+ All Categories
Home > Documents > Neoadjuvant Hormonal Therapy Before Radical Prostatectomy Decreases the Number of Positive Surgical...

Neoadjuvant Hormonal Therapy Before Radical Prostatectomy Decreases the Number of Positive Surgical...

Date post: 01-Jan-2017
Category:
Upload: lamthu
View: 214 times
Download: 0 times
Share this document with a friend
6
VOl. 154,429-434. Aqpt 1- Printed in USA NEOADJUVANT HORMONAL THERAPY BEFORE RADICAL ~ROSTATECTOMY DECREASES THE NUMBER OF POSITIVE SURGICAL MARGINS IN STAGE T2 PROSTATE CANCER: INTERIM RESULTS OF A PROSPECTIVE RANDOMIZED TRIAL HEIN VAN POPPEL, DIRK DE RIDDER, MIZ A. ELGAMAL, WIM VAN DE VOORDE, PATRICK WERBROUCK, KOEN ACKAERT, RAYMOND OYEN, GEERT PITI'OMVILS, LUC BAERT AND MEMBERS OF THE BELGIAN URO-ONCOLOGICAL STUDY GROUP* From the Departments of urn@, Pathology, Radio@ and Physics, Katholieke Uniwrsiteit Leuwn, Leuven and Departments of Urology. Kliniek Maria Voorrienigheid, Kortrijk and Miniek S t . - E l U t h , TunJrout, Belgium ABSTRACT Purpose: We investigated the effect of neoadjuvant treatment before radical prostatedomy for clinically localized prostate cancer. Materials and Methods: A total of 130 patients with stages T2b and T3 prostate cancer was randomized in a multicenter study: 62 underwent immediate radical prostatectomy and 65 received 560 mg. estramustine phosphate daily for 6 weeks preoperatively. Results: For clinical stage T2b tumors the neoadjuvant treatment resulted in a significant decrease in positive surgical margins compared to the nonpretreated group. This difference was not found for clinical stage T3 tumors. The impact on progression and survival still must be analyzed. Conclusions: Neoadjuvant treatment can be beneficial for clinical stage T!2 prostate cancer. Optimal treatment for stage T3 tumors remains controversial. KEY WORDS: pmtatecbmy, prostatic neoplasms, homonee, carcinomn Radical prostatectomy has become the standard treatment for early stage localized prostate cancer. Many urologists have extended the indication for radical prostatectomy to patients with locally advanced disease. It was suggested that for stage T3 tumors the addition of hormonal treatment preoperatively or postoperatively could improve the 5-year survival rate.1.2 However, the use of hormonal treatment before radical prostatectomy is controversial as is the optimal treatment for stage T3 prostate cancer. Presently, no sub- group of patients with stage T3 tumors can be identified who could benefit from radical prostatectomy. To improve the results of surgery for locally advanced tumors, neoadjuvant hormonal treatment has been advocatr ed.3 All investigators reported downsizing of the prostate gland, and some also found downstaging and even downgrad- ing of the tumor.4-6 Others could not reproduce these find- ings.7-= A decrease in blood loss and better operability after hor- monal treatment were noted by some ~urgeons4~ 10 but these were not confirmed by our own experience.11Most studies re- port a limited number of patients and none of these studies was randomized. To appreciate the value of neoadjuvant treatment, we de- signed a prospective randomized multicenter study, compar- ing radical prostatectomy alone versus radical prostatectomy aRer preoperative estramustine phosphate in patients with stages T2b and T3 prostate cancer. The clinical or radiolog- ical assessment of the effect of neoadjuvant therapy on the prostate tumor is unreliable because of the inherent problem of staging errors (understaging and overstaging). Therefore, Accepted for publication January 20, 1995. * Participating centers: K. Ackaert, Turnhout; C. Assenmacher, Uccle; L. Baert, Leuven; I. Billiet, M. Hardeman, J. Mattelaer and P. Werbrouck, Kortrijk; G. Boeckx,Antwerpen;J. Casselman and R. De BRlyne, Oostende; M. DHoedt, Waregem; K. Delaere, Heerlen; A. Leonard, Lier; B. MorteImans and A. Valcke, Bonheiden; G. Renders, Gent; J. L. Van Houcke, Roeselaere and P. Van Oyen, Brugge, Belgium. the short-term aim of the study was the evaluation of the number of positive margins. Since the tumor volume was shown to decrease more rapidly than the benign hyperplastic tissue following androgen deprivation,l2 it could be expected that this fact should be translated in a lower number of positive margins. MATERIALS AND METHODS A prospective multicenter randomized trial was designed to study the effect of neoadjuvant treatment before radical prostatectomy in 200 patients with stages T2b and T3 pros- tate cancer according to the new TNM ~lassification.13 The study was recently closed for patient entry, while the first 130 files were analyzed. Patients with newly diagnosed his- tologically proved prostate cancer, fit for radical prostatec- tomy and without antecedents of cardiovascular disease were included. Pretreatment evaluation included clinical history, digital rectal examination, transrectal ultrasound with vol- ume estimation following the ellipsoid method,14 chest x-ray, radioisotope bone scan, computerized tomography of the pel- vis with eventual puncture of the suspicious lymph nodes as we previously reported,15 prostate specific antigen (PSA) measurement using the Hybritech technique and routine blood tests. Pretreatment randomization was done centrally, and stratification was done for clinical stage and per center. On 1 arm patients underwent immediate (within 2 weeks) radical retropubic prostatectomy with staging lymphadenectomy. On the other arm patients were first treated with oral estra- mustine phosphate for 6 weeks at a dose of 560 mg. daily (140 mg. at 10 a.m., 140 mg. at 3 p.m. and 280 mg. at 10 p.m.). ARer that period digital rectal examination, transrectal ul- trasound and PSA measurement were repeated, and radical prostatectomy with lymphadenectomy was perform&. A to- tal of 100 mg. acetylsalicylic acid was given daily during the period of estramustine phosphate intake. Tolerability and compliance with the hormonal treatment were noted. 429
Transcript

