Craig D. Zippe

Comparison of the Efficacy of Local Therapies for Localized Prostate Cancer in the Prostate-Specific Antigen Era: A Large Single-Institution Experience With Radical Prostatectomy and External-Beam Radiotherapy

PURPOSE To review biochemical relapse-free survival (bRFS) rates after either external-beam radiotherapy (RT) or radical prostatectomy (RP) for localized prostate cancer. PATIENTS AND METHODS All 1,682 patients had pretreatment prostate-specific antigen (PSA) levels and biopsy Gleason scores (bGS) assigned. No adjuvant therapy was administered after local treatment. RP was the treatment in 1,054 patients (63%) and RT in 628 patients (37%). Median follow-up was 51 months (range, 1 to 134). The median follow-up for RP versus RT patients was 50.5 v 51.0 months. Biochemical relapse was considered detectable PSA levels (> 0.2 ng/mL) in RP patients and three consecutive rising PSA levels in RT patients. The analysis was repeated with a more stringent definition of biochemical control after either RP or RT-namely, reaching and maintaining a PSA level < or = 0.5 ng/mL-and excluding patients receiving any androgen deprivation (AD). RESULTS Eight-year bRFS rates for RP versus RT were 72% and 70%, respectively (P =.010). Multivariate analysis indicated T stage (P <.001), pretreatment PSA (P <.001), bGS (P <.001), year of therapy (P <.001), and neoadjuvant AD (P =.019) to be the only independent predictors of relapse. Age (P =.78), race (P =.29), prior transurethral resection of prostate (P =.81), and treatment modality (P =.96) were not independent predictors of treatment failure. Fifty-one percent of RP patients had favorable tumors (T1 to T2A, pretreatment PSA < or = 10 ng/mL, bGS < or = 7), compared with only 34% of RT patients (P <.001). Repeat analysis with a stringent definition of biochemical failure and excluding patients receiving AD indicated no impact of treatment modality on outcome. CONCLUSION Eight-year biochemical failure rates were identical between RT and RP in any subgroup. Outcome is determined mainly by pretreatment PSA levels, bGS, clinical T stage, and, for RT patients, radiation dose.

Saturation Technique Does Not Improve Cancer Detection as an Initial Prostate Biopsy Strategy

PURPOSE We reported on the results of a sequential cohort study comparing office based saturation prostate biopsy to traditional 10-core sampling as an initial biopsy. MATERIALS AND METHODS Based on improved cancer detection of office based saturation prostate biopsy repeat biopsy, we adopted the technique as an initial biopsy strategy to improve cancer detection. Two surgeons performed 24-core saturation prostate biopsies in 139 patients undergoing initial biopsy under periprostatic local anesthesia. Indication for biopsy was an increased PSA of 2.5 ng/dl or greater in all patients. Results were compared to those of 87 patients who had previously undergone 10-core initial biopsies. RESULTS Cancer was detected in 62 of 139 patients (44.6%) who underwent saturation biopsy and in 45 of 87 patients (51.7%) who underwent 10-core biopsy (p >0.9). Breakdown by PSA level failed to show benefit to the saturation technique for any degree PSA increase. Men with PSA 2.5 to 9.9 ng/dl were found to have cancer in 53 of 122 (43.4%) saturation biopsies and 26 of 58 (44.8%) 10-core biopsies. Complications included 3 cases of prostatitis in each group. Rectal bleeding was troublesome enough to require evaluation only in 3 men in the saturation group and 1 in the 10-core group. CONCLUSIONS Although saturation prostate biopsy improves cancer detection in men with suspicion of cancer following a negative biopsy, it does not appear to offer benefit as an initial biopsy technique. These findings suggest that further efforts at extended biopsy strategies beyond 10 to 12 cores are not appropriate as an initial biopsy strategy.

