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INTERVIEW WITH DR NANCY DAWSON:

DR NEIL LOVE:In addition to case discussions and reviews of key clinical trial results, Prostate Cancer Update will also ask our visiting professors to identify key recent journal articles that have important implications to clinical practice. I asked Dr Nancy Dawson to do a mini journal club for us, and she selected several key recent papers and provided her thoughts on the clinical implications.

DR NANCY DAWSON: The first one is the article by Matt Smith looking at pamidronate in the prevention of osteoporosis in men who are on androgen deprivation therapy. In that clinical trial, men who were being treated with hormonal therapy, in this case it was combined hormonal therapy for non-metastatic disease, were randomized to pamidronate given every three months versus no pamidronate. In that clinical trial, they were able to show that there is a significant decrease in bone mineral density in the men who were on hormonal therapy without a bisphosphonate. The patients who received the pamidronate had no significant loss of bone mineral density compared to their baseline with this every three months bisphosphonate therapy. I think that's a very impressive study.

We know from literature on osteoporosis in women, that women who have decreased bone mineral density are more likely to develop fractures. We know that from the literature that's developing that men on androgen deprivation therapy have decreased bone mineral density. Now, we don't know that their having more fractures for sure, there's some literature to show that, but it's not clear that they're having a significant number of fractures. But there's emerging data that would suggest if we could prevent this decrease in bone mineral density then we would be potentially preventing significant fractures in men and potentially improving something that would have a significant negative impact on their quality of life. So if you extrapolate from all of that, I think this is an important study supporting the early use of bisphosphonates in men that you're going to be treating with androgen deprivation therapy. So I think that's a very important study.

Another study that actually is not yet in print but it's been presented in abstract form looks at zoledronic acid, a bisphosphonate that's 100 percent more potent than pamidronate. This is a large, multi-institutional, double-blinded, placebo-controlled clinical trial in men who had hormone-refractory prostate cancer; they had castrate levels of testosterone. These men who either had currently documented bone metastasis or a history of bone metastasis were randomized to zoledronic acid versus a placebo. And in this clinical trial, they were able to show that skeletal-related adverse events, such as pathological fractures were significantly less in the men treated with the zoledronic acid compared to those who received placebo.

These results have actually been the basis for the recent FDA approval of this product in men with bone metastasis from prostate cancer to prevent skeletal- related events. So it's been approved for that use. So again, this is another study showing the emerging role of bisphosphonates in men with prostate cancer. In both men who are on androgen deprivation therapy and develop osteoporosis as a complication of that therapy, and men with bone metastases who are at risk for developing fractures as complication of those metastases, these are therapies that may decrease those risks. So I consider those very important studies that were published and presented in the last year.

DR LOVE: Is there any evidence that using bisphosphonates actually decreases the chance of developing a bone metastasis?

DR DAWSON: There is an ongoing study right now, actually addressing that question. There's an ongoing trial in men who have PSA only hormone-refractory prostate cancer, so they have a rising PSA level on androgen deprivation therapy, but they do not yet have bone metastasis. These patients are being randomized to zoledronic acid, Zometa, versus a placebo. That trial was actually recently temporarily suspended but now is reopening and what they are looking at is whether it actually will prevent the development of bone metastasis. We don't have that answer yet, but there's a very important study going on right now actually asking that question.

DR LOVE: Do you think that at this point using bisphosphonates in men on androgen deprivation should be considered standard and are there any organizational guideline people looking at that?

DR DAWSON: There are committees that have been formed to actually come up with some guidelines. We don't have specific guidelines yet in place. My personal opinion is that we should be initiating bisphosphonate therapy in men with known bone metastases to prevent these skeletal related complications. I am less certain that we should standardly require that all men on hormonal therapy go on a bisphosphonate at this point in time. But I'm moving in that direction. The Smith trial did influence my thinking on this and I'm moving in the direction of supporting that all men who are on hormonal therapy get bisphosphonates.