VOl. 154,429-434. A q p t 1- Printed in U S A

NEOADJUVANT HORMONAL THERAPY BEFORE RADICAL ~ROSTATECTOMY DECREASES THE NUMBER OF POSITIVE SURGICAL MARGINS IN STAGE T2 PROSTATE CANCER: INTERIM RESULTS OF A

PROSPECTIVE RANDOMIZED TRIAL HEIN VAN POPPEL, DIRK DE RIDDER, MIZ A. ELGAMAL, WIM VAN DE VOORDE, PATRICK WERBROUCK, KOEN ACKAERT, RAYMOND OYEN, GEERT PITI'OMVILS,

LUC BAERT AND MEMBERS OF THE BELGIAN URO-ONCOLOGICAL STUDY GROUP* From the Departments of urn@, Pathology, Radio@ and Physics, Katholieke Uniwrsiteit Leuwn, Leuven and Departments of Urology.

Kliniek Maria Voorrienigheid, Kortrijk and Miniek S t . - E l U t h , TunJrout, Belgium

ABSTRACT

Purpose: We investigated the effect of neoadjuvant treatment before radical prostatedomy for clinically localized prostate cancer.

Materials and Methods: A total of 130 patients with stages T2b and T3 prostate cancer was randomized in a multicenter study: 62 underwent immediate radical prostatectomy and 65 received 560 mg. estramustine phosphate daily for 6 weeks preoperatively.

Results: For clinical stage T2b tumors the neoadjuvant treatment resulted in a significant decrease in positive surgical margins compared to the nonpretreated group. This difference was not found for clinical stage T3 tumors. The impact on progression and survival still must be analyzed.

Conclusions: Neoadjuvant treatment can be beneficial for clinical stage T!2 prostate cancer. Optimal treatment for stage T3 tumors remains controversial.

KEY WORDS: pmtatecbmy, prostatic neoplasms, homonee, carcinomn

Radical prostatectomy has become the standard treatment for early stage localized prostate cancer. Many urologists have extended the indication for radical prostatectomy to patients with locally advanced disease. It was suggested that for stage T3 tumors the addition of hormonal treatment preoperatively or postoperatively could improve the 5-year survival rate.1.2 However, the use of hormonal treatment before radical prostatectomy is controversial as is the optimal treatment for stage T3 prostate cancer. Presently, no sub- group of patients with stage T3 tumors can be identified who could benefit from radical prostatectomy.

To improve the results of surgery for locally advanced tumors, neoadjuvant hormonal treatment has been advocatr ed.3 All investigators reported downsizing of the prostate gland, and some also found downstaging and even downgrad- ing of the tumor.4-6 Others could not reproduce these find- ings.7-=

A decrease in blood loss and better operability after hor- monal treatment were noted by some ~urgeons4~ 10 but these were not confirmed by our own experience.11 Most studies re- port a limited number of patients and none of these studies was randomized.

To appreciate the value of neoadjuvant treatment, we de- signed a prospective randomized multicenter study, compar- ing radical prostatectomy alone versus radical prostatectomy aRer preoperative estramustine phosphate in patients with stages T2b and T3 prostate cancer. The clinical or radiolog- ical assessment of the effect of neoadjuvant therapy on the prostate tumor is unreliable because of the inherent problem of staging errors (understaging and overstaging). Therefore,

Accepted for publication January 20, 1995. * Participating centers: K. Ackaert, Turnhout; C. Assenmacher,

Uccle; L. Baert, Leuven; I. Billiet, M. Hardeman, J. Mattelaer and P. Werbrouck, Kortrijk; G. Boeckx, Antwerpen; J. Casselman and R. De BRlyne, Oostende; M. DHoedt, Waregem; K. Delaere, Heerlen; A. Leonard, Lier; B. MorteImans and A. Valcke, Bonheiden; G. Renders, Gent; J. L. Van Houcke, Roeselaere and P. Van Oyen, Brugge, Belgium.

the short-term aim of the study was the evaluation of the number of positive margins. Since the tumor volume was shown to decrease more rapidly than the benign hyperplastic tissue following androgen deprivation,l2 it could be expected that this fact should be translated in a lower number of positive margins.

MATERIALS AND METHODS

A prospective multicenter randomized trial was designed to study the effect of neoadjuvant treatment before radical prostatectomy in 200 patients with stages T2b and T3 pros- tate cancer according to the new TNM ~lassification.13 The study was recently closed for patient entry, while the first 130 files were analyzed. Patients with newly diagnosed his- tologically proved prostate cancer, fit for radical prostatec- tomy and without antecedents of cardiovascular disease were included. Pretreatment evaluation included clinical history, digital rectal examination, transrectal ultrasound with vol- ume estimation following the ellipsoid method,14 chest x-ray, radioisotope bone scan, computerized tomography of the pel- vis with eventual puncture of the suspicious lymph nodes as we previously reported,15 prostate specific antigen (PSA) measurement using the Hybritech technique and routine blood tests.

