RESUMEN
Neoadjuvant hormone therapy (NHT) prior to radical prostatectomy (RP) results in residual foci of atrophic glands, which can be difficult to identify with hematoxylin-eosin staining, raising the possibility that the low positive-margin rates are an artifact of pathologic understaging. The purpose of this study was to evaluate changes in prostate specific antigen (PSA) and prostatic acid phosphatase (PAP), as well as proliferation marker Ki-67 and Bcl-2 oncoprotein, by immunostaining after 8 months of NHT. Twenty-nine men with clinically confined prostate cancer who received 8 months of NHT and had both pretreatment biopsy and RP specimens obtained at Vancouver Hospital constituted the treatment group. The control group consisted of 23 RP specimens from patients not receiving NHT. Sections were stained with antibodies against PSA, PAP, proliferation marker Ki-67, and the antiapoptosis protein Bcl-2. The PSA and PAP immunostaining were graded for percentage of positive tumor cells and intensity of staining, while Ki-67 and Bcl-2 staining was graded according to the percentage of positive tumor cells. Absent or low percentage-positive PSA and PAP staining was observed in 40% to 50% of the NHT-treated RP specimens but none of the needle biopsy or untreated control RP specimens. Low-intensity PSA and PAP staining was detected only in RP specimens after NHT treatment, and then in only 20% of cases. Low or absent Ki-67 staining was noted in 78% of the NHT- treated RP specimens, compared with only 13% of the matched pre-NHT needle biopsies and 26% of untreated RP specimens. The percentage of specimens with high (>5%) Ki-67 staining decreased from 37% in the pre-NHT needle biopsies to 8% in the NHT-treated RP specimens. Bcl-2 staining increased after treatment with NHT, with 20% of the needle biopsies having high (>5%) Bcl-2 staining compared with 53% of the NHT-treated RP specimens. The frequency of low Bcl-2 staining (<1%) decreased from 53% in the pre-NHT needle biopsies to 27% in the NHT-treated RP specimens. Although PAP and PSA staining decreased after NHT, both markers remain sufficiently positive to be used as epithelial markers to help detect residual foci of prostate cancer that are difficult to identify on H&E-stained slides after NHT. Increased Bcl-2 after NHT, even in early-stage disease, is consistent with its role in the prevention of apoptosis and progression to androgen independence. Low levels of Ki-67 staining indicates a low probability of proliferation and outgrowth of androgen-independent clones after 8 months of NHT.
RESUMEN
This report reviews the long-term follow-up of a prospective Phase II evaluation of intermittent androgen suppression in the treatment of prostate cancer. A total of 87 patients have been entered in this protocol. At the time of this report, 50 men have been followed for a minimum of 3 years. Treatment was initiated with combined androgen blockade and continued for at least 6 months until a serum PSA nadir was observed. Medication was then withheld until the serum PSA increased to mean values between 10 and 20 ng/mL. This cycle of treatment and no treatment was repeated until the regulation of PSA became androgen independent. The total time in the study ranges from 40 to 126 months, with a mean of 65.5 months. The off-treatment period in the first cycle for the men with long-term follow-up was associated with an improvement in the sense of well-being and recovery of libido and potency in men who reported normal or near-normal sexual function before the start of therapy. The average time off therapy (percentage time off therapy) for cycles 1, 2, 3, and 4 was 15 months (54%), 10 months (48%), 8 months (45%), and 7 months (40%), respectively. The study group included 9 patients treated because of a rising PSA concentration after radiation therapy for locally advanced cancer. These patients have been off therapy for an average of 22 and 13 months in treatment cycles 1 and 2, respectively. Six patients with rising PSA values after radical prostatectomy and with follow-up exceeding 36 months have been off therapy for an average of 19 and 11 months in treatment cycles 1 and 2, respectively. Of the 87 patients, 23 have had their disease progress to androgen independence at a median of 32 months of treatment, and 13 have died cancer-specific deaths at a median of 48 months. Prostate cancer is amenable to control by intermittent androgen suppression. This approach affords an improved quality of life when the patient is off therapy, with reduced toxicity and costs. Phase II trials suggest that there is not a negative impact on patient outcome. Randomized protocols are currently in progress to determine whether survival is affected in a beneficial or adverse way by such treatment in men with locally recurrent or metastatic cancer.
