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Randomized Study of Neoadjuvant Testicular Androgen Ablation Therapy Before Radical Prostatectomy in Men with Clinically Localized Prostate Cancer
0022-5347/96/1554-1357$03.00/0
THEJ ~ ) ~ T ~OF A IUHOLI)(:Y . Copyright 0 1996 by AMEHICAN UIWLWICAL ASSOCIATION, INC
Vol. 155, 1357-1360, Apnl 1996 Printed tn U S A .
RANDOMIZED STUDY OF NEOADJUVANT TESTICULAR ANDROGEN ABLATION THERAPY BEFORE RADICAL PROSTATECTOMY IN MEN WITH CLINICALLY LOCALIZED PROSTATE CANCER BRUCE L. DALKIN,* FREDERICK R. A H M A " , RAYMOND NAGLE
AND
CYNTHIA S. JOHNSON
From the Departments of Surgery I Urology, Pathology and Medicine /Hematology/Medical Oncology, University of Arizona College of Medicine, and Tucson Veterans Aftairs Medical Center, Tucson, Arizona
ABSTRACT
Purpose: We determined whether 12 weeks of neoadjuvant testicular androgen ablation thera p y using a luteinizing hormone-releasing hormone agonist could improve pathological outcomes in men undergoing radical retropubic prostatectomy for clinically localized (stages TlC, T2A and T2B) prostatic carcinoma. Materials a n d Methods: A total of 56 participants was randomized to receive either monthly injections of a luteinizing hormone-releasing hormone agonist at 4-week intervals followed by radical retropubic prostatectomy (28) o r to undergo immediate radical retropubic prostatectomy alone (28). Operations were performed via a similar technique and all prostatic specimens were processed histologically in their entirety. Results: There w a s no improvement in pathological outcome using a luteinizing hormonereleasing hormone agonist preoperatively compared to surgery alone. Of 28 m e n undergoing immediate radical retropubic prostatectomy 23 h a d organ-confined (17) o r specimen-confined (6) disease versus 22 of 28 who received luteinizing hormone-releasing hormone neoadjuvant thera p y for 12 weeks preoperatively (16 with organ-confined and 6 with specimen-confined disease, p = 1.00).In addition, when the study population was analyzed by pretreatment prostate specific antigen (PSA) levels (10ng./ml. o r less, o r greater than 10 nglml.) there w a s also no difference in pathological outcome ( p = 0.65 for PSA greater than 10 a n d p = 0.32 for PSA less than 10). Conclusions: Neoadjuvant androgen ablation therapy for 12 weeks before radical prostatectomy in patients with clinically localized adenocarcinoma of the prostate does not result i n improved pathological outcomes. KEY WORDS:prostatic neoplasms, adenocarcinoma, gonadorelin, hormones Concomitant with the increase in the number of men diag- ans AfTairs Medical Unit, and counseled regarding therapeunosed with prostate cancer in recent years has been an in- tic options. If the patient elected radical retropubic prostacrease in the number of men undergoing radical prostatec- tectomy as the primary treatment modality, they were given tomy for treatment of clinically localized disease.' Although the option of entering into this study. To be eligible a particrecent studies suggest that there may be some improvement ipant had to have a prostate specific antigen (PSA) level of in surgical pathological outcomes, a population of men re- greater than 4.0 ng./ml. and a clinical stage TlC, T2A or T2B mains who have a poor pathological result.' Neoadjuvant lesion. In addition, all patients had a bone scan that was not therapies have resulted in surgical down staging in other suspicious for metastatic disease. malignancies. In prostate cancer a reversible systemic therTreatment arms. After obtaining informed consent as set apy associated with a high objective response is medical forth by the University of Arizona human subjects commitandrogen ablation, which can be accomplished either with a tee, patients were randomized to undergo radical retropubic luteinizing hormone-releasing hormone agonist alone or com- prostatectomy alone or with 12 weeks of preoperative therbined with an androgen receptor blocker. We evaluated in a apy with a luteinizing hormone-releasing hormone agonist. randomized fashion the ability of neoadjuvant androgen ab- Patients randomized to the surgery only group underwent lation using 12 weeks of luteinizing hormone-releasing hor- bilateral pelvic lymph node dissection and radical retropubic mone agonist therapy before radical prostatectomy in men prostatectomy 6 to 8 weeks after biopsy. Those randomized to with clinically localized (stages TlC, T2A and T2B) adeno- the luteinizing hormone-releasing hormone agonist plus surcarcinoma of the prostate to improve pathological outcomes. gery group received 3.6 ng. goserelin acetate subcutaneously every 28 days for 3 injections, followed 5 to 10 days later by MATERIAL AND METHODS pelvic lymphadenectomy and radical retropubic prostatecPatient p o p u l a t i o ~Patients . diagnosed with clinically 10- tomy. All operations were performed by or under the direction of calized adenocarcinoma of the prostate who had greater than a lo-year projected survival were recruited from the urology 1of us (B. L. D.) to evaluate an important variable in surgical clinics at Arizona Health Sciences Center and Tucson Veter- outcome studies, that is surgical skill. The surgical technique was that of anatomical radical prostatectomy with 2 modifications. The apical dissection was performed by incising the Accepted for publication September 1, 1995. Supported in part by a research grant from Zeneca Pharmaceuti- endopelvic fascia on both sides of the prostate, and identifycals. * Requests for re rints: De artment of SurgeryKJrologY. Univer- ing a plane between the dorsal venous complex and anterior sity of Arizona Coiege of dedicine, 1501 North Campbell h e . , urethra. A right-angle clamp was passed between the dorsal vein and urethra, and the dorsal vein was ligated with free Tucson, Arizona 85724. 1357
1358
NEOADJUVANT TESTICULAR ANDROGEN ABLATION THERAPY BEFORE PROSTATECTOMY