Pretreatment randomization was done centrally, and stratification was done for clinical stage and per center. On 1 arm patients underwent immediate (within 2 weeks) radical retropubic prostatectomy with staging lymphadenectomy. On the other arm patients were first treated with oral estra- mustine phosphate for 6 weeks at a dose of 560 mg. daily (140 mg. at 10 a.m., 140 mg. at 3 p.m. and 280 mg. at 10 p.m.). ARer that period digital rectal examination, transrectal ul- trasound and PSA measurement were repeated, and radical prostatectomy with lymphadenectomy was perform&. A to- tal of 100 mg. acetylsalicylic acid was given daily during the period of estramustine phosphate intake. Tolerability and compliance with the hormonal treatment were noted.

429

430 NEOADJUVANT HORMONAL THERAPY BEFORE RADICAL PROSTATECTOMY

TABLE 1. Prostate volume and PSA distribution in the different patient groups Post-Estramustine PSA (ng.,ml, ~ Post-Estramustine Phosphate

Stage No' Pts. voL (") Phosphate Vol. (cc) PSA (ng./ml.)

T2: - 16.2 2 13.9 - Surgery alone 37 39.9 z 14.4

Surgery plus estramustine phosphate 36 42.5 L 24.5 29.2 2 19.7 14.2 2 10.6 1.02 2 1.06 T3: - 15.3 2 14.3 - Surgery alone 25 36.7 2 14.4

Surgery plus estramustine phosphate 29 40.9 2 17.6 35.6 2 14.9 17.7 2 14.7 1.40 2 1.35

All radical prostatectomy specimens were examined by a review pathologist (W. VdV.) in a blinded manner, using the whole-organ multiple step-section technique as described previously.16~17 Surgical specimens were inked and fixed in 10% neutral buffered formalin for 48 to 96 hours. Seminal vesicles were separated from the prostate and cut in longi- tudinal sections. The prostate was serially sectioned with a meat slicer perpendicular to the rectal surface at 4 mm. intervals.17 All whole mount sections were embedded in par- affin, and slides were cut at 5 pm. from the caudal surface and stained with hematoxylin and eosin. To assess basal and apical surgical margins, sagittal biopsies of the most basal and apical sections were examined.18 The modified TNM classification was used for pathological staging.13 The tumors were graded according to the Cleason system.19 The surgical margins were assessed by histological examination of the inked surface of the prostatectomy specimen. PSA levels were measured after 1 month and then every 3 months thereafter.

Operative blood loss and operating time were noted, and a subjective difficulty score (1-easy, %normal and 3 - a - cult) of the procedure was assigned by the urologist. Statis- tical analysis was performed by an independent statistician (G. P.) using the Student t test for the different groups, with a significance level of 1%.

RESULTS

The initial results concerning tumor stage and grade, re- section margins and postoperative PSA level, as well as drug tolerance and surgery-related parameters were analyzed in the first 130 evaluable patients. Mean patient age was 67 years (range 52 to 76). Two patients (1 in each arm) died of a myocardial infarction preoperatively. One patient in the es- tramustine phosphate group suffered a pulmonary embolism preoperatively and, therefore, was treated with radiotherapy instead of radical prostatectomy. Of the remaining 127 pa- tients, the 2 groups were well balanced in regard to initial stage, prostate volume and pretreatment PSA level (table 1).

Compliance was good in 87% of the patients who received estramustine phosphate. Dose adjustments (reduction of the daily dose to 420 or 280 mg.) were necessary in 13% of the patients. In 1 patient treatment was stopped because of gastrointestinal intolerance. Adverse events, mainly tem- porary gynecomastia or nipple tenderness and gastrointesti- nal problems, were noted in a third of the patients.

In the estramustine phosphate group downsizing of the prostate gland was estimated on transrectal ultrasound pre- operatively. The prostate volume decreased from 42.5 2 24.5 to 29.2 t 19.7 cc (approximately 30%) for the initial stage T2b tumors and from 40.9 2 17.6 to 35.6 2 14.9 cc (nearly 15%) for the initial stage T3 tumors (table 1). This difference in percentage of downsizing between the 2 groups was sig- nificant (p ~ 0 . 0 5 ) .

Clinical downstaging from an initial stage T3 to a stage T2 tumor, assessed by digital rectal examination, was noted in 14 preoperatively treated patients (48%). No clinical down- staging was observed in the stage T2b group, since 33 of the 36 tumors were still considered clinical stage T2b after neo- adjuvant therapy and the remaining 3 were upstaged to clinical stage T3.

The influence of neoadjuvant estramustine phosphate on the pathological stage in the different groups is shown in table 2. In the clinical stage T2 category 32.4% were, in fact, pathological stage T3 after radical prostatectomy per se while only 16.7% were pathological stage T3 after estramus- tine phosphate treatment plus radical prostatectomy. Among clinical stage T3 tumors the neoadjuvant treatment did not decrease the number of pathological stage T3 lesions, since approximately 40% proved to be pathological stage T3 in the pretreated (41.3%) and nonpretreated (44%) groups.

For the appreciation of an eventual downgrading effect, the Gleason score of the radical prostatectomy specimens w a ~ compared between the pretreated and control groups (table 3). Fewer patients with initial stage T2 tumors had poorly differentiated cancers than those with clinical stage T3 le- sions. For the pathological stage T2 group significantly more tumors were low grade after estramustine phosphate than without pretreatment (p <0.01). There was no clear differ- ence in tumor differentiation between those with and without neoadjuvant therapy for the pathological stage T3 group.

