Faculty Bibliography

OBJECTIVES/OBJECTIVE:Cryotherapy of the prostate represents a potential treatment for localized recurrent prostate cancer after radiation therapy. We report our experience and evaluate the predictive factors for prostate-specific antigen (PSA) recurrence. METHODS:Between October 1994 and April 1999, 43 patients underwent salvage cryoablation. All patients had biopsy-proven recurrent prostate cancer without seminal vesicle invasion, negative bone scans, and negative lymph node dissection. Patients had received 3 months of combined hormonal therapy before cryosurgery. Biochemical recurrence-free survival (bRFS) was defined as a PSA value less than 0.1 ng/mL. RESULTS:Complications included incontinence (9%), obstruction (5%), urethral stricture (5%), rectal pain (26%), urinary infection (9%), scrotal edema (12%), and hematuria (5%). The mean follow-up was 21.9 months (range 1.2 to 54). Twenty-six patients (60%) reached a serum PSA nadir less than 0.1 ng/mL, 16 (37%) had a PSA less than 4 ng/mL, and 1 (3%) had a PSA less than 10 ng/mL. The bRFS rate was 79% at 6 months and 66% at 12 months. The bRFS rate was higher for patients who had an undetectable postcryotherapy PSA than for patients who did not reach a PSA less than 0. 1 ng/mL (73% versus 30%, P = 0.0076). Using multivariate analysis, a PSA nadir greater than 0.1 ng/mL was an independent predictor of PSA recurrence. CONCLUSIONS:Current salvage cryotherapy of the prostate can result in undetectable serum PSA levels with low morbidity. Our data support the current safety and efficacy profile. We believe that cryotherapy is a viable option in the treatment of patients who have biopsy-proven local failure after radiation therapy for prostate cancer. Further refinements in technique and equipment may enhance cryosurgical results.

OBJECTIVE:To determine the complication rates and biochemical recurrence after cryoablation of the prostate, using an argon gas-based system, in patients with localized prostate cancer. PATIENTS AND METHODS/METHODS:Between October 1997 and June 1999, 35 patients underwent cryoablation of the prostate (19 after radiation therapy failure and 16 as a primary treatment for localized prostate cancer). All patients had biopsy-confirmed prostate cancer with no seminal vesicle invasion, negative bone scans and a negative lymph node dissection. Patients received 3 months of combined hormonal therapy before cryosurgery. One surgeon performed all the procedures. Biochemical recurrence was defined by an increase in prostate specific antigen (PSA) of >/= 0.2 ng/mL above the PSA nadir. RESULTS:The complications were rectal pain (26%), urinary infection (3%), scrotal oedema (12%), haematuria (6%) and incontinence (6%). Complication rates were higher in those patients who failed after radiation therapy than in those who did not receive radiation (incontinence 11% vs 0%, rectal pain 37% vs 12%) but the difference was not statistically significant. Twenty-two patients (63%) had an undetectable serum PSA nadir (< 0.1 ng/mL) after cryotherapy and 30 (84%) patients had a PSA value of < 1.0 ng/mL. After a mean follow-up of 8.3 months (range 0.2-18), nine patients had biochemical recurrence. The biochemical recurrence-free survival (BRFS) was 70% at 9 months. Patients who had an undetectable PSA nadir had a statistically higher BRSF at 9 months than did patients who had a detectable PSA nadir (89% vs 55%, respectively, P = 0.03). Similarly, patients with a preoperative serum PSA level of < 10 ng/mL had a statistically higher BRFS than patients who had a PSA level of > 10 ng/mL (86% vs 42% at 9 months, P < 0.001). CONCLUSION/CONCLUSIONS:A PSA level before cryotherapy of < 10 ng/mL and an undetectable PSA nadir after cryotherapy were associated with the highest BRFS. Cryoablation of the prostate, with low morbidity, seems to be a viable option in managing patients by salvage therapy after radiation therapy and for the primary treatment of clinically localized prostate cancer.

