Original Paper Urol Int 1992;49:141-145
Department of Urology, University Hospital of Zurich. Switzerland
Keyw ords
Locally advanced prostatic carcinoma Downstaging Radical prostatectomy Local recurrence
Endocrine Treatment prior to Radical Retropubic Prostatectomy in Patients with T3Prostate Cancer: A Retrospective Study of 22 Patients
Abstract Twenty-two patients with locally advanced prostatic carcinoma stage T3, No, Mo have been treated with LH-RH agonists during a mean time of 5 months prior to radical retropubic prostatectomy. Although tumors appeared to be confined to the organ in 68% of the patients after endocrine treatment, pathological examination of the surgical specimens showed in 89% evidence of extraprostatic disease, which questions the clinical impression of ‘downstag ing'. A disparity between the tumor grade of the biopsy and that of the opera tive specimen as well as an increased size of tumor-involved lymph nodes despite endocrine treatment led us to speculate that a certain proportion of patients will bear the risk of disease progression during preoperative androgen deprivation. Furthermore, there was local recurrence early in the postopera tive course and at the high rate of 39%.
Introduction
The effectiveness of radical prostatectomy as a treat ment of prostatic carcinoma confined to the organ is unquestioned and shows the best long-term results. An anatomical approach to radical retropubic prostatectomy, as described by Walsh et al. [ 1], reduces the morbidity to a minimum without altering its therapeutic efficacy. Unfor tunately, prostatic cancer is often diagnosed only when disease is already locally advanced. The marked regres sion in primary carcinomatous lesions of the prostate that results from endocrine therapy led Vallett [2] in 1944 to extend the indication for a radical operation to stage T3
Received: Januars 20. 1992 Accepted: Januars 30. 1992
tumors. This group first reported the use of this combined therapy, and further reports [2-8] appeared on this topic. In light of these reports, we decided to treat patients with locally advanced prostate carcinoma with androgen de privation prior to radical prostatectomy, with the idea of ‘downstaging’ the primary lesion. The aim of this retrospective study was to investigate the influence of preoperative hormonal therapy on clini cal and pathological findings and on the postoperative outcome.
D.A. Gobet. MD Department of Urology University of Zurich CH-8091 Zurich (Ssvitzerland)
€> 1992 S. Karger AG. Basel 0042-1138/92/0493-0141 S2.75/0
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:36:31 AM
D.A. Gobet H. Knonagel D. Hauri
From 1987 to 1990, we studied 22 patients with locally advanced prostatic carcinoma stage T 3, No, Mo G i_3 (according to the classifi cation of the UICC 1987 [9]), who were in general condition for a radical prostatectomy. The mean age of the patients was 66 years (range 56-73). Primary staging included biopsy of the prostate, com puterized axial tomography (CAT scan) and bone scan. All 22 patients were preoperatively treated with a combination of the LHRH agonist (Decapcptyl®, 3.75 mg i.m.) every month and the steroi dal antiandrogen cyproteroneacctate (Androcur®, 100 mg orally) 3 times a day, starting with the first depot injection of the LH-RH ago nists, for a total of 2 weeks. Endocrine therapy was given until rectal palpation revealed a significant decrease in palpable tumor size com patible with possible curative surgery. The average duration of preoperative endocrine therapy was 5 months (range 3-10). In 10 patients, CAT scans were performed after hormonal therapy to res tage radiologically the local extent of the disease. Eighteen out of 22 patients underwent radical retropubic prostatectomy with pelvic lymphadenectomy, 3 underwent pelvic lymphadcnectomy only be cause of lymph node involvement, and 1 patient refused radical sur gery and underwent subsequent radiation therapy. In 2 patients, prostatectomy was performed despite pelvic lymph node involve ment because of their young ages (57 and 63 years, respectively). Whenever possible, surgery was carried out according to a modified nerve-sparing method [ 1, 10]. Postoperative follow-up ranged from 1 to 37 months (mean 16 months) in 3- to 5-month intervals. In cases where rectal examination was suspect for tumor recurrence, a transrcctal biopsy was done. In biopsies showing local recurrence, distant metastases were excluded by CAT and bone scan.
