PREDICTORS OF PATHOLOGICAL STAGE BEFORE NEOADJUVANT ANDROGEN WITHDRAWAL THERAPY AND RADICAL PROSTATECTOMY

Purpose

This prospective randomized trial was used to compare predictive factors for organ confined margin negative status after radical prostatectomy with and without a 3-month course of neoadjuvant androgen withdrawal therapy.

Materials and Methods

A total of 213 patients with localized adenocarcinoma of the prostate were randomized to radical prostatectomy with or without a 3-month course of 300 mg. neoadjuvant cyproterone acetate daily. Multivariate logistic regression analysis was used to determine significant predictors of organ confined margin negative status after radical prostatectomy in both groups. Parameters evaluated included baseline prostate specific antigen (PSA 4 or less, 4.1 to 10, greater than 10 ng./ml.), clinical stage (T2c versus T2b or less), biopsy Gleason score and percentage of surface area of biopsies involved with cancer. The multivariate analysis was repeated with PSA density and the natural logarithm of PSA to optimize the model.

Results

In the radical prostatectomy alone arm a model incorporating only PSA density was the best predictor of organ confined margin negative status. In the neoadjuvant androgen withdrawal therapy arm a model incorporating biopsy Gleason score, PSA density and clinical stage was the best predictor.

Conclusions

The conventional predictors of pathology at radical prostatectomy, biopsy Gleason score, PSA density and clinical stage retain significance as predictors in patients treated with a 3-month course of neoadjuvant androgen withdrawal therapy before radical prostatectomy.     

ANDROGEN DEPRIVATION WITH SALVAGE SURGERY FOR RADIORECURRENT PROSTATE CANCER: RESULTS AT 5-YEAR FOLLOWUP

Purpose

We studied the effect of the combination of androgen deprivation with salvage surgery in patients with radiorecurrent prostate cancer.

Materials and Methods

Salvage cystoprostatectomy or radical prostatectomy was performed in 29 patients with radiorecurrent prostate cancer. Of the 29 patients 24 had been treated with neoadjuvant hormonal therapy before salvage surgery, while in 5 an initial trial of androgen deprivation had failed preoperatively.

Results

The positive surgical margin rate for all patients was 31%. Margin involvement correlated strongly with disease specific and disease-free survival. At a mean followup of 5.3 years disease specific survival was 95% in men with negative surgical margin compared with 44% in those with positive surgical margins (p = 0.002). Similarly, clinical and biochemical disease-free survival was 80% in patients with negative surgical margins, while only 44% of those with positive surgical margins remained disease-free (p = 0.05). Surgical margins were positive in 80% of the men in the androgen deprivation failure group and in 21% in the neoadjuvant hormonal therapy group (p = 0.001). The disease specific survival rate after an initial trial of androgen deprivation failed was only 20% compared with 92% after neoadjuvant hormonal therapy was given preoperatively (p = 0.001).

Conclusions

The combination of neoadjuvant hormonal therapy with salvage surgery for radiorecurrent prostate cancer resulted in a low incidence of surgical margin involvement, which correlated strongly with disease specific and disease-free survival. Patients with radiorecurrent prostate cancer in whom an initial trial of androgen deprivation fails appear to be poor candidates for salvage prostatectomy.     

RADICAL PROSTATECTOMY FOR PROSTATE CANCER: THE PERINEAL APPROACH INCREASES THE RISK OF SURGICALLY INDUCED POSITIVE MARGINS AND CAPSULAR INCISIONS

Purpose

We compare the incidence of positive surgical margins in patients who underwent perineal or retropubic radical prostatectomy for clinically localized (stage T1, T2) prostate cancer.

Materials and Methods

In this retrospective, nonrandomized study we reexamined the specimens of 94 consecutive patients who underwent radical perineal (48) or retropubic (46) prostatectomy for clinically localized prostate cancer (stage T1, T2) and with pathological stage pT2 (intracapsular), pT3A (established extracapsular extension without positive margins) or pT3B (extracapsular extension with positive margins) without lymph node involvement (N0). We assessed the presence or absence of extracapsular cancer with or without positive margins, incisions of the prostatic capsule exposing cancer (surgically induced positive margins) or benign glandular tissue. Patients were followed for 3 to 66 months (mean 25) using an ultrasensitive prostate specific antigen assay with a lower detection limit of less than 0.05 ng./ml.