Role of viagra after radical prostatectomy

OBJECTIVES To determine whether the response to sildenafil citrate (Viagra) in patients with erectile dysfunction after radical prostatectomy was influenced by the presence or absence of neurovascular bundles, the interval from surgery to the initiation of drug therapy, and the dose of the drug. METHODS Baseline and follow-up data from 91 patients presenting with erectile dysfunction after radical prostatectomy were obtained. The patients were stratified according to the type of nerve-sparing (NS) procedure: bilateral NS, unilateral NS, and non-NS. They were interviewed using the Cleveland Clinic Post Prostatectomy (CCPP) questionnaire and the International Index of Erectile Function (IIEF) questionnaire. RESULTS The presence or absence of the neurovascular bundles influenced the ability to achieve vaginal intercourse. In the patients who had undergone bilateral NS, 71.7% (38 of 53) responded; in those with unilateral NS, 50% (6 of 12) responded; and in those with non-NS, 15.4% (4 of 26) responded. The IIEF questionnaire confirmed the quality of the positive responses, with significant improvements in response to question 3 (frequency of penetration), question 4 (frequency of maintenance of erection), and question 7 (satisfaction with intercourse). The magnitude of improvement in responses was higher in the bilateral NS group than in the unilateral NS and non-NS groups (P <0.05). When the data of the 48 positive responders were analyzed, no difference in the response rate was found when the interval from surgery to drug therapy was stratified by the following three intervals: 0 to 6 months (44%), 6 to 12 months (55%), and greater than 12 months (53%). Of the positive responders, 14 (29.1%) required the 50-mg dose, and 34 (70.9%) required the 100-mg dose. The most common side effects were transient headaches (28.6%), flushing (21.9%), dizziness (8.8%), dyspepsia (6.5%), and nasal congestion (5.4%), with an increase in the incidence of headaches seen at the higher dose (P = 0.04). CONCLUSIONS Successful treatment of erectile dysfunction with sildenafil citrate after radical prostatectomy depends on the presence of the neurovascular bundles. Our data suggest that the response to sildenafil is not related to the interval between the surgery and initiation of drug therapy but is related to the dose.

Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer.

OBJECTIVES To better identify factors affecting prostate-specific antigen (PSA) level elevation after radical prostatectomy alone in men with clinical Stage T1-2 prostate cancer, we have reviewed our experience in the PSA era with 337 cases. The identification of these factors permits better understanding of the impact of case selection on treatment outcome in prostate cancer. METHODS The charts of all patients treated with radical prostatectomy alone between 1987 and 1993 were reviewed. Patients with clinical Stage T3 disease, without preoperative Gleason scores or PSA levels, with synchronous bladder cancer, and who received adjuvant or neoadjuvant therapy were excluded. The distribution of cases by pretreatment PSA levels was as follows: 4 ng/mL or less (16%); greater than 4 to 10 ng/mL (48%); greater than 10 to 20 ng/mL (22%); and greater than 20 ng/mL (14%). The median pretreatment PSA level for the entire group was 8 ng/mL. Only 26 patients (8%) had pathologically positive pelvic lymph nodes. The overall margin involvement rate was 43%. Margin involvement rates increased with increasing preoperative PSA levels. One hundred eighty-two patients (54%) had surgical Gleason scores of 7 or higher and 208 (62%) had extracapsular extension. The median follow-up time was 36 months. RESULTS The 3- and 5-year relapse-free survival (RFS) rates were 74% and 61%, respectively, with relapse being defined as either a clinically detectable recurrence or detectable/rising PSA levels. Among preoperative factors, PSA level was the only independent factor predicting relapse (P = 0.006); the 5-year RFS was 89% in patients with preoperative PSA levels of 4 ng/mL or less; 62% for PSA level of 4 to 10 ng/mL; 56% for PSA level to 10 to 20 ng/mL; and 26% for a PSA level greater than 20 ng/mL. Among pathologic parameters, margin involvement was the most potent independent factor predicting relapse (P < 0.001), followed by Gleason score (P = 0.002) and capsular penetration (P = 0.006). The 5-year RFS rates for margin-positive versus margin-negative patients were 37% versus 80%, respectively (P < 0.001). With pretreatment PSA levels of 10 ng/mL or less, lymph node involvement was seen in 3%, and margin involvement in 36%; the 5-year RFS rate was 71%. With pretreatment PSA levels of greater than 10 ng/mL, lymph node involvement was seen in 16%, and margin involvement in 57%; the 5-year RFS rate was 42%. However, patients with an initial PSA level greater than 10 ng/mL and positive margins had a 5-year RFS rate of 22% versus 73% in patients with a PSA level of 10 ng/mL or less or negative margins (P < 0.001). All clinical relapses were accompanied by a rise in PSA. In patients manifesting a clinical recurrence, PSA elevations preceded clinical recurrences by an average of 15 months (range 0 to 71). Only 34 cases (10%) had clinical failures within 5 years. CONCLUSIONS Pretreatment PSA is the most potent clinical factor independently predicting biochemical relapse. The great range in the relapse-free survival rates predicted by preoperative PSA levels demonstrates the importance of pretreatment PSA levels in case selection. Gleason score, extracapsular extension, and surgical margin involvement are also independent predictors of biochemical relapse. Achieving negative margins, even in relatively advanced disease, provides excellent long-term local control.

