Neoadjuvant Androgen Ablation Before Radical Prostatectomy in cT2bNXM0 Prostate Cancer
Neoadjuvant Androgen Ablation Before Radical Prostatectomy in cT2bNXM0 Prostate Cancer
Abstract & Commentary
Synopsis: Patients who are found to have positive surgical margins following radical prostatectomy have a much higher rate of disease progression than do patients with negative margins. The Lupron Depot Neoadjuvant Prostate Cancer Study Group recruited 303 patients with clinical stage T2b prostate cancer and randomized them to either 3 months of total androgen suppression followed by prostatectomy, or prostatectomy alone. This updated publication based on 5 years of follow-up reported that neoadjuvant hormones had no effect on recurrence rates despite significant pathological downstaging and, therefore, should not be recommended.
Source: Soloway MS, et al. J Urol. 2002;167: 112-116.
The lupron depot neoadjuvant prostate Cancer Study Group conducted a trial from February 1992 through April 1994, and recruited 303 patients with clinical stage T2b disease who agreed to be randomized to surgery alone or hormonal pretreatment followed by prostatectomy. Patients were accrued at 27 institutions in the United States and Puerto Rico. The goal of the study was to determine whether pathologic downstaging would translate into better disease-free and overall survival. T2b patients were selected because a high percentage of them were typically upstaged to T3 at the time of surgery. All patients were < 75 years old and had a prostate-specific antigen (PSA) < 50 with negative bone scans and palpable disease consistent with stage T2b, ie, more than half of 1 lobe. Demographically, the 2 study groups were similar. The mean age in both groups was 65 years, and three quarters or more were white. The mean PSA in the neoadjuvant hormones arm was 14.3 (r, 0.6-50.3), and the mean PSA in the surgery alone group was 12.5 (r, 0.7-54.8). Total androgen suppression (TAS) therapy consisted of 3 monthly injections of leuprolide along with flutamide 250 mg t.i.d. A fourth leuprolide injection was administered within 48 hours of surgery, but the rationale for the last shot was not mentioned.
There were 149 patients randomized to the neoadjuvant arm, of whom 138 were evaluable, and 154 randomized to the surgery alone arm, of whom 144 were evaluable. PSA levels were followed every 6 months for 5 years. PSA failure was defined as PSA > 0.4 ng/mL. There were 245 patients who underwent radical retropubic prostatectomy and 18 who underwent perineal procedures. The surgical approach in 12 patients was unknown. Nerve-sparing was attempted in 44% of the neoadjuvant hormones group and was successful in 89% of those. In the other group, it was attempted in 43% and was successful in 90% of those. A single pathologist at each institution was responsible for examining the surgical specimens, and all the pathologists met jointly on 2 occasions to discuss their findings. Specimens were sectioned at 2-mm intervals, and a positive margin required there to be ink on neoplastic cells.1
There were no significant differences in the numbers of patients in each group who were found to have seminal vesicle invasion (15% TAS group vs 22% surgery- alone group) or lymph node metastases (6% in both groups). The mean prostate volumes for the 2 groups did not vary significantly (35 cc TAS group vs 44 cc surgery alone group) nor did the mean Gleason score (6.7 TAS vs 6.4). There was a statistically significant improvement favoring the TAS group in capsular penetration (47% vs 78%; P < .001); positive urethral margin status (6% vs 17%; P < .01); positive surgical margin status (18% vs 48%; P < .001); and either positive surgical margin/lymph nodes/seminal vesicles (29% vs 57%; P < .001). Nevertheless, at 5-year follow-up, there was no difference in PSA recurrence rates for the 2 groups: 64.8% TAS patients and 67.6% surgery-alone patients had PSA relapses (P = .66). In the surgery alone group, 51.7% of the patients with positive margins relapsed, while 17.4% of the patients with negative margins relapsed (P < .001). In the TAS group, the percentages were 46.2% and 33% (P = .31). The only factor that was significantly related to margin status in logistical regression analysis was use of neoadjuvant hormones.