Results

The overall incidence of positive margins in cancer tissue was 56% in the perineal and 61% in the retropubic group, and biochemical failure-free survival was 67% each. However, surgically induced positive margins in patients with organ confined disease were more frequent in the perineal than retropubic group (43 versus 29%, p <0.05) and associated with a 37% risk of biochemical failure (prostate specific antigen greater than 0.1 ng./ml.) at mean followup. In addition, capsular incisions exposing benign tissue were more frequent in the perineal than retropubic group (90 versus 37%, p <0.05) irrespective of pathological stage.

Conclusions

Although overall positive margins and biochemical failure rates are similar or identical for the perineal and retropubic approaches for organ confined prostate cancer, the perineal approach is associated with a significantly higher risk of capsular incisions and surgically induced positive margins and, thus, a higher risk of biochemical failure.     

Postoperative Radiotherapy for Stage pT3 Carcinoma of the Prostate: Improved Local Control

Purpose

We determined whether radiotherapy after radical prostatectomy leads to improved results in patients with stage pT3 carcinoma of the prostate.

Materials and Methods

In a prospective nonrandomized study of 203 patients with clinical stage T2 prostate cancer treated with radical prostatectomy 88 underwent surgery alone, 89 received early postoperative radiotherapy generally because of pathological stage T3 disease and 26 received delayed radiotherapy for local recurrence. The disease was stage pT3N0/X in 135 patients.

Results

For patients with pathological stage T3 cancer actuarial local recurrence rates were significantly decreased in the early postoperative radiotherapy group compared to the surgery only group (p = 0.005), while actuarial metastatic rates (p = 0.6) and cause specific survival rates (p = 0.04) were not significantly different. Multivariate analysis for all patients in both groups identified adverse features of increased postoperative prostate specific antigen levels, seminal vesicle involvement, lack of postoperative radiotherapy and positive lymph nodes. Late toxicity was severe (Radiation Therapy Oncology Group grade 3 or 4) in 13 surgery only and 17 early postoperative radiotherapy group patients. Of those who were potent postoperatively the incidence of impotence in the early postoperative radiotherapy group was 89 percent compared to 59 percent in the surgery only group (p = 0.003). For patients treated with delayed radiation for clinical local recurrence the actuarial local control rate was 54 percent after 10 years.

Conclusions

Local radiotherapy appears to improve local control of stage pT3 cancer but has no impact on overall survival.     

Randomized Study of Neoadjuvant Testicular Androgen Ablation Therapy Before Radical Prostatectomy in Men with Clinically Localized Prostate Cancer

Purpose

We determined whether 12 weeks of neoadjuvant testicular androgen ablation therapy using a luteinizing hormone-releasing hormone agonist could improve pathological outcomes in men undergoing radical retropubic prostatectomy for clinically localized (stages T1C, T2A and T2B) prostatic carcinoma.

Materials and 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) or 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 was no improvement in pathological outcome using a luteinizing hormone-releasing hormone agonist preoperatively compared to surgery alone. Of 28 men undergoing immediate radical retropubic prostatectomy 23 had organ-confined (17) or specimen-confined (6) disease versus 22 of 28 who received luteinizing hormone-releasing hormone neoadjuvant therapy 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 (10 ng./ml. or less, or greater than 10 ng./ml.) there was also no difference in pathological outcome (p = 0.65 for PSA greater than 10 and 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 in improved pathological outcomes.     

Impalpable Invisible Stage T1c Prostate Cancer: Characteristics and Clinical Relevance in 100 Radical Prostatectomy Specimens-A Different View

Purpose

We analyzed 100 consecutive radical prostatectomy specimens to evaluate the extent and clinical relevance of the stage T1c cancers discovered.