DR LOVE: Would it make any sense just to monitor bone density? Or is there no point in even looking at it because it's going to drop anyhow?

DR DAWSON: Well, this is sort of an evolution. Years ago I didn't do that, I didn't do anything as far as monitoring it. Now I am obtaining baseline bone mineral density on men going on hormonal therapy. Or if they are already on hormonal therapy and they haven't had one, I'm getting one. If it's abnormal, they get started on a bisphosphonate. If it's normal, I discuss the information that's out there that supports therapy with a bisphosphonate, and after this discussion some of the men are starting bisphosphonates and others are not.

DR LOVE: What are some of the other papers that are coming out that you think are important?

DR DAWSON: I think that the paper by Grimm et al from the Seattle Prostate Institute on the ten-year follow up on brachytherapy is another important paper. The comment is frequently made when discussing brachytherapy that we don't have long enough follow up on modern-day brachytherapy to say whether it's as good as the results we see with radical prostatectomy for example. But I think that this paper does provide us some long-term follow up that shows us in fact the evidence is that brachytherapy is a very effective treatment for low-risk prostate cancer.

Specifically in this particular trial they looked at 125 consecutively treated patients with low-risk prostate cancer. In patients who had PSA less than 10, Gleason scores of 2 to 6, and low-stage prostate cancer, 87 percent of them had no evidence of disease in ten years and only 12 percent patients had a biochemical failure. Of that 12 percent, 6 percent had PSA only failure, 3 percent had localized disease failure, and 3 percent had distant disease failure. Those are very respectable results for the treatment of lower-risk prostate cancer, and I think this is an important paper to be aware of when counseling your patients regarding the different options and what they might expect the outcome would be should they choose brachytherapy as their treatment.

DR LOVE: Any other papers?

DR DAWSON: I think that the study that was reported by Worth et al in Urology this last year, looking at bicalutamide as immediate therapy in men with either, locally treated prostate cancer or patients with locally advanced prostate cancer compared to placebo, is an important paper. One of the reasons why this is an important paper is, it's the first large trial to address the issue of whether adjuvant hormonal therapy improves outcome in men who've been treated with radical prostatectomy. The trial, which was a multi-center, international trial, randomized men, as I mentioned to bicalutamide or placebo. And what this trial demonstrated was that the patients who had immediate hormonal therapy had a decrease incidence of time to PSA progression, time to clinical progression, time to development of distant metastasis favoring the patients that received the bicalutamide.

What the trial cannot tell us, at this time, is the impact on survival. That's because the trial is too early and there haven't been enough deaths or events to be able to analyze survival as an endpoint. But it gives us the first hint at the potential benefit of adjuvant hormonal therapy in patients with localized prostate cancer. So it's important because if you look at the endpoint being a delay in time to progression, and that's an important endpoint to some of our men and to some of us, then we can see that this supports early hormonal therapy as being beneficial. If the only endpoint that we care about is whether a man lives longer or not, then this paper tells us that there's a study that's been completed and that we need to stay tuned because there's going to be more information to follow. So now, we are certainly aware that this study has been done, that the early results show some benefit as far as time to progression and that we need to look forward to further follow up on this study to see whether it impacts on survival or not.

DR LOVE: Any prediction on what you think is going to be seen?

DR DAWSON: Well, I would hope that a delay in time to progression would lead to improvement in survival. That certainly would be my hope. I doesn't always turn out to be true, so I guess I'll need to stay tuned as well.

DR LOVE: Do you think that just the delay in time to progression would be enough of a benefit given the side effects of therapy to justify treatment?

DR DAWSON: I think it's something that we need to talk to patients about. I think patients need to be informed. There is evidence that supports that early hormonal therapy will delay their time in progression, and that we don't know whether that will result in improvement in survival. I think individual men would have to be informed of this information and be informed of the potential toxicity of this hormonal therapy to be able to make a decision. I think getting this information to the patient to let them decide how they weigh whether a delayed time to progression is worth it to them.