The incidence of positive resection margins was calculated separately for the posterolateral aspect, apex and base of the prostate. A patient could present with a positive margin at more than 1 area. Considering the totality of prostate speci- mens, regardless of stage and randomization arm, positive surgical margins were encountered a t the posterolateral as- pect in 37.8% of the cases, a t the apex in 29.1% and at the prostate base in 14.1%. The results of further breakdown for each group are shown in table 4. Positive margins decreased

TABLE 2. Comparison between clinical and pathological stages in the diflerent patient groups

No. Pathologvzal Stage (70) Clinical Stage No. Pts.

pT2 PT3 T2:

Surgery alone 37 25 (67.6) 12 (32.4) Surgery plus estramus- 36 30 (82.31 6 (16.7)

tine phosphate T3:

Surgery alone 25 14 (56.0) 11 144.0) Surgery plus estramus- 29 17 (58.61 12 (41.31

tine phosphate

TULE 3. Tumor gradin2 (Gleason score) on the radical - prostatectomy specimen of different patient groups

- '2 Gleason Score

Stage No' Pts' Low Moderate High (2 to 4) ( 5 to 71 I8 to 10)

---- Initial T2 Initial T3 0T2:

73 47.9 45 1 7.0 54 30.0 55.0 15.0

Surgery alone 42 38.9 5 2 8 8.3 Surgery plus estramus- 44 57 1 37.1 5.7

Surgery alone 24 28 6 51 .O 20 1 Surgery plus estramus- 17 90 r? th .2 "3 1

tine phosphate pT3:

tine phosphate _ _ ~ ~~ ~ ~ ~ --

4a1 NEOADJUVANT HORMONAL THERAPY BEFORE RADICAL PROSTATECTOMY

TABLE 4. surgical mnrginrr at the level of the poster#&teml aspect, apex and prostate base in the difierent patient groups

No. (%) No. Pts.

Posterolat. Aper Baee stage --

T2: surgery alone 37 17 (45.9) 10 (27.0) 4 (10.8) surgeryp1usestramw1- 36 7U9.4) S(13.9) 3 (8.3)

tine phospbate T3:

surgery alone 25 lO(40.0) 7 (28.0) 2 (8.0) surgery plw estramua- 29 14 (48.3) 15 (51.7) 9 (31.0)

Totals 127 48 (37.8) 37 (29.1) 18 (14.1) - - - - tine prosphate

significantly (p <0.01) from 45.9 to 19.4% at the posterolab erd aspect of the prostate and from 27 to 13.9% at the apex in the pretreated clinical stage T!2 group. For clinical stage T3 tumors the incidence of positive margins increased with the neoadjuvant therapy h m 40.0 to 4.3% for the postero- lateral aspect, 28.0 to 51.7% for the apex and 8.0 to 31.0% for the prostate base.

The PSA values were determined before any treatment, &r neoadjuvant treatment and after radical prostatectomy. m e preoperative values showed a good balance betwen subgroups. After neoadjuvant treatment the mean PSA level was 1.02 2 1.06 ngJml. for the stage T2b group and 1.40 ? 1.35 ng./ml. for the stage T3 group (table 1). PSA values after radical prodtatectomy were further related to the initial clin- ical stage in the entire group and in the group with positive or negative surgical margins (table 5). From the analysis of different small groups, no statistical relevant conclusion can be drawn. However, there is a tendency to note higher post- operative PSA values in the stage T3 group, especially in patients receiving estramustine phosphate with ongoing fol- lowup, and this tendency was more pronounced in the pres- ence of positive surgical margins. Table 6 shows the number of patients with nondetectable PSA levels after radical pros- tatectomy with or without estramustine phosphate. Again, these subgroups are too small for statistical evaluation.

Table 7 compares the amount of blood loss and operative time in the different patient groups. Due to the high standard deviations, no statistically significant difference was found between stages T2 and T3 disease, or between patients who did and did not receive neoadjuvant treatment. Also, the difficulty score was not different in the separate groups.

DISCUSSION

We report the interim results of a randomized study com- paring radical prostatectorny alone versus neoadjuvaut treat- ment plus radical prostatectomy for locally advanced pros- tate cancer. A n analysis of radical prostatectomy specimens concerning tumor pathological stage, grade and surgical mar- gins was performed.

The idea of neoadjuvant hormonal treatment is certainly not new7 but to date these studies have included only a small number of patients treated in a nonrandomized fashion.2.4.6-11.20 An ideal neoadjuvant treatment should de- crease the tumor volume within a reasonable interval to- gether with inhibiting the metastatic potential of the tumor cells. The treatment should be well tolerated and reversible. Mostly maximal androgen blockade is used in neoadjuvant studies.6.7.21.22 We have chosen estramustine phosphate as the neoadjuvant drug. Estramustine phosphate is widely used in second-line treatment for metastatic prostate can- cer.= It is a known prostate specific cytotoxic agent, combin- ing the hormonal effect of estrogens with an antimitotic spindle blocker effect.24.25

There is no agreement on the duration of neoadjuvant therapy2.m but most treatments are given for 3 months, which means that surgery must be postponed for a consider- able period with embarrassing psychological distress for the patient. Therefore, the duration of preoperative hormonal deprivation should be as short as possible. With estramus- tine phosphate the decrease in prostate and tumor volume was most impressive during the initial 4 weeks of treatment as illustrated by transrectal ultrasound studies. After this period the involution continues at a much lower rate."