Materials and Methods

All cases were diagnosed by systematic prostatic puncture biopsies because of abnormal prostate specific antigen (PSA) or PSA density. Surgical specimens were examined with the whole organ multiple step-section technique (4 mm.) to identify primary tumor location (peripheral or transition zone cancer), tumor volume, tumor volume divided by prostate volume (percent tumor volume), Gleason score, pathological T stage and positive surgical margins. Tumors smaller than 0.5 cm.³ and without unfavorable pathology (Gleason score 7 or more, or positive surgical margins) were considered insignificant.

Results

Median patient age, PSA, tumor volume and Gleason score were 64 years, 8.8 micro g./l., 1.6 cm.³ and 6, respectively. Of the specimens 46 (46%) had transition zone cancer that was clinically undetectable due to anterior location, while peripheral zone cancers were small, diffuse, anterolateral or in large glands with low percent tumor volume. Transition zone cancer showed greater PSA, PSA density, tumor volume and percent tumor volume than peripheral zone cancer (p = 0.08, 0.03, 0.0002 and 0.0004, respectively), yet with similar Gleason score (p = 0.4). Of the tumors 34 (34%) were locally advanced (stage pT3 and/or positive surgical margins, mostly anterior in 16 transition zone cancers, and apical or posterolateral in 18 peripheral zone cancers), whereas 22 were insignificant (6 transition and 16 peripheral zone cancers). Prostatic puncture biopsies with a core cancer length of less than 3 mm. could have predicted 18 of 19 insignificant tumors but underestimated 13 (33%) and 6 (17%) significant transition and peripheral zone cancers.

Conclusions

The majority of our stage T1c tumors were significant with a distinguished high incidence of transition zone cancer. Therefore, they were large but occult. Transition zone cancer behaved differently than peripheral zone cancer, and warranted considerations during treatment of stage T1c prostate carcinoma.     

Free-to-Total Prostate Specific Antigen Ratio as a Single Test for Detection of Significant Stage T1c Prostate Cancer

Purpose

We investigated whether impalpable, invisible (stage T1c) but significant prostate cancer can be detected better by determining the free-to-total prostate specific antigen (PSA) ratio of equivocal PSA serum levels.

Materials and Methods

The specificity of free-to-total PSA ratio using research monoclonal enzyme immunoassays was compared to that of PSA greater than 4.0 ng./ml. in 117 consecutive patients with PSA 3 to 15 ng./ml. (Hybritech Tandem-R assay) due to untreated benign prostatic hypertrophy or prostate cancer. Of the patients 77 percent underwent adenectomy or radical prostatectomy with thorough pathological evaluation of surgical specimens.

Results

Benign prostatic hypertrophy had a greater median free-to-total PSA ratio than stages T1c and T2 or greater prostate cancer (0.16 versus 0.09 and 0.11 ng./ml., p = 0.0001 and p = 0.0268, respectively). In stage T1c prostate cancer, areas under receiver operating characteristic curves were 0.58 and 0.84 for PSA and free-to-total PSA ratio, and free-to-total PSA ratio correlated with prostate volume (r = 0.49, p = 0.005) and Gleason score (r = -0.37, p = 0.036). Pathologically, 84 percent of stage T1c cancers were significant and comparable to stage T2 or greater cancers.

Conclusions

Free-to-total PSA ratio enhances the efficacy of PSA measurement by improving specificity for detecting impalpable, invisible but significant stage T1c prostate cancer.     

Pathological Characteristics and Prognosis of Nonpalpable and Palpable Prostate Cancers with a Hybritech Prostate Specific Antigen of 4 to 10 ng./ml

Purpose

We compared the surgical pathological findings and postoperative course of patients with palpable and nonpalpable prostate cancers.

Materials and Methods

All patients with untreated prostate specific antigen (PSA) 4 to 10 ng./ml. who underwent radical prostatectomy between December 1984 and December 1993 were reviewed to select 61 with clinical stage T1c (nonpalpable) and 209 with stages T2a to c (palpable) disease.

