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Tracks 1-2

DR LOVE: Can you discuss your work evaluating the correlation between clinical outcomes and the duration of testosterone suppression after the completion of six months of hormonal therapy in men with high-risk, localized prostate cancer who were treated with radiation therapy?

DR D’AMICO: Our study confirmed that as men age, six months of hormonal therapy provides a longer interval of testosterone suppression. In other words, it takes longer for their testosterone levels to return to baseline. If patients were younger than 60 years old, it took a year for testosterone levels to return to baseline. If patients were older than 70 years old, it took about a year and a half to two years for their testosterone levels to return to baseline. Approximately 10 percent of the patients never had a return to baseline testosterone levels following a minimum of five years of observation (D’Amico 2007; [1.1]).

As the duration of testosterone suppression after the completion of six months of hormonal therapy increased, the time to prostate cancer-specific and allcause mortality increased. This suggests an association between the duration of testosterone suppression and the likelihood of dying from prostate cancer in this particular cohort (D’Amico 2007; [1.2]).

When we evaluated the men with high-grade cancer (Gleason scores of 8 to 10) and plotted the cumulative incidence of prostate cancer deaths — stratified by whether their testosterone levels returned to baseline within two years or later — a striking difference was evident in those who died of prostate cancer.

Essentially, all the prostate cancer deaths in this observational study occurred in the men whose testosterone levels rebounded quickly. Prostate cancer deaths were not observed in those whose testosterone levels did not rebound within the first two years (D’Amico 2007).

Perhaps we’ve never been able to show in randomized trials with surgery a benefit from a short course of hormonal therapy because they included young men with a median age in the low sixties in whom the testosterone levels rebounded quickly.

Short-term hormonal therapy in that group may be homeopathic, whereas in the RTOG and European studies of radiation therapy, the patients tended to be a decade older, be less virile and have lower testosterone levels. This may be why even a short course of hormonal therapy in those men appears to be beneficial.

Track 3

DR LOVE: What are your thoughts about these data, Laurie?

DR KLOTZ: One of the problems with the study is that recovery to baseline was utilized as the determinant, although a lot of data suggest that most men’s testosterone levels, after six or eight months of androgen deprivation, recover to approximately 50 percent of baseline.

If they achieve 80 or 90 percent of baseline, they still have, from the perspective of a prostate cancer cell, a pretty substantial androgenic stimulus.

DR D’AMICO: That’s a good point. We evaluated several different cut points for testosterone levels: baseline, 200 ng/dL — which is hypogonadal — and 100 ng/dL.

As we went to lower numbers, from baseline to 200 ng/dL to 100 ng/dL, the effect remained but the
p-value increased because the power to detect a difference was decreasing.

Again, perhaps the reason all five randomized trials of surgery with three months of hormonal therapy (Aus 2002; Klotz 2003; Selli 2002; Schulman 2000; Soloway 2002) did not show a benefit is that in these men, short-course hormonal therapy was homeopathic and their testosterone was not suppressed for long. I’m not convinced that adding hormonal therapy to surgery may not produce a benefit — it may.

DR KEANE: Laurie did a study comparing eight versus three months of neoadjuvant hormonal therapy, and hormonal therapy didn’t work there (Gleave 2001).

DR KLOTZ: In an earlier Canadian study in the high-risk subset — in a retrospective stratification analysis — there was a benefit to three months of neoadjuvant therapy (Klotz 2003). Also, none of the neoadjuvant studies were enriched for patients with high-risk disease. So we don’t know the answer in patients with high-risk disease.

DR CRAWFORD: I have to comment on these trials of neoadjuvant hormonal therapy with surgery. They have varied the duration of hormonal therapy from three, four or eight months. They all show some histologic benefit, but they don’t show a difference in PSA recurrence or survival.

We have to remember that these are long-term studies in prostate cancer. Even in our adjuvant radiation therapy trial, for which the radiation oncologists love to talk about a big benefit, there is no survival benefit. Yet we accept radiation therapy as an adjuvant in high-risk prostate cancer.

My bet is that the Soloway trial (Soloway 2002), the Debruyne trial (Schulman 2000) and the Canadian trial (Klotz 2003) will show a survival benefit at 15 years, similar to the Messing trial when it was first evaluated at five years (Messing 1999).

DR ROACH: I would like to take your bet, Dave. The fact is that these studies will not show a difference with long-term follow-up because no difference was evident in PSA failure. The risk of dying from prostate cancer in this patient population is too low, and the sample sizes from the studies are too small.

The bottom line is that 15 years from now, they will continue to be negative studies. The fact is that the benefit from hormonal therapy and radiation therapy results from a biologic interaction that does not occur with surgery.

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