Prostate-specific Antigen Relapse Research Articles

An Exploratory Study of Endorectal Magnetic Resonance Imaging and Spectroscopy of the Prostate as Preoperative Predictive Biomarkers of Biochemical Relapse After Radical Prostatectomy

Radical prostatectomy has significant side effects. Preoperative information predicting its long-term outcome would be valuable to patients and physicians. We determined whether pretreatment endorectal magnetic resonance imaging/magnetic resonance spectroscopic imaging predicts biochemical recurrence after radical prostatectomy. Of 202 patients who underwent endorectal magnetic resonance imaging/magnetic resonance spectroscopic imaging from January 2000 to December 2002 before radical prostatectomy 130 satisfied study inclusion criteria and were included in analysis. We compared imaging factors with potential predictive capability to biochemical recurrence data, including magnetic resonance imaging risk score based on local disease extent and magnetic resonance spectroscopic imaging index lesion characteristics, such as the number of voxels and degree of metabolic abnormality (magnetic resonance spectroscopic imaging grade). We evaluated associations of these imaging variables with time to biochemical recurrence by Cox proportional hazards regression adjusted for known predictors of biochemical recurrence, such as stage, grade and prostate specific antigen. At a median 68-month followup there were 26 biochemical failures. Risk score, lesion volume and high grade voxels each correlated with time to biochemical recurrence. In a model combining clinical parameters risk score, lesion volume and at least 1 high grade voxel the magnetic resonance spectroscopic imaging variables remained significant but the magnetic resonance imaging score dropped out. Index lesion volume on magnetic resonance spectroscopic imaging and high grade magnetic resonance spectroscopic imaging voxels correlate with time to biochemical recurrence after radical prostatectomy even when adjusted for clinical data. Results suggest the preoperative predictive usefulness of endorectal magnetic resonance imaging/magnetic resonance spectroscopic imaging in patients considering radical prostatectomy.

A multi-institutional analysis comparing adjuvant and salvage radiation therapy for high-risk prostate cancer patients with undetectable PSA after prostatectomy

Background and purpose In men with adverse pathology at the time of radical prostatectomy (RP), the most appropriate timing to administer radiotherapy (RT) remains a subject for debate. To determine whether salvage radiotherapy (SRT) upon early prostate-specific antigen (PSA) relapse is equivalent to immediate adjuvant radiotherapy (ART) post RP. Material and methods 130 patients receiving ART and 89 receiving SRT were identified. All had an undetectable PSA after RP. Homogeneous subgroups were built based on the status (±) of lymphatic invasion (LVI) and surgical margins (SM), to allow a comparison of ART and SRT. Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT. The multivariate analysis was performed using the Cox Proportional hazard model. Results In the SM−/LVI− and SM+/LVI− groups, SRT was a significant predictor of a decreased bDFS from the date of surgery, while in the SM+/LVI+ group, there was a trend towards significance. From the end of RT, SRT was also a significant predictor of a decreased bDFS in three patient groups: SM−/LVI−, SM+/LVI− and SM+/LVI+. Gleason score >7 showed to be another factor on multivariate analysis associated with decreased bDFS in the SM−/LVI− group, from the date of surgery and end of RT. Preoperative PSA was a significant predictor in the SM−/LVI− group from the date of RP only. Conclusions Immediate ART post RP for patients with high risk features in the prostatectomy specimen significantly reduces bDFS after RP compared with early SRT upon PSA relapse.

Significant prognostic factor of immunohistochemical HER‐2 expression using initial prostate biopsy specimens with M1b prostate cancer

We examined whether human epidermal growth factor-2(HER-2) overexpression could be a useful marker of outcome after hormone therapy in patients with M1b prostate cancer (PC). The subjects were 102 patients who were diagnosed with M1b PC at Aichi Medical University Hospital. HER-2 expression was determined by immunohistochemical (IHC) staining using initial needle biopsy specimens for diagnosis. The results were classified into four grades (0, 1+, 2+, 3+), and scores of 1+ or greater were considered overexpression and defined as positive. The results showed a rating of 0 in 72 subjects, 1+ in 10, 2+ in 14, and 3+ in 6; 30 subjects (29.4%) were classified as HER-2 positive. Comparison of clinical data of HER-2 positive and negative subjects obtained at baseline revealed many of the subjects with high-grade tumors by Gleason score were HER-2 positive (P = 0.030). The prostate-specific antigen (PSA) relapse was observed in 76 subjects and cause-specific death occurred in 44. A significant difference was observed only in the item HER-2 (negative vs. positive) by multivariate Cox proportional hazard analysis. The 5-year PSA relapse-free rate was 0% in subjects with HER-2 positive (26/30), and 43.9% in subjects with HER-2 negative (50/72, P = 0.0192). The 5-year cause-specific survival rate was 40.9% in subjects with HER-2 positive (30/102), and 67.3% in subjects with HER-2 negative (72/102, P = 0.0301). HER-2 overexpression as determined by IHC staining using needle biopsy specimens for diagnosis with M1b PC is a significant prognostic factor for PSA relapse after hormone therapy and unfavorable outcome.

Second-Line Antiandrogen Therapy in Japanese Men with Advanced Prostate Cancer Relapsed after Primary Combined Androgen Blockade: Who Will Benefit from Second-Line Hormonal Therapy?