Results
Influence o f Androgen Deprivation on Clinical Tj Prostate Cancer Local Response. All 22 patients showed a significant decrease in palpable tumor size after androgen depriva tion. In 15 patients (68%), digital rectal examination after therapy disclosed malignancy confined to the prostate, whereas in the remaining 7 patients tumor extension beyond the organ was still suspected. Radiological Response. Computerized tomography at the time of diagnosis suggested disease outside the organ in 18 of the patients; invasion of the seminal vesicle in 12 cases, periprostatic invasion in 5 cases and regional lymph node involvement in 1 case. The 4 patients with radiologically detectable tumors confined to the prostate had a palpable stage T3 tumor. In 8 patients with radiolog ically documented extraprostatic tumor extension, CT was performed after endocrine treatment. CT after andro gen deprivation disclosed stage T2 lesions in 7 patients (88%). Although the enlarged iliac lymph node in 1 patient showed a significant decrease in size, this was still considered a metastatic lymph node.
142
Gobct/Knönagel/Hauri
Table 1. Tumor grade of biopsy specimens and surgical speci mens in 18 patients with stage T 3 prostate cancer and androgen deprivation prior to radical prostatectomy (n = 18) T3 tumor grade
Biopsy specimen
Surgical specimen
n
%
n
%
G, Gi Gj
3 15 0
17 83 0
0 14 4
0 78 22
Table 2. Preservation of the neurovascular bundle and postoper ative continence in 18 patients with stage T3 prostate cancer and androgen deprivation prior to radical prostatectomy (n = 18)
Continent Slight stress incontinent Total incontinent
No nerve sparing
Uni- or bilateral nerve sparing
n
%
n
%
4 3 0
57 43 0
6 5 0
55 45 0
Findings at Operation Examination of frozen sections of the removed pelvic lymph nodes before radical prostatectomy revealed lymph node metastases in 5 of 21 operated patients (24%). In every case of positive lymph nodes, tumor involvement had already been suspected macroscopically during the operation because of enlargement of them. Except for the 1 patient with known lymph node metas tases, all other patients did not show evidence of lymph node involvement in the initial CAT scan. CAT scans immediately before surgery were not performed in the later patients. Eighteen patients finally underwent radical prostatectomy. In 14 patients (78%), the carcinoma showed intraoperatively extension of the tumor beyond the organ. Therefore, bilateral preservation of the neuro vascular bundle was possible only in 4 patients (22%). In 7 patients (39%), the neurovascular bundle had to be resected unilaterally, and in the remaining 7 patients (39%) no nerve-sparing procedure was possible. Pathological Stage o f Surgical Specimens In 16 of 18 patients (89%), histological sections of the tumors revealed capsular penetration, seminal vesicle in-
Androgen Deprivation prior to Radical Prostatectomy
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:36:31 AM
Patients and Methods
vasion and urethral infiltration. Among the 16 tumors in stage pT3, the capsule alone was involved in 6 cases, the seminal vesicles alone in 3 cases, the urethra alone in 1 case, both the capsule and the seminal vesicles in 4 cases, and both the capsule and urethra in 2 cases. When ana lyzed microscopically, only 2 patients exhibited tumors confined to the prostate.
Potency. Six of 11 patients (55%) operated with uni- or bilateral nerve-sparing preservation had postoperative erections sufficient for penetration. In 3 patients (27%), additional intracavernous injection of a vasoactive agent was required to achieve sufficient erections.
Discussion
Postoperative Results Progression. Overall, 11 patients (61 %) did not present clinical evidence of disease after a mean follow-up of 13 months (range 1-36). Seven patients (39%) showed biop sy-proven local recurrence after a mean follow-up of 15 months (range 4-37). The workup of these patients with local progressive disease revealed distant métastasés in 4 patients (57%), which were diagnosed after a mean fol low-up of 17 months (range 10-25). Local recurrence cor related with the frequency of the performed nerve-sparing surgical technique; in the 7 patients with local postopera tive recurrence, 10 of 14 neurovascular bundles (71%) had been preserved at operation. In the 11 patients with out local progression, 6 of 22 neurovascular bundles (27%) had been preserved. Continence. There was no total loss of urinary control following radical prostatectomy. Eight patients (44%) had a slight stress incontinence requiring 1-2 pads daily, and 10 patients (56%) were continent. Unilateral or bilateral preservation of the neurovascular bundle had no in fluence on postoperative urinary continence as shown in table 2. Two patients suffered a total urinary incontinence 13 and 27 months after operation, because of local pro gression with sphincter infiltration requiring further ther apy.
