You are here: Home: PCU 1 | 2007: Anthony V D’Amico, MD, PhD

Tracks 1-16

Track 1 Recent developments in the management of high-risk localized prostate cancer Track 2 Hormonal therapy and risk of cardiovascular morbidity Track 3 Duration of hormonal therapy and cardiovascular events Track 4 Relationship between duration of testosterone suppression and clinical outcomes of men with high-risk localized disease Track 5 Duration of testosterone suppression and patient age Track 6 Use of bicalutamide monotherapy Track 7 Hormonal therapy for intermediate- or high-risk prostate cancer Track 8 Treatment approach based on postprostatectomy PSA doubling time Track 9 Fraction of patients presenting with intermediate- or high-risk disease Track 10 Use and duration of maximal androgen blockade Track 11 Effect of finasteride for hair loss on interpretation of PSA screening results Track 12 Dose-escalated radiation therapy and hormonal therapy for high-risk disease Track 13 Tolerability of docetaxel Track 14 Increase in a multimodality approach in the care of patients with prostate cancer Track 15 Future research directions in prostate cancer Track 16 Clinical trials of systemic therapy in combination with docetaxel for intermediate- and high-risk prostate cancer

Select Excerpts from the Interview

Track 1

DR LOVE: What are some of the key research issues in the management of high-risk localized disease?

DR D’AMICO: Ongoing clinical trials are examining the role of docetaxel in addition to standard therapies for patients at high risk. Some are evaluating docetaxel in addition to radiation therapy, and others are evaluating hormonal therapy or docetaxel with surgery and hormonal therapy. The trials will probably close in 2008 or 2009, and that’s one piece of the puzzle related to attempts to improve tumor control.

The other new research piece involves quality-of-life factors and side effects. In general, men who are older than 65 years of age are predisposed to metabolic abnormalities as a result of the use of hormonal therapy.

A publication in the Journal of Clinical Oncology (Keating 2006) showed that men receiving hormonal therapy are more likely to develop diabetes and more likely to be admitted to the hospital for myocardial infarction (MI), or at least chest pain.

Two abstracts discussed at the ASCO Prostate Cancer Symposium — one a retrospective examination of the CaPSURE database (Tsai 2007) and one a prospective meta-analysis of three randomized studies (D’Amico 2006) — show that the occurrence of fatal MIs is significantly increased with as little as three months of hormonal therapy among men older than age 65.

With this information and the fact that hormonal therapy increases curability in men undergoing radiation therapy for high-risk disease, we have to be more intelligent about how we use hormonal therapy, how we think about what we do and how we counsel men before starting hormonal therapy.

Specifically, for men with known vascular disease or diabetes, consideration of a cardiovascular consult or stress test before the hormonal therapy is initiated may be worthwhile. Evidence suggests that these fatal MIs occur within the first two years — so they occur relatively shortly after starting the hormonal therapy. It’s not a late effect — it’s a subacute effect.

Tracks 4-5

DR LOVE: Can you review your data on the duration of actual androgen suppression, as opposed to the duration of treatment, and how this affects outcomes?

DR D’AMICO: Our study presented at the 2007 ASCO Prostate Cancer Symposium asked, does any relationship exist between the duration of testosterone suppression and the time to cancer-specific death following radiation therapy and six months of hormonal therapy?

The answer is yes, a relationship does exist. The longer a man’s testosterone stays suppressed after only six months of hormonal therapy, the more likely he is to survive and not die of prostate cancer (D’Amico 2007; [2.1]). In a nutshell, the study results indicate that it’s not how much hormonal therapy you administer but how long androgen suppression lasts that matters.

I believe the duration of testosterone suppression will be one of the most important messages in 2007. Right now it’s unclear whether all men with Gleason 8, 9 or 10 prostate cancer require long-term hormonal therapy to achieve the benefits shown in the studies in which long-term hormonal therapy is the standard.

Currently, two or three years of hormonal therapy is the standard duration for men with Gleason 8 to 10 prostate cancer. The question now becomes, is it two or three years of hormonal therapy, or is it two or three years of testosterone suppression, which in some men will be two years of hormonal therapy and in other men may be only six months?

DR LOVE: Or is it five years?

DR D’AMICO: That’s another question, so it could all be up in the air. What’s clear now is that what really matters is effective length of testosterone suppression and not effective length of hormonal therapy administration.

