A biopsy-integrated algorithm for determining Gleason 6 upgrading risk stratifies risk of active surveillance failure in prostate cancer.

INTRODUCTION: A significant proportion of patients that fail active surveillance (AS) for prostate cancer management do so because of cancer upgrading. A previously validated upgrading nomogram generates a score that predicts risk of biopsy Gleason 6 upgrading following radical prostatectomy in lower-risk populations that are candidates for Active Surveillance (Cancer, 2013). OBJECTIVES: We hypothesize that the upgrading risk (UR) score generated by this nomogram at diagnosis improves the ability to predict patients that will subsequently fail AS. METHODS: To evaluate the nomogram, retrospective data from several institutional cohorts of patients who met AS criteria, group 1 (n = 75) and group 2 (n = 1230), were independently examined. A UR score was generated using the coefficients from the nomogram consisting of PSA density (PSAD), BMI, maximum % core involvement (MCI), and number of positive cores. AS failure was defined as Gleason score (GS) >6, >50 % maximum core involvement, or >2 positive cores on biopsy. Univariate and multivariate Cox proportional-hazards regression models, upgrading risk score, and other clinicopathologic features were each assessed for their ability to predict AS failure. RESULTS: Clinicopathologic parameters were similar in both groups with the exception of mean PSAD (0.13 vs. 0.11, p < 0.01) and follow-up (2.1 vs. 3.2 years, p = 0.2). Most common cause of AS failure was GS > 6 (group 1) compared to >2 positive cores (group 2). On univariate analysis in both populations, features at diagnosis including PSAD and the UR score were significant in predicting AS failure by upgrading (Gleason > 6) and any failure. Multivariate analysis revealed the UR score predicts AS failure by GS upgrading (HR 1.8, 95 % CI 1.12-2.93; p = 0.01) and any failure criteria (HR 1.7, 95 % CI 1.06-2.65); p = 0.02) for group 1. Likewise, the UR score in group 2 predicts AS failure with GS upgrading (HR 1.3, 95 % CI 1.15-1.42; p < 0.0001) and any failure criteria (HR 1.18, 95 % CI 1.18-1.38; p < 0.0001). An ROC generated an AUC of 0.66. Decision curve analysis demonstrated a high net benefit for the UR score across a range of threshold probabilities. Based on these outcomes, at 3 years, patients in the lowest risk quartile have a 15 % risk of AS failure versus a 46 % risk in the highest quartile (p < 0.0001). CONCLUSIONS: The UR score was predictive of pathologic AS failure on multivariate analysis in several AS cohorts. It outperformed single clinicopathologic criteria and may provide a useful adjunct using clinicopathologic data to stratify patients considering AS.

Role of HPC2/ELAC2 in hereditary prostate cancer.

The HPC2/ELAC2 gene on chromosome 17p was recently identified as a candidate gene for hereditary prostate cancer (HPC). To confirm these findings, we screened 300 prostate cancer patients (2 affected members/family) from 150 families with HPC for potential germ-line mutations using conformation-sensitive gel electrophoresis, followed by direct sequence analysis. The minimum criteria for our families with HPC was the presence of 3 affected men with prostate cancer. A total of 23 variants were identified, including 13 intronic and 10 exonic changes. Of the 10 exonic changes, 1 truncating mutation was identified, a Glu216Stop nonsense mutation. This nonsense variant was found in 2 of 3 affected men in a single family. The remaining nine alterations included five missense, three silent, and one variant in the 3' untranslated region. To additionally test for potential associations of polymorphic variants and increased risk for disease, we genotyped two common polymorphisms, Ser217Leu and Ala541Thr, in 446 prostate cancer patients from 164 families with HPC and 502 population-based controls. The frequency of the Leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the Thr541 variant (5.4% among patients versus 5.2% among controls). In contrast to previous reports, we found no association of the joint effects of Leu271 and Thr541 (odds ratio, 1.04; 95% confidence interval, 0.57-1.89). Overall, our results did not reveal any association between these two common polymorphisms and the risk for HPC. The finding of a nonsense mutation in the HPC2/ELAC2 gene confirms its potential role in genetic susceptibility to prostate cancer. However, our data also suggest that germ-line mutations of the HPC2/ELAC2 are rare in HPC and that the variants Leu217 and Thr541 do not appear to influence the risk for HPC. Cumulatively, these results suggest that alterations within the HPC2/ELAC2 gene play a limited role in genetic susceptibility to HPC.