The most significant side effects of bicalutamide monotherapy are gynecomastia, breast tenderness and breast pain. The majority of patients had one of those symptoms. So, a patient may decide that some possible breast tenderness or breast enlargement would be worth it in order to delay progression and possibly delay the onset of metastasis. Another patient, given the same information may decide it's not worth it. I think it is worth it to inform patients of these results to help them make decisions about what's right for them.

DR LOVE: What other papers have come out that you think are important to community urologists?

DR DAWSON: I think the update on the RTOG trial 8531 that came out in the International Journal of Radiation Oncology, also known as the Red Journal, is an important clinical trial. That is a trial that was started quite a few years ago and this is an update of those results. In this particular trial, almost 1,000 patients were randomized to radiation alone or radiation followed by hormonal therapy with the hormonal therapy given continuously until progression. And in this clinical trial again, there was evidence that hormonal therapy delayed time to progression, delayed PSA progression, delayed development of metastasis, but overall the addition of hormonal therapy in this trial did not improve overall survival.

In the update though, they did do some subset analysis that I think it's important for urologists to be aware of. Patients with high Gleason scores, 8 to 10, showed improvement in their survival and their prostate cancer-free survival by the addition of hormonal therapy. This is important when counseling patients about what therapy they should take. If you have a patient who has particularly high-risk disease who you are counseling about what you feel is his best treatment, it would be important to be aware that men with high Gleason scores seemed to have improved survival when they have hormonal therapy added to their radiation therapy.

Based on my belief that the early use of chemotherapy is also probably going to be very important in these high-risk patients, I also think the patients, if at all possible, should be enrolled on clinical trials. Specifically, trials that not only include hormonal therapy but also ask the question of whether chemotherapy improves how they do. But outside of the setting of the clinical trial, I think that in counseling patients one needs to be aware that there's a survival benefit to adding hormonal therapy to radiation therapy, especially in the subset of high-risk patients with high Gleason scores.

DR LOVE: I also asked Dr Dawson to present a couple of interesting case from her practice and she began with a 50-year-old man who presented a year-and-a-half ago with urinary symptoms, problems with stream and flow, and nocturia.

DR DAWSON: He went to see an urologist and his PSA was elevated, it was 11. His prostate exam was abnormal. He'd had a PSA and a prostate exam three years before and both were completely normal. He had a biopsy and he had 2 of 3 cores of one side positive for a Gleason 4+5 = 9 tumor. And 3 of 3 cores on the left side which were positive for a 5+4 = 9 Gleason score tumor, involving 100 percent of all 3 cores. So this was a fellow who had, what everyone would agree, was very high-risk disease. He was 58 years old with no other significant medical problems. Scans - bone scans, CAT scan - showed no other incidents of metastatic disease, no obvious extra capsular extension. So it appears he has organ-confined, very-high risk bilobular prostate cancer. His PSA is over 10, Gleason score of 9 with one side actually having a 5 as the most predominant pattern.

The question is what's the best management for this patient? Can you treat this man with single-modality therapy? Can he be cured with a prostatectomy? Can he be cured with radiation therapy alone, or is this the patient that needs to be very strongly encouraged to enroll in a clinical trial that looks at multi-modality therapy?

DR LOVE: Or receive some other kind of therapy?

DR DAWSON: Or some other kind of therapy off trial. When I saw this patient, I told him that I thought that he would not be a great candidate for prostatectomy because it was highly unlikely his disease would not have penetrated through the capsule. There are some people that would consider doing a prostatectomy, I can't say if that's totally wrong, but I told him at that time, if he wanted to have a prostatectomy that was his choice. And, he actually had a prostatectomy, which he did not get.

