Click here to see image

Hormonal therapy combined with radiation therapy

ANTHONY V D’AMICO, MD, PHD: The study we published in JAMA was a randomized trial with 206 men comparing 3D-conformal external beam radiation therapy (total dose of 70.35 Gray) with or without six months of combined hormonal blockade administered for two months before, two months during and two months after radiation therapy.

In the study, 57 percent of the patients had a PSA that was greater than 10 ng/mL, and 73 percent of the patients had a Gleason Score of seven or higher. This was a study of patients with highgrade cancer. For the most part, patients had T1c disease. More than half the patients had PSA-detected disease and about 50 percent had T2 or palpable tumors.

The primary endpoint of the trial was progression-free survival. Because the effect of hormonal therapy on cancerrelated death was higher than expected, we saw a difference in overall survival, just like the Bolla trial. At five years, progression-free survival was 82 percent for the patients treated with hormonal therapy plus radiation therapy versus 57 percent for those treated with radiation therapy alone. This means the patients treated with radiation therapy alone had a PSA elevation and were on hormonal therapy 25 percent more frequently.

Cancer-specific mortality at five years was zero in the patients treated with hormonal therapy plus radiation therapy versus six percent in the patients treated with radiation therapy alone; overall survival demonstrated a 10 percent difference (88 percent versus 78 percent, respectively). The absolute number of deaths due to prostate cancer was six in the radiation therapy-only arm and zero in the hormonal therapy plus radiation therapy arm. Out of 206 patients, a six-event difference in prostate cancer deaths was enough to account for a survival difference, mainly because we initially screened patients for cardiovascular disease. The hazard ratio for overall survival was two, which means a twofold reduction in deaths in the men randomly assigned to combined hormonal therapy plus radiation therapy.

Click here to see image

Click here to see image

The validation that the combination of hormonal therapy and external beam radiation therapy provides a survival benefit compared to radiation therapy alone is an important clinical message.

A number of randomized studies have evaluated this comparison, particularly in men with localized high-risk disease.

Click here to see image

“High risk” in this scenario is defined as a Gleason Score of seven or higher or a PSA level greater than 10 ng/mL.

The most recent study, published in JAMA in August 2004, demonstrated a 10 percent survival benefit at five years for men who received six months of hormonal therapy in combination with radiation therapy compared to men who received radiation therapy alone. Hormonal therapy consisted of flutamide with either leuprolide or goserelin.

Two questions remain in this scenario: (1) Is combined hormonal blockade necessary? and (2) Are six months of hormonal therapy adequate in patients with Gleason eight, nine or 10 disease, even if it is T1c or T2?

Click here to see image

The studies preceding the trial published in JAMA were RTOG-9202 and the Bolla trial. The Bolla trial — an EORTC study — found that three years of hormonal therapy is better than no hormonal therapy. RTOG-9202 found that two years and four months was better than just four months of hormonal therapy. It was not an overall survival benefit but a cancer-specific survival benefit of 3.4 percent at five years.

The question still remains whether long-term hormonal therapy is necessary and safe. A European randomized study comparing three years to six months of hormonal therapy should answer the question more definitively. If long-term hormonal therapy truly is better, I suspect that older men (over 70 years of age), in whom occult cardiovascular disease can be prevalent, will benefit least, whereas younger men who don’t have cardiovascular issues may benefit most.

Click here to see image

ANTHONY L ZIETMAN, MD: RTOG-8610 and RTOG-9202 are maturing. Every time they’re republished, the benefit from adjuvant androgen deprivation therapy seems to be confirmed. We now think about the use of adjuvant androgen deprivation with radiation therapy as follows: Patients with low-risk disease don’t need it, and patients with high-risk disease do. We can probably use less hormonal therapy if the patient has a Gleason seven tumor and a PSA below 20 ng/mL. The patient needs more, maybe two or three years of hormonal therapy, if he has both a high Gleason Score and PSA.

The patients with intermediate-risk disease are an intriguing group. Anthony D’Amico published in JAMA 2004 the results from a randomized trial in which a little over 200 men with intermediate- risk prostate cancer were randomly assigned to receive radiation therapy alone or with six months of hormonal therapy. Combined androgen blockade was administered two months before, two months during and two months after conventional-dose radiation therapy. Not only did the trial show a diseasefree survival advantage, but it has also shown an overall survival advantage at only five years.

