Professor and Chairperson,
Department of Urology
Medical University of South Carolina

History

This very fit accountant owned his own business, played tennis and had excellent sexual function. His wife was in her mid-forties, and they had three children. His PSA had risen from 4 ng/mL, one year ago, to 12 ng/mL. A biopsy revealed Gleason 7 prostate cancer in both lobes, with a nodule on the right side. A bone scan and CT scan were both negative. He decided to have a radical perineal prostatectomy and lymph node sampling. The lymph nodes were negative, but the final pathology revealed Gleason 8 prostate cancer with right seminal vesicle invasion.

FOLLOW-UP

The perineal prostatectomy — which was non-nerve-sparing — went very well, and he had an excellent postoperative recovery with a PSA of zero at four weeks. He elected to receive adjuvant radiation therapy in combination with goserelin and bicalutamide. Two years later, his PSA is still zero. He has occasional hot flashes that used to bother him, but not anymore. He tires more easily and does not play as much tennis. He did not develop gynecomastia.

DISCUSSION

Selection of primary local therapy

I did not feel brachytherapy was an option because of the questionable results in patients with Gleason 7 prostate cancer. Although he was a candidate for external beam radiation therapy, I pointed out that most of the data for conformal radiation therapy has, at best, 12 to 13 years of follow-up.

I felt he would do fine over the next number of years and that he needed a treatment with more long-term data. If all the margins and nodes were negative when we removed his tumor, he had a very good chance of remaining disease-free. I did, however, point out that a Gleason 7 is not a Gleason 6, and that it has a poorer prognosis.

The primary focus for the patient and his wife was in curing the disease; that was the main driving force for their decision. Given what they had told me, I felt the best option was to approach it as aggressively as possible by sampling the lymph nodes and removing the prostate.

Since he had cancer in both lobes of the prostate, my advice was not to have a nervesparing prostatectomy. I told him that if potency was paramount to his existence, then he should have radiation therapy, because it would certainly preserve potency longer than a non-nerve-sparing radical perineal prostatectomy. They were an extremely close couple and despite the fact that their physical activity would or might be curtailed, they were willing to accept it.

Postprostatectomy options

The seminal vesicle invasion was very upsetting. I told him that most patients with seminal vesicle involvement ultimately develop metastatic disease. I felt that cure was unlikely and that he had two major options at that point. One was to observe and the other was to accept the fact that he probably still had the disease present and to offer him — once his continence returned — radiation therapy plus hormones.

Adjuvant radiation therapy and hormone therapy

I was extrapolating from the Bolla data, which demonstrated a survival advantage for external beam radiation therapy plus three years of hormone therapy over radiation therapy alone in advanced local disease. I told him that we did not know if he would do as well with just hormone therapy alone. That is the focus of a study that is being conducted, but it is not accruing well.

He elected radiation therapy and hormone therapy. The plan was to keep him on treatment for three years. He asked about maximum androgen blockade (MAB), and after a long conversation, he went on goserelin plus bicalutamide.

We discussed the pros and the cons of MAB. I told him that at this stage of the disease, we did not know if MAB was necessary, since in the absence of documented metastatic disease, we do not know if blocking flare is an issue. However, there was a possibility that the testosterone surge might make the disease more aggressive. He said, “I want to be as careful as I can, so I think I will go on the combination and stay on the combination for the three years.”

Duration of adjuvant hormonal therapy

I have set three years as my target in this man, because the only study that has shown an absolute survival advantage for all stages of the disease was the Bolla study. There is a trial by Hanks (RTOG 9202) evaluating a combination of neoadjuvant plus adjuvant hormone therapy given for 24 months. In a subgroup analysis, that study did show a survival advantage for the patients with the higher Gleason grades. So, it may be that you only need 24 months of treatment. But, I tend to go with the Bolla data.

The real issue will arise after three years of hormonal therapy. I intend to tell him to stop treatment, but I don’t know if he will want to. Judging from my last conversation, he is going to say, “Well, what are we going to do to follow this? Can I go on intermittent androgen ablation?”

Adjuvant bicalutamide monotherapy

Had the results from the Early Prostate Cancer (EPC) trial been available at the time of this man’s surgery, he would certainly have been a candidate for bicalutamide 150 mg. He had poor-prognosis prostate cancer with a PSA of zero, and he was interested in some form of hormonal therapy.

The EPC trial is a combination of three different studies — Scandinavian, European and American. The results from the Scandinavian study, which consists primarily of patients on watchful waiting, have been impressive. The initial data indicate that for the group on bicalutamide 150 mg, there is a significant decrease in objective progression in terms of changes on the bone scan. So, the Scandinavian study may turn out to be a study of early antiandrogen therapy compared to watchful waiting in localized prostate cancer. With regards to the American trial, it is still very early. It was a two-year analysis, and there have been very few events.