Results

Nonpalpable cancers were smaller (2.99 versus 4.42 cc for palpable tumors), had smaller volumes of Gleason grade 4 or 5 cancer (0.66 versus 1.32 cc, respectively) and were less likely to have positive surgical margins (13 versus 22 percent, respectively) or significant (1 cm. or more) capsular penetration (10 versus 26 percent, respectively). Nonpalpable and palpable cancers had similar rates of seminal vesicle invasion (3.3 versus 4.3 percent, respectively) and positive lymph nodes (1.6 versus 0 percent, respectively). More than 90 percent of patients with nonpalpable cancer were biochemically cancer-free postoperatively, and the remainder were alive with disease after a mean followup of 25.1 months, compared to 69 percent disease-free, 28 percent alive with disease and 2.5 percent dead of prostate cancer after a mean followup of 43.8 months among those with palpable disease.

Conclusions

We conclude that nonpalpable prostate cancers are pathologically more favorable than palpable prostate cancers with PSA 4 to 10 ng./ml. Our preliminary results also indicate that nonpalpable cancers are less likely to recur postoperatively than palpable cancers with a similar PSA range.     

HORMONAL TREATMENT BEFORE RADICAL PROSTATECTOMY: A 3-YEAR FOLLOWUP

Purpose

Hormonal treatment administered before radical prostatectomy has been shown to decrease the rate of positive surgical margins. We determine whether preoperative hormonal treatment has any impact on the subsequent failure rate.

Materials and Methods

We prospectively evaluated 122 patients with stages T1bNxM0 to T3aNxM0, grades 1 to 3 prostate cancer, including 64 randomly assigned to immediate radical retropubic prostatectomy and 58 randomly assigned to radical retropubic prostatectomy preceded by 3 months of pretreatment with a gonadotropin-releasing hormone agonist. We performed intention to treat analysis on the data with failure defined as lymph node involvement, serum prostate specific antigen greater than 0.5 ng./ml., or the need for postoperative hormonal or radiation adjuvant treatment.

Results

The positive margin rate was 23.6 versus 45.5% in the pretreatment plus prostatectomy versus prostatectomy only groups (p = 0.016). There were 20 failures (34.5%) in the pretreatment plus prostatectomy subgroup and 26 (40.6%) in the prostatectomy only group (p = 0.48). A negative surgical margin was associated with a significantly lower risk of progression than a positive surgical margin (20.8 versus 50.0%, p = 0.0016), and progression was delayed by approximately 1 year after hormonal pretreatment. However, at a median followup of 38 months there was no difference in progression-free survival (p = 0.57).

Conclusions

Although hormonal pretreatment significantly decreased the positive margin rate, it did not result in any difference in progression-free survival when followup exceeded 3 years. Thus, our current results do not support the routine administration of hormonal treatment before radical prostatectomy.     

PROGNOSTIC IMPLICATIONS OF A POSITIVE APICAL MARGIN IN RADICAL PROSTATECTOMY SPECIMENS

Purpose

We evaluated the prognostic implication of a positive surgical margin at the prostatic apex to define the risk of failure after radical prostatectomy.

Materials and Methods

Radical prostatectomy specimens of 590 patients operated on between 1990 and 1994 were reviewed by 2 uropathologists (D. G. and W. S.) to determine the percentage of patients with a positive margin at the apex in the absence of positive margins, extraprostatic extension or involvement of seminal vesicles and pelvic lymph nodes. In this group of 33 patients, the significance of a positive apex could be determined without the influence of any other stage related prognostic factors. Treatment failure was defined as prostate specific antigen greater than 0.4. All 33 patients have been followed between 3.5 and 65.5 months (median 38.7).

Results

Among 590 patients 236 (40%) had disease completely confined to the prostate. A total of 217 patients (37%) had either positive surgical margins (M+) or extraprostatic extension and of these, only 33 (5.5%) had an apical positive margin in an otherwise prostate confined tumor. Of 33 apical positive margin patients only 3 in whom surgery failed had a progressively detectable prostate specific antigen 3.5 to 65.5 months after surgery.

Conclusions

A positive surgical margin at the prostatic apex in the absence of positive margins or extraprostatic extension elsewhere does not confer a worse prognosis than organ confined disease. In this study the recurrence rate for patients with positive apical margins was the same as for those with confined disease.     