I would strongly encouraged him to enroll on the ongoing Intergroup clinical trial that would randomize him to two years of hormonal therapy with or without chemotherapy. This is the sort of patient that I feel has probably a very high risk of developing metastatic disease and a very high risk of developing hormone refractory disease in his course, so that is the sort of patient that would be ideal for the early use of chemotherapy. Right now we haven't proven that the early use of chemotherapy improves on how these people do, so they really need to be enrolled in clinical trials.

DR LOVE: Another thing that's interesting about that study is both arms get hormonal therapy.

DR DAWSON: Both arms get hormonal therapy for two years because most people feel these patients are going to relapse, and many people believe that early hormonal therapy is likely to delay relapse and the time to progression. When this trial was designed, it was originally designed with a no treatment arm. After much debate among experts in prostate cancer it was felt that the trial could not be done, at least not in the United States, without an arm that included hormonal therapy. This is very controversial because ideally you would have a no hormonal therapy arm, a hormonal therapy alone arm and, you can even actually have a chemotherapy alone arm and a chemotherapy- hormonal therapy arm. But that gets too complicated and too large.

DR LOVE: But the implications of the trial design are that hormonal therapy would be a baseline and then the question is whether to add chemotherapy.

DR DAWSON: Right.

DR LOVE: And this is the Intergroup study?

DR DAWSON: That's the Intergroup study.
DR LOVE: What exactly are the randomization arms?
DR DAWSON: The arms are two years of combined hormonal therapy - Zoladex and Casodex for twenty four months, compared to two years of Zoladex and Casodex with Mitoxantrone and Prednisone. The chemotherapy is given for 6 cycles, the Mitoxantrone is the IV chemotherapy and it's given every three weeks.

DR LOVE: You presented this as an option to this man?

DR DAWSON: I presented this as an option to this man, however I did not recommend prostatectomy. In fact, the patient elected to go on another clinical trial that we're doing. It is a pilot trial at the University of Maryland that uses external beam radiation therapy, followed by brachytherapy, followed by adjuvant chemotherapy. In this case it's Taxotere chemotherapy weekly, three out of every four weeks for 3 cycles in combination with hormonal therapy for two years.

DR LOVE: When you presented these clinical trials options to him, I would assume that you also discussed options if he weren't going to be in a trial.

DR DAWSON: Right.

DR LOVE: What were those?

DR DAWSON: I told him if he did not go on a trial that I would recommend radiation therapy in combination with hormonal therapy. I actually said, off study I would have to defer to the data that's out there, which is the Bolla Trial that is three years of hormonal therapy. So I said off study I would follow that trial, since that's the trial that should improve survival by adding hormonal therapy to radiation therapy. That particular trial was predominantly T3 patients, he was not clinically a T3 but he probably pathologically was.

DR LOVE: What do you think about watching people with PSA elevations without treating them?

DR DAWSON: I've looked at the data that's out there, the Medical Research Council data which looked at men with locally advanced and metastatic disease that were asymptomatic. It was in the localized patients not the metastatic patients that there was a survival benefit. Not only was there a delay in complication, but also there was a survival benefit. And there's the Bolla trial, radiation plus hormonal therapy where the survival was better when you added hormonal therapy. And then there's the Messing trial that is for lymph node-positive patients where early hormonal therapy impacted on survival. So none of those are post prostatectomy, rising PSA papers, but if you look at all that data it certainly looks to me that earlier is better than later impacting on survival.

The flip side of it, if you asked, for example the Hopkins' contingency, they would say that there is no trial that addresses or shows an improvement in survival for that patient population. But there are other papers sort of like, and if a equals b and b equals c, and c equals d, then why shouldn't a equal d.

DR LOVE: Is it your impression that men would value having a delay in PSA progression?