OBJECTIVE:Angiogenesis is believed to play an important role in tumor progression and metastasis. The goal of this study was to investigate the clinical utility of vascular invasion in prostate cancer patients treated by radical prostatectomy as a predictor of PSA recurrence. METHODS:Between 1993 and 1998, 241 patients underwent radical prostatectomy at our institution and had routine analysis of vascular and/or lymphatic invasion (V/LI). V/LI was correlated with preoperative parameters including digital rectal examination (DRE), Gleason score (GS) on biopsy and serum PSA, with the pathological findings and with biochemical recurrence. RESULTS:V/LI incidence was 12.4% (30 of 241 patients). Of the 30 patients with V/LI, 28 (93%) had GS > or =7 (67%) had a pT3 disease and 7 had SV invasion (23%). V/LI was not associated with DRE and GS on prostate needle biopsy. However, V/LI was correlated with the worst pathological findings including pT3 disease, seminal invasion, positive surgical margins and GS on prostate specimen > or = 7. Biochemical recurrence-free survival was 92.5% for the patients without V/LI as compared to 30.1% for patients with V/LI on prostate specimen examination (p = 0.0001). Multivariate analysis showed that preoperative serum PSA, Stage and V/LI were independent predictors of PSA recurrence. Patients with pT2 disease without V/LI had a biochemical recurrence-free survival of 99 vs. 31% in patients with V/LI (p = 0.0001). CONCLUSION/CONCLUSIONS:This study demonstrated that V/LI is strongly associated with biochemical recurrence after radical prostatectomy. The routine analysis of V/LI should be considered as a routine evaluation of the radical prostatectomy specimen.

OBJECTIVES/OBJECTIVE:Cellular senescence is a unique cellular response pathway thought to be closely associated with the aging process. The senescent phenotype is characterized by the loss of a cell's ability to respond to proliferative and apoptotic stimuli even while normal metabolic activity and vitality is maintained. Recently, a novel biomarker, senescent-associated beta-galactosidase (SA-beta-gal), was found to identify cells with the senescent phenotype. In the present study, we examined whether human prostatic epithelial cells adopt a senescence-associated phenotype after prolonged culture and analyzed a series of human benign prostatic hyperplasia (BPH) specimens to determine whether the cellular senescence process might be a factor in the development of BPH. METHODS:A primary culture of epithelial cells was established from the normal tissue of the peripheral zone of a radical prostatectomy specimen and was serially passaged until senescence. Forty-three human prostate specimens were obtained subsequent to radical prostatectomy or transrectal ultrasound-guided biopsy. The cultured cells and tissue specimens were histochemically stained to reveal the expression of SA-beta-gal, the cellular senescence biomarker. RESULTS:As has been reported for other types of cultured cells, human prostatic epithelial cells demonstrated widespread expression of the cellular senescence marker, SA-beta-gal, on prolonged culture. In our survey of hypertrophied human prostate tissues, 17 specimens (40%) of the 43 analyzed demonstrated positive staining for SA-beta-gal. In these tissues, SA-beta-gal expression was noted only in the epithelial cells. No statistical correlation (P = 0.42) between the chronologic age of the patient donor and SA-beta-gal expression was found. However, a high prostate weight (greater than 55 g) was found to correlate strongly with the expression of the SA-beta-gal biomarker (P = 0. 0001). CONCLUSIONS:Cultured prostatic epithelial cells expressed SA-beta-gal on reaching replicative senescence in vitro. The survey of human BPH specimens for the senescent marker showed that prostatic epithelial cells in patients with BPH with more advanced enlargement of the prostate (greater than 55 g prostate weight) expressed SA-beta-gal, and the prostates from patients with BPH that weighed less than 55 g tended to lack senescent epithelial cells. On the basis of these results, we propose that the accumulation of senescent epithelial cells may play a role in the development of the prostatic enlargement associated with BPH.

PURPOSE/OBJECTIVE:To describe our approach to intraoperative preplanning (INTRA-OP) for prostate implants and compare it to our standard method using a pre-implant volume study (STAND). METHODS AND MATERIALS/METHODS:Twenty patients (10 STAND, 10 INTRA-OP) were evaluated. Time required for each step of the INTRA-OP procedure was recorded. Overall procedure times and operating room times were obtained for all sessions. Postimplant dosimetry was CT-based. RESULTS:Mean times required for each stage of the INTRA-OP procedure were as follows: Pre-implant TRUS/prostate stabilization, 26 min; image transfer, 4 min; volume outlining, 8 min; plan generation, 18 min; initial needle loading, 17 min; seed implantation, 57 min. Mean time for the implantation session was 150 min for the INTRA-OP and 120 min for the STAND groups (p = 0.002). However, this difference is negated if the preplanning volume study is included. In addition, there was a trend toward a shorter time for the INTRA-OP patients when evaluating mean total operating room times (200 min vs. 220 min; p = 0.07). The mean postimplant %D80 for the INTRA-OP patients was 104. 8% vs. 116.2% for the STAND group (p = 0.1). The corresponding %D90 values were 85.3% and 94.6%, respectively (p = 0.08). CONCLUSION/CONCLUSIONS:Intraoperative preplanning increased the time required for the implantation session, but appeared to decrease overall operating room time. The overall convenience of the procedure makes intraoperative preplanning an attractive technique for transperineal ultrasound-guided prostate brachytherapy.