ties. A curved Kocher clamp was placed on the anterior @n, rather than having a capsular incision resulting in a prostatic dorsal venous complex and the dorsal vein was positive margin. Finally, all patients regardless of pathologtransected. Using a tonsil clamp, a plane in the penurethral ical outcome had a postoperative nadir PSA level that was tissues between the lateral border of the urethra and the undetectable. Statistical methods. Fisher’s exact tests were used to ananeurovasnrlar bundle was identified. A line tip, short, rightangle clamp was passed in this plane behind the urethra, lyze the association between treatment (lutehizing hormonewhich was then transected under direct vision using a NO. 15 releasing hormone plus radical retropubic prostatectomy verblade anteriorly, and a No. 12 blade posterior and laterally. sus radical retropubic prostatectomy alone) and pathological The Foley catheter was brought up in the field and outcome (favorable versus unfavorable). A favorable pathotransected. The posterior fascia was incised under direct logical outcome was defined as organ-confined or organvision, and a plane was developed between the anterior rectal confined plus specimen-confined. All other pathological outwall and prostate in the midline. Right-angle clamps were comes were considered unfavorable. Therefore, analysis was then used to clamp and divide the neurovascular bundles far performed using 2 x 2 tables. from the apex of the prostate. If a nerve sparing procedure RESULTS was to be performed the neurovascular bundle was dissected off the lateral aspect of the prostate at this point. Nerve Of61 men enrolled into the study 56 completed the protosparing surgery was considered only in patients with strong col. Five patients (2 randomized to receive preoperative lupre-operative erections, a pretreatment PSA of less than 10 teinizing hormone-releasing hormone and 3 to undergo radng./ml. and 1side of the prostate negative for malignancy on ical retropubic prostatectomy alone) failed to undergo biopsy. Only unilateral nerve sparing was performed. surgery because of a preoperative PSA level less than 4.0 The second modification involved use of a “peel”technique ng./ml. in 1 and failed preoperative cardiac clearance in 2, at the bladder neck. After completion of the seminal vesicle while 1 refused surgical intervention and in 1 surgery was and vas deferens portions of the procedure, the plane be- aborted midway through the operation because of bleeding. tween the bladder neck and base of the prostate was identi- The pretreatment patient characteristics of age, clinical fied. Using sharp dissection this plane was established and stage of tumor, number of positive cores on biopsy, histologincised for 360 degrees around the prostate. After completion ical grade of disease and pre-biopsy PSA level are given in of dissection down to mucosa, the mucosa was opened on the table 1. The 2 arms of the study were balanced for the anterior side and this incision was extended around to com- aforementioned pretreatment criteria. plete the 360-degree incision, which allowed for easy identiTable 2 shows the pathological staging outcomes for the fication of the ureteral orifices as well as preserving native overall population. Using organ-confined disease as the only bladder neck fibers. The bladder neck tissue was evaluated favorable pathological outcome, there was no statistically by frozen section and no patient had evidence of prostate significant difference between the 2 treatment groups (p = tissue or prostate cancer. 1.00). Using organ-confined or specimen-confined disease as Pathological processing. The prostate, including the semi- favorable pathological outcomes, there again was no statisnal vesicles, was first coated on the outside with india ink to tically significant difference between the 2 treatment groups define the surgical margin. Serial 5 mm. sections were made (p = 1.00). across the prostate in a plane vertical to the rectal surface. The pathological outcomes for men based on a pretreatAfter fresh specimens were snap-frozen from select areas, the ment PSA level of 10 ng./ml. or less are shown in table 2. remainder of the prostate was futed in 10% formalin. Each 5 There was no statistically significant difference between the mm. section was divided into 4 quadrants and submitted 2 groups (p = 1.00), with organ-confined disease as the only with 1 quadrant to each cassette. The apical section was favorable pathological outcome or with organ-confined or further subdivided and processed separately. The entire specimen-confined disease as the favorable outcomes (p = prostate was sectioned and stained with hematoxylin and 0.32). Table 2 also shows the pathological staging results for eosin, including sections taken through the seminal vesicles. men whose PSA level was greater than 10 ng./ml. before Each section was examined, and the most common and next biopsy. Again, there was no statistically significant differmost common Gleason histological grades were recorded and reported as a Gleason score. The tumors were outlined on a form corresponding to each sagittal section. From this outline TABLE1. Clinical prognostic valuables in 56 randomized patients the largest tumor volume was estimated and reported in No. Pts. cubic centimeters. The entire surgical margin was examined Radical Retropubic for the presence or absence of tumor, as well as for any Radical Retropubic Prostatectomy + evidence of perforation of the capsule and lymph node inProstatectomy Alone Luteinizing Hormonevolvement. These data were used to stage the disease patho(28 pts.) Releasing Hormone logically as organ-confined (all tumor present within the (28 D t S . ) capsule of the prostate without evidence of seminal vesicle or Clinical stage: pelvic lymph nodes disease), specimen-confined (carcinoma 16 Tlc 17 through the prostatic capsule but within the inked margins, 12 T2a 8 0 T2b 3 also without seminal vesicle or pelvic lymph node involveNo. pos. cores: ment), margin positive (carcinoma through the prostatic cap2 or Less 11 10 sule at the inked margin, also without evidence of seminal 8 3-4 8 vesicle or pelvic lymph node involvement), seminal vesicle More than 4 2 3 7 Not known 7 invasion (carcinoma involvement in the tissue planes surHistology (grade): rounding the seminal vesicles) and pelvic lymph node disease Low (2-4) 6 8 (microscopic evidence of carcinoma in the obturatorhliac 21 Moderate (5-7) 16 lymph node packets). 1 High ( & I O J 4 PSA level (ng./ml.1: For the purpose of our study, patients with positive mar4.1 - 10 18 16 gins, seminal vesicle invasion or pelvic lymph node involve9 10.1 - 20 9 ment were considered to have a poor pathological outcome. More than 20 1 3 Of note, no patient with margin positive disease had an Mean age was 64.7 years (range 48 to 76) in the surgery only ~ o u and p 65.5 iatrogenic positive margin, that is all patients had obvious years lrange 50 to 76) in the-surgery plus luteini’zin-g hormone-releasing extension of tumor through the capsule to the positive mar- hormone group.