DR DAWSON: I think for some men, yes. I have patients who watch their PSA so closely and when it goes from .001 to .01 they go into a panic. I have other men who as long as it is a reasonable number, they're OK. But those patients, and there are many, many out there, who are watching their PSA extremely closely, and the quality of their lives is directly linked to whether their PSA stays down or not, for those men, absolutely. If you can keep their PSA from going up, you would impact positively on the quality of their life. But for other men, I have patients who actually will say, I'll check again in six months, I'll be back then. You're going to find that most men will care, in my opinion, and would like to do something to keep their PSA from going up. But you're still going to find, it's not going to be a rare patient who is not going to consider that real important.

There are actually trials in design right now that will probably become the next Phase III Intergroup trial, which will be chemotherapy plus hormonal therapy versus hormonal therapy in rising PSA.

DR LOVE: It's always interesting to look at the design of current clinical trials to try to get an idea of what the clinical research leaders think about things. It's interesting that you mentioned this trial looking at rising PSAs because again the control arm is hormonal therapy. A lot of times the control arm in clinical trials reflects what is considered standard of care and then the experimental arm is a modification of that. Do you think that the standard of care in the community right now for rising PSAs is to treat with hormonal therapy?

DR DAWSON: Yes, I do.

DR LOVE: There are people on the other side who would say, you can wait until the patient develops clinical evidence of metastatic disease. How would you counter that argument?

DR DAWSON: I would give them the exact statement I tell patients when they come to see me because I'm regularly referred patients whose PSAs are rising and they come and say well what do you recommend and why? I say, there are no clinical trials that tell us that in a patient after prostatectomy or radiation that your survival is going to be improved by early hormonal therapy. But that there are three randomized, Phase III clinical trials that we do have results on that support the benefit of early hormonal therapy. I tell them about the Medical Research Council trial, which was a trial of asymptomatic men with locally advanced or metastatic disease who were treated with early hormonal therapy versus delay hormonal therapy. That trial showed that there was an improvement in the non-metastatic patient with regard to improvement in overall survival and improvement in prostate cancer-free survival, or prostate cancer-specific survival. It also showed a decrease in the complications of having prostate cancer - the development of spinal cord compressions, the development of fractures, the development of renal failure and so. So that is one trial that shows a benefit to early hormonal therapy.

The EORTC trial by Bolla with men with localized prostate cancer who are treated with radiation therapy with either three years of hormonal therapy versus radiation therapy alone or with hormonal therapy at the time of progression. And again, that trial showed a survival benefit to early versus delayed hormonal therapy, which is really what that trial tells us.

The third trial is the ECOG trial by Messing et al that was reported in the New England Journal of Medicine approximately two years ago. It looked at men who had a prostatectomy and were found to have metastatic disease to their lymph nodes, and they were randomized, again to either immediate hormonal therapy or delayed until they had progression. That trial also showed, a not unexpected delay in time to progression, but it also showed an improvement in survival, a significant improvement in survival. It was a small study that was never completed. But my feeling about that is, it says it's even more positive because you can see the significant result with a one hundred-person trial. So all of this information, although not exactly the clinical scenario we're describing, which is the man who's had a prostatectomy or radiation and his PSA is going up. But it is similar enough for me to say that there is increasing evidence that early hormonal therapy improves survival. So that's what I tell patients.

They usually next ask me how early is early? How about if I wait until next year or the year after? I can't tell them that starting now versus starting later matters. I can't tell them it doesn't matter either. I just say I have the information about early versus delayed until progression and I can't tell what the timing needs to be. Then we get into other conversations, actually that that leads to, at what level of PSA are you likely to have metastatic disease? For example patients whose PSAs are less than 10, usually they don't have documented bone metastases. So there's further information that I usually provide patients with about how long "they can safely wait". But I usually tell them that I feel that early hormonal therapy has been shown to be beneficial.

DR LOVE: What happened with the man?

DR DAWSON: The man went on our clinical trial, he did well. He's tolerating his therapy well. His main toxicity from the treatment actually was urinary frequency from the seeds and that's actually getting better. His PSA is undetectable. He's now out a little over a year-and-a-half from presentation. He has an undetectable PSA and he's working full time and feeling well. He actually has a problem with impotence from the hormonal therapy and has just enrolled on a trial where we are looking at Viagra to treat impotence for patients on hormonal therapy.