PURPOSE/OBJECTIVE:We investigate the potential use of the phytotherapeutic PC-SPES to treat human prostate cancer, and evaluate its in vivo and in vitro activity, and clinical efficacy. MATERIALS AND METHODS/METHODS:PC-SPES was evaluated for its ability to induce apoptosis on prostate cancer cell lines LNCaP, PC3 and DU145. The effect of oral PC-SPES on growth of PC3 tumors present in male immunodeficient mice was studied. A total of 30 male nude mice were divided in 5 groups. In groups 1 control and 2 full dose therapy was started the same day of the tumor injection. In groups 3 control, 4 half dose and 5 full dose PC-SPES therapy was initiated 1 week after tumor injection. A total of 69 patients with prostate cancer were treated with 3 capsules of 320 mg. PC-SPES daily. Serum prostate specific antigen (PSA) responses and side effects were evaluated. RESULTS:All of the cultured prostate cancer cell lines had a significant dose dependent induction of apoptosis following exposure to an alcoholic PC-SPES extract. Immunodeficient mice xenografted with the PC3 cell line had reduced tumor volume compared with sham treated controls when they were treated with a PC-SPES extract from the time of tumor cell implantation (931 +/- 89 versus 1,424 +/- 685 mm.3, p not significant) but not when the treatment was begun 1 week after tumor cell implantation. The testis, prostate, bladder and seminal vesicles of the treated mice were significantly reduced in weight compared with the sham treated animals. Of the patients with prostate cancer 82% had decreased serum PSA 2 months, 78% 6 months and 88% 12 months after treatment with PC-SPES. Side effects in the treated patient population included nipple tenderness in 42% and phlebitis requiring heparinization in 2%. CONCLUSIONS:An extract of the phytotherapeutic agent PC-SPES proved to be active in inducing apoptosis of hormone sensitive and insensitive prostate cancer cells in vitro, and in suppressing the growth rate of a hormone insensitive prostate cancer cell line in vivo. The overwhelming majority of patients with prostate cancer treated with the agent experienced a decrease in serum PSA but also demonstrated a side effect profile comparable to estrogen treatment.

Cryotherapy of the prostate represents a potential treatment for localized recurrent prostate cancer after radiation therapy. Current salvage cryotherapy of the prostate can result in undetectable serum PSA levels with low morbidity. Further refinements in technique and equipment may enhance cryosurgical results.

PURPOSE/OBJECTIVE:Herbal therapies are unconventional treatments that have been used for several different diseases. PC-SPES is an herbal mixture, composed of eight different herbs (chrysanthemum, isatis, licorice, Ganoderma lucidum, Panax pseudo-ginseng, Rabdosia rubescens, saw palmetto, and scutellaria), which has been used as an alternative in the treatment of prostate cancer. We report two cases of hormone-refractory prostate cancer patients, who showed a favorable response to therapy with this herbal combination, controlling the progression of the disease. METHODS:We report two cases of biopsy proven prostate cancer patients with metastatic disease, treated with total androgen blockade, progressing to an androgen-independent status. These patients were offered traditional therapies for hormone-resistant prostate cancer, and they chose to take PC-SPES. The follow-up as well as their evolution are described. RESULTS:PC-SPES extract decreased the prostate-specific antigen (PSA) value for both patients from an initial value of 100 and 386 ng/mL to 24 and 114 ng/mL after 1 year and 4 months, respectively, remaining stable until now. No gynecomastia or hot flashes were observed in these patients and the treatment was well tolerated. CONCLUSION/CONCLUSIONS:PC-SPES has shown a strong estrogenic in vitro and in vivo activity as an alternative tool in the management of prostate cancer patients. These cases suggest that PC-SPES might have some potential activity against hormone-independent prostate cancers.