DR LOVE: In the men in this study who were treated with hormonal therapy for six months, what is the longest time that the androgen suppression continued? Are any of these men out four or five years now?

DR D’AMICO: The median follow-up in our study is about seven years, and nine percent of these men have not returned to a normal testosterone level (D’Amico 2007). They remain permanently castrate after just six months of hormonal therapy.

DR LOVE: Do those patients have the best outcome?

DR D’AMICO: Absolutely.

Track 10

DR LOVE: You use maximal androgen blockade in your trial of six months of adjuvant therapy. Is that what you use in the clinical setting, and if so, what’s the rationale?

DR D’AMICO: That is what I do for a short course. For long-course hormonal therapy, in the RTOG databases, they use combined androgen therapy for the first four months and monotherapy for the next two years.

We don’t know whether combination androgen therapy is better than monotherapy, especially in the short-course setting. I can justify the combined therapy if it’s short course — the added toxicity from the combination therapy over the monotherapy is not much more for a short-course setting — but you wouldn’t want to continue it over the long term.

Regarding the rationale, there is no good answer. You can go back to the metastatic trials by Crawford and Eisenberger and try to argue that combined therapy helps a more favorable subset of men with metastatic disease, but that couldn’t be validated (Crawford 1989; Eisenberger 1998).

At this juncture, it’s combined therapy with a short course based on the way studies were run, not necessarily based on existing logic.

Track 12

DR LOVE: Where are we in terms of radiation therapy dose and outcome?

DR D’AMICO: A trial was presented at the 2007 ASCO Prostate Cancer Symposium in which men were randomly assigned to low- versus high-dose radiation therapy — 64 Gray versus 74 Gray. Sixty-four Gray is considered substandard radiation therapy these days.

All of these men also underwent a short course of hormonal therapy, and a benefit in PSA recurrence was still seen in the higher-dose arm (Dearnaley 2007; [2.2]).

This has been a question for a while — whether adding hormonal therapy to the high-dose radiation arm would still be beneficial — and the answer appears to be yes. This adds some credence to the idea of using dose-escalated radiation therapy and hormonal therapy, as opposed to standard-dose radiation therapy and hormonal therapy, for men with higher-risk disease.

Physicians ask, “If you’re treating a guy with high-risk disease and you’re using a hormonal therapy, what dose of radiation therapy do you deliver?” One can draw from two databases: the MD Anderson study, which used 75.6 Gray (Pollack 2002), and the Proton Study (RTOG 94-06), which used 79.2 Gray (Valicenti 2003). Therefore, I tell people that administering radiation therapy between 75.6 and 79.2 Gray is reasonable.

Track 13

DR LOVE: Can you comment on the use of adjuvant chemotherapy outside of a clinical trial?

DR D’AMICO: I’m the principal investigator on a study of radiation therapy and six months of hormones with or without docetaxel. People are asking, “For a young man, 40-something years old, with Gleason 9 disease, I don’t think radiation therapy and hormones will be enough. Would you add docetaxel?”

We know it can cause some toxicity, although it seems to have been generally well tolerated. No chemotherapeutic drug is without toxicity. So my answer right now is no, I wouldn’t use it off study, pending the results.

DR LOVE: How do you see taxanes affecting quality of life?

DR D’AMICO: Part of the issue is dosing. We’re administering 60 mg/m² every three weeks, which is a full dose, for three cycles during the two months of neoadjuvant hormonal therapy, and then we use weekly docetaxel at 20 mg/m2 during the eight weeks of radiation therapy. We’ve treated 50 people this way so far, and we haven’t had any hospital admissions. I thought we’d have a large increase in diarrhea, especially since we’re treating the pelvis, but the increase in diarrhea has been minimal.

Most of what people report are changes in blood counts, meaning we have to watch the platelets and the hemoglobin, but no one has received a transfusion. Some issues have arisen with neuropathies: tingling in the fingers and toes and changes in taste. Most, but not at all, of these issues have been transient and resolve after treatment is complete.

No nausea or vomiting has occurred with the docetaxel, at least not with the way it’s been administered. People do report fatigue, although it’s hard to discern whether that fatigue is caused by docetaxel and hormonal therapy or by hormonal therapy alone.

The chemotherapy is out of their system probably within a week after the last dose is administered, so we attribute the fatigue that lingers to the hormonal therapy.

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