1359
NEOADJUVANT TESTICULAR ANDROGEN ABLATION THERAPY BEFORE PROSTATECTOMY T.ABLE2. Putho[ogical results ____ No, pts.
No. With OrganConfined C a
_~---______
No. With Specimen- M a ~ ~ ; ~ Seminal Ves,cles Confined Ca
~No. ~With ~ P~O Pelvic ~~ o Lvmph Nodes
s
.-
0i:erall" Radical retropuhic prostatectomy alone Radical retropubic prostatectomy + adjuvant luteinwing hormone-releasing hormone
28 28
Radical retropubic prostatectomy alone Radical retropubic prostatectorny + adjuvant luteinizing hormone-releasing hormone
18 16
17 16
6
4
1
6
5
1
4 2
1 2
0 1
3 3
1 0
PSA 10 ng. lml. or less?
13 11
PSA more than 10 ng.1ml.f 10 4 2 Radical retropubic prostatectomy alone 12 5 4 Radical retropubic prostatectomy + adjuvant luteinizing hormone-releasing hormone * Favorable outcome: organ-confined and organ-confined plus specimen-confined p = 1.00. t Favorable outcome: organ-confined p = 1.00 and organ-confined plus specimen-confined p = 0.32. iFavorable outcome: organ-confined p = 1.00 and organ-confined plus specimen-confined p = 0.65.
ence between the 2 groups with organ-confined tumor as the only favorable pathological outcome ( p = 1.00), or with organconfined or specimen-confined disease as favorable pathological outcomes (p = 0.65). When clinical stage T l c lesions were evaluated, there was no benefit to neoadjuvant therapy. In the untreated group 12 a favorable (organ-confined plus of 16 patients ( 7 5 7 ~had ) specimen-confined) outcome versus 14 of 17 (82%,) in the luteinizing hormone-releasing hormone group ( p = 0.688). Similar results occurred with stage T2 lesions, with the untreated group actually doing somewhat better (11 of 12, or 91%, with a favorable pathological outcome versus 8 of 11,or 73%, in the luteinizing hormone-releasing hormone treated group, p = 0.317). In our pre-study projections we predicted a poor pathological outcome rate of 50%,in the control population. Predicting a 50% improvement in pathological outcome mandated 58 patients in each arm of the study (80%power to detect a 50% improvement with p <0.05). Mid study data analysis revealed a poor pathological outcome of only 18%in the control group. In addition, we essentially saw no difference in pathological outcomes for the control versus luteinizing hormonereleasing hormone treated groups (table 2). From a statistical significance standpoint, there was no validity in continuing the study. Even when subdividing the population to review only the stage T l c cases, a difference in pathological outcome of 7% (poor pathological outcome rate of 25% in controls versus 18% in luteinizing hormone-releasing hormone treated patients) would require 1,080 patients to show statistical significance to this 7% difference. The requirement of 1,080 patients for the study to support a relatively slight improvement in pathological outcome speaks against any clinical significance to a study of that size. Therefore, our sample size is adequate to support the questions raised in the study design, as well a s our stated conclusions. DISCUSSION
From our data,z as well as those of other^,:^-^ it is apparent that a significant percentage of men undergoing radical prostatectomy for clinically localized carcinoma of the prostate continue to have a less than optimal pathological outcome. Labrie et a1 reported on 161 patients diagnosed with stage B (134) or C (27) prostate cancer who were randomized to receive 3 months of neoadjuvant combination therapy with flutamide plus a luteinizing hormone-releasing hormone agmist followed by radical prostatectomy versus radical prostatectomy alone.6 Overall, there was an improved pathologleal outcome using neoadjuvant androgen ablation therapy. "he positive margin rates were 33.86 in the control group and only 7.8% in the treated group. Importantly, in our series
the most common presentation of a patient with prostate cancer included a normal digital rectal examination and a n elevated serum PSA level. This clinical scenario (stage T l c lesion) was not part of the study by Labrie et a16 and has not been investigated using neoadjuvant therapy. Three other similar randomized neoadjuvant studies exist. A Canadian study using 3 months of cyproterone showed decreased positive margin rates from 64.1% in the control group to 33.7% in the treated group.7 Soloway et a1 evaluated stage T2b lesions using a luteinizing hormone-releasing hormone agonist and flutamide for 3 months, and the positive margin rate was 48% in the control group and 18% in the treated group.RFinally, a Swedish cooperative group used a luteinizing hormone-releasing hormone analogue for 3 months and noted decreased positive margin rates from 46% in the control group to 24% in the treated group.9 Our results differ from these other studies in several ways. The rate of poor pathological outcomes (positive margins plus seminal vesicle or pelvic nodal involvement) in our control group was substantially lower (18%) than that in the other studies (64.1%, 48% and 46% ). Histological processing of the specimen cannot account for the difference, since our thorough evaluation could only increase the rate of positive margins. Our study was comprised mostly (59%)of stage T l c lesions, a clinical stage not well evaluated in the other randomized studies. The margin positive rate with stage T l c lesions in our control group was 7% (1 of 13 patients, excluding those with seminal vesicle and lymph