More than 40 years ago, Huggins and Hodges [11] demonstrated the partial androgen dependence of most prostatic caneers. They found beneficial effects of andro gen deprivation on primary tumor and metastases with tumor regression. There has been renewed interest in this topic by the possibility of downstaging stage T 3 prostate tumor by androgen deprivation before radical retropubic prostatectomy [2-7]. In our retrospective series of 22 patients with clinically diagnosed stage T3 prostate cancer treated with LH-RH agonists during a mean time of 5 months, regression of tumor was noted in all cases. The tumor appeared to be confined to the organ in 68% of the patients studied by digital rectal examination and in 88% of the radiologically documented cases. This finding is in accordance with other reports [3-5], Unfortunately, the histopathological sections of the prostatectomy speci mens did not confirm the striking clinical results, 89% showed evidence of extraprostatic disease. This indicates that despite the clinical finding of tumor downstaging after endocrine therapy, many patients will have persis tent locally advanced disease [4, 5, 7, 8, 12], It is therefore uncertain if the term downstaging is justified. On the other hand, Flamm et al. [7] reported in their series an excellent downstaging rate of 33%. However, already half of their downstaging cases presented with grade 1 tumors, whereas in our group no patient had a grade 1 tumor. Because there is a linear relationship between increasing tumor stage and grade [13-16], the possibility of preoper ative overstaging in cases of low-grade tumors should be considered. We believe that the inaccuracy of noninvasive methods for assessing the stage of prostate tumor [ 14] may also be responsible for a presumed downstaging effect. A disparity between the pathological grading of the biopsy and the operative specimens is well known [3, 7, 17]. In 39% of our cases, the cancer grade was higher in the surgical specimen than in the needle biopsy. Although this may be due to a sampling error in the biopsy, we sus pect, like Scott and Boyd [3], that endocrine treatment also played some role. We assume that during androgen deprivation the androgen-independent cells of the pros-
143
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Tumor Grade o f Surgical Specimens and Correlation with Biopsy Specimens In 11 of 18 cases (61%), the pathological grading assigned to the biopsy specimen was confirmed by analy sis of the operative specimen; in 7 cases (39%), the final grading was higher than that of biopsy specimens, and in no instance was it lower. Detailed initial and final tumor grades are listed in table 1. Microscopic analysis of tumors that had invaded lymph nodes revealed in all 5 cases a poorly differentiated pattern (grade 3) although biopsy specimens without ex ception had shown only a moderate differentiation (grade 2). The tumor grade of the surgical specimens of 2 men who were prostatectomized despite lymph node involve ment was corresponding with the poorly differentiated (grade 3) histological result of lymph nodes.
tatc tumor had the opportunity to proliferate continuous ly, whereas androgen-dependent cells succumbed to atro phy leading to a different histopathological pattern with an apparent change in tumor grade [ 18], This speculation is supported by two further facts: firstly, lymph node metastases in 24% of our patients showed grade 3 tumor although the primary grade of biopsy revealed in every case grade 2 tumor, and secondly all lymph node metas tases appeared enlarged and were clearly identified macroscopically during the operation despite the lack of enlargement in the initial CAT scan prior to endocrine treatment. Although the number of patients studied is small, in the light of these results, we would like to suggest that a certain proportion of patients will bear the risk of disease progression during preoperative androgen depri vation. A prospective randomized study comparing radi cal prostatectomy in T3 prostate cancer with and without endocrine treatment prior to surgery will be required to answer to this subject. In our series, local recurrence was found in 39% of the operated patients with a mean interval to recurrence of 15 months, while the total mean follow-up was 16 months. Postoperative results in patients previously treated with LH-RH agonists arc at present not available. But there are some reports [ 15, 19-22] of patients with clinical stage T3 disease treated by radical prostatectomy without endo crine treatment, who also showed local recurrence in the early follow-up. Their reported local progression rate of 4.5-30% was clearly lower, and the total mean follow-up was longer. Nevertheless, in some of these studies, the authors had included clinical stage T2 patients, whose radical prostatectomy specimens demonstrated patholog ical stage T3 disease. However, our results of local control after this short postoperative follow-up are so far discou