DR LOVE: That's interesting. Have you seen people respond to Viagra?

DR DAWSON: Yes. But I believe the response rate to Viagra is probably relatively low, but no one has actually done the study that I'm aware of, to actually determine what the benefit of Viagra is in men on androgen deprivation therapy.

DR LOVE: So you've seen men actually respond?

DR DAWSON: Yes, but it does not appear to be as high as it is for example for men who have impotence post prostatectomy.

DR LOVE: Do you think part of it might be a difference in libido?

DR DAWSON: Part of it is the difference in libido because they have a decreased interest and what we've discovered is that men actually have to be educated about how Viagra works. A lot of men were under the impression that they take the Viagra and then it would make them interested and they would automatically get an erection. Actually, when the men are educated about the fact that you have to go through the normal stimulation and arousal period, mood setting, etc., the response to the Viagra goes up significantly.

DR LOVE: I know you brought one other case. Let's talk about that man.

DR DAWSON: Yeah, this is a very delightful gentleman who I'm glad I'm still following. He's currently 80 years old. He was diagnosed when he was 70 back in 1991 with prostate cancer, and at the time he was picked up on a routine exam. His PSA was 30 and he had a hard nodule on the right lobe of his prostate and his clinical stage was T3 N0 M0. So he didn't have distant disease and he was treated with external beam radiation therapy, which would be considered standard therapy for this gentleman. At the time, he was not treated with hormonal therapy, and initially his PSA dropped from 32 to about 12 and then it started to almost immediately rise again.

So in 1993 about two years later, it had risen sufficiently that he was started on monthly Zoladex, and that was very effective in getting a good PSA response. At the time, he did not have distant disease and his PSA dropped to about .1, and it continued to stay down for the next few years. In 1996, the fellow, he's a photographer and he travels a lot, elected to have a bilateral orchiectomy because he didn't want the inconvenience of getting the shots. Then over the next couple of years his PSA started to rise around the time you would expect he would start to become hormone refractory. In '97, he was started on Casodex as a secondary anti-androgen but did not get any benefit from that. It was started at a dose of 50 milligrams a day which is actually less than I would normally try as a second-line of hormonal therapy. I usually use the 150-milligram dose.

DR LOVE: Do you normally continue the LHRH agonist?

DR DAWSON: I normally continue the LHRH agonist and I think that there are a couple of reasons to do that. One, there's actually been some retrospective reviews of some of Cooperative Group trials that have shown that men who continued on their testicular androgen deprivation have a slight improvement in survival. So that's retrospective. But more interestingly, there's actually a clinical trial that was done 20 years ago before we understood completely the hormonal effects in prostate cancer, in which they actually gave men testosterone as a potentially therapeutic modality in hormone-refractory disease. Over 90 percent of the men got significantly worse when exposed to testosterone and when it was taken away most of their symptoms again resolved. My feeling is that these men have at least some hormone-sensitive disease, so that if you give them their androgen back, it would be allowed to flair. People have also described men who have been taken off their LHRH analog and then been put back on it, and had secondary responses to doing that. So I believe there are hormone-sensitive cells even in the setting of progressing disease and that I think we need to continue to suppress those hormone-sensitive cells.

DR LOVE: Of course in breast cancer classically you see multiple responses to hormonal therapies - a woman progresses on one hormonal therapy and starts another one. Have you seen responses, you said you use 150 milligrams Casodex in that situation?

DR DAWSON: The literature supports up to 30-40 percent response to a secondary anti-androgen in that high dose and I have seen quite a few patients have a good benefit from it. There's almost no toxicity over what they were already having from their LHRH analog. So it's very well tolerated and it can be a benefit to some of these patients when they're progressing.