THE USE OF PERCENT FREE PROSTATE SPECIFIC ANTIGEN FOR STAGING CLINICALLY LOCALIZED PROSTATE CANCER

Purpose

The free-to-total serum prostate specific antigen (PSA) ratio (percent free PSA) has been demonstrated to have clinical use for early detection of men with prostate cancer with total PSA levels between 4.0 and 10.0 ng./ml. Several studies evaluating the usefulness of percent free PSA for the staging of clinically localized prostate cancer have provided conflicting results. We further investigate the usefulness of percent free PSA for staging of clinically localized prostate cancer.

Materials and Methods

In 263 men with clinically localized prostate cancer who underwent radical prostatectomy total PSA and free PSA were measured preoperatively. Pathological stages were classified as organ confined in 134 cases, capsular penetration in 92, seminal vesicle involvement in 7, involvement of the surgical margins in 20 and lymph node involvement in 10.

Results

Percent free PSA was significantly different between men with organ confined versus nonorgan confined tumors (p <0.0001) and between those with favorable versus unfavorable pathology (p <0.0001). A cutoff of 12% free PSA provided a 72% positive predictive value and 52% negative predictive value for favorable pathology. A cutoff of 15% free PSA provided a 76% and 53% positive and negative predictive value, respectively, for organ confined disease.

Conclusions

These data demonstrate that the use of percent free PSA may be of additional value for the staging of clinically localized prostate cancer. The recommendations for cutoff levels of percent free PSA for detection and staging of localized prostate cancer are preliminary and can only be given for this particular assay. A large multicenter trial, controlling for age, stage and grade distribution, as well as for a uniform pathological evaluation and comparable total and free PSA assays, is required to elucidate this issue further.     

Ki-67 Expression is a Prognostic Marker of Prostate Cancer Recurrence after Radical Prostatectomy

Purpose

We assessed the cellular proliferation of clinically localized prostate cancer by immunohistochemistry using the monoclonal antibody MIB to Ki-67 antigen in an attempt to identify associations between proliferative indexes and disease progression following radical prostatectomy.

Materials and Methods

Ki-67 proliferative antigen was evaluated using MIB 1 monoclonal antibody in archival paraffin embedded radical prostatectomy specimens from 180 patients followed for 1 to 9 years (mean 4.4). The percentage of tumor nuclei expressing Ki-67 antigen was measured and assigned an MIB 1 score (none or rare-negative, 1+-low score and 2 to 4+-high score) and analyzed for prostate specific antigen, stage, age, race, grade and serological recurrence postoperatively.

Results

There was a significant association between MIB 1 score and nuclear grade (p less than 0.001), Gleason score (p less than 0.001) and pathological stage (p = 0.01). Patients with a high MIB 1 score had earlier progression and a lower 5-year recurrence-free survival rate (44 percent) than those with negative MIB 1 scores (71 percent, p less than 0.001). In multivariate Cox regression analysis with backward elimination, pathological stage (p less than 0.01), pretreatment prostate specific antigen (p = 0.04) and MIB 1 score (p = 0.05) were statistically significant predictors of disease-free survival, and patients with a high MIB 1 score were 3.1 times as likely to have recurrence as those with a negative score. Controlling for stage, patients with organ confined disease and a high MIB 1 score had a lower 5-year disease-free survival rate (68 percent) than those with a low MIB 1 score (95 percent, p greater than 0.01).

Conclusions

Proliferative activity as measured by the Ki-67 proliferative antigen, MIB 1, appears to be a prognostic marker of recurrent prostate cancer after radical prostatectomy.     

Do Close but Negative Margins in Radical Prostatectomy Specimens Increase the Risk of Postoperative Progression?

Purpose

When tumor extends close to the margin of resection yet does not extend to the inked edge of the gland, it is unclear whether patients have an adverse prognosis compared to cases with greater distance between the tumor and margin.