Estramustiae phosphate has already been used for down- staging purposes years ago.= In a previous open study we used estramustine phosphate for 6 weeks in 25 patients. There was an apparent decrease in serretory as well as proliferative activity of malignant tissues, which was much more impressive than that noted after 3 month of nonste- roidal antiandrogen monotherapy.ae The morphological changes were comparable to those reported in the literature with 3 months of maximal androgen blockade.s.21 Thus, es- tramustine phosphate was chosen because of its dual anti- mitotic activity and the possible shortening of the preopera- tive treatment period to 6 weeks.

Although it was shown that oral estramustine phosphate does not increase the risk for thrombogenesis (as do estro- gens),sO other reports noted cardiovascular side effects in a

TABLE 5. PSA values after 3, 6 and 9 months for the entire m u p and for patients with wsitive or neaative suraical marains

Stage Entire Group Pos. Margins Neg. M a g i n s

No. pts. PSA (naJml.) No. pls. PSA (nalml.) No. Pta. PSA (naJml.) ~ -~ ~-

3 Mos. T2:

Surgery alone 30 0.31 f 0.57 13 0.58 2 0.73 17 0.06 f 0.05 Surgery plus estramustine phosphate 22 0.35 2 0.57 6 0.28 2 0.39 16 0.04 2 0.06

Surgery alone 12 0.26 2 0.65 4 0.63 2 0.91 8 T3:

0.02 f 0.04 Surgery plus estramustine phosphate 21 0.77 f 1.36 14 1.01 2 1.55 7 0.08 2 0.07

6 MOS. T2:

Surgery alone 17 0.26 2 0.45 8 0.43 2 0.60 9 0.12 2 0.17 Surgery plus estramustine phosphate 23 0.60 t 1.78 7 1.26 2 2.72 16 0.30 2 0.94

T3 : Surgery alone 9 0.85 f 1.34 3 1.40 2 1.84 6 0.60 2 0.81 Surgery plus estramustine phosphate 13 1.06 2 2.14 8 1.54 2 2.49 5 0.10 f 0.07

9 MOS. T2:

Surgery alone 14 0.22 t 0.38 6 0.37 2 0.51 8 0.10 Surgery plus estramustie phosphate 12 0.06 2 0.06 5 0.08 2 0.07 7 0.05 ? 0.08

Surgery alone 9 0.73 f 0.99 3 1.10 2 1.20 6 0.20 Surgery plus estramustine phosphate 9 2.19 2 0.41 6 3.25 2 4.67 3

T3:

0.03 2 0.05

432 NEOADJUVANT HORMONAL THERAPY BEFORE RADICAL PROSTATECTOMY

Tmm 6. Number of patients with undetectabk P a levels in t h different groups after 3, 6 and 9 months

No. Pts./Total (Oh)

(85 pta.) (62 pta.) (44 pis.) Stage 3 Mos. 6 Mos. 9 Mos.

12: Surgery alone 25/30 (83) 15117(88) 13114 (93) Surgery plus estramus- 22/22 (100) 2003 (87) 12/12 (100)

tine phosphate T3

Surgery alone 10112 (83) 7/9 (78) 6/9 (67) Surgery plus estramus- 17/21 (81) 11/13 (85) 6/9 (67)

tine phosphate Totala 74485 (871 53/62(85) 37/44 (84)

TABLE 7 . Blood loss and operation time in different patient groups Mean 2 SD

12: Surgery alone 37 1,141 2 730 140.7 2 39.0 Surgery plus estramus- 36 1,360 2 1,108 144.9 2 50.6

tine phosphate T3:

Surgery alone 25 1,540 2 1,396 145.5 2 29.4 Surgery plus estramus- 29 1,067 2 1.100 133.7 2 45.0

tine phosphate

significant number of patients under estramustine phos- phate administration.31 Therefore, aspirin was given as pro- phylaxis to prevent or lower the possible thromboembolic effects of oral estramustine p h o ~ p h a t e . ~ ~ Nevertheless, 1 pa- tient had a pulmonary embolism that might have been drug- related. The gynecomastia was reversible in all patients a n d the gastrointestinal intolerance could usually be treated by simple gastrokinetic agents. In any event, the tolerance for estramustine phosphate in the setting of this trial was much better than that observed in patients treated for metastatic or hormone-resistant prostate cancer.23

Neoadjuvant treatment is known to produce downsizing of the prostate gland. The decrease in prostate size in our series was not as marked as that obtained by some who adminis- tered at least 3 months ofhormonal treatment.2z4 However, it was comparable to that reported by others.33.s The analysis in our series showed that this downsizing was more pro- nounced in the clinical stage T2 than in the stage T3 group. This discrepancy may be related to an inevitable inter-center variation in the assessment of prostate size before and aRer treatment.

Downstaging of a prostate tumor is difficult to evaluate because of the manifest inability to stage clinically prostate cancer precisely before any treatment. Indeed, it was shown that 50 to 60% of stage T2 tumors are clinically under- ~taged,3~.36 while 20% of stage T3 tumors are clinically overstaged.36 After hormonal treatment the staging becomes even more unreliable with either digital rectal examina- tion, transrectal ultrasound or magnetic resonance imag-

Although we were aware of these staging problems, the downstaging effect was assessed in our study. In no patient was the tumor downstaged from stage T2b to clinically un- apparent stage T1, while downstaging was assumed in 48% of the stage T3 tumors. On the other hand, nearly 60%) of the stage T3 cancers were pathological stage T2. This higher percentage of overstaging may be explained by the selection of patients who entered the study. Indeed, any patient with suspicion of extracapsular extension either on digital rectal examination or transrectal ultrasound was considered to have stage T3a disease. In a multicenter study the aDDreci-

ing.lL12.37

i

1

ition of extracapsular extension may be influenced by the subjective evaluation of the tumor stage.