DR LOVE: Is that the typical second therapy you give to men progressing on LHRH agonists?

DR DAWSON: Sometimes I give high doses of bicalutamide. There is a problem with reimbursement for 150 milligrams of bicalutamide or Casodex. Currently the FDA-approved dose in newly diagnosed metastatic disease, or in addition or in combination with radiation therapy is 50 milligrams. So, sometimes there can be a significant problem with reimbursement for the higher dose. Alternatively, I've used the combination of Ketoconazole and Hydrocortisone as a second-line hormonal therapy, and in fact, that's exactly what this gentleman got when I saw him.

DR LOVE: So he progressed on the 50 milligrams of Casodex?

DR DAWSON: Right. That was stopped and his PSA continued to rise. When I saw him about two-and-a-half years ago, his PSA was about 90. At that time, I started him on Ketoconazole and Hydrocortisone. Ketoconazole inhibits P450 mediated enzymes so it inhibits both testicular and adrenal androgenesis. It's combined with Hydrocortisone somewhat for historical reasons.
Aminoglutethimide is another second-line hormonal therapy that causes many patients to have adrenal insufficiency. Ketoconazole actually does not cause adrenal insufficiency commonly, it's about 1 percent of the time, but over time Ketoconazole has been given with Hydrocortisone for the concern about the adrenal insufficiencies. You could probably give it by itself, but Ketoconazole is usually given with Hydrocortisone because of concern about adrenal insufficiency.

And of course, steroids alone have a benefit in prostate cancer in 20 percent of patients as far as causing declines in PSA. So Ketoconazole and Hydrocortisone together in men who are progressing through their initial androgen-deprivation therapy has been actually shown to have about a 60 percent chance of causing their PSA to drop. So it actually has a pretty high response rate and it's actually pretty well tolerated.

The worst thing about Ketoconazole is the potential to cause nausea. When I used to give Ketoconazole several years ago, I would try to give it at full dose, which is 400 milligrams three times a day just right off the bat. Probably 30-40 percent of patients would have severe nausea and vomiting when I did that. Over time I developed the treatment strategy of starting them on 200 milligrams, three times a day, and have them come back to see me in two weeks to see how they are tolerating it. If they are tolerating it well, I increase the dose slowly over the next couple of weeks adding one tablet a day until I get up to the intended 400 milligrams three times a day after about a month. When I do it that way, almost no one has to stop it for nausea and vomiting. I haven't had a patient come off it for that toxicity in the last several years since I've been trying to start at the lower dose and then taper up.

DR LOVE: So the mechanism of action here is suppression of adrenal androgen production, correct?

DR DAWSON: Correct.

DR LOVE: What about using the third generation aromatase inhibitors such as anastrozole, letrozole and the other drugs out there like that, for the same purpose?

DR DAWSON: Some have proposed testing those drugs, and I haven't actually seen much data on them. Liarozole was a drug that was tested as well. It's not an aromatase inhibitor, but another drug similar to Ketoconazole. It had some activity but not enough for it to become FDA-approved drug.

DR LOVE: So this man got the Ketoconazole, and how did he do?

DR DAWSON: Well his PSA dropped to less than 1.

DR LOVE: Wow.

DR DAWSON: He had basically no toxicity and remained less than 1 for the next two plus years. He still does not have metastatic disease. His bone scan and his CAT scan at the time I first saw him, when his PSA was almost 100, showed no metastatic disease. Recent re-evaluation shows that he still has no metastatic disease. His PSA is going up and it was up to 121 over the last couple of months. We have just stopped his Ketoconazole and I have tapered his Hydrocortisone and I have started him on 1 milligram of DES a day. He's still asymptomatic and still doesn't have distant metastatic disease. I started him on a third-line, fourth-line for him, hormonal manipulation and his PSA, which was checked last week, is down to 5.

DR LOVE: What would be the mechanism of action of DES in this situation?