Materials and Methods

Among radical prostatectomy specimens with negative margins the distance between the most peripheral tumor and the surgical margin of resection was measured in 52 cases with and 49 without progression. All patients had clinically confined disease (stages T1 or T2) with subsequent progression or a minimum 5-year followup without evidence of disease. No patient received preoperative or postoperative radiotherapy or hormonal therapy until progression occurred. All men underwent a postoperative serum prostate specific antigen test to evaluate progression. Seminal vesicles and lymph nodes were pathologically free of tumor. All prostates were serially sectioned, completely embedded and assessable regarding margins of resection.

Results

Patients with progression were no more likely to have tumor close to the margin than those without progression. In a regression analysis analyzing the effect of Gleason score, distance between tumor and margin, location of closest margin and pathological stage as related to progression, only grade was predictive of progression (p <0.00001).

Conclusions

It is not necessary for pathologists to designate these margins as close, since biologically this finding has no significance. Furthermore, physicians who are involved in treatment of patients after radical prostatectomy for prostate cancer should not alter therapy depending on whether margins are reported as close.     

Resistance to Apoptosis and Up Regulation of Bcl-2 In Benign Prostatic Hyperplasia After Androgen Deprivation

Purpose

Benign prostatic hyperplasia (BPH) is related to advancing age and the presence of androgens and occurs in virtually all older men. BPH causes morbidity, most often by urinary obstruction, in a substantial fraction of men over sixty. Both finasteride and androgen ablation induce partial diminution in BPH that occurs over weeks to months. This is in contrast to the often rapid involution seen in both normal prostatic epithelium and prostatic carcinoma in response to androgen withdrawal. This study was performed to analyze the response of prostatic cells, and in particular BPH, to acute androgen ablation.

Materials and Methods

We subjected a cohort of 26 men to androgen ablation with goserelin, a gonadotrophin releasing hormone agonist, for 3-4 weeks prior to radical prostatectomy for prostate cancer. Preablation biopsy specimens and prostatectomy specimens were immunohistochemically stained for apoptotic cells and for expression of apoptosis regulatory proteins Bcl-2, Bax, Bcl-x, and Bak.

Results

Normal prostatic epithelial cells and prostate cancer responded to hormone deprivation by undergoing apoptosis, but in 19/26 specimens prostatic hyperplasia had a total absence of apoptosis. In all 26 specimens, benign prostatic hyperplasia demonstrated increased expression of the Bcl-2 protein, but no change in the expression of Bax, Bcl-x, and Bak. In contrast, adjacent normal and malignant prostatic epithelium showed positive staining for apoptosis and did not alter Bcl-2 expression in response to androgen ablation.

Conclusions

BPH demonstrated increased staining for Bcl-2 after androgen deprivation that may render hyperplastic epithelium relatively resistant to apoptosis induced acutely by androgen withdrawal.     

Malignant Cytological Washings from Radical Prostatectomy Specimens: A Possible Mechanism for Local Recurrence of Prostate Cancer Following Surgical Treatment of Organ Confined Disease

Purpose

Local recurrence of prostate cancer following complete and successful resection of organ confined disease has been variably reported in men. We hypothesized that observed secretions from the cut distal urethra during radical prostatectomy may contain malignant prostatic epithelial cells and contribute to this problem.

Materials and Methods

A prospective study was done of prostate cytology specimens from 50 consecutive men with clinically organ confined adenocarcinoma of the prostate undergoing radical retropubic or radical perineal prostatectomy. Direct cytological evaluation by 1 examiner was used to identify malignant or benign cells in these washings.

Results

Of 33 radical perineal and 17 radical retropubic prostatectomy specimens organ confinement was confirmed in 58 percent. Malignant prostatic epithelial cells were observed in 24 percent of all cytology specimens. Of cytological washings from prostates with pathologically confirmed organ confined cancers 17 percent showed malignant cells. While perineural invasion was noted in a majority of tumors with positive washings, only Gleason grade was a statistically significant predictor of recurrence (p = 0.009). Surgical approach did not alter the rate of positive cytology.