Treatment of erectile dysfunction after radical prostatectomy with sildenafil citrate (Viagra)

OBJECTIVES To determine whether the response to the new oral medication, sildenafil citrate (Viagra), was influenced by the presence or absence of the neurovascular bundles, as recent reports on its success did not specify the efficacy of the drug in patients with erectile dysfunction after radical prostatectomy. METHODS Baseline and follow-up data from 28 healthy patients presenting with erectile dysfunction after radical prostatectomy were obtained. Patients receiving any neoadjuvant/adjuvant hormones or adjuvant radiation therapy were excluded. Patients reported what their erectile status was before surgery, before sildenafil therapy, and after using a minimum of four doses of sildenafil. Both the patients and their spouses were interviewed using the Cleveland Clinic post-prostatectomy questionnaire, which includes questions about response to therapy, duration of intercourse, spousal satisfaction, side effects, and related topics. The patients were compared on the basis of the type of surgical procedure they had undergone-nerve sparing or non-nerve sparing. A positive response to sildenafil was defined as erection sufficient for vaginal penetration. RESULTS Of the 15 patients who had bilateral nerve-sparing procedures, 12 (80%) had a positive response to sildenafil, with a mean duration of 6.92 minutes of vaginal intercourse. These 12 patients also reported a spousal satisfaction rate of 80%. All 12 of the responders had a positive response within the first three doses, and 10 of the 12 responded with the first or second dose. None of the 3 patients who had undergone a unilateral nerve-sparing procedure responded, nor did any of the 10 patients who had undergone a non-nerve-sparing procedure. The two most common side effects of the drug were transient headaches (39%) and abnormal color vision (11%). No patients discontinued the medication because of side effects. CONCLUSIONS Successful treatment of erectile dysfunction in a patient after prostatectomy with sildenafil citrate may depend on the presence of bilateral neurovascular bundles. No patient who had undergone a non-nerve-sparing procedure responded. Whether patients who undergo unilateral nerve-sparing procedures will respond to sildenafil is still unclear because of the small number of patients in our study. These findings should encourage urologists to continue to perform and perfect the nerve-sparing approach. The ability to restore potency with an oral medication after radical prostatectomy will impact our discussion with the patient on the surgical morbidity of radical prostatectomy.

Early use of vacuum constriction device following radical prostatectomy facilitates early sexual activity and potentially earlier return of erectile function