DR DAWSON: Estrogens in prostate cancers have cytotoxic activity against prostate cancer cells and they also work by suppressing hormones through the pituitary access.

DR LOVE: But in this man who was orchidectomized it would be, presumably a direct effect?

DR DAWSON: It would have to be a direct effect.

DR LOVE: Have you seen men who are orchidectomized or on LHRH agonists respond to the DES?

DR DAWSON: Well, one of my favorite patients is another gentleman who is in his early 80s who was progressing and had distant metastatic disease. He was having significant pain from bone metastases and he was progressing through his LHRH analog. He had gotten an anti-androgen and progressed through that. He progressed through withdrawal of his anti-androgen and was having significant pain. He did not want chemotherapy. We actually did a couple of things; we actually radiated a particular area in his back that was quite painful. We actually gave him some Strontium 89 and that was of some benefit. But with a PSA of over 2000, I started him on 1-milligram a day of DES and his PSA when down to less than 1.

DR LOVE: And this was with the LHRH agonist on board?

DR DAWSON: LHRH agonist on board.

DR LOVE: Wow.

DR DAWSON: His PSA now has stayed down at less than 1 for over a year. Most recently, it has slightly increased to 2. I increased his DES dose from 1- milligram to 2-milligrams and it seems to be steady at about 1.5. But his PSA was over 2000. He has no pain right now, he has no symptoms and he is caring for his elderly wife who was recently in a car accident.

DR LOVE: What are you going to do with this patient if and when he progresses and assuming he's just still PSA on DES? What's the next trick in your bag?

DR DAWSON: Hmmm.

DR LOVE: What about that herb thing?

DR DAWSON: PC Spes? (Laughter)

DR LOVE: Yeah.

DR DAWSON: They just took PC Spes off the market. I suspect it will be put back on the market. PC Spes is the Chinese and American herbs that are estrogenic. It doesn't require a physician to prescribe it. It's relatively expensive. I'm not sure that a patient would respond to PC Spes who's progressed through DES. I actually have seen that.

I had a patient, he's now deceased, but I followed him for hormone-refractory metastatic disease for quite some time. And he actually, partly by his initiation, alternated on and off DES and PC Spes and anti-androgens. He would actually rotate them, and he did have second and third responses to PC Spes when it was restarted, even after DES. So I have seen people respond to alternate estrogens, and PC Spes does have other things in it besides estrogen. In cell lines it's been shown to be cytotoxic and have a lot of immuno-stimulatory, etc.

DR LOVE: Any other hormonal therapies you'd use on him?

DR DAWSON: Well I haven't used Aminoglutethimide in him yet.

DR LOVE: Do you think that would work in the face of progression?

DR DAWSON: Through Ketoconazole?

DR LOVE: Yes.

DR DAWSON: I wouldn't expect it to work but, if you look at this like breast cancer, and one was trying to avoid chemotherapy, one could become creative and try something like Arimidex, like you mentioned, try an aromatase inhibitor. You could also consider tamoxifen. Tamoxifen has been looked at in hormone-refractory prostate cancer and there are responses to tamoxifen.

DR LOVE: So basically you are trying to find some kind of therapy that won't cause him toxicity that you can try rather than just observing him off therapy?

DR DAWSON: Right. I actually offered this particular patient two options when he progressed through Ketoconazole and Hydrocortisone. I offered him the option of DES, 1-milligram a day, which is the option he took. I also offered him a clinical trial.

We have an ongoing clinical trial looking at the drug Iressa, which is an Epidermal Growth Factor Receptor inhibitor. Epidermal growth factor receptor is overexpressed in several solid tumors including prostate cancer and in fact, it appears that it is more frequently overexpressed in more advanced disease. So there's a rationale there and this drug is currently being evaluated in PSA only hormone-refractory prostate cancer. There was a clinical trial that was completed in hormone-refractory disease looking at Iressa that suggested that it might be an active agent to test in prostate cancer.

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