Conclusions

Malignant prostatic epithelial cells can be identified in the prostatic washings from men with pathologically organ confined prostate cancer. Surgical approach did not change the cytological findings. Gleason grade is a statistically significant predictor of cytological malignancy. These cells may represent a mechanism of failure following successful radical prostatectomy.     

SURGICAL MODIFICATIONS OF RADICAL RETROPUBIC PROSTATECTOMY TO DECREASE INCIDENCE OF POSITIVE SURGICAL MARGINS

Purpose

We sought to determine whether recent surgical modifications in the technique of radical retropubic prostatectomy decrease the incidence of positive surgical margins.

Materials and Methods

We reviewed the records of 144 consecutive patients a mean of 60.8 years old who underwent radical retropubic prostatectomy using a modified surgical technique. Mean prostate specific antigen was 8.6 ng./ml. and mean Gleason grade was 5.8. Surgical modifications included division of the dorsal venous complex of the penis 10 to 15 mm. distal to the prostatic apex; transection of the urethra 3 mm. beyond the prostatic apex; division of the anterior aspect of the urethra, leaving the investing periurethral musculature intact, and division of the posterior aspect of the urethra en bloc with the striated urethral sphinter; sharp dissection of the rectourethralis muscle and remaining attachments of the prostate to the rectum; wide excision of the neurovascular bundle posterolateral to the prostate when adjacent induration or tumor is present, and division of the bladder neck, leaving a 5 mm. cuff of bladder tissue with the prostate.

Results

Of 144 consecutive patients 16 (11.1%) had positive surgical margins at a total of 20 sites, including 7 (35%) at the apex, 8 (40%) posterolateral, 3 (15%) anterior and 2 (10%) at the bladder neck. These results compare favorably with the positive surgical margin rates after radical prostatectomy previously reported in the literature.

Conclusions

These surgical modifications appear to have decreased the incidence of positive surgical margins after radical retropubic prostatectomy.     

LONG-TERM OUTCOME IN PATIENTS WITH pTxN+ ADENOCARCINOMA OF PROSTATE TREATED WITH RADICAL PROSTATECTOMY AND EARLY ANDROGEN ABLATION

Purpose

We assessed retrospectively the outcome after bilateral pelvic lymphadenectomy and radical prostatectomy for pathological pTxN+ adenocarcinoma of the prostate when treated with or without adjuvant androgen ablation therapy.

Materials and Methods

A total of 790 men treated with radical prostatectomy for prostatic adenocarcinoma were found to have pTxN+ disease and treated further with or without androgen ablation therapy. Mean patient age was 64 years (range 40 to 79). Mean followup was 6.5 years, (range up to 25). Clinical stages were T2 or less in 60% of the cases, T3 in 38% and N+ in 2%. Gleason scores were 6 or less in 31% and 7 or greater in 69%. Deoxyribonucleic acid ploidy was diploid in 43%, tetraploid in 39% and aneuploid in 18%. Of the patients 96 (12%) received no androgen ablation therapy, with the remainder getting ablation therapy within 90 days of radical prostatectomy.

Results

Of the patients 186 (24%) died, with 109 (14%) dying of prostatic anedocarcinoma. Overall (and cause specific) survival probabilities at 5, 10 and 15 years were 87 (91), 69 (79) and 39% (60%), respectively. Patients with diploid tumors had better cause specific survival than those with nondiploid tumors (p = 0.009). Patients with diploid tumors were less likely to have progression biochemically, locally or systematically than those with nondiploid tumors (p = 0.038). Androgen ablation therapy had no effect on cause specific survival in nondiploid patients. Diploid patients treated with androgen ablation therapy for up to 10 years had no improvement in disease specific survival compared to those with no androgen ablation therapy. However, cancer death was significantly reduced after 10 years (p <0.002). The local control rate of pTxN+ cases that receive radical prostatectomy and androgen ablation therapy at 15 years is virtually identical to that of stage pT2c cases at our institution (79 +/− 3.0 versus 80% +/− 3.5%, respectively). There were no deaths secondary to radical prostatectomy, and complications were within the experience of that seen in patients with localized disease.

