Early results of radical prostatectomy and adjuvant endocrine therapy for prostate cancer with or without preoperative androgen deprivation

Background : The effects of preoperative androgen deprivation were explored in the patients who received radical prostatectomy and subsequent adjuvant endocrine therapy for prostate cancer.
Methods: Stage A₂, B or C prostate cancers were randomized to one of two groups: (i) group I ( n = 90), who received androgen deprivation (leuploride and chlormadinone acetate) for 3 months preoperatively followed by radical prostatectomy and adjuvant endocrine therapy (leuploride only); and (ii) group II ( n = 86), who underwent the surgery followed by 3 month androgen deprivation and subsequent adjuvant endocrine therapy. The effects of preoperative androgen deprivation on clinical relapse (serum prostate specific antigen (PSA) > 1.98 ng/mL, local recurrence or distant metastasis) and PSA relapse (PSA > 0.2 ng/mL) were evaluated at 2 years after randomization.
Results: There was no significant difference in clinical or PSA relapse-free survival and quality of life measures between the two groups, although relapses occurred significantly more frequently in patients who had more advanced stages, higher pretreatment PSA values or lower histologic differentiation in either group. Subgroup analysis indicated that clinical relapse-free survival in stage C cancer tended to be better in patients with preoperative androgen deprivation than in those patients without it ( P < 0.1).
Conclusions : Preoperative androgen deprivation may be beneficial for stage C prostate cancer patients receiving radical prostatectomy and adjuvant endocrine therapy over the 2 year observation period. A longer follow up is needed to clarify the exact extent of benefit in terms of survival and quality of life.     

Prostate specific antigen doubling time after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy

PURPOSE: We determined the predictors of prostate specific antigen (PSA) doubling time in patients with relapse after radical prostatectomy as well as whether PSA doubling time is shorter in those treated versus not treated with neoadjuvant androgen deprivation therapy. MATERIALS AND METHODS: We calculated PSA doubling time in 204 patients with PSA relapse after radical prostatectomy who were or were not treated with neoadjuvant androgen deprivation therapy. Analysis of covariance was used to determine the effect of clinical and pathological parameters on PSA doubling time, and the proportion of variability explained by these parameters. RESULTS: Clinical stage, and combined clinical stage and margin status, clinical stage and androgen deprivation therapy status, androgen deprivation therapy status and time to PSA relapse, and androgen deprivation therapy status and pretreatment PSA were significant predictors of PSA doubling time. Any variable or combination of variables explained up to only 21% of PSA doubling time variability. When stratified by pretreatment PSA, clinical stage and biopsy grade, the difference in doubling times in patients treated with or without neoadjuvant androgen deprivation therapy was significant only for 4.1 to 10 ng./ml. PSA. In this group mean doubling time plus or minus standard deviation in patients receiving neoadjuvant androgen deprivation therapy and those treated only with radical prostatectomy was 7.6+/-1.0 and 15.4+/-2.6 months, respectively. CONCLUSIONS: Our study indicates that it is difficult to predict PSA doubling time in an individual. The small proportion of variability in PSA doubling time explained by the interaction of androgen deprivation therapy status and other variables indicates that these factors are not clinically significant.     

Improving the Risk–Benefit Ratio of Endocrine Therapy in Prostate Cancer

ContextUntil very recently, it was known that endocrine therapy could improve progression-free survival but few studies could demonstrate a survival advantage in patients treated with early endocrine therapy.ObjectivesTo summarise indications and outcomes of endocrine therapy in prostate cancer and to review the different ways of reducing side-effects from this treatment modality.Evidence acquisitionSeveral randomised and nonrandomised clinical trials that deal with endocrine therapy for prostate cancer, its benefits, and its side-effects and that were published in the English literature were reviewed.Evidence synthesisAdjuvant endocrine therapy after local therapy for localised prostate cancer (T1-2 N0 M0) offers no survival advantage and has many side-effects. Treatment of locally advanced prostate cancer (T3-4 N0 M0, T1-4 N1 M0) with early androgen deprivation only has also been shown not to be superior to deferred androgen deprivation in either overall or prostate cancer-specific survival. In locally advanced prostate cancer, either radical prostatectomy or radiotherapy must be included to gain benefits from early androgen deprivation. Patients with prostate-specific antigen (PSA) relapse after local therapy for localised prostate cancer constitute a very specific group. PSA doubling time and tumour differentiation offer the opportunity to select different patient subgroups for endocrine therapy. In short-term analyses, intermittent androgen suppression seems to have fewer side-effects with equal effectiveness in cancer control; however, there are no data for either overall or prostate cancer–specific survival. Some side-effects of prolonged androgen suppression can be prevented with adjuvant medication. Biphosphonates have been demonstrated to prevent bone loss, while oestrogen receptor modulators, such as toremifene citrate, seem to alleviate side-effects such as bone metabolism, altered lipid profile, and hot flushes.ConclusionsEndocrine therapy is indicated in specific patient subgroups. Treatment strategies and adjuvant medication help to diminish treatment-associated toxicity.     

Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results.

PURPOSE: In the initial report of the Lupron Depot Neoadjuvant Prostate Cancer Study Group patients who received 3 months of androgen deprivation had a significant decrease in the positive margin rate. We monitored these patients for 5 years and to our knowledge present the longest followup of any neoadjuvant trial. MATERIALS AND METHODS: A multi-institutional prospective randomized trial was performed between February 1992 and April 1994 involving patients with stage cT2b prostate cancer, including 138 who received 3 months of leuprolide plus flutamide before radical prostatectomy and 144 who underwent radical prostatectomy only. Patients were followed every 6 months with serum prostate specific antigen (PSA) testing for 5 years. Biochemical recurrence was defined as PSA greater than 0.4 ng./ml. RESULTS: At 5 years there was no difference in the biochemical recurrence rate. PSA was less than 0.4 ng./ml. in 64.8% of the patients in the neoadjuvant androgen ablation plus prostatectomy and 67.6% in the prostatectomy only group (p = 0.663). CONCLUSIONS: Although 3 months of androgen deprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgical margins, a 5-year followup does not indicate any difference in the recurrence rate. Until studies document improvement in biochemical or clinical recurrence with longer periods of treatment, induction androgen deprivation before radical prostatectomy is not indicated.     

Preoperative Endocrine Therapy for Clinical Stage A2, B, and C Prostate Cancer: An Interim Report on Short-Term Effects

Background Preoperative endocrine therapy has been suggested to improve surgical radicality and/or patient prognosis in prostate cancer.
Methods Patients with clinical stage A₂, B, and C prostate cancer were randomized to either group I (n = 113) or group II (n = 111). Croup I patients were to receive preoperative endocrine therapy consisting of leuprolide and chlormadinone for 3 months, followed by radical prostatectomy with lymph node dissection. Group II patients were to undergo the surgery before endocrine therapy. Results: Group I patients showed a remarkable decrease in prostate-specific antigen (PSA) (mean ± SE: 41.8 ± 8.6ng/mL to 2.7 ± 0.7 ng/mt) and prostate volume (29.8 ± 1.7 mL to 21.2 ± 1.6 mL) during the preoperative therapy. Histopathologic analysis showed a significant difference in the rates of down-staging (19.1 % in group I versus 3.3% in group II), positive surgical margins (63.8% versus 81.3%) and positive lymph node metastasis (20.7% versus 36.5%). No significant difference was detected in operating features. Subgroup analyses indicated that beneficial effects were correlated positively with degree of histologic differentiation and negatively with the basal PSA level.
Conclusions Preoperative endocrine therapy reduced local extention of prostate cancer, and the effects depended on histologic differentiation and PSA level. Long-term follow-up data are needed to determine the effects on the patient prognosis.     

