Discussion

Management of High Risk Localized Prostate Cancer

Dr. Michael Glodé: My impression is that no one ever diesof local recurrence. For patients who come in with a risingPSA and bone metastases, few do not have local diseasecontrol.

Dr. James Montie: Local control yes but do they havelocal elimination of the cancer? I think effective local treat-ment is necessary but not sufficient. The people who aregoing to be at high risk most likely have high volume dis-ease. I do not think we can expect systemic adjuvant therapyto compensate for insufficient local therapy. If we want tocure these people, we have to get rid of the local disease oneway or the other and then add systemic treatment.

Dr. Ian Thompson: In the multivariate analysis thatTangen made of the Southwest Oncology Group (SWOG)8894 series for patients with metastatic disease, when youcontrol for every other variable that predicts outcome, pa-tients lived significantly longer if they did not have theprostate.

Dr. Christopher Sweeney: That is potentially con-founded by a different biology, which you cannot adjust for.Namely, patients who present with metastatic disease havea more aggressive disease de novo.

Dr. Peter Carroll: We found the same result, but wewere concerned that there was a silent predictor that we didnot recognize and of course it had potential lead time bias.

Doctor Glodé: I would argue that these patients wouldlive longer because if they can undergo a prostatectomy thenthey are self-selected to be healthier patients.

Dr. Gregory Swanson: Something that is germane tothis discussion is the results of SWOG 8794 that we pre-sented at the American Society of Therapeutic Radiologyand Oncology meeting. In that study half of the men withpathological T3 disease got immediate adjuvant radiationpostoperatively and half did not (about 210 patients in eacharm). In the radiation arm there were fewer metastaticfailures but the difference was not statistical. Much moreinteresting was local recurrence rate, which was lower withradiation. So that randomized study tells us it is not sys-temic risk. Most of the benefits of the radiation in that studywere improving local control.

Dr. Mack Roach: I think the salvage therapy data pro-vide some of the strongest evidence to say that there are a lotmore local recurrences than people commonly acknowledge.There are patients with increasing PSA levels, and if youirradiate them, at least half have PSA responses, even if thelevels do not stay down durably.

Doctor Carroll: I think the real challenge now is thatprostate cancer can be a local/regional nonmetastatic dis-ease. The idea of extended node dissection in prostatectomyas local/regional therapy may actually have an advantage.We did not mention node dissection, but we have clearlygone to more extended node dissections. The average num-ber of nodes removed in this country at prostatectomy is 5.6,

that is bilateral node dissection. Now that we have gone to

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more extended dissection, we are clearly picking up nodeswe would not have picked up previously. These patients mayeven have undetectable PSA levels despite the presence ofnodal disease. So for high risk stratification, we should in-clude extended node dissection at the time of surgery.

Doctor Montie: Or if you are going to give an adjuvanttreatment, then adjuvant treatment should include them.

Doctor Roach: It certainly should be studied. Thereshould be a trial and off-study, if patients are at risk, weshould treat them. It would be great to have a study to proveit in the postoperative setting but I think it would be an easystudy to do.

Doctor Montie: So again, it goes to the concept thatlocal/regional elimination of the disease is still important,even though the patient is at high risk. The question is, whatis a better way to do it, if we go back to the quality of lifeissues? There are a large group of people in the high riskcategory who have resectable disease but with positive mar-gins. So if you want to make your numbers in your serieslook really good, you do not touch those people. If we want tomake an impact on the disease, then we need to be moreaggressive one way or the other.

Doctor Sweeney: I get asked the question by patientswith high risk, high volume disease, whether they shouldhave a robotic or open procedure.

Doctor Carroll: If you look at the literature overall, thepositive margin rate for T1/T2 disease is the same, roboti-cally or open, as long as the surgeon has gotten over thelearning curve. However if you look at the margin positiverates in the literature for T3 disease, for the robot it is about40%. If it is a T3a or high risk lesion, I think control of themargin is better, especially at the base of the prostate, withopen rather than robotic.

Dr. Sam Chang: We have looked at our robotic seriesand, similar to what you are saying, for TI and T2 disease,the real difference was experience. The margin rate wasnearly 30% in the first 100 surgeries, approximately 20% inthe second 100 and less than 10% for the third 100 for one ofour surgeons, and continues to be this low, which is quitesimilar to our open series. However when we look at the T3cases the positive margin rate is about 30% to 35% with arobot, which has improved only a little bit with experience,not significantly. Our positive margin rate with open pros-tatectomy is about 25% to 28%.

Doctor Carroll: Doctor Swanson, I am intrigued by thisissue of targeting and your comments about the implant. Sothe thought now is whether some of the failures of externalbeam radiation therapy are due to a targeting problem. Areyou telling me that the standard now should be an implantwith external beam for high risk patients?

Doctor Swanson: In my practice that is the standard.Fully 25% or 30% of my patients get both. It becomes aquestion of the risk factors that we discussed. We look at

things like the Gleason score, the PSA and whether the

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DISCUSSIONS56

tumor is palpable or not, to try to determine who we think isat the risk to warrant that.

Doctor Carroll: How about length of hormones? Is thatyour own personal treatment strategy?

Doctor Swanson: I give neoadjuvant hormones quitefrequently because I believe in the premise that most of theeffect of hormone therapy is by the downsizing. I actuallythen stop it and use PSA as a guide because I do not want tocommit people to long-term toxicity unless they absolutelyneed it. So unlike Bolla and the Radiation Therapy OncologyGroup studies, which give everybody with high risk the 2 to3 years, I actually gauge it based on response to my initialtreatment.

