Classic Manuscripts in Urology: Neoadjuvant Hormones Prior to Radical Prostatectomy

With the emergence of prostate specific antigen (PSA) testing in the late 1980's and 1990's, the incidence of prostate cancer, specifically localized prostate cancer, increased dramatically. While the proportion of patients with localized treatment increased, a significant proportion of patients harbored cancer that extends beyond the prostatic capsule (pT3). Patients with disease outside of the prostate gland were known to be at higher risk for PSA recurrence, metastasis and death from prostate cancer. It was also know that advanced and metastatic prostate cancers could be treated with androgen deprivation therapy (ADT) – which could create a dramatic decrease in PSA level, metastases and prostate gland size (if present). It was therefore hypothesized that neoadjuvant (treatment before surgery) ADT could consolidate prostate cancers and facilitate a more complete, "better" surgical resection. 

 A number of urologists employed neoadjuvant ADT and retrospective analyses of these patients confirmed that the prostate would shrink under the influence of castration and hinted that the incidence of positive surgical margins may be decreased. Therefore a number of prospective, clinical trials were designed to investigate the role of neoadjuvant ADT, opened in the early 1990's and were published within a few years of each other. The results of those trials offer level I evidence regarding the use of neoadjuvant ADT still used today.

 
Soloway MS, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, Puras-Baez A. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group. J Urol. 1995 Aug;154(2 Pt 1):424-8.

Soloway MS, Pareek K, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, Puras-Baez A; Lupron Depot Neoadjuvant Prostate Cancer Study Group. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002 Jan;167(1):112-6.

 
The Lupron Depot Neoadjuvant Prostate Cancer Study Group led by Dr. Mark Soloway, MD, was the largest, prospective study of the time to investigate neoadjuvant ADT. Three-hundred three patients were randomized to radical prostatectomy or radical prostatectomy after 3-months of ADT with 7.5mg lueprolide acetate depot. All patients had biopsy-proven cT2b (able tumor occupying more than half of 1 lobe in a mobile gland) prostate cancer. All patients underwent radical prostatectomy with a consistent lymph node dissection template and all pathological specimens were analyzed in the same fashion according to protocol.

While the radical prostatectomies performed after ADT were rated as more difficult by the surgeons involved, there were no differences in blood loss, operative time or blood transfusion between the groups; and the surgery only group had a higher rate of rectal and ureteral injuries! With regard to oncologic outcomes, there were a number of important outcomes noted in the initial study:

• There was no difference in rates of patients with seminal vesical invasion or positive lymph nodes in either group.
• The neoadjuvant ADT group demonstrated:
  • decreased prostate volume/weight
  • decrease in preoperative PSA
  • less extraprostatic extension
  • a lower rate of positive surgical margins (18% vs. 48%, P<0.001)
    • specifically, rates of urethral margin involvement were lower
  • increased rate of Gleason upgrading to high-risk (8-10) disease
• In the neoadjuvant ADT group 29% of the patients had positive surgical margins, positive seminal vesicles or positive lymph nodes compared to 57% in the radical prostatectomy alone group (P<0.001).

Importantly, the follow-up study with 5-years of data demonstrated no difference in biochemical (PSA) recurrence rates, leading the authors to conclude:

"Although 3 months of androgen deprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgical margins, a 5-year follow-up does not indicate any difference in the recurrence rate. Until studies document improvement in biochemical or clinical recurrence with longer periods of treatment, induction androgen deprivation before radical prostatectomy is not indicated."

To explain this phenomenon, the authors demonstrated that biochemical (PSA) recurrence rates were, as expected, higher in patients with positive surgical margins. However, for patients undergoing neoadjuvant ADT, the biochemical recurrence rates were nearly double for patients with negative margins (33% vs. 17%) – indicating that ADT exerted a pathological effect that did not alter the biology of the disease. Explanations included that the lower rate of positive surgical margins may have been an artifact of ADT, making prostate cancer appear to be clear of the margin under hemaotxylin and eosin staining while it may, in fact, still be present at the border of the resection. Alternatively, ADT may have "pulled" prostate cancer back into the specimen leading to lower rates of positive surgical margins, but did not change the ability of that cancer to escape the gland.

 
Take home: This study confirmed the findings of other neoadjuvant ADT trials [1-3] that neoadjuvant ADT decreased the rates of positive surgical margins at the time of radical prostatectomy but did not influence long-term biochemical recurrence rates. This work is cited as the seminal work putting the "nail in the coffin" of neoadjuvant ADT before radical prostatectomy.



[1] C.C. Schulman, F.M.J. Debruyne, G. Forster, et al. 4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in 3N0M0 prostate cancer Eur Urol, 38 (2000), p. 706
[2] G. Aus, P. Abrahamsson, G. Ahlgren, et al. Hormonal treatment before radical prostatectomy: a 3-year followup J Urol, 159 (1998), p. 2013.

[3] F. Meyer, L. Moore, I. Bairati, et al. Neoadjuvant hormonal therapy before radical prostatectomy and risk of prostate specific antigen failure. J Urol, 162 (1999), p. 2024.

Classic Manuscripts in Urology will be posted on this blog on regular basis.  These articles are meant to highlight the achievements of our predecessors, recognize the work from which we build our careers and stimulate new conversations and discussion on a variety of urological topics.  Please feel free to comment on this manuscript, help point out its strengths and weaknesses, or suggest a new manuscript and topic.