ADAM P DICKER, MD, PHD: In radiation oncology, it’s almost a mantra that if we don’t achieve local control, we won’t achieve distant control. This is not only true in prostate cancer; it’s also true in breast cancer. Zietman published an article stating that the metastasis rate in prostate cancer is increased when local control is not achieved. Twenty years ago, everyone treated the whole pelvis with radiation to the nodes because it was believed that is where prostate cancer spreads; however, that practice was not based on any evidence. Roach’s Phase III trial, RTOG-9413, comparing whole pelvic to prostate-only radiation therapy and neoadjuvant to adjuvant combined androgen suppression, was the first to demonstrate that large-field radiation therapy with neoadjuvant and concurrent hormonal therapy had a benefit as measured by PSA.

It appears radiation therapy will probably cure microscopic disease in the nodes, but only when combined with hormonal therapy. I don’t anticipate that radiation therapy alone — at the dose we used, which was limited because of the small bowel — will cure micrometastatic disease. Some people believe hormonal therapy is synergistic with radiation. I’ve seen no evidence of that; rather, it probably has an additive effect.

I would not use the term “radiosensitizer” because hormonal therapy is active by itself, but it certainly augments radiation. I believe hormonal therapy plays a role, but how much of a role it plays locally is unclear. It’s also not clear that the dose used in the Bolla study is sufficient to cure patients. A number of investigators are retrospectively examining their data from patients who received a Bolla-like therapy in various doses during different time periods to determine whether an increase in dose translates to decreased bony metastases and improved survival.

MACK ROACH III, MD: The CaPSURE database would suggest there’s been a big increase in the use of hormone therapy with radiation therapy — appropriate use, by and large, in the sense that patients with intermediate and high-risk disease are receiving it. Some individuals are probably still being treated inappropriately because they are receiving hormone therapy for low-risk disease. Some of those may be patients who were trying to decide what they wanted to do and were feeling nervous and wanted to try something because they didn’t want to remain untreated. Some of the patients with low-risk disease may have received hormone therapy to shrink the prostate in preparation for brachytherapy.

However, I do suspect some physicians still utilize hormone therapy because they believe that hormone therapy and radiation therapy go hand in hand. Well, it turns out that in patients with low-risk disease, there’s no benefit, and hormone therapy causes hot flashes, osteoporosis, fatigue, anemia and impotence. So if you were not going to benefit the patient in terms of biochemical control or survival, I wouldn’t recommend it for patients with low-risk disease.

Click here to see image

Duration and benefit of adjuvant hormone therapy

LEONARD G GOMELLA, MD: We generally recommend two to three years of adjuvant hormonal therapy when treating patients with locally advanced disease, based primarily on the data from recent trials. Bolla’s EORTC trial showed superior outcomes in patients who received three years of hormonal therapy, and the RTOG-9202 showed that two years of hormonal therapy resulted in a survival advantage.

Admittedly, the duration of hormone therapy is controversial. Some institutional studies have suggested that as little as six months of hormonal therapy may be beneficial, and that’s possible, but our recommendations rely on the larger multi-institutional trials with thousands of patients. While the prospective randomized trials all show this approach is effective, particularly in patients with high-risk disease, it’s not advantageous for all patients. Patients with low-risk disease do not appear to benefit from the combination of hormones and radiation, and the side effects may detract from the patient’s quality of life and overall outcome. In the RTOG-9202 trial, an overall survival advantage was seen in patients with high Gleason Scores; however, in the patients with lower-risk disease, although the combination may enhance PSA control, we don’t see much improvement in survival.

DR DICKER: A couple of interesting recent research developments relate to the management of locally advanced prostate cancer. First, D’Amico et al reported results of a clinical trial that randomly assigned patients to receive radiation therapy with or without six months of total androgen suppression.

The group that received hormonal therapy demonstrated a survival advantage, which was surprising because the trial did not accrue a large number of patients. These data raise the question of whether six months of hormone therapy is adequate, or whether we need longer-duration therapy.

Another related article that touches on the duration of hormonal therapy is by a group in Finland who evaluated cognitive function in men — with an average age of 65 — before and after six and twelve months of hormonal therapy.