Dr. Charles Ryan: In our practice we have experienceusing intermittent hormone therapy for low volume meta-static disease, in which we will discontinue androgen depri-vation after a year or so. It is hard to reconcile that experi-ence with the long duration of androgen deprivation therapythat took place in the Radiation Therapy Oncology Groupstudies of 3 years and lifelong. So I wonder if we ever needto give hormone therapy for longer than a year in a patientwith localized disease, whatever the risk.

Doctor Roach: You might wonder, but the fact of thematter is that there have only been 3 trials with high riskpatients. They used 2 years, 3 years and lifelong adjuvanthormonal therapy. Maybe 1 year is as good but for breastcancer 1 year is not as good as 5 years or 3 years. In an eraof evidence based medicine, I have a hard time seeing howyou are going to justify choosing 1 year for someone withhigh risk disease. I give patients a choice. I say, “These arethe 3 studies—you can do 2 years, 3 years or lifelong.” Mostpeople pick 2 years.

Doctor Sweeney: We must remember patients treatedfor 2 years may be castrate for 3 years or longer because ofthe time to recover.

Doctor Roach: The longer you go the longer it takes torecover, but putting somebody on 1 year of adjuvant hor-mone therapy may be detrimental to his survival. We do notknow because we have not studied it.

Doctor Carroll: Doctor Sweeney, it seems that you aremaking the case for observation and then systemic therapy,so would that be across the board?

Doctor Sweeney: No, it is not for all patients, but Iwould argue that for the 68-year-old man with significantcomorbidity and a T1c lesion with a Gleason 6 on biopsy,what are the data to say these patients should all be treated?I would argue for treating them at progression with andro-gen deprivation therapy based on the Axleson data, which isactually a higher volume disease burden than what we seein the United States.

Doctor Carroll: It turns the treatment paradigm com-pletely around. You would come out with a strategy that youdo observation and systemic therapy, and then only inter-vene with surgery or radiation therapies in a more terminalevent rather than the initial event. The key would be thatyou need to quantitate the potential downside of leavingthem with androgen deprivation therapy.

Doctor Sweeney: I am saying they could be treated withsystemic therapy alone. This would avoid over treating themany who did not need treatment. On the other hand,watchful waiting in the United States consists of repeat

biopsies on a yearly basis to see if more aggressive disease is

occurring and then treat with definitive local therapy be-cause these cases would move into a risk strata 2 or 3 asdescribed by Thompson.

Doctor Carroll: In most surveillance trials, when thedisease progresses the patient gets focal therapy and con-tinued surveillance. However in your proposal patients aregiven systemic therapy and then considered for focal ther-apy.

Doctor Thompson: We all see the patient with localizedbut bad disease, and we would like to twist the medicaloncologists’ arm to start chemotherapy, but they are reallyhesitant to do so.

Doctor Sweeney: Outside a protocol, I would be hesi-tant to do it. Looking at the data sets that are out theresuggests that maybe there is no substantial contribution forlocalized therapy in that subgroup. However, I think theongoing Canadian study of hormonal therapy alone versushormonal therapy plus external beam radiation will tell usthe contribution of the local therapy and may tell us to givesystemic therapy alone at that time.

Doctor Carroll: We did a study of hormonal therapy asmonotherapy for clinically localized T1-T3 disease. Most ofthe patients actually had more intermediate risk features.We have intermediate 5 to 6-year outcomes, and these pa-tients do reasonably well in overall or cancer specific mor-tality. Now, we do have quality of life data that suggest thatthere are some clear tradeoffs, but hormonal therapy forlocalized disease has pretty good durability.

Doctor Ryan: One of my major concerns with the Cana-dian study will be to see what happens with the patientswho go on hormone therapy alone and become hormonerefractory. They are quite miserable when hydronephrosisand lower urinary tract symptoms develop.

Doctor Carroll: Doctor Akaza, our PSA response datalooked similar to yours in the short timeframe of 4 to 5 years.We looked for clinically localized T1-T3 disease. I think thekey would be to look at what the potential adverse effectsmight be in the low risk patients. In J-Cap (Japan StudyGroup of Prostate Cancer) do you collect quality of life in-formation?

Dr. Hideyuki Akaza: At this time no, but we are goingto try to collect adverse effect profiles. In Japan we have aunique cultural system. The average patient age is 70 to 74years, and the majority do not want to keep libido andpotency, even those who are 70 years old. In Japan there isno hormone replacement for the woman. So if the patient is74 to 75 years old, the wife also is likely 65 to 70 years old,and they do not do estrogen replacement treatment.

Doctor Thompson: Can you give us your thoughts onother types of androgen deprivation therapy used in Japan?

Doctor Akaza: In Japan we now have 3 types of andro-gen deprivation therapy, flutamide, bicalutamide and chlor-madinone acetate, which is a steroid androgen. The toxicitywith flutamide is high compared to the other two. So wechecked the percentage of antiandrogen being used. Number1 is bicalutamide, number 2 is chlormadinone acetate andnumber 3 is flutamide.

Doctor Carroll: In J-Cap do you note whether the pa-tients get additional forms of treatment, require a transure-thral resection or get radiation?

Doctor Akaza: Yes, the J-CaP system can follow every

event of the patients registered.