Soloway and associates concluded that there was no apparent adverse effect on the 5-year PSA relapse rate, but that hormonal pretreatment should generally be discouraged due to its cost and side effects.
Comment by Edward J. Kaplan, MD
Soloway et al found that downstaging their T2b patients did not confer a survival advantage. They postulated that cytologic alterations due to androgen deprivation may have made prostate cancer cells invisible to standard staining techniques, leading to false-negative margin reports. Unfortunately, since the study did not break out local recurrences vs. distant recurrences, we are left with the impression that surgical margins in downstaged glands are virtually prognostically irrelevant. This may or may not be the case. As a corollary in the radiation oncology literature, where hormones are used to cytoreduce large prostates prior to brachytherapy implants, Potters and colleagues reported a 5-year PSA relapse-free survival rate of 87% among 526 T1c-T2b brachytherapy patients treated with or without neoadjuvant androgen deprivation.1 As a rule, since the radioactive seeds are placed < 5 mm beyond the prostate capsule, if downstaging does leave occult microscopic disease behind, then it would be hard to imagine that the control rates in the 2 groups of brachytherapy patients would be the same.
Soloway et al settled on 3 months of neoadjuvant hormones because it was not too short and not too long. It is unclear why a fourth shot was given just prior to surgery. A broad range of patients was included in the trial, some with high PSAs, and others with low PSAs. PSA is well recognized as the most important prognostic factor in prostate cancer, so perhaps neoadjuvant hormones might benefit only those patients in an intermediate PSA risk group, such as patients whose PSAs are 10-20. It is certainly conceivable that patients with high PSAs would not be expected to benefit from downstaging of local disease because of the high likelihood of occult metastatic disease. Soloway et al only reported mean PSAs, so it is unclear how many patients actually had PSAs > 20.
At the discretion of the surgeon, nerve-sparing could be attempted. It is unclear whether this may have had an effect on margin status. We are also not told whether some centers were more successful than others in achieving negative margins, or how many patients each center contributed.
Soloway et al stated that "the PSA level that indicates biochemical failure and progression after radical prostatectomy is uncertain. We used a cut-off of 0.4 ng/mL." To support this notion, he cited an article by Amling and associates that explored the most appropriate cut point.3 In his review of 2782 men with clinical stage T1-2 cancer who underwent radical prostatectomy, Amling et al reported that the 5-year biochemical, ie, PSA, progression-free percentages for cut points 0.2, 0.3, 0.4, and > 0.5 ng/mL were 62%, 72%, 76%, and 78%. Amling et al suggested that PSA > 0.4 ng/mL might be the most appropriate cut point "since a significant number of patients with lower PSA do not have a continued increase in it." Many clinicians would take issue with the argument that a PSA at or below a point where "only 28-38% of patients" progress should be used as a benchmark for success. While 0.4 ng/mL might be useful for patients treated with radiotherapy, it seems too high when talking about prostatectomy patients. No data are provided regarding how many patients maintained a PSA of zero during the study period.
This study was an interesting step in evaluating the use of neoadjuvant hormones preceding radical prostatectomy. Soloway et al are looking forward to publication of the Canadian Urologic Oncology Group trial results, in which 3 vs. 8 months of androgen deprivation are being assessed.4
1. Soloway MS, et al. J Urol. 1995;154:424-428.
2. Potters L, et al. J Clin Oncol. 2000;18:1187-1192.
3. Amling CL, et al. J Urol. 2001;165:1146-1151.
4. Gleave ME, et al. J Urol. 2001;166:500-507.
Dr. Kaplan is Acting Chairman, Department of Radiation Oncology, Cleveland Clinic Florida, Ft. Lauderdale, FL; Medical Director, Boca Raton Radiation Therapy Regional Center, Deerfield Beach, FL.
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