Click here to see image

They found a significant decline in memory, time to process information, recall and visuomotor function associated with the decrease in testosterone. Their data do not directly connect hormonal therapy with the decline in psychomotor function, but it is clear to those who treat prostate cancer that long-duration therapy — more than one year — impacts patients’ mental acuity.

Clinicians are interested in determining the maximally effective therapy that can be delivered with minimal side effects. When combined with radiation therapy, total androgen suppression may be equivalent to longer-duration therapy with an LHRH agonist alone for the treatment of clinically localized prostate cancer.

DR ROACH: The patients with high-risk disease who are treated with external beam radiotherapy have been shown to benefit from long-term hormone therapy. The question of how long they should be treated is controversial.

Although it’s commonly done, no randomized trials have used one year of adjuvant hormone therapy. The shortest duration shown to improve survival was two years, and that was in RTOG-9202. The EORTC study reported by Bolla used three years of hormone therapy, and RTOG-8531 used hormone therapy for life.

In my opinion, recommending one year of adjuvant hormone therapy is experimental because it has not been proven. I think it may turn out that one year is as good as three years or four years, but in breast cancer, a longer duration of hormone therapy has been shown to be better than a shorter duration of hormone therapy. So in prostate cancer, I think patients with high-risk disease should be offered two years or more of adjuvant hormone therapy.

The most common duration of hormone therapy that I recommend for the typical patient who has T1/T2 disease and a PSA around 10 ng/mL is two years, although there are some patients with whom I do not feel comfortable stopping after two years. I have one patient whose PSA was in the thousands, and he had lymph node involvement. At present, he’s doing fine. He’s out three years, and his PSA is undetectable. However, I am afraid to discontinue his hormone therapy.

I suspect it’s possible he’ll be on hormone therapy for the rest of his life. But in the typical patient who’s been screened, detected early and treated aggressively with local-regional therapy, including lymph node radiation, my standard use of adjuvant hormone therapy is for two years.

Click here to see image

Intermittent hormonal therapy

DR GOMELLA: Intermittent hormonal therapy is not considered the standard of care, but we do use it in select patients. The data on this therapy are conflicting — some preliminary European studies show that it doesn’t adversely affect overall PSA recurrence or survival, whereas other studies report adverse outcomes in prostate cancer progression with intermittent therapy.

One of the challenges is that we are waiting for data on intermittent therapy from the large ECOG trial completed in the United States several years ago. The problem is that this trial evaluated intermittent therapy in patients with high PSA levels and metastatic disease. Most of us believe that intermittent therapy will probably be most effective in patients with a low disease burden and minimal PSA elevation.

In fact, we know from the Messing trial that some patients with micrometastatic disease receive hormonal therapy and never have a recurrence.

Certainly some patients who choose to discontinue hormonal therapy will not have disease relapse. This is anecdotal, but I have two young patients who had node-positive, micrometastatic disease with undetectable PSAs postoperatively.

After approximately three years of adjuvant hormonal therapy, they each asked me to take them off of hormonal therapy. They are now approaching almost 10 years since their diagnosis with no evidence of recurrence and they both have normal PSA levels.

What we really need are more studies on intermittent therapy for PSA-only recurrences with low levels. Because we don’t have the data, we can’t recommend intermittent therapy as a definitive treatment option; however, we can certainly discuss it with patients.

Neoadjuvant hormonal therapy trials

E DAVID CRAWFORD, MD: Years ago, studies of hormonal therapy administered prior to radical prostatectomy were conducted to determine if the positive surgical margin rate could be improved. Dr Soloway did a study in the United States, as did Dr Debruyne in Europe and Dr Gleave in Canada.

These studies showed that the use of hormonal therapy for three or eight months before surgery significantly decreased the positive margin rate. However, at three, five and even six years, no differences in the PSA failure rates were noted, which led people to believe that neoadjuvant hormonal therapy didn’t do anything. These trials, however, were not powered with enough numbers and follow-up time.

My prediction is that with time, some of these studies will show a difference in the PSA failure rates. In patients with local prostate cancer, we’re not going to obtain answers quickly. Sometimes it will take 10 or 15 years to observe a difference between the arms of a trial.

Adjuvant hormonal therapy in breast and prostate cancer

PROFESSOR SIR RICHARD PETO: Various reasons exist for the difference in the clinical research data between prostate cancer and breast cancer. First, breast cancer occurs in younger women while prostate cancer occurs in older men.