Radical prostatectomy for clinically localized prostate cancer: long-term results of 1,143 patients from a single institution.

PURPOSE: To determine the efficacy and complication rate of radical prostatectomy (RP) as a treatment option for clinically localized prostate cancer (clinical stage < or = T2c). METHODS: The study was a retrospective analysis of 1,143 consecutive patients (median age, 64 years; range, 38 to 79 y) who underwent RP at one institution (mean follow-up time, 9.7 years). Complications for this study population were compared with those of a contemporary group of 1,000 consecutive patients. RESULTS: Of 1,143 patients, 83 (7%) had a low clinical stage (T1) and 160 (14%) had a low histologic grade (Gleason score < or = 3); 648 (57%) had a high clinical stage (T2b or T2c) and 204 (18%) had a high histologic grade (Gleason score > or = 7). Only 113 (10%) died of prostate cancer, and 177 (15%) developed metastasis. Adjuvant treatment (androgen deprivation or radiation therapy) was given in 197 (17%) patients (> or = pT3) and provided virtually identical results as without adjuvant treatment. The 10- and 15-year crude survival rates for 1,143 patients were 75% +/- 1.5% (SE) and 60% +/- 2.2%, respectively; the cause-specific survival rates were 90% +/- 1.1% and 83% +/- 1.9%, respectively; and the metastasis-free survival rates were 83% +/- 1.3% and 77% +/- 1.9%, respectively (398 men at risk at 10 years and 138 men at risk at 15 years). The 10-year survival rate for patients with Gleason score > or = 7 was 74% +/- 3.9%. Only tumor grade was a significant predictor for disease outcome. The hospital mortality rate decreased from 0.7% for the 1,143 study patients to 0% for the more recent 1,000 patients. Severe incontinence declined to 1.4% for the more recent 1,000 patients. Most patients who underwent RP were healthy (Charlson comorbidity index). CONCLUSION: Survival at 15 years was similar to the expected survival rate. Current morbidity and mortality rates associated with RP were extremely low. Thus, RP has been a viable management option for men with clinically localized prostate cancer who have a life expectancy of more than 10 years.

The cell cycle inhibitors p21WAF1 and p27KIP1 are associated with survival in patients treated by salvage prostatectomy after radiation therapy.

We evaluated p27KIP1 and p21WAF1 expression in 52 patients treated by salvage radical prostatectomy and bilateral pelvic lymphadenectomy for biopsy-proven locally persistent or recurrent prostate cancer after external beam radiation therapy. We defined low and high expression based on the median value observed in our sample. Five-year distant metastasis-free survival and cancer-specific survival were 71 and 82%, respectively, for patients with low expression of p21 (< or =5%), compared with 94 and 100%, respectively, for those with high expression of p21 (>5%; P = 0.02 and 0.01, respectively). Five-year distant metastasis-free survival and cancer-specific survival were 71 and 82%, respectively, for patients with low expression of p27 (<50%), compared with 88 and 96%, respectively, for those with high expression of p27 (> or =50%; P = 0.06 and 0.01, respectively). These findings indicate that p21 and p27 expression levels are significant predictors of survival for patients selected for salvage prostatectomy for recurrent prostate cancer.

Cell proliferation in prostate cancer patients with lymph node metastasis: a marker for progression.

The biological aggressiveness of lymph node-positive prostate cancer is closely linked to cancer volume in nodal metastases. We evaluated MIB-1 (Ki-67) labeling index and bcl-2 expression in primary cancer and matched nodal metastases from 138 node-positive patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy between 1987 and 1992 at the Mayo Clinic. One hundred twenty-eight patients (93%) received androgen deprivation therapy within 90 days after radical prostatectomy. Mean patient age was 66 years (range, 51-78). The median follow-up was 6.7 years (range, 0.03-11). MIB-1 (Ki-67) labeling index was determined by digital image analysis, and nodal cancer volume was determined by the grid method. Systemic progression, defined as the presence of distant metastasis documented by biopsy or radiographic examination, was used as an outcome end point in the Cox proportional hazard models. MIB-1 labeling index in nodal metastases was predictive of systemic progression-free survival (P = 0.001). The 8-year systemic progression-free survival was 100% for those with MIB-1 labeling index <3.5% compared with 78% for those with MIB-1 labeling index > or =7.8%. MIB-1 labeling index correlated with Gleason score, DNA ploidy, and nodal cancer volume (P<0.001, 0.04, and <0.001, respectively). After controlling for nodal cancer volume, MIB-1 labeling index remained significant in predicting systemic progression-free survival (P = 0.047). bcl-2 expression in the primary cancer and lymph node metastasis was associated with systemic progression-free survival in univariate analysis (P = 0.027 and 0.048, respectively) but was not significant after adjusting for nodal cancer volume (P = 0.52 and 0.17, respectively). Our data indicate that assessment of cell proliferation in nodal metastasis is predictive of clinical outcome in prostate cancer patients with regional lymph node metastasis.

