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Use of PSA as an endpoint in clinical trials

ROBERT DREICER, MD: With each passing year, the number of patients with locally advanced prostate cancer — who are perhaps destined to do poorly relatively early — continues to decline as we detect disease earlier. This impacts our ability to perform adjuvant studies of chemotherapy. Currently, the FDA would not accept PSA failure as a clinical endpoint, so we have to wait for clinical progression or death. The FDA is actively considering these issues, and at least one forum was held last fall at the FDA, and another one is planned. Changes may be occurring in the agency’s attitude toward PSA as an endpoint, but as of today, it’s a dilemma. If we can only perform one study a decade, it will be a long time before we can answer the question about adjuvant chemotherapy in the treatment of prostate cancer.

As a clinical trial endpoint, PSA remains problematic in some settings. In patients with biochemical failure only, using PSA failure as a parameter of response remains unproven; however, in the adjuvant setting, I think most of us who take care of these patients would clearly accept time to PSA failure as an endpoint in patients undergoing radical prostatectomy — albeit not the only endpoint. Of course, reasonable assurances must be made to ensure that the PSA failures are real and not simply low levels of detectable PSA in patients who are not destined to progress. That’s the optimal use of PSA in how we manage patients today, and it would be problematic to not use PSA failure as at least an intermediate endpoint.

Clearly, in studies of hormonal therapy, PSA failure would not be a useful endpoint. Biologic or targeted therapies are also potentially problematic unless we understand what these drugs do to PSA expression at the cellular level. With chemotherapy, we increasingly have reason to believe it would have validity in the postprostatectomy setting.

Time to delay of PSA failure is probably a good surrogate to activity. That’s not to say you should end the trial based on that endpoint and not collect other data, but I believe it’s an endpoint that will have some value and allow us to begin testing agents in the adjuvant setting without having to expose patients to Phase III investigations. It would allow us to perform hypothesis-generation studies and select agents that make rational sense based on some of these early endpoints and then move on to formal Phase III studies.

Regarding the metastatic setting, Dr Crawford presented data at ASCO 2004 that were based on the preliminary analysis of the SWOG randomized trial S9916. These data suggested that a three-month change in PSA was, in fact, a surrogate for survival in the androgenindependent setting. Is it the same in the hormone-naïve environment? I don’t know, and that’s an important question.

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Use of multiple clinical variables to predict disease recurrence

J Clin Oncol 2005

We developed a nomogram that estimates the probability of a positive bone scan at any time after biochemical failure before the administration of hormonal therapy based on commonly available data, including the results of pathologic analysis of the operative specimen (status of surgical margin, presence of extracapsular extension, seminal vesicle invasion, and Gleason sum at time of radical prostatectomy) as well as postoperative follow-up (tPSA [trigger PSA], PSA slope, and PSA velocity). The advantage of this approach is seen in the predictive ability of our model: bone scan results were predicted with a concordance index of 0.93.

— Zohar A Dotan, MD, PhD et al.
J Clin Oncol 2005;23(9):1962-8.

JAMA 2005

A short PSA doubling time (PSADT) is associated with increased risk of clinical progression, metastasis, and prostate cancer–specific mortality. However, whether other clinical variables add information to PSADT is less clear. Using a cohort of patients all having biochemical recurrence after radical prostatectomy with prolonged follow-up, we identified 3 significant risk factors for prostate cancer–specific mortality: PSADT, pathological Gleason score, and time from surgery to biochemical recurrence. Using these variables, tables were constructed to estimate the 5-, 10-, and 15-year risk of prostate cancer–specific survival. …

…The 5-, 10-, and 15-year risk of prostate cancer survival for a patient not treated with early hormonal therapy with a PSADT in less than 3 months, recurrence 3 or more years after surgery, and a Gleason score between 8 and 10 was 50%, 1%, and less than 1%, respectively. For a similar patient but with a PSADT between 3.0 and 8.9 months, the 5-, 10-, and 15-year risk of prostate cancer survival was 78%, 19%, and < 1%, respectively. …Using the clinical variables of PSADT, Gleason score, and time to biochemical recurrence, patients could be stratified into groups with a varying risk of survival at year 15 of 94% vs < 1%, although the CIs for many of the subgroups were large. …

— Stephen J Freedland, MD et al.
JAMA 2005;294(4):433-9.