Obviously, a patient with a 40-year life expectancy is more interested in what happens in the long term than a patient with a 10-year life expectancy.

Second, the early hormonal treatments for prostate cancer were unpleasant. They consisted of castration and diethylstilbestrol (DES), which was discovered to be seriously cardiotoxic and would actually do more harm than good in terms of life expectancy. As soon as DES was no longer used and alternative means of turning off testicular function were discovered, trials began.

Hormonal therapy for prostate cancer substantially delays progression of the disease and moderately delays death from the disease. The effects of immediate hormonal treatment versus deferred hormonal treatment in a man with prostate cancer are comparable to the effects of five years of adjuvant tamoxifen in a woman with hormone-sensitive breast cancer. Additionally, hormonal therapy prevents a number of complications of metastatic disease, such as spinal metastases, ureteric obstruction and the need for further surgery.

The prostate cancer trials were not as large as the breast cancer trials, so the results were muddled by deaths from other causes. The curves are similar, but the prostate trials have statistical noise from the large numbers of deaths that are unrelated to prostate cancer or its treatment. When patients are older, deaths from other causes confuse trial results.

The problem with evaluating hormone therapy for prostate cancer is that only a few thousand men with prostate cancer were being randomly assigned to therapy, compared to tens of thousands of women with breast cancer. That is why the evidence of benefit in breast cancer is so much better.

In breast cancer, we have seen impressive decreases in death rates in middleaged women as a result of early use of tamoxifen and chemotherapy. I believe the effects of earlier treatment with hormonal therapy in prostate cancer over the next five or 10 years will be comparable to those produced by tamoxifen in breast cancer.

No good evidence indicates that bicalutamide treatment affects mortality from causes other than prostate cancer. Currently, the number of deaths from prostate cancer in the EPC trials is so limited that it is difficult to obtain any clear evidence of an effect on prostate cancer mortality. The question as to the effect on overall mortality is well worth asking, but it needs to be answered by separate analyses of prostate cancer mortality and nonprostate cancer mortality. One should ask, “Is there any evidence of hazard?” No. “Is there any evidence of benefit?” At some point, the answer to that question may well turn out to be “yes.”

No good evidence indicates that bicalutamide increases the overall death rate from causes other than prostate cancer. If you have no overall evidence and you begin looking for subgroups of this and subgroups of that, you’re almost bound to find a subgroup in which the results seem favorable and a subgroup in which the results seem unfavorable, but that is just statistical noise.

Role of combined hormonal blockade

DR D’AMICO: Off protocol, in patients with high-risk T1c or T2 disease, I use six months of combined hormonal blockade because that is what I used in the study I conducted.

In that study, about 27 percent of the patients did not complete the six months of flutamide, mainly because of elevations in their liver function tests (LFTs). They weren’t necessarily having toxicities from the flutamide, but we had a rule: If the LFTs exceeded two times the upper limit of normal, we discontinued the drug for that patient. Despite that, the survival benefit was still seen.

It is an open question whether combined hormonal blockade is really necessary; however, without an answer from a randomized trial, I follow the randomized trial results we have.

When we designed that trial in 1994, bicalutamide wasn’t available, so flutamide was used. Today, bicalutamide is used because it’s a once-a-day drug and it doesn’t have the same LFT issues.

In patients who have T3 or T4 disease by palpation, I use exactly what the RTOG utilized in their randomized study: two months of neoadjuvant combined hormonal blockade, two months of combined hormonal blockade concurrent with radiation therapy and two years of an LHRH agonist alone.

DR ROACH: We generally utilize monotherapy, because the trials have evaluated monotherapy in the adjuvant setting. However, the trial that studied two years of adjuvant hormone therapy used combined blockade for four months. The EORTC study, which looked at three years of hormone therapy, utilized combined blockade for one month. In RTOG-8531, in which they study adjuvant hormone therapy for life, they do not utilize combined hormone blockade. Most patients would prefer to take combined androgen blockade for four months and two years of hormone therapy.

In 2000, we published a paper — the “meta-analysis” of the RTOG trials. We took all of the trials, pooled them together, and stratified them by their risk of death. We concluded that patients with low-risk disease did not benefit from hormone therapy. Patients with intermediate- risk disease — very much like Dr D’Amico’s patients with intermediate- risk disease, except maybe a little bit higher risk — benefited from shortterm hormone therapy (four months, for example), and patients with highrisk disease needed long-term hormone therapy.