Endocrine therapy with or without radical prostatectomy for T1b-T3N0M0 prostate cancer

BACKGROUND: We retrospectively compared the 5-year survival rates of T1b-T3N0M0 prostate cancer patients treated either by endocrine therapy plus radical prostatectomy or endocrine therapy alone. METHODS: Clinical T1b-T3N0M0 prostate cancer patients were enrolled at 104 institutions in Japan. They were assigned to study 1 (n = 176), if they were indicated to prostatectomy, if not indicated, they were assigned to study 2 (n = 151). The indication of prostatectomy was based on the clinical judgement of physicians and/or patients. Those assigned to study 1 underwent prostatectomy and adjuvant endocrine therapy with or without preoperative androgen deprivation. Those assigned to study 2 were treated with leuprorelin acetate with or without chlormadinone acetate. They were followed-up every 3 months until death or for 5 years and over. RESULTS: Those assigned to study 1 were younger (mean age 67.2 vs 75.7 years), less advanced in clinical stage, and had lower prostate specific antigen levels (mean 43.8 vs 103.6 ng/mL). Death for any reason was observed less frequently in study 1 (n = 29, 16%) than study 2 (n = 50, 33%), and the 5-year overall survival rate was higher in study 1 (87 vs. 68%). However, prostate cancer deaths were comparatively seldom (9% in study 1 and 7% in study 2), resulting in the identical 5-year cause specific survival rate in both study groups (91%). In both study groups the overall survival was almost equal to the natural survival of age-matched men. CONCLUSIONS: Endocrine therapy offers a reasonable survival rate in T1b-T3 prostate cancer patients within a 5-year follow-up. Observation will be extended to determine 10-year outcomes.     

Medically and economically appropriate follow-up schedule for prostate cancer patients after radical prostatectomy

BACKGROUND: Our goal was to determine the optimal frequency and method of follow-up after radical prostatectomy to minimize medical cost without adversely affecting patients. METHODS: Two hundred and twenty-one patients who underwent a radical prostatectomy with or without adjuvant androgen deprivation from 1989 to 1999 were selected for the study. Eighty percent of the patients received postoperative androgen deprivation. Tumor recurrence was strictly defined as detectable serum prostate specific antigen (PSA) and/or clinical findings such as local tumor detection or bone metastasis. Thirty of 221 patients experienced tumor recurrence. Risk of tumor recurrence, procedures for detection of recurrence, and PSA doubling time after biochemical failure were analyzed. RESULTS: None of the 30 patients who were examined showed definitive local recurrence or metastatic sites on the imaging study at the time of initial PSA detection, and there were no observed recurrences in the absence of detectable serum PSA. In patients who showed elevated PSA within 12 months after radical prostatectomy, PSA levels rapidly increased with doubling times ranging from 1.2 to 13.7 months. Excluding those patients, the doubling time of PSA levels ranged from 2.8 to 31.5 months. CONCLUSIONS: Prostate specific antigen screening is sufficient to detect treatment failure after radical prostatectomy, irrespective of adjuvant hormone therapy. Based on the calculated doubling time, the longest advisable interval between checks of PSA levels is estimated to be four months within the first year after radical prostatectomy, and biannually or annually thereafter. Continuously elevated PSA levels or clinical symptoms indicate surveys for local recurrences and distant metastases.     

Prediction of organ-confined disease by prostate-specific antigen nadir after neoadjuvant therapy.

BACKGROUND: It is not clear whether or not serum prostate-specific antigen (PSA) levels after androgen deprivation prior to radical prostatectomy (neoadjuvant therapy) have any value in the prediction of the final pathologic stage. METHODS: We conducted a study on 49 patients who underwent retropubic radical prostatectomy following neoadjuvant therapy for clinical stage T1c, T2, and T3a prostate cancer. We evaluated progression-free survival based on the PSA failure rate and the predictive value of the PSA nadir after neoadjuvant therapy and other clinical factors to determine the most important predictor of organ confinement. RESULTS: Of the 49 patients, 30 had organ-confined disease. Of 31 patients without adjuvant therapy after surgery, the PSA failure-free rates at 2 years were 81.6 and 34.3% in the subset of organ-confined disease and non-organ-confined disease, respectively (P= 0.0031). Of the 18 patients with adjuvant androgen deprivation therapy after surgery, the PSA failure-free rate at 2 years was 100% and 59.7% in patients with organ-confined disease and non-organ-confined disease, respectively. Baseline PSA (P=0.037), PSA nadir (P<0.0001) and PSA density (P=0.003) significantly correlated with organ confinement. Multivariate logistic regression analysis revealed that the PSA nadir was the only independent predictor of organ confinement (P = 0.044). CONCLUSIONS: There was a trend that the patients with non organ-confined disease had a higher probability of PSA failure than did the patients with organ-confined disease. The PSA nadir after neoadjuvant therapy was the strongest predictor of organ confinement. The predictive value of the serum PSA nadir should be validated in well-designed larger population-based studies.     