Correlation of pretherapy prostate cancer characteristics with seminal vesicle invasion in radical prostatectomy specimens.

PURPOSE: This study was conducted to identify pretherapy factors associated with seminal vesicle invasion (SVI) in patients with localized carcinoma of the prostate (CaP), and to develop a model that would allow estimation of the likelihood for SVI at the time of initial diagnosis. METHODS AND MATERIALS: Between January 1988 and December 1993, 2959 patients underwent radical retropubic prostatectomy, with or without pelvic lymph node dissection, as initial therapy for clinical Stage T1a-3bN0-XM0 CaP. Preoperative patient and tumor-related characteristics were evaluated for an association with SVI in univariate and multivariate logistic regression analyses. A model was developed and probability plots were constructed to display the estimated likelihood for SVI in the patients with a new diagnosis of localized CaP. RESULTS: Within clinical tumor stage, three groups (T1a-2a, T2b-c, and T3a-b) were observed to have a distinctly different rate of SVI. Gleason primary grades were combined (1-2, 3 and 4-5) because of a similar observation. Univariate analysis identified clinical tumor stage (p < 0.0001), Gleason primary grade (p < 0.0001), and serum prostate-specific antigen level (p < 0.0001) as factors associated with the likelihood for SVI. Multivariate analysis confirmed the independent significance (p = 0.0001) of each of these factors. Patient age (p = 0.16) and history of prior transurethral resection of the prostate (p = 0.82) were not associated with this end point. Probability plots were constructed to display the likelihood of SVI as a function of pretherapy clinical tumor stage, Gleason primary grade, and serum prostate-specific antigen value. CONCLUSION: In the patient with a new diagnosis of localized CaP, clinical tumor stage as determined by digital rectal examination, diagnostic biopsy tumor (Gleason primary) grade, and pretherapy serum prostate-specific antigen value were significant factors for development of a model that estimated the likelihood of SVI. Estimates from this type of model may be of value in the pretherapy diagnostic evaluation of such patients, and may aid in the administration of radiation therapy.

Cancer volume of lymph node metastasis predicts progression in prostate cancer.

Clinical outcome is variable in prostate cancer patients with regional lymph node metastasis. We studied 269 patients who had regional lymph node metastasis at the time of radical retropubic prostatectomy and bilateral pelvic lymphadenectomy at the Mayo Clinic between January 1987 and December 1992. Two hundred fifty-three (94%) patients received androgen deprivation therapy within 90 days of radical prostatectomy. Patients ranged in age from 47 to 79 years (median, 67 years). Median follow-up was 6.1 years (range, 0.3-10.5 years). Nodal cancer volume (size) was measured by the grid-counting method. Cox proportional hazards models were used to determine the impact of numerous clinical and pathologic findings on systemic progression-free survival. Systemic progression was defined as the presence of distant metastasis documented by biopsies or radiographic examinations (abdominal computerized tomography, plain radiographs, or bone scan). Five-year progression-free survival was 90%. In predicting systemic progression using Cox multivariate analysis, only nodal cancer volume added significantly to the model containing the primary cancer variables (Gleason score, cancer volume, and DNA ploidy). The relative hazard rate for a doubling in nodal cancer volume was 1.6 (95% confidence interval, 1.3 to 2.0; p < 0.0001). Spearman rank analysis showed a correlation between nodal cancer volume and Gleason score of the primary cancer, the number of positive nodes, the aggregate length of metastases, and the largest nodal cancer diameter (correlation efficient = 0.37, 0.63, 0.96, and 0.95, respectively). Our data indicate that nodal cancer volume was the most significant nodal determinant of progression to distant metastasis in lymph node-positive prostate cancer patients. We recommend that the diameter of the largest metastasis be evaluated in patients with metastases, because this is a more powerful predictor of patient outcome than current methods, which recommend mere counting of the number of positive nodes.

