobenchmark yourself so that you are not being lead astray by

a change in the rate of PSA rise.