node involvement). Regardless of the biological reason, stage T l c lesions may be more likely to be locally contained. Therefore, attempts a t neoadjuvant treatments to improve pathological outcomes would be fruitless. Another possible explanation lies in the concept of iatrogenic positive margins or surgical incision of the prostatic capsule resulting in a positive margm. We had no iatrogenic positive margins in our study, a point not addressed in other neoadjuvant trials. Capsular incision with a positive margin has been reported commonly,10, accounting for 87% of positive apical margins in 1 study.'" Possibly, suboptimal surgical technique resulted in a greater positive margin rate for the control group in the other studies. Potentially, neoadjuvant treatment may decrease the incidence of iatrogenic positive margins (if, as noted previously, it is significant), a factor not investigated to date. The improved pathological outcomes using neoadjuvant therapy with stage T2 lesions in other studies is perpleldng. I t is difficult to believe that malignant cells in extraprostatic regions regress to an intraprostatic location with neoadjuvant treatment. Androgen ablation can result in cell death, and possibly neoadjuvant therapy affects the histopatholog-
,
1360
NEOADJUVANT TESTICULAR ANDROGEN ABLATION THERAPY BEFORE PROSTATECTOMY
ical evaluation of the specimen, making the cancer and its extraprostatic extension more difficult to assess. Importantly, pathological stage is only a short-term end point. Although pathological outcomes may be improved using neoadjuvant androgen ablation, the natural biological potential may not be affected. More appropriate long-term end points, such as biochemical failure (detectable PSA level) or disease-specific survival, must show improvement with neoadjuvant androgen ablation before recommending its clinical use. CONCLUSIONS
The purpose of this study was to assess whether neoadjuvant androgen ablation using a luteinizing hormone-releasing hormone agonist alone improved pathological outcomes in men with clinically localized adenocarcinoma of the prostate. There was no benefit to neoadjuvant androgen ablation therapy in our population, nor were we able to identify a subset of patients, based on PSA or clinical stage, who benefited from such treatment. We cannot recommend the use of luteinizing hormone-releasing hormone agonist therapy before radical prostatectomy in men with clinically localized adenocarcinoma of the prostate in an effort to improve pathological outcomes. REFERENCES
1. Catalona, W.J., Richie. J. P., Ahmann, F. R., Hudson, M. A, Scardino, P.T., Flanigan, R. C., deKernion, J. B.. RatlifF, T. L., Kavoussi, L. R., Dalkin. B. L., Waters, W. B., MacFarlane, M. T. and Southwick, P. C.: Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of multicenter clinical trial of 6,630men. J. Urol., 151: 1283,1994. 2. Ehreth, J. T., Miller, J. I., McBeath, R. B., Hansen, K K , Ahmann, F. R., Dalkin, B. L. and SchX, M.,Jr.: Prostatespecific antigen obtained under optimal conditions determines
extracapsular adenocarcinoma of the prostate. Brit. J . Urol., 76: 21,1995. 3. Hudson, M. A., Bahnson, R. R. and Catalona, W.J.: Clinical use of prostate specific antigen in patients with prostate cancer. J. Urol., 142 1011,1989. 4. partin, A. W.,Carter, H. B., Chan, D. W., Epstein, J. I., Oesterling, J. E., Rock,R. C., Weber, J. P. and Walsh, P. C.: prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J. Urol.,143: 747, 1990. 5. Lange, P. H., Emole, C. J., Lightner, D. J., Fraley, E. E. and Vessella, R.: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J. Urol., 141: 873,1989. 6. Labrie, F.,Cusan, L., Gomez, J. L., Diamond, P. and Suburu, R.: Down-staging of early stage prostate cancer before radical prostatectomy the tirst randomized trial of neoadjuvant combination therapy with flutamide and a luteinizing hormonerelease hormone agonist. Urol. Symposium, 44: 29, 1994. 7. Goldenberg, S. L., Klotz. L. H..Jewett, M. A S., Srigley, J., Barkin, J..Mador, D., Fradet, Y.,Chin, J. L., Paquin, J. M. and Laplank, S.: Randomized, controlled study of neoadjuvant reversible androgen withdrawal therapy with cyprotemne acetate in the surgical management of localized prostate cancer. J. Urol., part 2,lb3:254A,abstract 103,1995. 8. Soloway, M. S.,Shari& R., Wajsman, Z., McLeod, D., Wood, D. P., Jr. and h a s - B a e z for the Lupron Depot Neoadjuvant Prostate Cancer Study Group: Randomized prospective study comparing radical prostatectomy alone versus radical prostatectnmy preceded by androgen blockade in clinical stage B2 (T2bNxMO) prostate cancer. J. Urol., 154: 424, 1995. 9. Pedersen, K. V., Lundberg, S., Hugosson, J., Aus, G., Schelin, S., Ahlgren, G. and Abrahamsson, P A : Neoadjuvant hormonal treatment with triptorelin versus no treatment prior to radical prostatectomy: a prospective randomized multicenter study. J. Urol., part 2,163:39lA,abstract 651,1995. 10. Ackerman, D. h, Barry,J. M., Wicklund, R. A., Olson, N. and Lowe, B. A: Analysis of risk factors associated with prostate cancer extension to the surgical margin and pelvic node metastases at radical prostatedomy. J. Urol., 150: 1845,1993. 11. Voges, G.E.,McNeal, J. E., Redwine, E. A, Freiha, F. S. and Stamey, T. A: Morphologic analysis of surgical margins with positive findings in prostatectomy for adenocarcinoma of the prostate. Cancer, 69:520,1992.