raging considering a procedure carried out with the inten tion to cure. It seems that preoperative androgen depriva tion had no beneficial effect on radical surgery. It is possi ble that our potency-sparing surgical technique has nega tively influenced the rate of local recurrence. We found a rate of preservation of neurovascular bundles of 71 % in patients with proven local recurrence as compared to 27% in patients without local progression. This observation argues for cautious performance of a potency-sparing sur gical technique in pretreated stage T3 carcinoma. The increasing tumor size in patients with stage T3 dis ease is associated, independently of a preoperative endo crine treatment, with an increased incidence of dissemi nated tumors, [ 16,23, 24] which in turn is associated with a higher probability of failure following surgery. This pro pensity for microscopic dissemination is not detectable by current techniques prior to surgery [17], Metastatic disease in the early postoperative course is. therefore, not a question of the surgical technique, but a question of preoperative selection [25]. We observed in 24% of our patients regional lymph node metastases at operation, which correlates with other reports [4. 7, 15], In 57% of our patients with local progression, distant metastases were found at almost the same time. Arguments against the extirpative procedure in locally advanced disease have been based on increased morbidi ty, mainly urinary incontinence [26]. The reported inci dence of postoperative urinary incontinence is however below 2% [ 10, 27], In our study, there was no total loss of continence, 44% showed a slight stress incontinence. It is possible that tumor regression following endocrine treat ment enables the surgeon to perform a more precise dis section at the apex of the prostate.
References
144
4 Thompson 1A, Lowe BA. Carroll PR. Narayan P: A multicenter study of hormonal 'downstag ing' of clinical stage C carcinoma of the pros tate followed by radical prostatectomy (ab stract 413). J Urol 1991; 145(suppl):316A. 5 Morgan WR. Myers RP: Endocrine therapy prior to radical retropubic prostatectomy for clinical stage C prostate cancer: Pathologic and biochemical response (abstract 414). J Urol 1991:145(su ppl ):316A.
Gobet/Knönagcl/Hauri
6 Monfelte G, Dupont A. Labrie E. Boivin JC. Têtu B: Multiple advantages prior and post radical prostatectomy with combined endo crine therapy. AbstrScss 22 Round Table Pros tate Cancer. 9th Congr F.ur Assoc Urol, Am sterdam. 1990. Eur Urol 1990:18(suppl l):97. 7 Flamm J, Fischer M. Hôltl W. Pfliiger H. Tomschi W: Complete androgen deprivation prior to radical prostatectomy in patients with stage T3 cancer of the prostate. Eur Urol 1991:19: 192-195.
Androgen Deprivation prior to Radical Prostatectomy
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1 Walsh PC. L.epor H, Eggleston JC: Radical prostatectomy with preservation of sexual function: Anatomical and pathological consid erations. Prostate 1983:4:473-485. 2 Valett BS: Radical perineal prostatectomy sub sequent to bilateral orchiectomy. Del State Med J 1944;16:19-20. 3 Scott WW, Boyd HL: Combined hormone con trol therapy in radical prostatectomy in the treatment of selected cases of advanced carci noma of the prostate: A retrospective study based upon 25 years of experience. J Urol 1969;101:86-92.
14 Therhorst B. Friedrichs R: Frühergebnisse nach radikaler Prostatektomie bei Patienten mit Kapscldurchbruch. Samenblaseninfiltration und Mikrometastasen. Urologe [A] 1990: 29:91-95. 15 Zincke H, Utz DC. Benson RC. Patterson DE: Bilateral pelvic lymphadencctomy and radical retropubic prostatectomy for stage C adenocar cinoma of prostate. Urology 1984:24:532— 539. 16 Stamey TA: Prostatakarzinom - Klinische und morphometrische Grundlagen. Urologe [A] 1990:30:348-360. 17 Lange PH, Narayan P: Understanding and undergrading of prostate cancer. Urology 1983; 21:113-118. 18 Kozlowski JM, Ellis WJ, Grayhack JT: Ad vanced prostatic carcinoma. Early versus late endocrine therapy. Urol Clin North Am 1991: 18:15-24. 19 Gibbons RP. Cole BS. Richardson RG. Correa RJ. BranncnGE. Mason JT. Taylor WJ. Hafermann MD: Adjuvant radiotherapy following radical prostatectomy: Results and complica tions. J Urol 1986; 135:65—70.