Treatment of patients with high risk localized prostate cancer: results from cancer of the prostate strategic urological research endeavor (CaPSURE)

PURPOSE: Pretreatment risk assessment models facilitate more appropriate selection of treatment for prostate cancer. However, men with high risk disease remain a challenge with significant potential for primary treatment failure. We characterize patterns of treatment for high risk prostate cancer in a community based cohort. MATERIALS AND METHODS: In the Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) database, a longitudinal disease registry of men with prostate cancer, we identified those with nonmetastatic, high risk disease based on T stage, tumor grade and serum prostate specific antigen (PSA). Differences in primary treatment, and the use of neoadjuvant and adjuvant therapy in patients at low, intermediate and high risk were assessed. In the high risk cohort predictors of the type of primary treatment, and the use of neoadjuvant and adjuvant androgen therapy were identified. RESULTS: Of the cancers 34%, 40% and 26% were low, intermediate and high risk, respectively. Differences in primary treatment type among the 3 risk groups were statistically significant (p <0.0001) with increasing external beam radiation therapy and androgen deprivation, and decreased surgery, brachytherapy and surveillance in men with high risk cancers. In this group older age, higher PSA and nonprivate insurance were associated with decreased use of radical prostatectomy. More than half of the men at high risk receiving radiation therapy also received androgen deprivation, which was significantly higher than in the low and intermediate risk groups (p <0.0001). Factors associated with androgen deprivation in high risk disease were primary therapy, PSA, Gleason sum, T stage, body mass index, insurance status and ethnicity. PSA and Gleason sum were the primary determinants of adjuvant radiation after prostatectomy. CONCLUSIONS: Men with high risk but nonmetastatic prostate cancer are more likely to receive radiation therapy as well as androgen deprivation with the latter as primary therapy or in conjunction with local treatment. These data stress the importance of pretreatment risk stratification, education regarding appropriate combinations of local and systemic therapies, and the consideration of novel clinical trials in patients at higher risk.     

RACE AS AN INDEPENDENT PREDICTOR OF OUTCOME AFTER TREATMENT FOR LOCALIZED PROSTATE CANCER

PURPOSE: We analyze the outcome after prostatectomy or radiotherapy for localized prostate cancer with respect to race. MATERIALS AND METHODS: A total of 2,219 consecutive patients with prostate cancer were treated with radiotherapy (1,183) or radical prostatectomy (1,036) between June 1986 and June 1998. Initial prostate specific antigen (PSA) and biopsy Gleason scores were available in all cases. Androgen deprivation was used in 22% of men (492). Of the patients 86% (1,901) were white, including Hispanic and Asian, and 14% (318) were black. The outcomes of interest were biochemical relapse-free survival, clinical relapse-free survival and overall survival. Median followup was 24 months (range 2 to 140). RESULTS: There was no difference in the incidence of familial prostate cancer, patient age at presentation, clinical stage or biopsy Gleason scores between black and white men. However, black men had higher initial PSA levels (median 13.3 versus 8.6 for white men, p<0.001). The 5-year biochemical relapse-free survival rate was 59% for the entire group, 54% (95% confidence interval 44 to 63) for black men and 61% (95% confidence interval 57 to 65) for white men (p = 0.11). Multivariate analysis was performed for the variables of age, race, family history of prostate cancer (brother or father), initial PSA, biopsy Gleason sum, clinical T stage, treatment modality and androgen deprivation. Familial prostate cancer (p = 0.001), higher T stage (p<0.001), higher initial PSA (p<0.001), higher biopsy Gleason score (p<0.001) and use of androgen deprivation (p = 0.001) were independent predictors of biochemical failure and all other factors, including race, were not (p = 0.46). The projected 10-year clinical relapse-free survival rate was 74% for the entire group, and was identical for black and white men (p = 0.77). The projected 10-year overall survival rate for black and white men was 92 and 79%, respectively (p = 0.62). CONCLUSIONS: We have demonstrated a statistically nonsignificant trend for higher biochemical failure rates in black men presenting with localized prostate cancer. This trend could be due to the higher pretreatment PSA levels in black patients. Treatment recommendations should not differ with respect to race.     