Continent orthotopic urinary diversion in female patients: early Mayo Clinic experience.

OBJECTIVE: To review our initial experience with orthotopic neobladder urinary diversion in female patients. MATERIAL AND METHODS: We reviewed the clinical characteristics, operative reports, and pathologic results of five female patients who underwent radical or simple cystectomy and continent orthotopic urinary diversion. Peri-operative morbidity, postoperative daytime and nighttime continence, renal function, need for protective pads, and self-catheterization were documented. All urodynamic and upper urinary tract imaging studies were reviewed. RESULTS: Follow-up has ranged from 9 to 18 months in these initial patients. Thus far, all five women have achieved acceptable daytime continence, and four of five women have achieved nighttime continence. Only one patient augments volitional voiding with intermittent self catheterization. Complications consisted of urinary retention in one patient and development of a urinary tract and bladder calculus, which necessitated cystolitholapaxy, in another patients. Neobladder capacities have ranged from 400 to 600 mL with voided volumes up to 300 mL. Only one patient has had a substantial residual urine volume (300 mL). All upper urinary tract imaging studies have shown stable function, and urodynamic studies have revealed high-compliance, large-volume neobladder capacities in all patients. CONCLUSION: Bladder replacement pouches designed from detubularized bowel are gaining widespread acceptance among urologists and their patients. Although these operations have previously been limited to men because of concerns about cancer-involved margins and continence after cystectomy in female patients, recent advances in the knowledge of female pelvic anatomy and neurovascular innervation of the bladder neck and proximal urethra have facilitated nerve-preserving radical cystectomy in women that allows continence and volitional voiding through the urethra.

Platinum-based chemotherapy for advanced transitional cell carcinoma of the upper urinary tract.

OBJECTIVE: To report the results of platinum-based chemotherapy used at one medical center in patients with advanced transitional cell carcinomas (TCCs) of the upper urinary tract. MATERIAL AND METHODS: Between July 1981 and February 1993, 28 patients (mean age, 59.3 years) with advanced TCC of the upper urinary tract received cisplatin-based chemotherapy. Of the 28 patients, 14 received a median of 4 cycles of cisplatin, methotrexate, and vinblastine sulfate, 8 received a median of 4.5 cycles of methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin, 5 received a median of 5 cycles of etoposide and cisplatin, and 1 was treated with 7 cycles of only cisplatin. Overall survival estimates were constructed from nonparametric analysis with the Kaplan-Meier method. RESULTS: The overall response rate (partial and complete) to chemotherapy was 54%. The most responsive metastatic sites were the lung and lymph nodes-78 and 47% overall response rate, respectively. The estimated median duration of survival for the entire study group was 14 months. In the study population, only three patients were long-term survivors. A significant survival advantage was noted only in the few patients (with limited metastatic tumor volume) who had a complete response to therapy. Initial dose reductions in chemotherapy because of decreased baseline renal function were necessary in 79% of the patients. CONCLUSION: Removal of the primary lesion in the presence of metastatic or locally advanced disease does not apparently improve chemotherapy response rates or patient survival. In addition, many patients do not receive optimal dosing of systemic chemotherapy after nephrectomy. Therefore, by avoiding dose modifications, the overall response rates and survival may conceivably be improved. A diagnostic biopsy or nephron-sparing surgical procedure and neoadjuvant systemic therapy may be considered in patients with advanced TCC at the time of initial assessment in order to allow optimal dosing of chemotherapy.

Management and extended outcome of patients with synchronous bilateral solid renal neoplasms in the absence of von Hippel-Lindau disease.