Therefore, in our trial the histopathological examination by 1 review pathologist was used to evaluate stage and grade in different patient groups. Significantly fewer clinical stage T2 tumors had extracapsular extension in the pretreated group than in the nonpretreated group. Only 16.7% of the patients with clinical stage T2b prostate cancer who received 6 weeks of estramustine phosphate, had pathological stage T3 disease. This figure is significantly lower than the 34.4% in the nonpretreated stage T2b group and also much lower than the number of stage T2, pathological stage T3 tumors reported by others.36 Such clear effect is not found for clinical stage T3 tumors, suggesting that neoadjuvant estramustine phosphate for 6 weeks does not convert extracapsular exten- sion into a prostate confined lesion. Although complete dia- appearance of the tumor after maximal androgen blockade was reported by others,6 we still found tumor in all cases after whole specimen, systematic, step-section histopatholog- ical examination.

The assignment of a tumor grade after neoadjuvant treat- ment can be difficult, since involutional changes are not easy to differentiate from malignancy. 11,21.22,29 Due to the re- ported sampling errors with prostate puncture biopsy,38 we did not compare the diagnostic biopsy grade with the surgical specimen grade but instead we compared the whole tumor differentiation score within comparable subgroups with and without estramustine phosphate pretreatment. We found that in the pretreated clinical stage T2 group there were significantly fewer poorly differentiated tumors than in the stage T2 group without estramustine phosphate, which was not noted in the clinical stage T3 group. Although we are skeptical about a possible downgrading effect by hormonal therapy,20.29 we will be cautious in considering this effect in the final analysis of the study.

The impact of positive surgical margins of the radical pros- tatectomy specimens on the evolution of the disease is con- troversial, since not all patients with positive margins have progression. This discrepancy could be due to artifactual misinterpretation of the margin positivity because of im- proper handling and processing of the specimens.39 Following thorough examination of all specimens we found a significant decrease in the number of positive margins in pretreated stage T2 cancer patients compared to those who underwent radical prostatectomy only. This finding confirms resulte from others using neoadjuvant hormonal treatment.2.3’5 An inverse relationship was found in clinical stage T3 tumors. Others also reported a significantly greater incidence of pos- itive surgical margins in patients with stages T2c and T3 prostate cancer following maximal androgen blockade.9 It is not clear why in our series the number of positive margins at the level of the apex and base increased in stage T3 cancers after estramustine phosphate. A possible explanation is that the duration of estramustine phosphate administration is not sufficient for more advanced tumors, which could be even more relevant for poorly differentiated tumors (mainly stage T3) that are less sensitive to the estrogenic effect of estra- mustine phosphate. Another explanation could be the reac- tion of prostatic tissue to estramustine phosphate. It has been shown that estramustine phosphate produces a signif- icant lymphocytic infiltration, an increase in the stromal component and involutional changes in prostate acini that might induce fibrosis and adhesions.29 The latter condition can complicate proper apical and basal dissection, resulting in margin positivity, especially in small prostates.2 Finally, it was suggested that hormonal treatment could ~ v e the urol- ogist the impression that the tumor was clinically, indeed, downstaged and that he had performed a less extensive re- section.4D This fact could be responsible for the high locd recurrence rates reported after neoadiuvant treatment and

.. radical prostatectomy for stage T3 cancer.4 1

433 NEOADJUVANT HORMONAL THERAPY BEFORE RADICAL PROSTATECTOMY

The PSA level after radical prostatectomy is accepted to be a reliable prognostic factor and PSA relapse is becoming one of the first indicators of treatment failure after radical pros- tatectomy, which may precede clinical failure by months or years.42 Although our data on postoperative PSA are still limited and do not yet allow statistical analysis, the stage T3 plus estramustine phosphate group had higher postoperative PSA levels than the stage T3 cancer group without estramus- tine phosphate, which correlates with the incidence of posi- tive margins in both groups. The apparent regression of tumor, misdirecting the surgeon from appropriate wide exci- ion,^' can be responsible for residual PSA-producing neo- plastic tissue.

Some open studies claimed that surgery aRer hormonal therapy is easier (mainly because of downsizing),2 there is less hemorrhage and recovery of continence is better.4.10 Others mentioned that surgery was not easier,7.11 The ease of an operation is a subjective assessment. Also, in our study the surgeon was not blinded but neoadjuvant estramustine phosphate did not make the procedure obviously easier, faster or less bloody.

CONCLUSIONS

The role of neoadjuvant therapy before radical prostatec- tomy for locally confined as well as locally advanced prostate cancer remains to be defined. In our randomized multicenter study there seemed to be a benefit of 6 weeks of neoadjuvant estramustine phosphate for clinical stage T2b prostate can- cers, since fewer tumors showed extracapsular extension, poor differentiation or positive margins. This benefit was not found in clinical stage T3 tumors, which might require longer pretreatment. These findings do not necessarily indicate that neoadjuvant treatment improves the surgical curability and prolongs the interval to progression or disease-related sur- vival.

The optimal treatment for stage T3 tumors remains con- troversial. When neoadjuvant treatment is applied for stage T3 cancer, the extent of the surgery should not be influenced by the clinical impression of downstaging. Further research should be based on systematic preoperative diagnosis and staging in the frame of a randomized study performed at centers where a minimal variation is guaranteed in clinical, ultrasonographic and pathological evaluation and surgical expertise.