History

This man presented with a PSA of 8 ng/mL, T1c disease and Gleason 3+3 in both lobes of the prostate. He was potent and continent. In 1998, he underwent a nerve-sparing radical perineal prostatectomy. His margins were negative, and his postoperative PSA dropped to <= 0.02 ng/mL, our lowest limit of normal. He then entered the EPC trial and we later found out that he was randomized to bicalutamide. He had minimal effects on his breasts, but he did notice some tingling.

FOLLOW-UP

In 2001, over one year after completing two years of therapy with bicalutamide 150 mg, he was potent, continent and his PSA was 0.25 ng/mL. Two months later, his PSA was 0.3 ng/mL, and three months after that it had risen to 0.5 ng/mL. His bone scan was negative, and his ProstaScint® scan was negative in the pelvis but positive in the para-aortic and mesenteric areas. He was started on MAB. His PSA went back down to undetectable, and he had no great alteration in his symptoms.

DISCUSSION

When his PSA began to rise, I went back immediately and looked at his presenting pathology. I looked at his postoperative pathology, which was Gleason 3+3, and the margins, which were all negative. I looked at the timing of this event — three years after initial surgery. So, we were trying to define what caused this recurrence. Was it local or metastatic disease?

Based on the Gleason grade and the PSA, one would be tempted to say it was local. However, his PSA was doubling in less than six months. The timing was right on the cusp, between two to three years. If it were five years, it would more likely be local recurrence. If it were two years, it would more likely be metastatic disease. This man fell right in between where we would say probably local and probably metastatic.

Had the ProstaScint® scan been positive in the mesentery alone, I would have been worried, because there have been reports of false positives in the mesenteric area. But this patient had a rising PSA, which was doubling quite fast, and activity in the mesenteric and the paraaortic lymph nodes. In view of those findings, I put him on hormonal therapy with MAB.

Response to castration after bicalutamide monotherapy

We were able to find out that his initial randomization on the EPC trial was to bicalutamide rather than placebo, but the PSA increase occurred a year after completing therapy on the trial. There is relatively minimal data available on response rates to castration after antiandrogens, but we know that these do occur, and this man did respond to MAB.

History

This patient presented with a PSA of 7 ng/mL and a clinical stage T2a, Gleason 6 prostate cancer. He underwent a nerve-sparing, radical perineal prostatectomy. The subsequent pathology revealed a Gleason score of 7, a positive margin at the left base and extracapsular penetration. Postoperatively, his PSA went to zero. He declined participation in the bicalutamide EPC trial and also decided not to receive radiation therapy.

FOLLOW-UP

Three years later, his PSA was 0.3 ng/mL. Then two months after, it was 0.7 ng/mL. His bone scan and rectal exam were both negative. His ProstaScint® scan was negative in the pelvis, but there were three different sites in the chest that were positive. CT scan of his chest demonstrated several pulmonary nodules, and we confirmed by biopsy that this was recurrent prostate cancer. He was treated with maximum androgen blockade, and his PSA went down to zero. A CT scan has yet to be repeated.

DISCUSSION

Initially, I told this man he had about a 50% or greater chance of progression because of the pathology. It was a definite positive margin and there was extracapsular spread. Therefore, I felt that he needed to do something.

With regards to the radiation therapy that I recommended, he specifically asked, “Am I going to hurt myself by waiting and not receiving radiation therapy immediately?” I told him I did not really think he would hurt himself, if we watched his PSA very carefully and made sure to move quite quickly before the PSA reached 1.5 to 2 ng/mL. Radiation oncologists tell us that is the point at which one is more likely to have a favorable response in terms of normalizing the PSA. Of course, they also tell us that there is no evidence that intervening at that point is going to result in a survival advantage.

I also offered him participation in the EPC trial randomizing between bicalutamide and placebo, to which we were accruing patients at that time. However, he preferred delaying both radiation and hormonal therapy until a PSA indicated that there was disease activity.

Using the ProstaScint® scan to determine the pattern of recurrence

I think the ProstaScint® scan is much better than CT or MRI in certain situations. I still think there are too many false negatives and false positives with it though. However, when I am trying to determine whether a patient with a rising PSA has local disease, I’ll use the ProstaScint® scan to help guide my decision.

If the ProstaScint® scan indicates activity in the prostate itself, I will usually use local treatment. If there is no activity anywhere and the other factors add up to the recurrence being local, I’ll also give local treatment. But if the ProstaScint® scan is positive outside of the pelvis, I will usually not give radiation therapy.