OBJECTIVE: To gain information regarding long-term follow-up in patients with synchronous bilateral solid renal neoplasms in whom renal-preserving surgery is imperative. PATIENTS AND METHODS: We examined our surgical experience and the survival outcome, as evaluated by Kaplan-Meier and log-rank analysis, of 94 patients (64 men and 30 women) who presented to the Mayo Clinic in Rochester, Minn, from 1973 to 1998 with bilateral synchronous solid renal neoplasms in the absence of von Hippel-Lindau disease. Follow-up of these patients ranged from 1 to 25 years, with a mean of 5.86 years and a median of 4.18 years. Tumors were staged according to the TNM classification. Pathologic staging and grading were usually performed on the kidney with the most extensive cancer. The Cox proportional hazards model was used to assess the relationship of grade (1-4), tumor size, and enucleation as opposed to extended (1 cm) partial nephrectomy on overall, cancer-specific, local recurrence-free, and metastasis-free survival. RESULTS: Seventy-one patients (76%) had bilateral synchronous renal cell carcinoma, and 14 patients (15%) had a unilateral renal cell carcinoma with a contralateral benign solid neoplasm. Nine patients (10%) had bilateral benign solid lesions. Sixty-six patients (70%) underwent a single procedure, whereas 28 (30%) underwent staged surgical procedures. Fifty-one patients (54%) are alive, and 43 (46%) have died. Twenty patients (21%) died of metastatic disease, and 5 (5%) had a local recurrence. Cancer-specific survival of the 85 patients with at least 1 renal cell carcinoma still under observation was 81% (+/- 4.9% SE) and 59% (+/- 8.1% SE) at 5 and 10 years, respectively, and survival to local recurrence was 96% (+/- 2.6% SE) at 5 years and 93% (+/- 3.7% SE) at 10 years with 14 patients still under observation. Grade 3 was a statistically significant factor for metastasis (P < .001). A significant difference in metastasis-free survival and cancer-specific survival was noted dependent on pathologic T stage (P < .001 and P = .02, respectively), with patients with local pT3 disease having a higher rate of metastasis and cancer-specific death. Multivariate analysis revealed that tumor grade was associated with metastasis-free survival (P = .002) and tumor size with cancer-specific survival (P = .04). There was no statistical significance on survival outcome end points according to procedure performed, i.e., enucleation vs extended partial nephrectomy. CONCLUSION: Long-term results of renal-preserving procedures for a series of patients with bilateral solid renal neoplasms indicate that grade, stage, and tumor size are significant predictors of outcome. Mean follow-up of over 5 years supports nephron-sparing techniques in selected patients because local recurrence was infrequent compared with distant metastasis.

Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney.

OBJECTIVE: To report the long-term follow-up of a matched comparison of radical nephrectomy (RN) and nephron-sparing surgery (NSS) in patients with single unilateral renal cell carcinoma (RCC) and a normal contralateral kidney. PATIENTS AND METHODS: Between August 1966 and March 1999, 1492 and 189 patients with unilateral RCC and a normal contralateral kidney underwent RN and NSS, respectively. Patients with renal impairment, previous nephrectomy, bilateral or multiple RCCs, metastasis, and familial cancer syndromes were excluded. A total 164 patients in each cohort were matched according to pathological grade, pathological T stage, size of tumor, age, sex, and year of surgery. The Kaplan-Meier method and stratified Cox proportional hazards model were used to estimate and compare overall, cancer-specific, local recurrence-free, and metastasis-free survival and survival free of chronic renal insufficiency. The 2 groups were evaluated for early (< or = 30 days) complications and proteinuria at last follow-up. RESULTS: At last follow-up, 126 RN patients (77%) and 130 NSS patients (79%) were alive with no evidence of disease. There was no significant difference observed between patients who had RN and those who had NSS with respect to overall survival (risk ratio, 0.96; 95% confidence interval [CI], 0.52-1.74; P = .88) or cancer-specific survival (risk ratio, 1.33; 95% CI, 0.30-5.95; P = .71). At 10 years, similar rates of contralateral recurrence (0.9% for RN vs 1% for NSS) and metastasis (4.9% for RN vs 4.3% for NSS) were seen in each group, whereas the rate of ipsilateral local recurrence for patients who underwent RN and NSS was 0.8% and 5.4%, respectively (P = .18). There was no significant difference in the early complications between the RN and NSS groups. However, patients who underwent RN had a significantly higher risk for proteinuria as defined by a protein/osmolality ratio of 0.12 or higher (55.2% vs 34.5%; P = .01). At 10 years, the cumulative incidence of chronic renal insufficiency (creatinine > 2.0 mg/dL at least 30 days after surgery) was 22.4% and 11.6%, respectively, for the RN and NSS groups (risk ratio, 3.7; 95% CI, 1.2-11.2; P = .01). CONCLUSIONS: This retrospective study of patients with unilateral RCC and a normal contralateral kidney suggests that NSS is as effective as RN for the treatment of RCC on long-term follow-up. The increased risk of chronic renal insufficiency and proteinuria after RN supports use of NSS.