Click here to see image

SWOG-S9921: MAB with or without mitoxantrone/ prednisone after prostatectomy

DR CRAWFORD: This ongoing trial, which is very important, randomly assigns men who have had a radical prostatectomy and are at high risk for recurrence to combined androgen blockade for two years with or without chemotherapy. We have almost 500 patients enrolled on this study, and we need about 1,400 to complete it. SWOG-S9921 sets out to define whether adding something to radical prostatectomy makes a difference.

IAN M THOMPSON, MD: Clearly, one of the two most important issues in early prostate cancer is how best to treat high-risk prostate cancer. This issue of adjuvant therapy sits kind of at bookends to the other important issue, which is how to determine clinically important prostate cancer. The issue of adjuvant treatment for high-risk cancer is the bookend that highlights the fact that some men clearly have bad prostate cancer for which monotherapy is inadequate. The question is, what should additional therapy include, be it radiation therapy, hormonal therapy, chemotherapy, biologic response modifiers, or combinations thereof?

If you look at the men in the SWOGS9921 study, men tolerate treatment with mitoxantrone/prednisone extremely well. The task is explaining to the men that he needs additional therapy because he has high-risk disease and that he can expect to have some hot flashes while on two years of hormonal therapy. As urologists, we oftentimes think a cytotoxic is much worse than an LHRH. However, in our experience, once men understand the side-effect profile of the hormonal therapy and chemotherapy, the two therapies are seen as approximately equal in terms of side effects and toxicities.

Ongoing clinical trials evaluating docetaxel in patients with earlier-stage disease

DR D’AMICO: We are conducting a trial in patients with high-risk disease. Patients are treated with radiation therapy and hormonal therapy with or without docetaxel. The chemotherapy will be administered for two cycles prior to the start of radiation therapy, concurrent with hormonal therapy and weekly during radiation therapy, so it’s approximately four months of chemotherapy.

Dr Howard Scher is conducting a trial of hormonal therapy with or without docetaxel in patients with rapidly rising PSAs (eg, doubling times less than three to six months) following surgery or radiation therapy. Dr Mario Eisenberger will be conducting a postoperative adjuvant study in men with high-risk features at prostatectomy (ie, seminal vesicle invasion, Gleason Score of 8 to 10); patients will receive hormonal therapy and be randomly assigned to docetaxel or no further therapy.

It’s important to select patients carefully for these studies. For example, the vast majority of patients with a PSA failure after local therapy don’t die from prostate cancer. We know now that it’s the rate of rise of the PSA — and not the PSA failure itself — that’s important, so patients whose PSAs are rising quickly are the patients you want to enroll in these studies. The toxicity from chemotherapy occurs up front, and even younger men require some down time during the chemotherapy regimen. They have to be willing to accept an acute decrement in quality of life for a benefit that’s not yet proven.

The study I’m conducting in men with high-risk disease is powered for a hazard ratio of 1.5, whereas the hazard ratio in our study with hormonal therapy was two. With the chemotherapy, we’re hoping to see half the improvement that we saw with hormonal therapy. If we had a 10 percent benefit from hormonal therapy at five years, we’d be happy with a five percent benefit from chemotherapy. I’m powering the study for survival, pending the validation of a surrogate (eg, progression-free survival). We evaluated progression-free survival in the study of hormonal therapy and radiation therapy because, when that trial was designed in 1994, that endpoint was in vogue for hormonal therapy. The benefit from hormonal therapy was more than expected. We also saw a difference in survival; however, no data for chemotherapy in localized prostate cancer in a randomized setting indicate that progression-free survival can be used as an endpoint.

In our trial, prevention of bone metastases is a secondary endpoint that is clinically relevant. If you design a prostate cancer clinical trial powered for survival, you’ll have plenty of power to go back and evaluate progression-free, diseasefree and cancer-specific survival. But if you power the trial for an earlier endpoint, you may not have enough power to evaluate the ultimate endpoint. We expect this study will accrue in two years and be reported three to five years later.