20 Bosch RJLH. Kurth Kll. Schroeder FH: Surgi cal treatment of locally advanced (T3) prostatic carcinoma: Early results. J Urol 1987; 138:816— 822. 21 Flocks RH: The treatment of stage C prostatic cancer with special reference to combined sur gical and radiation therapy. J Urol 1973:109: 461-468. 22 Schroeder FH. Belt E: Tumors treated by total perineal prostatectomy. J Urol 1975:114:257260. 23 Walsh PC. Lepor H: The role of radical prosta tectomy in the management of prostatic can cer. Cancer 1987:60:526—537. 24 McNeal JE: Origin and development of carci noma in the prostate. Cancer 1969:23:24-34. 25 Schroeder FH: Treatment of localised prostatic carcinoma. Horm Res I989;32(suppl I ):44— 46. 26 Tomlinson RL. Currie DP. Boyce BH: Radical prostatectomy: Palliation for stage C carci noma of the prostate. J Urol 1977:1 17:85-87. 27 Lindner A. De Kernion JS. Smith RB. Katskc FA: Risk of urinary incontinence following ra dical prostatectomy. J Urol 1983:129:1007— 1011.
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8 Knönagel H. Hauri D: Reversible Vorbehand lung des T3 Prostatakarzinoms vor der radika len Prostatektomie mit LH-RH-Dcpot (ab stract V39). Kongr Dt Ges Urol. Freiburg. 1989. 9 International Union against Cancer: TNMclassification of urological tumors, ed 4. Gene va. U ICC. 1987. 10 Hauri D. Heinzeimann M. Konstantinidis K: Radical prostatectomy in cases of prostatic car cinoma: The problem of postoperative urinary' incontinence. Urol Int 1988:43:257-264. 11 Huggins C. Hodges CV: Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phospha tases in metastatic carcinoma of the prostate. Cancer Res 1941; 1:293-297. 12 Fair WR. Heston WDW: Is combined modality therapy appropriate for apparently localized carcinoma of the prostate? Urol Clin North Am 1991:18:477-480. 13 Kramer SA. Sphar J. Brendler CB. Glenn JF, Paulson DF: Experience with Gleason's histo pathologic grading in prostatic cancer. J Urol 1980:124:223-228.
Department of Urology, University Hospital of Zurich. Switzerland
Keyw ords
Locally advanced prostatic carcinoma Downstaging Radical prostatectomy Local recurrence
Endocrine Treatment prior to Radical Retropubic Prostatectomy in Patients with T3Prostate Cancer: A Retrospective Study of 22 Patients
Abstract Twenty-two patients with locally advanced prostatic carcinoma stage T3, No, Mo have been treated with LH-RH agonists during a mean time of 5 months prior to radical retropubic prostatectomy. Although tumors appeared to be confined to the organ in 68% of the patients after endocrine treatment, pathological examination of the surgical specimens showed in 89% evidence of extraprostatic disease, which questions the clinical impression of ‘downstag ing'. A disparity between the tumor grade of the biopsy and that of the opera tive specimen as well as an increased size of tumor-involved lymph nodes despite endocrine treatment led us to speculate that a certain proportion of patients will bear the risk of disease progression during preoperative androgen deprivation. Furthermore, there was local recurrence early in the postopera tive course and at the high rate of 39%.
Introduction
The effectiveness of radical prostatectomy as a treat ment of prostatic carcinoma confined to the organ is unquestioned and shows the best long-term results. An anatomical approach to radical retropubic prostatectomy, as described by Walsh et al. [ 1], reduces the morbidity to a minimum without altering its therapeutic efficacy. Unfor tunately, prostatic cancer is often diagnosed only when disease is already locally advanced. The marked regres sion in primary carcinomatous lesions of the prostate that results from endocrine therapy led Vallett [2] in 1944 to extend the indication for a radical operation to stage T3
Received: Januars 20. 1992 Accepted: Januars 30. 1992
tumors. This group first reported the use of this combined therapy, and further reports [2-8] appeared on this topic. In light of these reports, we decided to treat patients with locally advanced prostate carcinoma with androgen de privation prior to radical prostatectomy, with the idea of ‘downstaging’ the primary lesion. The aim of this retrospective study was to investigate the influence of preoperative hormonal therapy on clini cal and pathological findings and on the postoperative outcome.