To assess the efficacy of vacuum constriction devices (VCD) following radical prostatectomy (RP) and determine whether early use of VCD facilitates early sexual activity and potentially earlier return of erectile function. This prospective study consisted of 109 patients who underwent nerve-sparing (NS) or non-nerve-sparing (NNS) RP between August 1999 and October 2001 and developed erectile dysfunction following surgery. The patients were randomized to VCD use daily for 9 months (Group 1, N=74) or observation without any erectogenic treatment (Group 2, N=35). Treatment efficacy was analyzed by responses to the Sexual Health Inventory of Men (SHIM) (abridged 5-item International Index of Erectile Function (IIEF-5)), which were stratified by the NS status. Patient outcome regarding compliance, change in penile length, return of natural erection, and ability for vaginal intercourse were also assessed. The mean patient age was 58.2 years, and the minimum follow-up was 9 months. Use of VCD began at an average of 3.9 weeks after RP. In Group 1, 80% (60/74) successfully used their VCD with a constriction ring for vaginal intercourse at a frequency of twice/week with an overall spousal satisfaction rate of 55% (33/60). In all, 19 of these 60 patients (32%) reported return of natural erections at 9 months, with 10/60 (17%) having erections sufficient for vaginal intercourse. The abridged IIEF-5 score significantly increased after VCD use in both the NS and NNS groups. After a mean use of 3 months, 14/74 (18%) discontinued treatment. In Group 2, 37% (13/35) of patients regained spontaneous erections at a minimum follow-up of 9 months after surgery. However, only four of these patients (29%) had erections sufficient for successful vaginal intercourse and rest of patients (71%) sought adjuvant treatment. Of the 60 successful users, 14 (23%) reported a decrease in penile length and circumference at 9 months (range, 4–8 months) compared to 12/14 (85%) among the nonresponders. However, in control group 22/35 reported decrease in penile length and circumference. Early use of VCD following RP facilitates early sexual intercourse, early patient/spousal sexual satisfaction, and potentially an earlier return of natural erections sufficient for vaginal penetration.

Declining Rates of Extracapsular Extension After Radical Prostatectomy: Evidence for Continued Stage Migration

PURPOSE Prostate-specific antigen (PSA)-based screening is responsible for a profound clinical stage migration in newly detected prostate cancers. Extracapsular extension (ECE) is an important predictor of outcome after radical prostatectomy (RP). We examined trends in the rate of ECE for cancers detected by PSA screening in 731 RP specimens between 1987 and 1997, when screening became routine urologic practice in the United States. METHODS The rates of ECE were examined in 311 prostates with nonpalpable (stage T1c) disease and 420 with palpable but clinically localized (stage T2) disease. Specimens were step-sectioned and examined by a senior pathologist. Rates of ECE were compared with respect to time, and logistic regression was used to identify predictors of ECE. RESULTS The rate of ECE decreased from 81% to 36% during the 10-year observation period. Multivariateanalysis involving clinical tumor stage, preoperative serum PSA level, and Gleason score demonstrated that year of treatment was an independent predictor of ECE, with a two-fold reduction of risk occurring during the study period (P <. 001; odds ratio, 1.96; 95% confidence interval, 1.37 to 2.78). CONCLUSION PSA screening has resulted in a downward trend in pathologic stage in clinically localized prostate cancer, independent of preoperative PSA level, tumor stage, and Gleason score. This time-dependent downward stage migration suggests the need for continuous updating of predictive nomograms and caution in interpreting differences in contemporarily treated patients compared with historical controls. Further study is needed to determine whether this trend will translate into improved disease-free survival.

Biochemical failure does not predict overall survival after radical prostatectomy for localized prostate cancer: 10-year results

OBJECTIVES To compare rates of overall survival in men with biochemical failure (bF) to those with no bF after radical prostatectomy for localized prostate cancer. METHODS Radical prostatectomy was performed in 1132 consecutive patients between June 1986 and September 1998, and bF (prostate-specific antigen [PSA] 0.2 ng/mL or greater) was documented in 213 patients (19%), with a mean follow-up of 56 months (range 1 to 125). Ninety-nine patients were treated with androgen ablation and/or radiation therapy at the time of bF. Kaplan-Meier estimates of bF, metastasis-free survival, and overall survival were generated and compared using the log-rank test. RESULTS The 10-year overall survival rates for patients with bF (88%) versus no bF (93%) were similar (P = 0.94). The survival rates of patients with bF were not statistically different than those of patients without bF when compared by age older than 65 years, preoperative PSA greater than 10 ng/mL, biopsy or specimen Gleason score 7 or greater, clinical Stage T2b-3, presence of extracapsular extension, positive surgical margins, and seminal vesicle invasion. Patients who received second-line treatment also had a similar 10-year overall survival rate (86%, P = 0.97). For the 213 patients with bF, the metastasis-free survival rate at 10 years was 74%. The overall survival rate for patients with distant metastasis (56%) was markedly lower (P <0.001) than for those without distant metastasis. CONCLUSIONS At 10 years, patients with a PSA recurrence after radical prostatectomy for localized disease have an excellent overall survival equivalent to those without a detectable PSA. Within this period, the clinical significance of a detectable PSA needs to be further evaluated.