THEJ ~ ) ~ T ~OF A IUHOLI)(:Y . Copyright 0 1996 by AMEHICAN UIWLWICAL ASSOCIATION, INC
Vol. 155, 1357-1360, Apnl 1996 Printed tn U S A .
RANDOMIZED STUDY OF NEOADJUVANT TESTICULAR ANDROGEN ABLATION THERAPY BEFORE RADICAL PROSTATECTOMY IN MEN WITH CLINICALLY LOCALIZED PROSTATE CANCER BRUCE L. DALKIN,* FREDERICK R. A H M A " , RAYMOND NAGLE
AND
CYNTHIA S. JOHNSON
From the Departments of Surgery I Urology, Pathology and Medicine /Hematology/Medical Oncology, University of Arizona College of Medicine, and Tucson Veterans Aftairs Medical Center, Tucson, Arizona
ABSTRACT
Purpose: We determined whether 12 weeks of neoadjuvant testicular androgen ablation thera p y using a luteinizing hormone-releasing hormone agonist could improve pathological outcomes in men undergoing radical retropubic prostatectomy for clinically localized (stages TlC, T2A and T2B) prostatic carcinoma. Materials a n d Methods: A total of 56 participants was randomized to receive either monthly injections of a luteinizing hormone-releasing hormone agonist at 4-week intervals followed by radical retropubic prostatectomy (28) o r to undergo immediate radical retropubic prostatectomy alone (28). Operations were performed via a similar technique and all prostatic specimens were processed histologically in their entirety. Results: There w a s no improvement in pathological outcome using a luteinizing hormonereleasing hormone agonist preoperatively compared to surgery alone. Of 28 m e n undergoing immediate radical retropubic prostatectomy 23 h a d organ-confined (17) o r specimen-confined (6) disease versus 22 of 28 who received luteinizing hormone-releasing hormone neoadjuvant thera p y for 12 weeks preoperatively (16 with organ-confined and 6 with specimen-confined disease, p = 1.00).In addition, when the study population was analyzed by pretreatment prostate specific antigen (PSA) levels (10ng./ml. o r less, o r greater than 10 nglml.) there w a s also no difference in pathological outcome ( p = 0.65 for PSA greater than 10 a n d p = 0.32 for PSA less than 10). Conclusions: Neoadjuvant androgen ablation therapy for 12 weeks before radical prostatectomy in patients with clinically localized adenocarcinoma of the prostate does not result i n improved pathological outcomes. KEY WORDS:prostatic neoplasms, adenocarcinoma, gonadorelin, hormones Concomitant with the increase in the number of men diag- ans AfTairs Medical Unit, and counseled regarding therapeunosed with prostate cancer in recent years has been an in- tic options. If the patient elected radical retropubic prostacrease in the number of men undergoing radical prostatec- tectomy as the primary treatment modality, they were given tomy for treatment of clinically localized disease.' Although the option of entering into this study. To be eligible a particrecent studies suggest that there may be some improvement ipant had to have a prostate specific antigen (PSA) level of in surgical pathological outcomes, a population of men re- greater than 4.0 ng./ml. and a clinical stage TlC, T2A or T2B mains who have a poor pathological result.' Neoadjuvant lesion. In addition, all patients had a bone scan that was not therapies have resulted in surgical down staging in other suspicious for metastatic disease. malignancies. In prostate cancer a reversible systemic therTreatment arms. After obtaining informed consent as set apy associated with a high objective response is medical forth by the University of Arizona human subjects commitandrogen ablation, which can be accomplished either with a tee, patients were randomized to undergo radical retropubic luteinizing hormone-releasing hormone agonist alone or com- prostatectomy alone or with 12 weeks of preoperative therbined with an androgen receptor blocker. We evaluated in a apy with a luteinizing hormone-releasing hormone agonist. randomized fashion the ability of neoadjuvant androgen ab- Patients randomized to the surgery only group underwent lation using 12 weeks of luteinizing hormone-releasing hor- bilateral pelvic lymph node dissection and radical retropubic mone agonist therapy before radical prostatectomy in men prostatectomy 6 to 8 weeks after biopsy. Those randomized to with clinically localized (stages TlC, T2A and T2B) adeno- the luteinizing hormone-releasing hormone agonist plus surcarcinoma of the prostate to improve pathological outcomes. gery group received 3.6 ng. goserelin acetate subcutaneously every 28 days for 3 injections, followed 5 to 10 days later by MATERIAL AND METHODS pelvic lymphadenectomy and radical retropubic prostatecPatient p o p u l a t i o ~Patients . diagnosed with clinically 10- tomy. All operations were performed by or under the direction of calized adenocarcinoma of the prostate who had greater than a lo-year projected survival were recruited from the urology 1of us (B. L. D.) to evaluate an important variable in surgical clinics at Arizona Health Sciences Center and Tucson Veter- outcome studies, that is surgical skill. The surgical technique was that of anatomical radical prostatectomy with 2 modifications. The apical dissection was performed by incising the Accepted for publication September 1, 1995. Supported in part by a research grant from Zeneca Pharmaceuti- endopelvic fascia on both sides of the prostate, and identifycals. * Requests for re rints: De artment of SurgeryKJrologY. Univer- ing a plane between the dorsal venous complex and anterior sity of Arizona Coiege of dedicine, 1501 North Campbell h e . , urethra. A right-angle clamp was passed between the dorsal vein and urethra, and the dorsal vein was ligated with free Tucson, Arizona 85724. 1357
1358
NEOADJUVANT TESTICULAR ANDROGEN ABLATION THERAPY BEFORE PROSTATECTOMY