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Management of PSA relapse

Prostate Cancer Update Special Edition 2005

GREGORY S MERRICK, MD: I’m relatively conservative in managing PSA recurrences. If we’re going to treat those patients with hormonal therapy, I do not recommend the institution of androgen deprivation therapy until the PSA doubling time becomes less than 12 months. Once the doubling time is less than 12 months, I think we have to seriously consider it.

The big question then becomes continuous versus intermittent therapy. I have always been a proponent of intermittent because it allows a better quality of life. We like to leave a patient on therapy for nine to 12 months and, if the PSA becomes undetectable, to stop the androgen deprivation therapy until we once again see the PSA exceed some arbitrary point, whether it’s 10 or 15 ng/mL.

I believe intermittent androgen deprivation is a marvelous way to approach patients with biochemical failures, especially those who are older, with concomitant medical problems. We’ve had great success with watching men along these lines. They all appear to respond to the subsequent second or third challenge of hormonal therapy. The one thing that you do note, however, is that with each cycle, the time off hormonal therapy tends to decrease.

Prostate Cancer Update
Special Edition 2005

DR D’AMICO: In terms of PSA recurrence, one point that’s become apparent across the specialties and now is coming into the community is that the rate of PSA rise dictates the time interval to a positive bone scan. For patients with PSA levels moving rather quickly, even men in their mid to late seventies, unless they have really significant comorbid illnesses that are going to take their life this year, I think it is important to carefully consider the hormonal therapy.

Another issue is this: When you use hormonal therapy for a man in the rising PSA setting, how long should you administer it? Forever? Intermittently? For a short course? This question is completely unanswered. A Portuguese study was presented at the AUA this year of intermittent versus continuous therapy for men with rising PSA or node-positive or metastatic disease. While the study only included 800 men, no difference was seen in overall survival between intermittent versus continuous treatment.

I will say that with 800 patients, the trial is likely not large enough to rule out a small benefit to continuous therapy. But this is the first small study of intermittent versus continuous therapy suggesting equality. Equality in this study however is probably limited to a five to seven percent difference. These trials have to be powered as equivalence studies, which means they need thousands of men. The SWOG study is such a study, but is not yet ready to report. So I don’t think we’re ready to say intermittent and continuous therapy are equivalent yet. But it is a big issue, because lifelong hormonal therapy in the rising PSA setting is not without consequence.

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Defining the optimal time to initiate hormonal therapy

DANIEL P PETRYLAK, MD: Randomized trial data suggest that earlier hormone therapy is beneficial at the point of PSA progression, but no data absolutely indicate benefit in the asymptomatic patient with a rising PSA. We know from studies of combination therapy that patients at high risk will benefit from early hormonal therapy plus radiation therapy. Ed Messing’s trial randomly assigned patients who had positive lymph nodes after prostatectomy to immediate hormonal therapy versus delayed hormonal therapy. The trial demonstrated that earlier hormonal therapy was beneficial.

A number of important questions must be answered. Does a threshold value of PSA need to be defined for these patients? Does PSA doubling time depend on regional clinical characteristics? We need to investigate these questions.

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DR DREICER: Earlier versus deferred hormonal therapy is a major breaking point in the GU community — particularly among the zealous believers in early androgen deprivation and the more nihilistic among us. In my own practice, because we see a large number of patients with biochemical failure, I have alternative, immunomodulatory investigational options. Putting that aside, PSA doubling time is increasingly useful to predict which patients are more likely to develop systemic progression in the hormone-naïve setting.

I discuss the controversies of early androgen deprivation with patients and discuss why my colleagues are advocates of earlier therapy. When the patient asks me, ultimately, where I stand on the matter, I tell him that I respect the toxicity profile of androgen deprivation therapy. For a long time we have undersold the impact of androgen deprivation on quality of life.

I tend to advocate early androgen deprivation therapy for the motivated patient with a shortening PSA doubling time, which sometimes occurs after a relative period of stability. Now, is that correct? I don’t know the answer to that question, but in my practice, that’s the situation in which I talk to patients in a more proactive way.

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RTOG-9601: Radiation therapy with or without bicalutamide 150 mg

DR GOMELLA: This Phase III randomized study is in patients with PSA relapse following radical prostatectomy. The study is closed to accrual, and we are anxiously awaiting the data. This will be one of the most exciting trials to be reported because it will determine whether it’s beneficial to combine hormonal manipulation with radiation therapy in the salvage setting.