SCREENING AND MONITORING FOR BLADDER CANCER: REFINING THE USE OF NMP22

PURPOSE While detecting bladder cancer, bladder tumor markers demonstrate improved sensitivity compared with urinary cytology but the current limitation is the low specificity and positive predictive value, that is high false-positive rate. We examined the clinical categories of the false-positive results, established relative exclusion criteria, and recalculated the specificity and positive predictive value of this assay with these criteria. MATERIALS AND METHODS A total of 608 patients considered at risk for bladder cancer presented to a urology clinic and submitted a single urine sample. Of the 608 patients 529 (87%) presented with de novo hematuria or chronic voiding symptoms without a diagnosis of bladder cancer. There were 79 (13.0%) patients being monitored with a known history of bladder cancer. Each urine sample was examined via cytology, urinalysis, culture and NMP22 protein assay. All patients underwent office cystoscopy, and transurethral resection and/or biopsy if a bladder tumor was suspected. RESULTS Of the 608 patients 226 (37.2%) presented with microscopic hematuria, 143 (23.5%) with gross hematuria and 239 (39.3%) had chronic symptoms of urinary frequency or dysuria. There were 52 (8.6%) patients who had histologically confirmed bladder cancer. Of these 52 cancers NMP22 detected 46 (88.5%), whereas cytology identified only 16 (30.8%). When atypical cytology was considered positive, cytology detected 32 (61.5%) cases. In the 135 patients with increased NMP22 values the 46 identified tumors were accompanied by 89 false-positive values yielding a specificity of 83.9% and a positive predictive value of 34.1%. These false-positive results were divided into 6 clinical categories. Exclusion of these categories improved the specificity and positive predictive value of NMP22 to 99.2% and 92.0%, respectively, yielding results similar to urinary cytology (99.8% and 94.1%). CONCLUSIONS Awareness and exclusion of the categories of false-positive results can increase the specificity and positive predictive value of NMP22, enhancing the clinical use of this urinary tumor marker.

NMP22 IS A SENSITIVE, COST-EFFECTIVE TEST IN PATIENTS AT RISK FOR BLADDER CANCER

BACKGROUND This study was designed to determine the clinical utility of NMP22 as a urinary marker for the early detection of transitional cell carcinoma (TCC) of the bladder in patients with hematuria or other indications for risk of malignancy. Its utility will be measured by sensitivity and specificity estimates as compared to cystoscopy. Since urine cytology is normally collected in this population of patients, it will also be analyzed and compared to cystoscopy. MATERIALS AND METHODS Each patient submitted a single voided urine which was stabilized with the NMP22 urine collection kit or preserved in the appropriate cytology medium for cytopathologic testing. All patients provided the urine samples before cystoscopic exam. Of the 146 patients, there were 43 patients with microscopic hematuria and 13 with gross hematuria. Other indications for cystoscopy included unexplained or medically refractory voiding. There were 8 patients with biopsy confirmed bladder cancer and 138 patients with benign conditions of the bladder. RESULTS The median NMP22 value for the bladder cancer malignancies was 27.8 U/mL (95% Confidence interval: 10.5-32.1 U/mL). The median NMP22 value for the benign conditions of the bladder was 3.25 U/mL (95% Confidence interval: 2.5-3.8 U/mL). The urinary NMP22 values from the bladder cancer group was statistically different (p < .000001 Mann-Whitney U test) than the NMP22 values in the benign conditions group. Using a reference value of 10.0 U/mL, the sensitivity of NMP22 was 100% with a specificity of 90%, while cytology had a sensitivity of 25% and a specificity of 100%. Due to its high negative predictive value, using NMP22 alone could have eliminated 124 cystoscopies with total savings ranging from