ties. A curved Kocher clamp was placed on the anterior @n, rather than having a capsular incision resulting in a prostatic dorsal venous complex and the dorsal vein was positive margin. Finally, all patients regardless of pathologtransected. Using a tonsil clamp, a plane in the penurethral ical outcome had a postoperative nadir PSA level that was tissues between the lateral border of the urethra and the undetectable. Statistical methods. Fisher’s exact tests were used to ananeurovasnrlar bundle was identified. A line tip, short, rightangle clamp was passed in this plane behind the urethra, lyze the association between treatment (lutehizing hormonewhich was then transected under direct vision using a NO. 15 releasing hormone plus radical retropubic prostatectomy verblade anteriorly, and a No. 12 blade posterior and laterally. sus radical retropubic prostatectomy alone) and pathological The Foley catheter was brought up in the field and outcome (favorable versus unfavorable). A favorable pathotransected. The posterior fascia was incised under direct logical outcome was defined as organ-confined or organvision, and a plane was developed between the anterior rectal confined plus specimen-confined. All other pathological outwall and prostate in the midline. Right-angle clamps were comes were considered unfavorable. Therefore, analysis was then used to clamp and divide the neurovascular bundles far performed using 2 x 2 tables. from the apex of the prostate. If a nerve sparing procedure RESULTS was to be performed the neurovascular bundle was dissected off the lateral aspect of the prostate at this point. Nerve Of61 men enrolled into the study 56 completed the protosparing surgery was considered only in patients with strong col. Five patients (2 randomized to receive preoperative lupre-operative erections, a pretreatment PSA of less than 10 teinizing hormone-releasing hormone and 3 to undergo radng./ml. and 1side of the prostate negative for malignancy on ical retropubic prostatectomy alone) failed to undergo biopsy. Only unilateral nerve sparing was performed. surgery because of a preoperative PSA level less than 4.0 The second modification involved use of a “peel”technique ng./ml. in 1 and failed preoperative cardiac clearance in 2, at the bladder neck. After completion of the seminal vesicle while 1 refused surgical intervention and in 1 surgery was and vas deferens portions of the procedure, the plane be- aborted midway through the operation because of bleeding. tween the bladder neck and base of the prostate was identi- The pretreatment patient characteristics of age, clinical fied. Using sharp dissection this plane was established and stage of tumor, number of positive cores on biopsy, histologincised for 360 degrees around the prostate. After completion ical grade of disease and pre-biopsy PSA level are given in of dissection down to mucosa, the mucosa was opened on the table 1. The 2 arms of the study were balanced for the anterior side and this incision was extended around to com- aforementioned pretreatment criteria. plete the 360-degree incision, which allowed for easy identiTable 2 shows the pathological staging outcomes for the fication of the ureteral orifices as well as preserving native overall population. Using organ-confined disease as the only bladder neck fibers. The bladder neck tissue was evaluated favorable pathological outcome, there was no statistically by frozen section and no patient had evidence of prostate significant difference between the 2 treatment groups (p = tissue or prostate cancer. 1.00). Using organ-confined or specimen-confined disease as Pathological processing. The prostate, including the semi- favorable pathological outcomes, there again was no statisnal vesicles, was first coated on the outside with india ink to tically significant difference between the 2 treatment groups define the surgical margin. Serial 5 mm. sections were made (p = 1.00). across the prostate in a plane vertical to the rectal surface. The pathological outcomes for men based on a pretreatAfter fresh specimens were snap-frozen from select areas, the ment PSA level of 10 ng./ml. or less are shown in table 2. remainder of the prostate was futed in 10% formalin. Each 5 There was no statistically significant difference between the mm. section was divided into 4 quadrants and submitted 2 groups (p = 1.00), with organ-confined disease as the only with 1 quadrant to each cassette. The apical section was favorable pathological outcome or with organ-confined or further subdivided and processed separately. The entire specimen-confined disease as the favorable outcomes (p = prostate was sectioned and stained with hematoxylin and 0.32). Table 2 also shows the pathological staging results for eosin, including sections taken through the seminal vesicles. men whose PSA level was greater than 10 ng./ml. before Each section was examined, and the most common and next biopsy. Again, there was no statistically significant differmost common Gleason histological grades were recorded and reported as a Gleason score. The tumors were outlined on a form corresponding to each sagittal section. From this outline TABLE1. Clinical prognostic valuables in 56 randomized patients the largest tumor volume was estimated and reported in No. Pts. cubic centimeters. The entire surgical margin was examined Radical Retropubic for the presence or absence of tumor, as well as for any Radical Retropubic Prostatectomy + evidence of perforation of the capsule and lymph node inProstatectomy Alone Luteinizing Hormonevolvement. These data were used to stage the disease patho(28 pts.) Releasing Hormone logically as organ-confined (all tumor present within the (28 D t S . ) capsule of the prostate without evidence of seminal vesicle or Clinical stage: pelvic lymph nodes disease), specimen-confined (carcinoma 16 Tlc 17 through the prostatic capsule but within the inked margins, 12 T2a 8 0 T2b 3 also without seminal vesicle or pelvic lymph node involveNo. pos. cores: ment), margin positive (carcinoma through the prostatic cap2 or Less 11 10 sule at the inked margin, also without evidence of seminal 8 3-4 8 vesicle or pelvic lymph node involvement), seminal vesicle More than 4 2 3 7 Not known 7 invasion (carcinoma involvement in the tissue planes surHistology (grade): rounding the seminal vesicles) and pelvic lymph node disease Low (2-4) 6 8 (microscopic evidence of carcinoma in the obturatorhliac 21 Moderate (5-7) 16 lymph node packets). 1 High ( & I O J 4 PSA level (ng./ml.1: For the purpose of our study, patients with positive mar4.1 - 10 18 16 gins, seminal vesicle invasion or pelvic lymph node involve9 10.1 - 20 9 ment were considered to have a poor pathological outcome. More than 20 1 3 Of note, no patient with margin positive disease had an Mean age was 64.7 years (range 48 to 76) in the surgery only ~ o u and p 65.5 iatrogenic positive margin, that is all patients had obvious years lrange 50 to 76) in the-surgery plus luteini’zin-g hormone-releasing extension of tumor through the capsule to the positive mar- hormone group.