RTOG-8531 showed that patients who received radiation and hormones together after radical prostatectomy for unfavorable prostate cancer had a survival advantage over patients who only received radiation therapy. I believe RTOG-9601 will also be a positive study because we know the effectiveness of bicalutamide 150 mg in the adjuvant setting. Based on the Iverson and See data, it would be a stretch to think the combination would not be more effective than radiation therapy alone.

Bicalutamide 150 mg is approved in over 50 countries around the world; however, it has not received FDA approval in the United States. In Europe, bicalutamide is commonly used as step-up therapy in which patients receive oral agents, such as a 5-alpha reductase inhibitor, with a small dose of bicalutamide. The bicalutamide dose is then increased up to 150 mg before the patients are started on an LHRH analog as their definitive therapy.

Currently at our center, the medical oncologists’ standard salvage regimen for patients whose disease is failing standard androgen ablation is bicalutamide 150 mg. We have seen responses to this regimen last for over a year and a half, so it appears to be reasonable salvage therapy and can be offered to patients. It does appear that a small percentage of men may have an increased cardiac toxicity associated with the drug. The number of men who had adverse cardiac outcomes and the number of increased death rates in the low-risk arms of the EPC studies with bicalutamide 150 mg were low, but noticeable. These findings may have been statistical aberrations or statistical noise; nonetheless, they need to be further examined.

Although bicalutamide 150 mg is not currently approved for salvage therapy in the United States, I believe it’s appropriate to discuss it with patients for whom it may be suitable, such as those who are sexually active and want to maintain their sexual functioning.

Bicalutamide can preserve sexual function, whereas a high percentage of men on an LHRH analog therapy experience significant sexual dysfunction. Quality of life and determining what’s important to the patient have become central issues when considering treatment alternatives in prostate cancer.

Intermittent androgen deprivation therapy

LAURENCE KLOTZ, MD: I think the role of intermittent androgen deprivation therapy for patients with D2 disease is not that compelling. Of course, the more common situation is a rising PSA after the failure of local therapy, and the majority of these patients are being treated with hormonal therapy too early and aggressively. Many of them, such as a 75-year-old man who received radiation therapy five years ago and now has a PSA of 3 ng/mL, are probably not at risk of death from prostate cancer. Opinions vary, but my view is that many of these patients are not at risk. The data are clear that these patients do not need to be treated at that point.

If they are going to be treated, however, the less treatment the better, and intermittent androgen deprivation therapy is appropriate, even if the trials show a modest adverse effect on survival. I think the patients who are at risk of not doing well on intermittent androgen deprivation therapy are those with quite advanced, relatively rapidly progressing, life-threatening disease.

Impact of brachytherapy on PSA

DR ZIETMAN: We’ve learned that after brachytherapy, we have to sit on our hands for three or four years. If the PSA goes up, we need to ignore it. In fact, we could make a case for not checking the PSA at all in the first three years, which is hard to sell to patients. The median time to the PSA bounce is about 18 months, and it should be heading down again within the third or the fourth year. If it’s not, something is probably wrong. The PSA after brachytherapy keeps going down, and at seven or eight years, the median PSA is lower than at four or five years.

Bicalutamide monotherapy for rising PSA

DR KLOTZ: Certainly, people talk about the benefit of bicalutamide 150 mg in terms of sparing libido, but I think the bone mineral density story is more compelling. Bicalutamide 150 mg actually increases bone mineral density because the high levels of testosterone are converted into estrogen, which is a bone mineral density- sparing hormone. To me, that is really the strong argument for its use.

There are two caveats, however. First is the question of whether bicalutamide 150 mg is equivalent in terms of duration of survival. The second issue is gynecomastia. A number of my patients who are on the bicalutamide EPC trial have had breast reduction surgery. They’re quite happy, but this was definitely an issue for them.

I have not used much prophylactic radiation in these patients. I probably should use more of it, but it doesn’t work in everyone, and it’s radiation to the chest. The patients aren’t too keen about it, so I haven’t really employed it. There are studies using tamoxifen, but one of the problems is that if it’s the estrogen that’s contributing to the increase in bone mineral density, maybe by using tamoxifen to block gynecomastia, you’re blocking the benefit to bone mineral density. From a theoretical perspective, it is possible tamoxifen will have an adverse effect.