Adjuvant hormone therapy in patients with positive surgical margins after radical prostatectomy

BACKGROUND: We carried out a retrospective study comparing radical prostatectomy plus adjuvant hormone therapy with radical prostatectomy plus surveillance in patients with positive surgical margins to evaluate whether adjuvant hormone therapy is beneficial for disease free survival. PATIENTS AND METHODS: Sixty-five patients with positive surgical margins after radical prostatectomy were included in this study. Twenty-six patients received adjuvant hormone therapy. Thirty-nine patients underwent surveillance with salvage hormone therapy at PSA failure. None of these 65 received androgen deprivation prior to surgery. Treatment outcomes were measured in terms of progression free survival. RESULTS: Five year clinical progression free survival rates for the patients with positive surgical margins in the adjuvant therapy group and surveillance group were 85.9% and 80.0% respectively (p = 0.85). Clinical progression free survival between the groups was not statistically different in terms of seminal vesicle involvement and tumor grade. The difference of clinical progression free survival between the two groups approached statistical significance in poorly differentiated tumor (p = 0.08). CONCLUSIONS: We conclude that adjuvant hormone therapy is not beneficial in terms of progression free survival in patients with positive surgical margins. Nevertheless, adjuvant hormone therapy could be beneficial in patients with poorly differentiated prostate cancer.     

Significance of androgen deprivation prior to radical prostatectomy,with special reference to prostate-specific antigen

Summary A total of 37 selected patients with clinical stage T2b or T3 prostate cancer received androgen deprivation prior to radical retropubic prostatectomy. A luteinizing hormone-releasing hormone (LHRH) analog alone was given to 15 individuals; 19 received an LHRH analog with flutamide. Three underwent bilateral orchiectomy instead of chemical castration. The duration of androgen deprivation prior to radical prostatectomy varied from 3 to 16 months, with 31 individuals undergoing induction therapy for 3–6 months. Three received androgen deprivation for more than 1 year. In all, 15 patients had clinical stage T2b disease and 22, stage T3 prostate cancer. The prostate size decreased approximately 30%–50% following induction therapy. Prostate-specific antigen (PSA) values decreased in all 19 instances where this was obtained. In all, 6 of 15 (40%) patients with clinical T2b lesions and 9 of 22 (41%) with clinical T3 tumors had a positive surgical margin; 5 (13%) had 1 or more positive lymph nodes. Androgen deprivation was continued following surgery in 13 cases. Only one patient received postoperative radiation therapy. After a mean follow-up period of 33 months, 35 (95%) patients are alive. Two patients died, one of poorly differentiated prostate cancer with subsequent metastasis and one of a myocardial infarction 33 months after surgery without showing any evidence of disease. Of 23 patients without postoperative adjuvant therapy, 6 (26,1%) progressed (PSA level, >0.4 ng/ml). None of the patients who underwent adjuvant therapy progressed over a follow-up period of 6–75 months (mean, 38 months). Although the low incidence of positive lymph nodes and the apparent reduction in tumor size after androgen deprivation are encouraging, the benefits of this approach must await the completion of ongoing randomized trials.     

Clinical outcome of patients with lymph node positive prostate cancer after radical prostatectomy versus androgen deprivation

OBJECTIVE(S): To compare the outcome of patients with stage D1 (TxN+M0) prostate cancer undergoing radical prostatectomy or androgen deprivation alone. PATIENTS AND METHODS: Eighty-two patients treated for lymph node positive prostate cancer were retrospectively analyzed for time to progression, tumor-specific and overall survival. Furthermore, subsequent tumor and treatment related morbidity requiring intervention including frequency and duration of associated hospital stays was recorded. RESULTS: The extent of lymph node metastasis was significantly lower in 50 patients undergoing radical prostatectomy (+/- early androgen deprivation) compared to 32 receiving androgen deprivation only. The treatment groups, however, did not differ with regard to other characteristics including age, comorbidity, stage, grade and preoperative PSA. Mean actuarial progression-free, and tumor-specific survival was significantly longer for the radical prostatectomy patients (36% and 47%, respectively at 10 years) compared to androgen deprivation (15% and 32%, respectively). The latter group required more secondary interventions resulting in more frequent and overall longer hospital stays. CONCLUSIONS: Patients undergoing radical prostatectomy for stage D1 prostate cancer possibly benefit with regard to the necessity for secondary interventions and, at least for limited (solitary) nodal disease, in terms of progression-free and tumor-specific survival. However, the latter observation may be biased by a larger extent of lymph node metastasis in the androgen deprivation group.     