Primary chemotherapy for clinical stage II nonseminomatous germ cell testicular tumors: selection criteria and long-term results.

OBJECTIVE: To determine the treatment option for patients with low-volume stage II nonseminomatous germ cell testicular tumors (NSGCTT) that yields the best survival, is associated with the least morbidity, and avoids "double therapy"--that is, chemotherapy and retroperitoneal lymph node dissection (RPLND). DESIGN: We reviewed our institutional experience with 28 patients with stage II NSGCTT who received primary chemotherapy between August 1983 and October 1992. MATERIAL AND METHODS: The 28 study patients (mean age, 28 years; range, 20 to 52) with low-volume stage II NSGCTT were treated with bleomycin, etoposide, and cisplatin. The correlation of response rates with volume of disease and predominant histologic cell type was determined. The duration of survival was measured from the initiation of chemotherapy to the appearance of progressive disease or death or the date of last follow-up visit. RESULTS: Of the 28 patients treated, 27 (96%) achieved a complete response--20 (71%) with only chemotherapy and an additional 7 (25%) with chemotherapy plus surgical treatment. Twenty-seven patients (96%) remained free of disease after a median follow-up of 72 months. The most frequent complication was cisplatin-associated paresthesias or tinnitus which was noted in 13 patients (46%). In 11 of 15 patients (73%), attempts to have children have been successful. CONCLUSION: Excellent long-term survival rates in patients with stage II NSGCTT can be achieved with primary chemotherapy. In this series, 71% of patients were spared RPLND. The need for postchemotherapy RPLND seemed to be related to the initial metastatic tumor volume and possibly the histologic features of the primary tumor. Continued refinement in surgical techniques and chemotherapeutic regimens will necessitate the comparison of these two treatment approaches in a randomized prospective trial.

Current status of transurethral thermotherapy at the Mayo Clinic.

With the ever-expanding elderly population in the United States, benign prostatic hyperplasia (BPH) has become a widespread condition. Although surgical intervention (open prostatectomy and transurethral resection of the prostate) was the typical management approach for BPH in the past, other options currently include drug therapy and transurethral thermotherapy, a minimally invasive procedure that involves the targeting of heat deep within the prostate transition zone while cooling the surrounding anatomic structures with circulating water. Two thermo-therapy-devices--the Prostatron and the T3 transurethral thermoablation therapy catheter--have been studied in randomized controlled clinical trials at the Mayo Clinic. Both devices were shown to be effective in a substantial subset of patients with BPH: symptom scores decreased, peak urinary flow rates increased, and total serum prostate-specific antigen levels increased, an indication of destruction of adenomatous tissue. All patients were able to complete the treatment without the need for general or regional anesthesia, and thermotherapy was associated with few postprocedural events. Although this therapeutic strategy is currently used selectively in patients with lateral lobe prostatic adenoma, improvements in technology and understanding of the thermoregulatory properties of the prostate should broaden the application of thermotherapy devices in the management of BPH.

PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer.