D.A. Gobet. MD Department of Urology University of Zurich CH-8091 Zurich (Ssvitzerland)
€> 1992 S. Karger AG. Basel 0042-1138/92/0493-0141 S2.75/0
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:36:31 AM
D.A. Gobet H. Knonagel D. Hauri
From 1987 to 1990, we studied 22 patients with locally advanced prostatic carcinoma stage T 3, No, Mo G i_3 (according to the classifi cation of the UICC 1987 [9]), who were in general condition for a radical prostatectomy. The mean age of the patients was 66 years (range 56-73). Primary staging included biopsy of the prostate, com puterized axial tomography (CAT scan) and bone scan. All 22 patients were preoperatively treated with a combination of the LHRH agonist (Decapcptyl®, 3.75 mg i.m.) every month and the steroi dal antiandrogen cyproteroneacctate (Androcur®, 100 mg orally) 3 times a day, starting with the first depot injection of the LH-RH ago nists, for a total of 2 weeks. Endocrine therapy was given until rectal palpation revealed a significant decrease in palpable tumor size com patible with possible curative surgery. The average duration of preoperative endocrine therapy was 5 months (range 3-10). In 10 patients, CAT scans were performed after hormonal therapy to res tage radiologically the local extent of the disease. Eighteen out of 22 patients underwent radical retropubic prostatectomy with pelvic lymphadenectomy, 3 underwent pelvic lymphadcnectomy only be cause of lymph node involvement, and 1 patient refused radical sur gery and underwent subsequent radiation therapy. In 2 patients, prostatectomy was performed despite pelvic lymph node involve ment because of their young ages (57 and 63 years, respectively). Whenever possible, surgery was carried out according to a modified nerve-sparing method [ 1, 10]. Postoperative follow-up ranged from 1 to 37 months (mean 16 months) in 3- to 5-month intervals. In cases where rectal examination was suspect for tumor recurrence, a transrcctal biopsy was done. In biopsies showing local recurrence, distant metastases were excluded by CAT and bone scan.
Results
Influence o f Androgen Deprivation on Clinical Tj Prostate Cancer Local Response. All 22 patients showed a significant decrease in palpable tumor size after androgen depriva tion. In 15 patients (68%), digital rectal examination after therapy disclosed malignancy confined to the prostate, whereas in the remaining 7 patients tumor extension beyond the organ was still suspected. Radiological Response. Computerized tomography at the time of diagnosis suggested disease outside the organ in 18 of the patients; invasion of the seminal vesicle in 12 cases, periprostatic invasion in 5 cases and regional lymph node involvement in 1 case. The 4 patients with radiologically detectable tumors confined to the prostate had a palpable stage T3 tumor. In 8 patients with radiolog ically documented extraprostatic tumor extension, CT was performed after endocrine treatment. CT after andro gen deprivation disclosed stage T2 lesions in 7 patients (88%). Although the enlarged iliac lymph node in 1 patient showed a significant decrease in size, this was still considered a metastatic lymph node.