REFERENCES

1. Zincke, H., Utz, D. C. and Taylor, W. F.: Bilateral pelvic lymph- adenectomy and radical prostatedomy for clinical stage C prostate cancer: role of adjuvant treatment for residual cancer and in disease progression. J. Urol., 135: 1199, 1986.

2. Soloway, M. S., Hachiya, T,, Civantos, F., Murphy, W. M., Gomez, C. C. and Ruiz, H. E.: Androgen deprivation prior to radical prostatectomy for T2b and T3 prostatic cancer. Urol- ogy, suppl., 43: 52, 1994.

3. Fair, W. R.: Why not neo-adjuvant therapy for prostatic carci- noma? Prog. Clin. Biol. Res., 370 305, 1991.

4. Monfette, G., Dupont, A. and Labrie, F.: Temporary combination therapy with flutamide and tryptex as adjuvant to radical prostatectomy for the treatment of early Stage prostate cancer. In: Early Stage Prostate Cancer: Diagnosis and Choice of Therapy. Edited by F. Labrie. New York: Elsevier Science Publishers B. V., pp. 41-51, 1989.

5. T&u, B., Srigley, J. R., Boivin, J. C., Dupont, A, Monfette, G., Pinault, S. and Labrie, F.: Effect of combination endocrine therapy (LHRH agonist and flutamide) on normal prostate and prostatic adenocarcinoma. A histopathologic and immu- nohistochemical study. h e r . J. Surg. Path., 16 111,1991.

6. Fair, W. R., Aprikian, A., Sogani, P., Reuter, V. and whitmore, W. F., Jr.: The role of neoadjuvant hormonal manipulation in localized prostatic cancer. Cancer, suppl., 71: 1031,1993.

7. McFarlane, M. T., Abi-Aad, A., Stein, A., Danella, J., Belldegrun, A. and deKernion, J. B.: Neoadjuvant hormonal deprivation in

patients with l d y advanced prostate cancer. J. Urol., 1M): 132, 1993.

8. Kennedy, T. J., Sonneland, A. M., Marlett, M. M. and Troup, R. H.: Luteinizing hormone-releasing hormone downstaging of clinical stage C prostate cancer. J. Urol., 14E 891. 1992.

9. Oesterling, J. E., Andrewe, P. E., Suman, V. J., Zincke. H. and Myers R. P.: Preoperative androgen deprivation therapy: arti- ficial lowering of serum prostate specific antigen without downstaging the tumor. J. Urol., 149: 779, 1993.

LO. Schulman, C. C. and Sassine, A. M.: Neoadjuvant hormonal treatment of locally advanced prostate cancer: does it make sense? Curr. Opin. Urol., 3 394, 1993.

11. Van Poppel, H., Ameye, F., Oyen, R., Van de Voorde, W. and Baert, L.: Neo-adjuvant hormonotherapy does not facilitate radical prostatehmy. Acta Urol. Belg., 80.73, 1992.

12. Pinault, S., T h , B., Gagnon, J., Monfette, G., Dupont, A. and Labrie, F.: Transrectal ultrasound evaluation of local prostate cancer in patients treated with LHRH agonist and in combi- nation with flutamide. Urology, 39: 254, 1992.

13. Schriider, F. H., Hermanek, P., Denis, L., Fair, W. R., Gospodarowicz, M. D., and Pavone-Macalm, M.: The TNM classification of prostate cancer. Prostate, suppl.. 4: 129,1992.

14. Littrup, P. J., Williams, C. R., Egglin, T. K and Kane, R. A: Determination of prostate volume with transrectal ultrasound for cancer screening. Part II. Accuracy of in vitm and in vivo techniques. Radiology, 178: 49,1991.

15. Van Poppel, H., Ameye, F., @en, R., Van de Voorde, W. and Baert, L.: Accuracy of combined computerized tomography and fine needle aspiration cytology in lymph node staging of local- ized prostatic carcinoma. J. Urol., 161: 1310, 1994.

16. Van de Voorde, W., Van Poppel, H., Haustermans, K, Baert, L. and Lauweryns, J.: Mu&-secreting adenocarcinoma of the prostate with neuroendocrine differentiation and Paneth-like cells. Amer. J. Surg. Path., 18: 200,1994.

17. Stamey, T. A, McNeal, J. E., Freiha, F. S. and Redwine, E.: Morphometric and clinical studies on 68 consecutive radical prostatectomies. J. Urol., 13% 1235,1988.

18. Ayala, A. G., Ro, J. Y., Babaian, R., T r o n m , T. and Grignon, D. J.: The prostatic capsule: does it exist? Its importance in the staging and treatment of prostatic carcinoma. Amer. J. Surg. Path., 1 3 21,1989.

19. Gleason, D. F.: Histologic grading of prostatic carcinoma. In. Pathology of the Prostate. Edited by D. G. Bostwick. New York Churchill Livingstone, &apt. 6, pp. 83-93, 1990.

20. Van Poppel, H., Ameye, F., Oyen, R., Van de Voorde, W. and Baert, L.: Radical proetateetomy for localized prostate cancer. Eur. J. Surg. Oncol., 18: 456,1992.

21. Murphy, W. M., Soloway, M. S. and Barrows, G. H.: Pathologic changes associated with androgen deprivation therapy for prostate cancer. Cancer, 68: 821,1991.

22. Hellstrom, M., Hhggman, M., Briindstedt, S., de la Tom, M., Pedersen, K, Jarlsfeldt, J., Wijbtrom, H. and Busch, C.: Histopathological changes in androgendeprived localized prostatic cancer. A study in total prostatectomy specimens. Eur. Urol., 24: 461, 1993.