OBJECTIVES: To characterize the clinical progression of disease in men who have undergone prostatectomy for clinically localized prostate cancer and have postoperative biochemical failure (elevated prostate-specific antigen [PSA] level) and to identify predictors of clinical disease progression, including the possible effect of PSA doubling time (PSADT). PATIENTS AND METHODS: Between 1987 and 1993, 2809 patients underwent radical retropubic prostatectomy for clinically localized (< or =T2) disease. In our database, all patients with postoperative biochemical failure (PSA level > or =0.4 ng/mL) were identified. The PSADT was estimated using log linear regression on all PSA values (excluding those values determined after administration of hormonal therapy) within 15 months after biochemical failure. All patients had regular PSA measurements from the time of surgery through the follow-up period. Systemic progression (SP) was defined as evidence of metastatic disease on a bone scan. Local recurrence (LR) was defined on the basis of digital rectal examination, transrectal ultrasonography, and biopsy. The SP-free survival and LR/SP-free survival (survival free of both LR and SP) after biochemical failure was estimated with use of the Kaplan-Meier method. Patients with prostate cancer treatment after biochemical failure had their follow-up censored from this study at the time of treatment. RESULTS: Postoperative biochemical failure occurred in 879 men (31%). The mean follow-up from time of biochemical failure was 4.7 years (range, 0.5-11 years). The mean time to biochemical failure was 2.9 years (median, 2.4 years). The overall mean SP-free survival from time of biochemical failure was 94% and 91% at 5 and 10 years, respectively. The mean LR/SP-free survival was 64% and 53% at 5 and 10 years, respectively. By using univariate analysis on the 587 patients with PSADT data, significant risk factors for SP were PSADT (P<.001) and pathologic Gleason score (P=.005); for LR/SP, significant risk factors included PSADT (P<.001) and pathologic Gleason score (P<.001). In multivariate Cox models analysis, only PSADT remained a significant risk factor for both SP and LR/SP (P<.001). Mean 5-year SP-free survival was 99%, 95%, 93%, and 64% for patients with PSADT of 10 years or longer, 1.0 to 9.9 years, 0.5 to 0.9 year, and less than 0.5 year, respectively; the respective mean LR/SP-free survivals were 87%, 62%, 46%, and 38%. The percentage of patients with PSADT of less than 0.5 year was considerably higher if the type of first clinical event was SP (48%) compared with LR (18%) (P<.001). CONCLUSIONS: For patients who have undergone radical prostatectomy, a rising PSA level suggests evidence of residual or recurrent prostate cancer. Many men remain free of clinical disease for an extended time after biochemical failure following radical prostatectomy for clinically localized prostate cancer. The PSADT appears to be an important predictor of SP and also of any clinical progression (local or systemic). These data may be useful when counseling men regarding the timing of adjuvant therapies.

Transurethral microwave thermotherapy for prostatism: early Mayo Foundation experience.

As part of a multicenter investigative trial, transurethral microwave thermotherapy of the prostate was used in 60 men with symptomatic benign prostatic hypertrophy. A single office treatment on the Prostatron, a device that provides concurrent microwave heating of the prostate and conductive cooling of the urethra, was well tolerated and caused no major adverse events. Symptomatic improvement, especially the decrease in nocturia and urgency, was dramatic, and urinary flow was improved at 6 weeks. Continued follow-up suggests that further improvement will be achieved and that transurethral microwave thermotherapy has a role in the treatment of benign prostatic hypertrophy.

Influence of prostate-specific antigen testing on the spectrum of patients with prostate cancer undergoing radical prostatectomy at a large referral practice.

OBJECTIVE: To analyze trends in the clinical stage and pathologic outcome of patients with prostate cancer who underwent radical prostatectomy at a large referral practice during the prostate-specific antigen (PSA) testing era. MATERIAL AND METHODS: Between January 1987 and June 1995, 5,568 patients with prostate cancer (4,774 with clinically localized disease of stage T2c or less) underwent pelvic lymphadenectomy and radical retropubic prostatectomy at our institution. Patient age, preoperative serum PSA level, clinical stage, pathologic stage, Gleason score, and tumor ploidy were assessed. Outcome was based on clinical and PSA (increases in PSA level of 0.2 ng/mL or more) progression-free survival. RESULTS: Patient age (65 to 63 years old; P<0.001) and serum PSA level (median, 8.4 to 6.8 ng/mL; P<0.001) decreased during the study period. The percentage of patients with clinical stage T1c prostate cancer increased from 2.1% in 1987 to 36.4% in 1995 (P<0.001), and clinical stage T3 cancer decreased from 25.3% to 6.5% (P<0.001). Nondiploid tumors decreased from 38.3% to 24.6% (P<0.001), and the proportion of patients with pathologically organ-confined disease increased from 54.9% to 74.3% (P<0.001). More cT1c than cT2 tumors were diploid (80% versus 72%; P<0.001), had a Gleason score of 7 or less (75% versus 65%; P<0.001), and were confined to the prostate (75% versus 57%; P<0.001). Five-year progression-free survival was 85% and 76% for patients with clinical stage T1c and T2, respectively (P<0.001). CONCLUSION: Since the advent of PSA testing, patients referred to our institution for radical prostatectomy have shown a significant migration to lower-stage, less-nondiploid, more often organ-confined prostate cancer at the time of initial assessment. Cancer-free survival associated with PSA-detected cancer (cT1c) is superior to that with palpable tumors (cT2). Whether these trends translate into improved long-term cancer-specific survival remains to be confirmed with longer follow-up.

A prospective randomized comparison of epidural infusion of fentanyl and intravenous administration of morphine by patient-controlled analgesia after radical retropubic prostatectomy.