Conclusions

Radical prostatectomy with androgen ablation therapy is a viable option for patients with pTxN+ disease, particularly in view of excellent local control rates and low morbidity. Patients with diploid tumors have a more favorable outcome than those with nondiploid tumors when treated with androgen ablation therapy.     

Clinical Efficacy of Bone Alkaline Phosphatase and Prostate Specific Antigen in the Diagnosis of Bone Metastasis in Prostate Cancer

Purpose

We investigated the usefulness of bone alkaline phosphatase isoenzyme and prostate specific antigen (PSA) determined by radioimmunoassay to predict bone scan evidence of metastasis in newly diagnosed untreated and treated prostate cancer.

Materials and Methods

We analyzed bone alkaline phosphatase enzyme concentrations in 350 men, including 150 controls, 100 with benign prostatic hyperplasia and 100 with prostate cancer (52 with stage T1 to 4, M0 and 48 with stages T1 to 4, M1 to 4). We also analyzed bone alkaline phosphatase enzyme concentrations in 61 stages T1 to 4, M0 prostate cancer cases during followup after radical prostatectomy or hormonal therapy, and 17 had clinical progression (9 with local, 5 with lymph node and 3 with bone metastases). Simultaneously, we analyzed PSA concentrations.

Results

Average bone alkaline phophatase enzyme levels were 12, 11.1 and 10.0 ng./ml. in the control, benign prostatic hyperplasia and stage M0 prostate cancer groups, respectively (p not significant), and 83.2 ng./ml. in patients with stage M1 to 4 disease (p less than 0.001). Considering that to diagnose bone metastasis the cutoff for bone alkaline phosphatase enzyme and PSA is 30 ng./ml. and 100 ng./ml., respectively, clinical effectiveness was 93.7 percent and 81.8 percent, respectively. Finally, measurement of both substances at the same time increased clinical effectiveness to 97.9 percent. During followup a bone alkaline phosphatase enzyme level that becomes greater than 30 ng./ml. (0 percent in the local and lymphatic progression groups, and 100 percent in the bone metastasis group) indicates the need to perform a bone scan.

Conclusions

We recommend the clinical use of bone alkaline phosphatase enzyme determined by radioimmunoassay and PSA measurement for the diagnosis of bone metastases and progression of prostate cancer because of the good sensitivity and specificity.     

LOW P27 EXPRESSION PREDICTS POOR DISEASE-FREE SURVIVAL IN PATIENTS WITH PROSTATE CANCER

Purpose

p27 is an inhibitor of the cell cycle with potential tumor suppressor function. Decreased levels of p27 protein expression have been correlated with poor prognosis in patients with breast and colorectal carcinomas. Although as many as a third of patients with clinically localized prostate cancer will have relapse after radical prostatectomy, predicting who will have recurrence remains enigmatic. We examined the ability of p27 protein levels to predict outcome in patients with clinically localized disease who underwent radical prostatectomy.

Materials and Methods

p27 protein expression was evaluated in 86 patients with clinical stage T1-2 prostate cancer who were treated with radical prostatectomy. Archived paraffin embedded specimens were sectioned and immunostained with p27 antibody, and scored by 2 independent observers in a blinded fashion. The absence or presence of p27 protein was then correlated with biochemical relapse in univariate and multivariate analyses.

Results

In a multivariate analysis that included age, preoperative prostate specific antigen, Gleason score and pathological stage p27 was a strong independent predictor of disease-free survival (p = 0.0184, risk ratio 3.04), second only to pathological stage (p = 0.0001, risk ratio 6.73). Even more strikingly, multivariate analysis demonstrated that p27 was the strongest predictor of biochemical recurrence (p = 0.0081, risk ratio 4.99) among factors studied in patients with pathological T2a-T3b disease.

Conclusions

Absent or low levels of p27 protein expression appear to be an adverse prognostic factor in patients with clinically organ confined disease treated by radical prostatectomy. This marker appears to be especially useful in those patients in whom surgery is believed to be potentially curative, that is patients with pathological T2-T3b disease. Patients with low or absent p27 protein expression may be candidates for novel adjuvant therapies.