1359
NEOADJUVANT TESTICULAR ANDROGEN ABLATION THERAPY BEFORE PROSTATECTOMY T.ABLE2. Putho[ogical results ____ No, pts.
No. With OrganConfined C a
_~---______
No. With Specimen- M a ~ ~ ; ~ Seminal Ves,cles Confined Ca
~No. ~With ~ P~O Pelvic ~~ o Lvmph Nodes
s
.-
0i:erall" Radical retropuhic prostatectomy alone Radical retropubic prostatectomy + adjuvant luteinwing hormone-releasing hormone
28 28
Radical retropubic prostatectomy alone Radical retropubic prostatectorny + adjuvant luteinizing hormone-releasing hormone
18 16
17 16
6
4
1
6
5
1
4 2
1 2
0 1
3 3
1 0
PSA 10 ng. lml. or less?
13 11
PSA more than 10 ng.1ml.f 10 4 2 Radical retropubic prostatectomy alone 12 5 4 Radical retropubic prostatectomy + adjuvant luteinizing hormone-releasing hormone * Favorable outcome: organ-confined and organ-confined plus specimen-confined p = 1.00. t Favorable outcome: organ-confined p = 1.00 and organ-confined plus specimen-confined p = 0.32. iFavorable outcome: organ-confined p = 1.00 and organ-confined plus specimen-confined p = 0.65.
ence between the 2 groups with organ-confined tumor as the only favorable pathological outcome ( p = 1.00), or with organconfined or specimen-confined disease as favorable pathological outcomes (p = 0.65). When clinical stage T l c lesions were evaluated, there was no benefit to neoadjuvant therapy. In the untreated group 12 a favorable (organ-confined plus of 16 patients ( 7 5 7 ~had ) specimen-confined) outcome versus 14 of 17 (82%,) in the luteinizing hormone-releasing hormone group ( p = 0.688). Similar results occurred with stage T2 lesions, with the untreated group actually doing somewhat better (11 of 12, or 91%, with a favorable pathological outcome versus 8 of 11,or 73%, in the luteinizing hormone-releasing hormone treated group, p = 0.317). In our pre-study projections we predicted a poor pathological outcome rate of 50%,in the control population. Predicting a 50% improvement in pathological outcome mandated 58 patients in each arm of the study (80%power to detect a 50% improvement with p <0.05). Mid study data analysis revealed a poor pathological outcome of only 18%in the control group. In addition, we essentially saw no difference in pathological outcomes for the control versus luteinizing hormonereleasing hormone treated groups (table 2). From a statistical significance standpoint, there was no validity in continuing the study. Even when subdividing the population to review only the stage T l c cases, a difference in pathological outcome of 7% (poor pathological outcome rate of 25% in controls versus 18% in luteinizing hormone-releasing hormone treated patients) would require 1,080 patients to show statistical significance to this 7% difference. The requirement of 1,080 patients for the study to support a relatively slight improvement in pathological outcome speaks against any clinical significance to a study of that size. Therefore, our sample size is adequate to support the questions raised in the study design, as well a s our stated conclusions. DISCUSSION
From our data,z as well as those of other^,:^-^ it is apparent that a significant percentage of men undergoing radical prostatectomy for clinically localized carcinoma of the prostate continue to have a less than optimal pathological outcome. Labrie et a1 reported on 161 patients diagnosed with stage B (134) or C (27) prostate cancer who were randomized to receive 3 months of neoadjuvant combination therapy with flutamide plus a luteinizing hormone-releasing hormone agmist followed by radical prostatectomy versus radical prostatectomy alone.6 Overall, there was an improved pathologleal outcome using neoadjuvant androgen ablation therapy. "he positive margin rates were 33.86 in the control group and only 7.8% in the treated group. Importantly, in our series
the most common presentation of a patient with prostate cancer included a normal digital rectal examination and a n elevated serum PSA level. This clinical scenario (stage T l c lesion) was not part of the study by Labrie et a16 and has not been investigated using neoadjuvant therapy. Three other similar randomized neoadjuvant studies exist. A Canadian study using 3 months of cyproterone showed decreased positive margin rates from 64.1% in the control group to 33.7% in the treated group.7 Soloway et a1 evaluated stage T2b lesions using a luteinizing hormone-releasing hormone agonist and flutamide for 3 months, and the positive margin rate was 48% in the control group and 18% in the treated group.RFinally, a Swedish cooperative group used a luteinizing hormone-releasing hormone analogue for 3 months and noted decreased positive margin rates from 46% in the control group to 24% in the treated group.9 Our results differ from these other studies in several ways. The rate of poor pathological outcomes (positive margins plus seminal vesicle or pelvic nodal involvement) in our control group was substantially lower (18%) than that in the other studies (64.1%, 48% and 46% ). Histological processing of the specimen cannot account for the difference, since our thorough evaluation could only increase the rate of positive margins. Our study was comprised mostly (59%)of stage T l c lesions, a clinical stage not well evaluated in the other randomized studies. The margin positive rate with stage T l c lesions in our control group was 7% (1 of 13 patients, excluding those with seminal vesicle and