HOWARD I SCHER, MD: Bicalutamide monotherapy does have some side effects, in terms of fatigue and gynecomastia, which can be significantly disfiguring. In the early 1990s when PSA was starting to be utilized, we were being referred patients from our surgical and radiation oncology colleagues with a rising PSA alone.

Recognizing that the toxicities of bicalutamide alone were different, we actually conducted a study and still have patients on it from 1993 using bicalutamide 200 mg, not the 150 mg dose, just trying to see if we could control the disease. We did observe that patients had disfiguring gynecomastia, in some cases requiring surgical reduction. But then again, of the original 50 patients who had a rising PSA, there were still eight on therapy in the year 2005. Almost an overwhelming majority had PSA responses. Again, this was a 200 mg dose. This is an option we bring up with patients.

In addition to discussing the gynecomastia with patients, we also have to discuss bicalutamide in the context of the randomized trials, which suggest that the outcomes may in fact be inferior to conventional hormones alone in patients with metastatic disease. What was of interest in the trial we conducted, and others as well, was that we’ve looked at the response in patients who’ve been on bicalutamide monotherapy and then cross to a GnRH analog.

The idea being, okay, we’ll protect your bones. You’ll be stronger while you’re on bicalutamide, and then we’ll add the conventional hormone later. It was only about 30 percent who responded with the crossover. So it’s clearly a different drug. Again, we do discuss it, but I think pound for pound, it’s probably not equivalent to more conventional hormones. That said, there are patients who will opt for it.

Role of chemotherapy in PSA relapse and locally advanced disease

DR DICKER: I usually refer patients with PSA relapse and no evidence of skeletal disease to medical oncologists who specialize in prostate diseases. I also encourage them to enroll in clinical trials that evaluate cytostatic therapy or some of the anti-androgen-type drugs. I believe most medical oncologists would be uncomfortable using cytotoxic therapy in a patient who does not have a positive scan. We don’t have any evidence that simply reducing PSA in a patient with nonradiographic metastatic disease has an impact. Chemotherapy has the potential to harm patients, and we don’t know the optimal duration for chemotherapy. We have preclinical data evaluating the anti-angiogenic effects of taxanes (both paclitaxel and docetaxel) in a variety of disease settings. I believe in the next year or two we’ll see chemotherapy being combined more frequently with hormones and radiation therapy in the locally advanced disease setting. We all agree that a Gleason eight, nine or 10 is locally advanced disease, but we see plenty of tumors with lower Gleason scores and 15 out of 15 positive biopsies. I put those patients in a locally advanced disease category because if they have surgery they will have positive margins, and some will have seminal vesicle and lymph node involvement. It’s a gray area, but patients with a Gleason seven, PSA less than 10 and appropriate performance status may benefit from hormones and chemotherapy.

DR SCHER: Regarding patients with a rapid PSA doubling time but with PSA-only disease, I’m not sure we fully know the natural history of that group. The tendency has been to use a second- and third-line hormone therapy first. Again, that will depend on the initial response, but I’ve seen situations where the second hormonal response exceeds the first. It doesn’t make sense, but that’s what has happened. There’s a real debate as to when to play the chemotherapy card.

I could probably count on one hand the number of times I’ve actually recommended chemotherapy for this group. It’s a not a curative treatment, so the real question is, when do you play that card? If it were curative, that would be a different story.

DR ROACH: Certain things make me nervous about not treating somebody with chemotherapy. If there are pretreatment high-risk features — a high-grade tumor, high Gleason score, high PSA, they were treated and now they’ve failed. The earlier they failed, the faster their PSA is rising; these are the issues that tend to make me want to be more aggressive with chemotherapy.

In patients who have low-risk features at the outset — the PSA and stage are not that high — and they have PSA-only failure, but their PSA is going up slowly, I would not recommend chemotherapy, although it’s possible that they would benefit. The data for androgen-independent disease is primarily based on patients who had extensive experience with hormonal therapy and had been through multiple manipulations with hormone therapy; they also had metastatic disease, by and large, as opposed to PSA-only failure. There are studies that are being contemplated in the RTOG and other places, based on patients with PSA-only failure, in which the PSA doubling time is being incorporated into the eligibility to try and select out patients who are at higher risk for death.

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