142
Gobct/Knönagel/Hauri
Table 1. Tumor grade of biopsy specimens and surgical speci mens in 18 patients with stage T 3 prostate cancer and androgen deprivation prior to radical prostatectomy (n = 18) T3 tumor grade
Biopsy specimen
Surgical specimen
n
%
n
%
G, Gi Gj
3 15 0
17 83 0
0 14 4
0 78 22
Table 2. Preservation of the neurovascular bundle and postoper ative continence in 18 patients with stage T3 prostate cancer and androgen deprivation prior to radical prostatectomy (n = 18)
Continent Slight stress incontinent Total incontinent
No nerve sparing
Uni- or bilateral nerve sparing
n
%
n
%
4 3 0
57 43 0
6 5 0
55 45 0
Findings at Operation Examination of frozen sections of the removed pelvic lymph nodes before radical prostatectomy revealed lymph node metastases in 5 of 21 operated patients (24%). In every case of positive lymph nodes, tumor involvement had already been suspected macroscopically during the operation because of enlargement of them. Except for the 1 patient with known lymph node metas tases, all other patients did not show evidence of lymph node involvement in the initial CAT scan. CAT scans immediately before surgery were not performed in the later patients. Eighteen patients finally underwent radical prostatectomy. In 14 patients (78%), the carcinoma showed intraoperatively extension of the tumor beyond the organ. Therefore, bilateral preservation of the neuro vascular bundle was possible only in 4 patients (22%). In 7 patients (39%), the neurovascular bundle had to be resected unilaterally, and in the remaining 7 patients (39%) no nerve-sparing procedure was possible. Pathological Stage o f Surgical Specimens In 16 of 18 patients (89%), histological sections of the tumors revealed capsular penetration, seminal vesicle in-
Androgen Deprivation prior to Radical Prostatectomy
Downloaded by: King's College London 137.73.144.138 - 3/7/2018 5:36:31 AM
Patients and Methods
vasion and urethral infiltration. Among the 16 tumors in stage pT3, the capsule alone was involved in 6 cases, the seminal vesicles alone in 3 cases, the urethra alone in 1 case, both the capsule and the seminal vesicles in 4 cases, and both the capsule and urethra in 2 cases. When ana lyzed microscopically, only 2 patients exhibited tumors confined to the prostate.
Potency. Six of 11 patients (55%) operated with uni- or bilateral nerve-sparing preservation had postoperative erections sufficient for penetration. In 3 patients (27%), additional intracavernous injection of a vasoactive agent was required to achieve sufficient erections.
Discussion
Postoperative Results Progression. Overall, 11 patients (61 %) did not present clinical evidence of disease after a mean follow-up of 13 months (range 1-36). Seven patients (39%) showed biop sy-proven local recurrence after a mean follow-up of 15 months (range 4-37). The workup of these patients with local progressive disease revealed distant métastasés in 4 patients (57%), which were diagnosed after a mean fol low-up of 17 months (range 10-25). Local recurrence cor related with the frequency of the performed nerve-sparing surgical technique; in the 7 patients with local postopera tive recurrence, 10 of 14 neurovascular bundles (71%) had been preserved at operation. In the 11 patients with out local progression, 6 of 22 neurovascular bundles (27%) had been preserved. Continence. There was no total loss of urinary control following radical prostatectomy. Eight patients (44%) had a slight stress incontinence requiring 1-2 pads daily, and 10 patients (56%) were continent. Unilateral or bilateral preservation of the neurovascular bundle had no in fluence on postoperative urinary continence as shown in table 2. Two patients suffered a total urinary incontinence 13 and 27 months after operation, because of local pro gression with sphincter infiltration requiring further ther apy.
More than 40 years ago, Huggins and Hodges [11] demonstrated the partial androgen dependence of most prostatic caneers. They found beneficial effects of andro gen deprivation on primary tumor and metastases with tumor regression. There has been renewed interest in this topic by the possibility of downstaging stage T 3 prostate tumor by androgen deprivation before radical retropubic prostatectomy [2-7]. In our retrospective series of 22 patients with clinically diagnosed stage T3 prostate cancer treated with LH-RH agonists during a mean time of 5 months, regression of tumor was noted in all cases. The tumor appeared to be confined to the organ in 68% of the patients studied by digital rectal examination and in 88% of the radiologically documented cases. This finding is in accordance with other reports [3-5], Unfortunately, the histopathological sections of the prostatectomy speci mens did not confirm the striking clinical results, 89% showed evidence of extraprostatic disease. This indicates that despite the clinical finding of tumor downstaging after endocrine therapy, many patients will have persis tent locally advanced disease [4, 5, 7, 8, 12], It is therefore uncertain if the term downstaging is justified. On the other hand, Flamm et al. [7] reported in their series an excellent downstaging rate of 33%. However, already half of their downstaging cases presented with grade 1 tumors, whereas in our group no patient had a grade 1 tumor. Because there is a linear relationship between increasing tumor stage and grade [13-16], the possibility of preoper ative overstaging in cases of low-grade tumors should be considered. We believe that the inaccuracy of noninvasive methods for assessing the stage of prostate tumor [ 14] may also be responsible for a presumed downstaging effect. A disparity between the pathological grading of the biopsy and the operative specimens is well known [3, 7, 17]. In 39% of our cases, the cancer grade was higher in the surgical specimen than in the needle biopsy. Although this may be due to a sampling error in the biopsy, we sus pect, like Scott and Boyd [3], that endocrine treatment also played some role. We assume that during androgen deprivation the androgen-independent cells of the pros-