PSA relapse prostate cancer: the importance of tailored therapy

Prostate specific antigen (PSA) is an invaluable tumor marker in the detection of early prostate cancer as well as a predictor of recurrence after treatment of localized disease. Current practice entails the use of factors such as pretherapy grade, stage and PSA, PSA doubling time, nature of previous therapy and patient age and functional status for a treatment recommendation. For a PSA relapse post radical prostatectomy, radiation therapy to the prostatic fossa is a primary therapeutic consideration. With careful patient selection, about 30 to 40% of patients are rendered disease free using this approach. For patients with radiation therapy as the primary treatment for their prostate cancer, salvage prostatectomy can be considered, but is rarely feasible. Systemic therapy with hormones is standard if patients are not candidates for the above mentioned salvage local therapies or if they relapse after exhaustive local therapies. Unfortunately androgen suppressive therapy is unlikely to induce cure, or prolonged remissions in PSA relapse prostate cancer. The strategy of addition of chemotherapy or biologic therapy to androgen suppressive therapy is under active investigation. The goal of this therapy is to make an impact on the time to progression to metastatic prostate cancer and correspondingly decrease prostate cancer related mortality. Preliminary results of studies incorporating early chemotherapy in combination with androgen suppressive therapy are encouraging, with improvement in time to progression and overall survival. The evaluation of biologic agents and agents with better toxicity profiles is ongoing. This is very important to make therapy widely applicable and to enable prolonged administration especially in a disease such as prostate cancer with a relatively long natural history. Strategies of adjuvant and neoadjuvant therapy in locally advanced prostate cancer are exploring the possibility of reducing the chance of PSA relapse by treating micrometastatic disease. This review discusses the current practices in risk stratification and management of PSA relapse prostate cancer. It also highlights the major clinical trials and areas of active investigation in this field.     

Clinical significance of nonpalpable prostate cancer with favorable biopsy features in Japanese men

OBJECTIVE: To assess the clinical significance of nonpalpable localized prostate cancers with relatively favorable six sextant biopsy features in Japanese men. PATIENTS AND METHODS: 136 nonpalpable prostate cancers of which biopsy features confined to (1) a Gleason score of 6 or less, (2) one or two positive cores per six sextant cores, and (3) 50% or less involvement of any positive core were collected. The Gleason score, tumor extension, and cancer volume were compared with preoperative serum PSA and PSA density for the patients who underwent radical prostatectomy. PSA doubling time was measured for the patients who were treated expectantly. RESULTS: Treatments chosen for 136 patients with favorable biopsy features were radical prostatectomy alone for 48 and with preoperative androgen deprivation for 30, radiation to the prostate for 12, androgen deprivation therapy for 21, and watchful waiting for 25. Of 48 patients who underwent radical prostatectomy without androgen deprivation therapy, 25% had nonorgan-confined cancers. Seven cancers (14.6%) were Gleason score of 7, but no cancers were 8 or greater. Among 42 prostatectomy specimens for which cancer volume was measured, 22 (52.4%) had cancer volume >0.5 cm(3). Pretreatment serum PSA levels were correlated neither with the Gleason score, tumor extension nor cancer volume. There was only one nonorgan-confined cancer in the 23 cancers for which PSA density was <0.2 ng/ml/g. The ability of PSA density to predict cancer volume <0. 5 cm(3) was 0.61 using a cut-off of 0.2 ng/ml/g. Of the 25 patients treated expectantly, the PSA doubling time was less than 2 years for 3 patients, while it was stable or fluctuated for 13. CONCLUSIONS: Tumor extension can be predicted based on PSA density in nonpalpable prostate cancer with favorable biopsy features, but predictability of cancer volume based on PSA or PSA density is not satisfactorily high. New parameters or biomarkers that complement needle biopsy findings are needed to predict clinical significance of T1c prostate cancer with favorable biopsy features.     