PURPOSE/OBJECTIVE:Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent androgen deprivation therapy. Prostate specific antigen (PSA) is altered during androgen deprivation therapy, and as a result the prognostic significance and accuracy of PSA values measured before serum testosterone has normalized are questionable because the patient is still effectively on androgen deprivation therapy. We determine the time it takes for serum testosterone to return to normal after withdrawal of androgen deprivation therapy. MATERIALS AND METHODS/METHODS:Serial serum testosterone was prospectively measured at 3-month intervals in 68 men after withdrawal of androgen deprivation therapy. The number of months to return to normal serum testosterone 270 ng./dl. or greater, was calculated for each patient. Patients were stratified according to duration of androgen deprivation, age and type of luteinizing hormone releasing hormone agonist used. RESULTS:Median patient age was 71 years (range 46 to 88). Median time to normalization of testosterone was 7 months (range 1 to 58). At 3, 6 and 12 months 28%, 48% and 74% of men had normal serum testosterone, respectively. Serum testosterone took significantly longer to return to normal in patients on androgen deprivation therapy for 24 months or greater compared to those on therapy for less than 24 months (log-rank p = 0.0034). There was no statistical significance based on age or type of luteinizing hormone releasing hormone agonist used. CONCLUSIONS:Androgen deprivation has an effect on serum testosterone that extends beyond the cessation of treatment. Serum testosterone should be measured in all men until normalization. These results should be applied to the interpretation of PSA levels after withdrawal of androgen deprivation therapy. In addition, these data have implications regarding dose scheduling and definition of biochemical (PSA) failure after primary therapy.

PURPOSE/OBJECTIVE:Urinary retention requiring catheterization is a known complication among prostate cancer patients treated with permanent interstitial radioactive seed implantation. However, the factors associated with this complication are not well known. This study was conducted to determine these factors. METHODS AND MATERIALS/METHODS:Ninety-one consecutive prostate cancer patients treated with permanent interstitial implantation at our institution from 1996 to 1999 were evaluated. All patients underwent pre-implant ultrasound and postimplant CT volume studies. Isotopes used were (125)I (54 patients) or (103)Pd (37 patients). Twenty-three patients were treated with a combination of 45 Gy of external beam radiation therapy as well as seed implantation, of which only 3 patients were treated with (125)I. Mean pretreatment prostate ultrasound volume was 35.4 cc (range, 10.0-70.2 cc). The mean planning ultrasound target volume (PUTV) was 39.6 cc (range, 16.1-74.5 cc), whereas the mean posttreatment CT target volume was 55.0 cc (range, 20.2-116 cc). Patient records were reviewed to determine which patients required urinary catheterization for relief of urinary obstruction. The following factors were analyzed as predictors for urinary retention: clinical stage; Gleason score; prostate-specific antigen; external beam radiation therapy; hormone therapy; pre-implant urinary symptoms (asymptomatic/nocturia x 1 vs. more significant urinary symptoms); pretreatment ultrasound prostate volume; PUTV; PUTV within the 125%, 150%, 200%, 250%, 300% isodose lines; postimplant CT volume within the 125%, 150%, 200%, 250%, 300% isodose lines; D90; D80; D50; ratio of post-CT volume to the PUTV; the absolute change in volume between the CT volume and PUTV; number of needles used; activity per seed; and the total activity of the implant. Statistical analyses using logistic regression and chi2 were performed. RESULTS:Eleven of 91 (12%) became obstructed. Significant factors predicting for urinary retention were the total number of needles used (p < 0.038); the pretreatment ultrasound prostate volume (p < 0.048); the PUTV (p < 0.02); and the posttreatment CT volume (p < 0.021). Two of 51 patients (3.9%) requiring 33 or fewer needles (median) experienced obstruction vs. 9 of 40 (22.5%) requiring more than 33 (p < 0.007). If the pretreatment ultrasound prostate volume was 35 cc or less (median), 3 of 43 (7%) vs. 8 of 36 (22%) with a volume greater than 35 cc experienced obstruction (p < 0.051). CONCLUSION/CONCLUSIONS:The number of needles required (perhaps related to trauma to the prostate) and the prostate volumes were significant factors predicting for urinary retention after permanent prostate seed implantation.