lymph node involvement). Regardless of the biological reason, stage T l c lesions may be more likely to be locally contained. Therefore, attempts a t neoadjuvant treatments to improve pathological outcomes would be fruitless. Another possible explanation lies in the concept of iatrogenic positive margins or surgical incision of the prostatic capsule resulting in a positive margm. We had no iatrogenic positive margins in our study, a point not addressed in other neoadjuvant trials. Capsular incision with a positive margin has been reported commonly,10, accounting for 87% of positive apical margins in 1 study.'" Possibly, suboptimal surgical technique resulted in a greater positive margin rate for the control group in the other studies. Potentially, neoadjuvant treatment may decrease the incidence of iatrogenic positive margins (if, as noted previously, it is significant), a factor not investigated to date. The improved pathological outcomes using neoadjuvant therapy with stage T2 lesions in other studies is perpleldng. I t is difficult to believe that malignant cells in extraprostatic regions regress to an intraprostatic location with neoadjuvant treatment. Androgen ablation can result in cell death, and possibly neoadjuvant therapy affects the histopatholog-
,
1360
NEOADJUVANT TESTICULAR ANDROGEN ABLATION THERAPY BEFORE PROSTATECTOMY
ical evaluation of the specimen, making the cancer and its extraprostatic extension more difficult to assess. Importantly, pathological stage is only a short-term end point. Although pathological outcomes may be improved using neoadjuvant androgen ablation, the natural biological potential may not be affected. More appropriate long-term end points, such as biochemical failure (detectable PSA level) or disease-specific survival, must show improvement with neoadjuvant androgen ablation before recommending its clinical use. CONCLUSIONS
The purpose of this study was to assess whether neoadjuvant androgen ablation using a luteinizing hormone-releasing hormone agonist alone improved pathological outcomes in men with clinically localized adenocarcinoma of the prostate. There was no benefit to neoadjuvant androgen ablation therapy in our population, nor were we able to identify a subset of patients, based on PSA or clinical stage, who benefited from such treatment. We cannot recommend the use of luteinizing hormone-releasing hormone agonist therapy before radical prostatectomy in men with clinically localized adenocarcinoma of the prostate in an effort to improve pathological outcomes. REFERENCES
1. Catalona, W.J., Richie. J. P., Ahmann, F. R., Hudson, M. A, Scardino, P.T., Flanigan, R. C., deKernion, J. B.. RatlifF, T. L., Kavoussi, L. R., Dalkin. B. L., Waters, W. B., MacFarlane, M. T. and Southwick, P. C.: Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of multicenter clinical trial of 6,630men. J. Urol., 151: 1283,1994. 2. Ehreth, J. T., Miller, J. I., McBeath, R. B., Hansen, K K , Ahmann, F. R., Dalkin, B. L. and SchX, M.,Jr.: Prostatespecific antigen obtained under optimal conditions determines
extracapsular adenocarcinoma of the prostate. Brit. J . Urol., 76: 21,1995. 3. Hudson, M. A., Bahnson, R. R. and Catalona, W.J.: Clinical use of prostate specific antigen in patients with prostate cancer. J. Urol., 142 1011,1989. 4. partin, A. W.,Carter, H. B., Chan, D. W., Epstein, J. I., Oesterling, J. E., Rock,R. C., Weber, J. P. and Walsh, P. C.: prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J. Urol.,143: 747, 1990. 5. Lange, P. H., Emole, C. J., Lightner, D. J., Fraley, E. E. and Vessella, R.: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J. Urol., 141: 873,1989. 6. Labrie, F.,Cusan, L., Gomez, J. L., Diamond, P. and Suburu, R.: Down-staging of early stage prostate cancer before radical prostatectomy the tirst randomized trial of neoadjuvant combination therapy with flutamide and a luteinizing hormonerelease hormone agonist. Urol. Symposium, 44: 29, 1994. 7. Goldenberg, S. L., Klotz. L. H..Jewett, M. A S., Srigley, J., Barkin, J..Mador, D., Fradet, Y.,Chin, J. L., Paquin, J. M. and Laplank, S.: Randomized, controlled study of neoadjuvant reversible androgen withdrawal therapy with cyprotemne acetate in the surgical management of localized prostate cancer. J. Urol., part 2,lb3:254A,abstract 103,1995. 8. Soloway, M. S.,Shari& R., Wajsman, Z., McLeod, D., Wood, D. P., Jr. and h a s - B a e z for the Lupron Depot Neoadjuvant Prostate Cancer Study Group: Randomized prospective study comparing radical prostatectomy alone versus radical prostatectnmy preceded by androgen blockade in clinical stage B2 (T2bNxMO) prostate cancer. J. Urol., 154: 424, 1995. 9. Pedersen, K. V., Lundberg, S., Hugosson, J., Aus, G., Schelin, S., Ahlgren, G. and Abrahamsson, P A : Neoadjuvant hormonal treatment with triptorelin versus no treatment prior to radical prostatectomy: a prospective randomized multicenter study. J. Urol., part 2,163:39lA,abstract 651,1995. 10. Ackerman, D. h, Barry,J. M., Wicklund, R. A., Olson, N. and Lowe, B. A: Analysis of risk factors associated with prostate cancer extension to the surgical margin and pelvic node metastases at radical prostatedomy. J. Urol., 150: 1845,1993. 11. Voges, G.E.,McNeal, J. E., Redwine, E. A, Freiha, F. S. and Stamey, T. A: Morphologic analysis of surgical margins with positive findings in prostatectomy for adenocarcinoma of the prostate. Cancer, 69:520,1992.