In a prospective, randomized study, continuous infusion of epidural fentanyl citrate (group E) was compared with patient-controlled intravenously administered morphine sulfate (group P) for analgesia in 66 men after radical retropubic prostatectomy. Although both methods provided satisfactory analgesia, the mean comfort level scores were lower (that is, greater comfort) in group E than in group P at all observation times. The difference in mean resting comfort level scores between groups E and P was statistically significant (P < or = 0.05) at 9 of the 11 observation times. In addition, significant differences in comfort level scores were noted at 8 of the 11 observation times during deep breathing, 5 of 11 during coughing, and 3 of 9 during ambulation. Maximal and minimal comfort level scores recorded by each patient during the course of the study were significantly lower (that is, less pain) in group E than in group P for all four categories of activity. The percentage of patients who reported no pain was significantly higher in group E than in group P at 9 of 11 observation times during resting and 5 of 11 observation times during deep breathing. No significant differences were noted in side effect profiles or duration of hospital stay. In summary, when two effective methods of analgesia used after radical retropubic prostatectomy were compared prospectively, patients who received epidural infusion of fentanyl were more comfortable than those with patient-controlled intravenous administration of morphine, as evidenced by lower mean, maximal, and minimal comfort level scores and a greater proportion of patients with complete relief of pain.

Stage B prostate adenocarcinoma. Flow cytometric nuclear DNA ploidy analysis.

Over a 16-year period (1966 to 1981), 349 patients underwent radical retropubic prostatectomy for pathologic stage B adenocarcinoma of the prostate. Nuclear DNA content was measured by flow cytometry on available archival material of 283 patients. Two hundred sixty-one patients (92%) had high-quality histograms. The ploidy distribution was as follows: DNA diploid, 177 (68%); DNA tetraploid, 74 (28%); and DNA aneuploid, 10 (4%). The average follow-up was 9.4 years. At the time of follow-up, 53 patients (20%) within the study group had developed tumor progression: 22 local, 23 systemic, and 8 both. The ploidy distribution of the population that developed tumor progression was 27 DNA diploid (51%), 16 DNA tetraploid (30%), and 10 DNA aneuploid (19%). This ploidy distribution is significantly different from that found for the nonprogression group with stage B disease. Overall, 31% of patients with DNA nondiploid tumors had tumors that progressed compared with 15% of patients with DNA diploid tumors. All (100%) DNA aneuploid tumors progressed. The DNA ploidy distribution of all pathologic stage B prostate cancers differs significantly from that found in more advanced stages (C and D1) previously reported for the same time interval. However, the ploidy distribution of stage B tumors that progressed closely resembles that of the stage C and D1 tumors. These results further support the working hypothesis that nuclear DNA content has marked prognostic significance for patients with adenocarcinoma of the prostate. It seems to us that analysis of ploidy by flow or static cytometry will become an essential tool for treating patients with localized prostate cancer.

Transurethral microwave thermotherapy: what role should it play versus medical management in the treatment of benign prostatic hyperplasia?

Both transurethral microwave thermotherapy (TUMT) and medical management by alpha-blockade or 5-alpha-reductase inhibition are increasingly being considered as alternatives to surgery for treatment of patients with benign prostatic hyperplasia (BPH). We review current evidence supporting the effectiveness and safety of TUMT and medical management. Factors for consideration in appropriately selecting patients for TUMT versus medical management are suggested. Available data indicate that TUMT confers greater long-term benefits than medical management as judged by symptom score and peak urinary flow rate improvements. TUMT-associated morbidity is comparatively low. Alpha-blockade affords more rapid relief than TUMT for patients with BPH; however, other strategies such as the use of temporary intraurethral endoprostheses during the acute post-TUMT recovery period may diminish or abolish the differences in time-course of symptom and flow rate improvement between TUMT and alpha-blockade. 5-Alpha-reductase inhibition with finasteride offers a favorable side-effect profile, although the magnitude of symptom and flow rate improvements is modest, and maximal effects of finasteride do not become manifest until after several months of treatment. As TUMT continues to evolve, increasing attention is being accorded the delivery of high thermal doses and precise targeting of the thermal energy delivered. The development of alpha-blockers with a more favorable side-effect profile continues to be a major focus of investigation. The potential clinical utility of combination therapy with TUMT and alpha-blockade is currently under investigation.