Effect of complete androgen blockade on pathologic stage and resection margin status of prostate cancer: progress pathology report of the Italian PROSIT study

doi:10.1016/S0090-4295(00)00866-9

Urology

Volume 57, Issue 1, January 2001, Pages 117-121

https://doi.org/10.1016/S0090-4295(00)00866-9 Get rights and content

Abstract

Objectives. To compare the pathologic stage and surgical margin status in patients undergoing either immediate radical prostatectomy or surgery preceded by 3 or 6 months of neoadjuvant hormonal treatment (NHT) in a prospective, randomized study.

Methods. Four hundred thirty-one men with prostate cancer were enrolled in the Italian randomized prospective PROSIT study. The whole-mount sectioning technique was used. By May 1999, the reviewing pathologist had evaluated 303 specimens. One hundred seven patients were untreated before radical prostatectomy was performed, and 114 and 82 patients had been treated for 3 and 6 months, respectively, with complete androgen blockade.

Results. Pathologic organ-confined disease was found in 63.1% of patients with clinical Stage B disease treated with 6 months of NHT versus 61.0% after 3 months of NHT and 37.5% after immediate surgery. Among patients with clinical Stage C tumors, pathologic staging found organ-confined disease in 62.5%, 32.1%, and 11.1% of patients after 6 months of NHT, 3 months of NHT, and immediate surgery, respectively. Three months of NHT produced a significant increase in negative margins both in patients with clinical Stage B and C disease, but the addition of another 3 months of treatment did not significantly improve this result. A lower degree of benefit was observed in patients with clinical Stage C tumors.

Conclusions. This study shows that complete androgen blockade before surgery is beneficial in men with clinical Stage B disease. The effects are more pronounced after 6 months of NHT than after 3 months.

Section snippets

Material and methods

The PROSIT study (study number 7054IT/0001) is a multicenter, open-label, prospective, randomized Phase III study assigning patients in a 1:1:1 ratio to one of the following three treatment arms: (a) immediate surgery; (b) neoadjuvant CAB for 3 months (12 weeks); and (c) neoadjuvant CAB for 6 months (24 weeks). CAB consisted of oral bicalutamide (Casodex) 50 mg/day and goserelin acetate (Zoladex) 3.5 mg every 28 days. The primary objective of the study was to evaluate whether NHT with CAB for 3

Results

In most patients, the prostate cancer originated in the peripheral zone, usually toward the apex. The location of the positive surgical margins was either in the apex or at the base. In a few instances, a positive margin was seen at the level of the posterolateral aspects of the gland. Morphologically, most specimens of both hormonally treated groups were Gleason score 7 or higher; both NHT groups had a higher Gleason grade than their respective initial values in the biopsies taken before the

Comment

The pathologic analysis of the specimens from the PROSIT study revealed that NHT before radical prostatectomy has a strong influence on some important parameters. As expected, the longer the duration of NHT, the more conspicuous the pathologic changes.

One third of the NHT prostate cancer cases were classified as high grade (Gleason score 8 to 10), and, of the 56% classified as intermediate grade (Gleason score 5 to 7), most were Gleason score 7.25, 26 These percentages were much higher than

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First studies with former therapy are more than 15-years-old and with questionable methodology: lack of power to have a clear idea of the impact on survival criteria such as overall survival or relapse-free survival. However, the impact of neoadjuvant hormone therapy on the classic risk factors for relapse (positive margins, intraprostatic disease, positive lymph nodes) was demonstrated by these studies and a Cochrane meta-analysis. The association with hormone therapy seems mandatory in comparison to treatment based solely on chemotherapy and/or targeted therapy. Promising data on the use of new drugs and their combinations arise: abiraterone acetate combined with LHRH analogue showed a fast PSA decrease and higher rates of pathologic complete response. Other results are promising with hormonal blockages at various key points.
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Citation Excerpt :
Whereas margin involvement reached 48% in T225 and 74% in T3 surgically treated patients17, it dropped to as low as 8%16 or even 0%24 following neoadjuvant MAB. The advantage was more significant for stage T2 (B) than for stage T3 (C) tumors.15,17 Although the detection of extracapsular extension and margin involvement was reported to be improved with the use of immunostaining for cytokeratins, prostate-specific antigen (PSA) and PAP26, others claim that the simple histologic examination is comparable to immunohistochemistry.22
Maximal androgen blockade (MAB), combining a luteinizing hormone releasing hormone (LHRH) agonist and a pure or non-steroidal anti-androgen, induces significant morphologic changes in the prostate. The tumor volume, density, capsular penetration, and surgical margin involvement are strongly reduced following such treatment. On histology, normal prostate tissue and tumor undergo marked atrophy and shrinkage. Although residual cancer cells are readily identifiable in most cases, they may often be sparse and easily overlooked. The increased Gleason score apparent after MAB is most likely related to fragmentation of acinar structures, and grading is not recommended following MAB. Residual cancer cells show features of lower activity and increased apoptosis. Such therapy-induced changes may be reversible, although occasional clones of cancer cells are apparently not affected and have probably developed resistance. Finally, MAB leads to marked but reversible morphologic changes and reduction in prevalence and extent of prostatic intra-epithelial neoplasia (PIN). Monotherapy using a variety of agents causes comparable but often less extensive changes.
Guideline for the Management of Clinically Localized Prostate Cancer: 2007 Update
2007, Journal of Urology
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At the same time, mortality rates from prostate cancer have been declining: 34,475 men died in 1995 compared with an estimated 30,350 in 2005.4 Several pivotal RCTs related to prostate cancer treatment have been completed, including a chemoprevention study,5 along with studies demonstrating prolongation of life in men with hormone-refractory metastatic disease6,7 and improved outcomes in men with nonmetastatic disease.8–35 With the use of new and combined treatments, the frequency and variety of complications have differed from those previously reported.
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Prostate cancer is curable only when treated at an early stage, when the tumor is still localized to the prostate gland. However, even in apparent cases of clinically localized disease, unsuspected extracapsular disease may significantly increase the risk of primary treatment failure. This risk is especially high if the patient has ≥1 of the following risk factors: a serum prostate-specific antigen level of >20 ng/ml, a Gleason score of >7, locally advanced disease (clinical stage T3/T4), and extensive disease on prostate biopsy. Various regimens of neoadjuvant hormonal therapy, chemotherapy, or both have produced mixed results and, in general, have not significantly influenced the rate of disease relapse (as defined by prostate-specific antigen level) in high-risk patients with localized prostate cancer. In addition, anti-angiogenic agents, gene therapy, molecular targeting agents, and other promising new therapies have been investigated in a neoadjuvant setting with limited results. Therefore, this patient population continues to pose a therapeutic dilemma for physicians.

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^☆: This study was supported by a research grant from Zeneca Italia S.p.A. Pharmaceuticals.

¹: A complete list of the participants in the Italian PROSIT study can be found in the .

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Adult urologyEffect of complete androgen blockade on pathologic stage and resection margin status of prostate cancer: progress pathology report of the Italian PROSIT study☆

Abstract

Section snippets

Material and methods

Results

Comment

J Urol

J Urol

Urology

J Urol

J Urol

Urology

J Urol

J Urol

J Urol

J Urol

Urology

Pathol Res Pract

Preoperative androgen-deprivation therapy for clinical stage T3 prostate cancer

Semin Urol Oncol

Hormonal treatment before radical prostatectomya 3-year follow-up

J Urol

Adult urology
Effect of complete androgen blockade on pathologic stage and resection margin status of prostate cancer: progress pathology report of the Italian PROSIT study☆