The role of radical prostatectomy in patients with clinically localized prostate cancer and a prostate-specific antigen level >20 ng/ml

OBJECTIVES: To determine the outcome of patients with a serum prostate-specific antigen (PSA) level >20 ng/ml that underwent radical prostatectomy (RP). METHODS: We retrospectively reviewed the medical records of 147 patients who underwent RP for clinically localized prostate cancer with a pre-treatment PSA (PSApt) >20 ng/ml. Fifty-two patients had positive pelvic lymph nodes and were excluded from analysis. Of 95 patients remaining, 15 were lost to follow-up. Therefore, the study group included 80 patients. The end points for this analysis were biochemical relapse-free survival (bRFS), surgical and post-operative complications and urinary continence. PSApt, pathological grade, surgical margin status, age, clinical stage and immediate androgen ablation were evaluated in a multivariate analysis regarding bRFS. RESULTS: Forty-nine resected specimens (61.2%) were pathologically classified as pT3 or pT4. After a mean follow-up of 64 months, the estimated 5-year bRFS rate was 58% for the overall group. Immediate androgen ablation was the only independent prognostic factor for biochemical relapse (P=0.001). Concerning the 21 patients who received an immediate androgen ablation after RP, the estimated 5-year bRFS rate was 92%. Complete urinary continence was achieved in 76.5% of patients. Early complications occurred in 13 patients (16.2%). CONCLUSIONS: Clinically localized prostate cancer with a PSApt >20 ng/ml is considered as having a poor prognosis. However, RP performed in these patients led to an acceptable morbidity and good functional results. Immediate adjuvant hormonal therapy seems mandatory in this setting to improve bRFS.     

PSP94 expression after androgen deprivation therapy: a comparative study with prostate specific antigen in benign prostate and prostate cancer

PURPOSE: To examine the clinical use of PSP94 (prostate secretory protein of 94 amino acids) as an androgen independent marker, we conducted a comparative study of prostate samples including benign tissue and cancers which did and did not have androgen deprivation. MATERIALS AND METHODS: Among 163 radical prostatectomy cases 75 had androgen deprivation before operation, while surgery was performed in the remainder without prior hormone treatment. Considering the pathological up grading following hormone therapy, contiguous sections from radical prostatectomy samples were stained for PSP94 and prostate specific antigen (PSA) by immunohistochemistry, and equivalent tumor foci were evaluated by assessing the intensity and extent of the staining. RESULTS: In untreated benign prostate tissue PSP94 and PSA staining was positive and identical in all sections in the no pretreatment group. However, PSP94 expression in the androgen deprivation group was significantly higher than PSA in intensity (p = 0.0005) and extent (p = 0.034). In untreated cancer cases PSP94 intensity and extent demonstrated strong inverse association with Gleason grade (p <0.0001). In contrast, PSA expression was high in every grade, resulting in no statistical association with tumor grade. In the androgen deprivation group PSA staining was decreased in every grade compared to the no pretreatment group. On the other hand, PSP94 expression was decreased in grade 3 tumor foci but increased in grades 4 and 5 tumor foci compared with samples of the corresponding grade in the no pretreatment group (p = 0.0034). CONCLUSIONS: PSP94 expression in benign prostate persists under androgen deprivation compared to PSA. PSP94 synthesis in high grade tumor appears to be activated in the absence of androgen stimulation, indicating the possible alternative pathways in the regulation of PSP94.     

Response to second-line hormonal manipulation monitored by serum PSA in stage D2 prostate carcinoma.

Changes in prostate-specific antigen (PSA) have been demonstrated to accurately assess response to initial hormone deprivation in metastatic prostate cancer patients. The role of PSA in monitoring response to second-line hormonal treatment has not been documented. In a group of 20 patients with an initial response to androgen deprivation and subsequent relapse, we monitored PSA levels before and after second-line therapy. Ten patients had a clinical response. Four had a more than 90 percent decrease in serum PSA compared with the level at initial progression. This clinical response was maintained for a mean of eighteen months. Six patients had a PSA decrease less than 90 percent; their clinical response was of a mean 5.5 months. Ten patients had no change or increase in PSA. Seven had no clinical response, and 3 responded for an average of four months. Although production of PSA might be under endocrine control, changes in PSA are useful for monitoring response to second-line hormonal therapy.     

