than 4 group who accounted for the increased failure in this popu-lation. These are data available to the authors but not presented.

Despite these limitations, the authors primary point that having ahigh grade cancer and low PSA is an ominous combination is probablycorrect and may improve counseling for patients. For example, becauseroughly two-thirds of these men remain free of failure at 5 years, theauthors are probably correct in concluding that currently this informa-tion can only be used for counseling patients and would probably notalter therapeutic decisions. However, it does represent an excellentsubgroup for future adjuvant studies. If the testosterone data are con-firmed, perhaps nonhormonal approaches should be used, particularlyin an adjuvant setting.

Edward M. MessingDepartment of UrologyUniversity of RochesterRochester, New York

REPLY BY AUTHORS

We would like to provide the requested data in support of thehypothesis that the higher PSA failure rate for patients with pros-tatectomy Gleason 7 or greater and PSA 4 or less versus greater than4 to 10 ng./ml. was due to the higher proportion of patients withGleason 8 to 10 versus 7 disease (25% versus 16%). Specifically, forpatients with Gleason 8 to 10 versus 7, the 5-year estimates of PSAfailure were 63% versus 29% (p � 0.0007) and 51% versus 20% (p�0.0001), respectively, for patients with PSA 4 ng./ml. or less (fig. 1)compared to PSA greater than 4 to 10 ng./ml. (fig. 2). Given thesignificantly higher PSA failure rates for patients with Gleason 8 to10 compared to Gleason 7 provided evidence to support that the

higher PSA failure rate in the 4 or less versus greater than 4 to 10ng./ml. cohorts was due to the higher proportion of patients withGleason 8 to 10 disease.

During male andropause plasma levels of free testosterone belowthe lower limit of normal are known to occur in a minority of menreaching 7% of men 40 to 60 years old, 20% older than 60 to 80 yearsand 35% older than 80 years.1 Therefore, while the subgroup of mendiagnosed with prostate cancer who are also hypogonadal may besmall as shown in this study (93 of 2,254, 4%), we agree that molec-ular factors other than those related to androgen may have a role inthe pathogenesis of prostate cancer in these men. Moreover, giventhat an increasing proportion of men would be expected to have alower than normal free testosterone level with advancing age,1 per-haps the findings of Carter et al, suggesting less favorable patholog-ical findings at radical prostatectomy with increasing age, may beexplained in part by lower free testosterone levels. Finally, we wishto raise the possibility that a lower than normal free testosteronelevel may not be a castrate level. Therefore, for the purpose of futuredesign of adjuvant therapy trials, answering the biological questionof whether prostate cancers in patients with a lower than normalfree testosterone level retain the same level, acquire a reduced levelor have complete absence of androgen sensitivity will be important.

1. Vermeulen, A. and Kaufman, J. M.: Ageing of the hypothalamo-pituitary axis in men. Horm Res, 43: 25, 1995

2. Carter, H. B., Epstein, J. I. and Partin, A. W.: Influence of ageand prostate-specific antigen on the chance of curable prostatecancer among men with nonpalpable disease. Urology, 53: 126,1999

FIG. 1. Postoperative estimates of PSA failure-free survival (PSAoutcome) for patients with prostatectomy Gleason score of 7 or moreand pretreatment PSA 4 ng./ml. or less statified by Gleason score.Number at risk at beginning of each interval is listed above timeaxis.

FIG. 2. Postoperative estimates of PSA failure-free survival (PSAoutcome) for patients with prostatectomy Gleason score of 7 or moreand pretreatment PSA greater than 4 to 10 ng./ml. statified by theGleason score. Number at risk at beginning of each interval is listedabove time axis.

HIGH GRADE, LOW PROSTATE SPECIFIC ANTIGEN PROSTATE CANCER 2031