23. Van Poppel, H. and Baert, L.: The present role of estramustine phosphate in advanced prostate cancer. Pmg. Clin. Biol. Res., 370: 323,1991.

24. Mareel, M. M., Storme, G. A, Dragonetti, C. H., De Bruyne, G. K, Hartley-Asp, B., Segers, J. L. and Rabaey, M. L.: Anti- invasive activity of estramustine on malignant MO4 m o m cells and on DU-145 human prostate carcinoma cells in vitro. Cancer Res., 48: 1842,1988.

25. Tew, K D. and Steams, M. E.: Hormone-independent, non- alkylating mechanism of cytotoxicity for estramwtime. Urol. Res., 16 155, 1987.

26. Sullivan, L., Gleave, M., Goldenberg, L., Bruchovsky, N. and Jones, E. C.: Long-term neoadjuvant hormonal therapy prior to radical prostatectomy in iocalized prostate cancer. J. Urol., part 2,161: 4354 abstract 831,1994.

27. Watanabe, H., Ohe, H., h d o , K, Sawamura, Y., Niiyima, T., Nakamura, S., Orikasa, S., Tanahashi, Y., Imamura, K. and Yoshida, H.: The effect of estramustine phosphate on prostatic cancer estimated by transrectal dtrasonotomanraDhv. Pros- - _ - tate, 2 155,1981.

28. Osafune. M.. Seike, H.. Ishibashi, M., Matauda. M. and Kotake. T.: &'tologic observation on influences of Estkcyt on pmsta& cancer. Acta Urol. Jap., 24.429, 1978.

434

29. Van de Voorde, W. M., Elgamal, A. A,, Van Poppel, H. P., Verbeken, E. K., Baert, L. V. and Lauweryns, J. M.: Morpho- logical and immunohistmhemical changes in prostate cancer following preoperative hormonal therapy. A comparative B. Saunders Co., vol. 2, chapt. 29, pp. 1159-1221, 1992. study in radical prostatectomies. Cancer, 74: 3164, 1994.

30. Agardh, C.-D., Nillson-Ehle, P., Lundgren, R. and Gustafson, A.: The influence of treatment with estrogens and estramustine Phosphate on Platelet agtPgation and Plasma IiPoProteins in non-disseminated prostatic carcinoma. J. Urol., 132: 1021, 1984.

31. De Voogt, H. J., Smith, P. H., Pavone-Macaluso, M., De Pauw, M. and Suciu, S.: Cardiovascular side effects of diethylstilbestrol, (Wmterone acetate, me*oX3'Progesterone acetate and estra- mustine phosphate used for the treatment of advanced pros- tatic cancer: results from European Organization for Research on Treatment of Cancer Urological Group trials 30761 and 30762. J. Urol., 135: 307, 1986.

32, collaborative overview of randomized trials of antiplatelet ther- apy 111. Reduction in venous thrombosis and pulmonary em- bolism by antiplatelet prophylaxis among surgical and medical

Antiplatelet ~ r i ~ l i ~ ~ ' Collaboration, ~ r i ~ , Med. J,, 308: 235, 1994.

33. Kojima, M., Watanabe, H., Ohe, H., Miyashita, H. and Inaba, T.: Kinetic evaluation of the effect of LHRH analog on prostate cancer using transrectal ultrasonotomography. Prostate, 1 0 11, 1987.

34. Peters, C. A. and Walsh, P. C.: The effect of nafarelin acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia. New Engl. J. Med., 311: 599, 1987.

NEOADJWANT HORMONAL THERAPY BEFORE RADICAL PROSTATECTOMY

35. Stamey, T. A. and McNeal, J. E.: Adenocarcinoma of the pros- tate. In: Campbell's Urology, 6th ed. Edited by P. C. Walsh, A. B. Retik, T. A. Stamey and E. D. Vaughan. Philadelphia: W.

36. Van den Ouden, D., Davidson, P. J. T., Hop, W. and Schroder, F. H.: Radical prostatectomy as a monotherapy for locally advanced (stage T3) prostate cancer. J. Urol., 151: 646, 1994.

37. Schiebler, M. L., Tomaszewski, J. E., Bezzi, M., Pollack, H. M., Kressel, H. Y., Cohen, E. K., Altman, H. G., Geffer, W. B., Wein, A. J. and Axel, L.: Prostatic carcinoma and benign prostatic hyperplasia: correlation of high-resolution MR and histopathologic findings. Radiology, 172 131, 1989.

38. Epstein, J. I. and Steinberg, G. D.: The significance of low-grade prostate cancer on needle biopsy. A radical prostatectomy study of tumor grade, volume, and stage of the biopsied and multifocal tumor. Cancer, 66: 1927, 1990.

logic findings with progression after radical retropubic pros- tatectomy. Cancer, 71: 3582, 1993.

39. Epstein, J. I., Pizov, G. and Walsh, P. C.: Correlation of patho-

40. Walsh, P. C.: Editorial comment. J. Urol., 150: 269, 1993. 41. Gobet, D. A,, Knonagel, H. and Hauri, D.: Endocrine treatment

prior to radical retropubic prostatectomy in patients with T3 prostate cancer: a retrospective study of 22 patients. Urol. Int., 49 141, 1992.

42. Partin, A. W., Borland, R. N., Epstein, J. I. and Brendler, C. B.: Influence of wide excision of the neurovascular bundle(s) on prognosis in men with clinically localized prostate cancer with established capsular penetration. J. Urol., 150 42, 1993.


Recommended