143
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Tumor Grade o f Surgical Specimens and Correlation with Biopsy Specimens In 11 of 18 cases (61%), the pathological grading assigned to the biopsy specimen was confirmed by analy sis of the operative specimen; in 7 cases (39%), the final grading was higher than that of biopsy specimens, and in no instance was it lower. Detailed initial and final tumor grades are listed in table 1. Microscopic analysis of tumors that had invaded lymph nodes revealed in all 5 cases a poorly differentiated pattern (grade 3) although biopsy specimens without ex ception had shown only a moderate differentiation (grade 2). The tumor grade of the surgical specimens of 2 men who were prostatectomized despite lymph node involve ment was corresponding with the poorly differentiated (grade 3) histological result of lymph nodes.
tatc tumor had the opportunity to proliferate continuous ly, whereas androgen-dependent cells succumbed to atro phy leading to a different histopathological pattern with an apparent change in tumor grade [ 18], This speculation is supported by two further facts: firstly, lymph node metastases in 24% of our patients showed grade 3 tumor although the primary grade of biopsy revealed in every case grade 2 tumor, and secondly all lymph node metas tases appeared enlarged and were clearly identified macroscopically during the operation despite the lack of enlargement in the initial CAT scan prior to endocrine treatment. Although the number of patients studied is small, in the light of these results, we would like to suggest that a certain proportion of patients will bear the risk of disease progression during preoperative androgen depri vation. A prospective randomized study comparing radi cal prostatectomy in T3 prostate cancer with and without endocrine treatment prior to surgery will be required to answer to this subject. In our series, local recurrence was found in 39% of the operated patients with a mean interval to recurrence of 15 months, while the total mean follow-up was 16 months. Postoperative results in patients previously treated with LH-RH agonists arc at present not available. But there are some reports [ 15, 19-22] of patients with clinical stage T3 disease treated by radical prostatectomy without endo crine treatment, who also showed local recurrence in the early follow-up. Their reported local progression rate of 4.5-30% was clearly lower, and the total mean follow-up was longer. Nevertheless, in some of these studies, the authors had included clinical stage T2 patients, whose radical prostatectomy specimens demonstrated patholog ical stage T3 disease. However, our results of local control after this short postoperative follow-up are so far discou
raging considering a procedure carried out with the inten tion to cure. It seems that preoperative androgen depriva tion had no beneficial effect on radical surgery. It is possi ble that our potency-sparing surgical technique has nega tively influenced the rate of local recurrence. We found a rate of preservation of neurovascular bundles of 71 % in patients with proven local recurrence as compared to 27% in patients without local progression. This observation argues for cautious performance of a potency-sparing sur gical technique in pretreated stage T3 carcinoma. The increasing tumor size in patients with stage T3 dis ease is associated, independently of a preoperative endo crine treatment, with an increased incidence of dissemi nated tumors, [ 16,23, 24] which in turn is associated with a higher probability of failure following surgery. This pro pensity for microscopic dissemination is not detectable by current techniques prior to surgery [17], Metastatic disease in the early postoperative course is. therefore, not a question of the surgical technique, but a question of preoperative selection [25]. We observed in 24% of our patients regional lymph node metastases at operation, which correlates with other reports [4. 7, 15], In 57% of our patients with local progression, distant metastases were found at almost the same time. Arguments against the extirpative procedure in locally advanced disease have been based on increased morbidi ty, mainly urinary incontinence [26]. The reported inci dence of postoperative urinary incontinence is however below 2% [ 10, 27], In our study, there was no total loss of continence, 44% showed a slight stress incontinence. It is possible that tumor regression following endocrine treat ment enables the surgeon to perform a more precise dis section at the apex of the prostate.
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