Issues in radiation therapy

DR ZIETMAN: Every five years, the Patterns of Care Study (PCS) group surveys about 60 academic or community-based institutions across the United States. It reviews five to 10 randomly chosen patients from each institution to obtain a snapshot of what’s going on nationally. In 2004, it reported the 1999 data and compared them to the 1994 data. Hormonal therapy is being used more frequently with radiation therapy in patients with localized prostate cancer, indicating the penetration of randomized trial data into clinical practice. When we break out hormonal therapy use by low-, intermediate- and high-risk prostate cancer, we find many men with low-risk disease who are receiving hormonal therapy with radiation therapy, a situation for which we have no randomized trial data showing any clear advantage.

High doses of radiation are now more frequently used. This trend is actually ahead of the randomized trial data. Both the PCS and the CaPSURE database are showing that external beam radiation therapy is being used less frequently and brachytherapy is being used more frequently in early-stage disease. In 1994, of the cases treated with radiation therapy in the United States, only three percent utilized brachytherapy.

By 1999, it was up to 36 percent, and I can assure you by now it’s well above that. The CaPSURE database demonstrates that external beam radiation therapy is being used only a third as frequently in the sites they surveyed.

DR DICKER: Based on retrospective data from Richard Stock, we know that to achieve good biochemical control, 90 percent of the prostate should receive approximately 145 Gray with an I-125 prostate implant. That doesn’t mean the patient won’t be cured if only 85 percent of the prostate is treated, but if a postimplant CT dosimetry showed only 70 percent or less of the prostate was treated, I would have some concerns.

It doesn’t matter whether the CT is performed on the day of the implant or one month later, but it’s better to receive feedback as soon as possible after the implantation. It’s difficult to remember problems you encountered in the operating room, especially if you performed multiple implants on the same day, and it’s important to understand why one patient didn’t receive a good dose.

When the prostate implant results in suboptimal coverage, I tell the patient we’re not happy with what we achieved in the operating room and, assuming I understand why things didn’t go well and the situation can be corrected, my preference is to reimplant.

Others prefer supplemental external beam radiation therapy, but it is difficult to know what dose of radiation therapy to use. I’ve performed 500 to 600 implants in my career, and I’ve only had to reimplant twice. Assuming you didn’t overdose the urethra or the rectum on the first implant, reimplantation shouldn’t cause an increase in complications.

DR ZIETMAN: Two randomized trials have compared high-dose to conventional-dose external beam radiation therapy. The MD Anderson trial evaluated approximately 300 patients. For the patients with a PSA > 10 ng/mL, there was a clear advantage in terms of freedom from biochemical or disease failure at five years with high-dose radiation (78 Gray) compared to conventional-dose radiation (70 Gray). No advantage was seen for high-dose radiation in patients with a PSA ≤ 10 ng/mL.

The second randomized trial — the Massachusetts General Hospital/Loma Linda University trial — compared highdose (79 Gray) to conventional-dose (70 Gray) radiation in men who mainly had low-risk disease. Of the 393 patients randomly assigned, approximately 250 had low-risk disease. The number of biochemical failure events at five years was halved for the patients with low-risk and intermediate-risk disease who were treated with high-dose radiation therapy.

DR ROACH: We have looked at our experience at UCSF in patients treated with implants versus those treated with external beam radiation therapy. If you use endorectal MR spectroscopy and look at what happens after external beam radiation therapy versus brachytherapy, there’s a tendency for the abnormal spectra to normalize more quickly with brachytherapy.

If you look at time to complete metabolic atrophy — the prostate goes from being active metabolically, which is normal, to an atrophic state, it is significantly shorter with a permanent implant. In a study that observed patients treated with external beam radiation therapy versus brachytherapy, we saw about 70 percent of our patients treated with brachytherapy had complete metabolic atrophy, compared to approximately 20 percent of patients treated with external beam radiation therapy.

If you evaluate PSA decline and pick an arbitrary cutoff of PSA less than 0.5 ng/mL, 90 percent of our patients who were treated with brachytherapy had a PSA at follow-up of less than 0.5 ng/mL. Less than half of the patients who were treated with external beam radiation therapy never got to 0.5 ng/ mL; the median PSA was around 0.9 ng/mL.

The metabolic response of the prostate is less dramatic with external beam radiation therapy. The PSA goes down to a lower level with an implant. This carries a number of implications. It doesn’t prove that brachytherapy is more effective at curing cancer, but it does suggest that it’s more effective at ablating the prostate and lowering PSA.

Select publications