Induction androgen deprivation plus prostatectomy for stage T3 disease: Failure to achieve prostate-specific antigen-based freedom from disease status in a phase II trial

Objectives

There is interest in treating prostate cancer with induction androgen deprivation prior to radical prostatectomy. Data on long-term prostate-specific antigen (PSA)-based survival analyses among patients treated with neoadjuvant hormonal therapy (NHT) and prostatectomy are limited. In 1991 we instituted a pilot study for T3 disease based on endorectal coil magnetic resonance imaging (eMRI), mandatory negative laparoscopic nodal dissection prior to hormonal manipulation, and prostatectomy followed by pathologic and PSA-based outcome determinations.

Methods

Of 26 patients, 21 had negative laparoscopic lymphadenectomy followed by 4 months of NHT (leuprolide ± flutamide) prior to radical prostatectomy. eMRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3-month intervals. Prostatectomy specimens were evaluated by 3-mm whole-mount step sections.

Results

Prior to prostatectomy, biochemical response was documented in all patients and downsizing was observed by eMRI in 57%. Pathologic downstaging to a lower stage (T2c or lower) was achieved in 48%. However, the actuarial 3-year freedom from biochemical relapse rate was only 24%.

Conclusions

Using laparoscopy to exclude node-positive patients and 4 months of NHT appears to result in pathologic and initial biochemical evidence of regression. These factors have not translated into improved freedom from biochemical relapse among patients with Stage T3 disease treated with NHT and prostatectomy. Recent data strongly suggest a beneficial effect in patients with clinical T2 disease treated with NHT and radical prostatectomy. The NHT and radical prostatectomy approach appeared to offer no clear advantage when compared with PSA-based benchmarks achieved with conformal irradiation or NHT followed by external beam treatment among patients with clinical T3 disease.     

Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin

PURPOSE: Positive surgical margins are common after radical prostatectomy, and the role of adjuvant therapy in such cases is controversial. We determined the benefit of postoperative external beam radiation therapy in patients with margin positive prostate cancer with respect to biochemical progression or cancer recurrence. To decrease confounding factors that may affect the likelihood of biochemical progression our study was limited to men with organ confined cancer and a single positive margin. MATERIALS AND METHODS: We retrospectively evaluated the records of a nested matched cohort of 76 patients with pathological stage T2N0 prostate cancer and a single positive margin who underwent adjuvant radiation therapy within 3 months of radical prostatectomy. There was a positive margin at the prostatic apex in 35 cases, prostatic base in 18, posterior prostate in 11, urethra in 7, and prostatic apex and urethra in 5. These patients were matched 1:1 with 76 controls who did not receive adjuvant radiation therapy. Neither group received androgen deprivation therapy. Patients and controls were matched exactly for the margin positive site, age at surgery, preoperative serum prostate specific antigen, Gleason score and DNA ploidy. Biochemical relapse was defined as posttreatment PSA greater than 0.2 ng./ml. RESULTS: Overall there was significant estimated improvement plus or minus standard error in 5-year clinical and biochemical progression-free survival in 88%+/-5% versus 59%+/-11% of patients treated with adjuvant radiation therapy versus no radiation therapy (p = 0.005). No patient who received radiation therapy had local or distant recurrence, while 16% of controls had recurrence (p = 0.015). When stratified by site of margin positivity, the 5-year estimated clinical and biochemical progression-free rate in 18 cases and controls with a positive base margin was 95%+/-15% and 65%+/-13%, respectively (p = 0.02). The rate in 35 cases and cases with a positive apex margin was 95%+/-5% and 64%+/-15%, respectively (p = 0.07). Limited sample size precluded analysis of the other sites. CONCLUSIONS: Patients with localized prostate cancer and a singe positive surgical margin appear to have a lower rate of biochemical relapse at 5 years when adjuvant radiation therapy is administered. Definitive evidence of the beneficial effect of adjuvant radiation therapy for patients with involved surgical margins awaits conclusion of randomized clinical trials.