Objectives: To identify patients who benefit from the salvage hormonal therapy in men with advanced prostate cancer who relapsed after primary hormonal therapy. Patients and Methods: The study included 68 patients treated with primary combined androgen blockade followed by second-line antiandrogen therapy at prostate-specific antigen (PSA) relapse. The cause-specific survival after second-line therapy was compared according to various clinical factors. Results: Of the several variables isolated as prognostic factors, the duration of response to first-line therapy remained as an independent prognostic factor by multivariate analysis. The comparative survival curves constructed according to the duration of response in first-line therapy and the responsiveness to second-line therapy clearly discriminate the patients' survival. The nadir PSA level in first-line therapy was well substituted for the responsiveness to second-line therapy, thereby enabling to predict the clinical outcome using the readily available variables before second-line therapy. Namely, the patients who failed to attain the duration of response ≥12 months and the nadir PSA <0.2 ng/ml in first-line therapy are unlikely to benefit from second-line therapy. Conclusions: These results may imply an inherent unresponsiveness to salvage hormonal therapy in patients who showed insufficient response to primary hormonal therapy and therefore an early introduction of chemotherapy might be an option for such patients.

Comparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT

Purpose We report on a retrospective comparison of biochemical outcomes using an ultra-high dose of conventionally fractionated intensity-modulated radiation therapy (IMRT) vs. a lower dose of IMRT combined with high-dose-rate (HDR) brachytherapy to increase the biologically effective dose of IMRT. Methods Patients received IMRT of 86.4 Gy ( n = 470) or HDR brachytherapy (21 Gy in three fractions) followed by IMRT of 50.4 Gy ( n = 160). Prostate-specific antigen (PSA) relapse was defined as PSA nadir + 2. Median followup was 53 months for IMRT alone and 47 months for HDR. Results The 5-year actuarial PSA relapse-free survival (PRFS) for HDR plus IMRT vs. ultra-high-dose IMRT were 100% vs. 98%, 98% vs. 84%, and 93% vs. 71%, for National Comprehensive Cancer Network low- ( p = 0.71), intermediate- ( p < 0.001), and high-risk ( p = 0.23) groups, respectively. Treatment ( p = 0.0006), T stage ( p < 0.0001), Gleason score ( p < 0.0001), pretreatment PSA ( p = 0.0037), risk group ( p < 0.0001), and lack of androgen-deprivation therapy ( p = 0.0005) were significantly associated with improved PRFS on univariate analysis. HDR plus IMRT vs. ultra-high-dose IMRT ( p = 0.0012, hazard ratio [HR] = 0.184); age ( p = 0.0222, HR = 0.965); and risk group ( p < 0.0001, HR = 2.683) were associated with improved PRFS on multivariate analysis. Conclusion Dose escalation of IMRT by adding HDR brachytherapy provided improved PRFS in the treatment of prostate cancer compared with ultra-high-dose IMRT, independent of risk group on multivariate analysis, with the most significant benefit for intermediate-risk patients.

KLK15 is a prognostic marker for progression-free survival in patients with radical prostatectomy

In search of biomarkers for prostate cancer, we evaluated the expression of the human kallikrein-related peptidase KLK15 in samples of prostatic adenocarcinomas from radical prostatectomies. Twenty-five pairs of cancerous and adjacent normal prostatic tissue were selected by laser capture microdissection. The tissue was used for quantification of KLK15 mRNA by reverse-transcriptase polymerase chain reaction. Immunohistochemical expression of the KLK15 protein in 193 samples of prostatic adenocarcinoma was analysed in relation to clinicopathological parameters of the patients and disease progression. Expression of KLK15 correlated with the pathological tumour stage and Gleason score of the cases, both at mRNA and at protein level. While mRNA expression in the tumour was elevated, the protein level of KLK15 was reduced compared with adjacent normal tissue and to prostatic intraepithelial neoplasia. Univariate Kaplan-Meier analysis showed a significant association of dichotomised KLK15 levels with disease progression defined by prostate-specific antigen relapse (p = 0.001). Multivariate analysis according to the Cox proportional hazards regression model identified dichotomised KLK15 expression, corrected for the patient parameters age, preoperative prostate-specific antigen level, pathological tumour stage, Gleason score and surgical margin status, as an independent prognostic factor for poor outcome (inclusion model, hazard ratio 1.802, 95% confidence interval 1.037-3.132, p = 0.037). We suggest KLK15 as a new independent tumour marker for patients at risk for disease progression after radical prostatectomy.

Radical prostatectomy as initial monotherapy for patients with pathologically confirmed high‐grade prostate cancer

To report the long-term outcome of high-grade prostate cancer treated with radical prostatectomy (RP) as initial monotherapy, analyse the effect of clinical and pathological variables on survival, and report cancer-related symptoms. A retrospective chart review was conducted to identify patients with Gleason 8-10 prostate cancer found on pathological review in men undergoing RP as initial therapy for clinically localized disease between 1988 and 2005. Kaplan-Meier analysis was used to calculate event-free survival. Univariable and multivariable analyses were used to assess the effects of clinical and pathological variables on prostate-specific antigen (PSA) recurrence. After excluding 20 patients, 119 were identified with pathologically confirmed high-grade cancers at the time of RP. The overall median (interquartile range) follow-up was 73 (41-113) months. Twenty-four (20%) patients had organ-confined cancer, 60 (50%) had specimen-confined cancer, and 14 (12%) had nodal metastasis. Kaplan-Meier analysis showed overall survival rates at 5 and 10 years, respectively, of 90% and 75%, cancer-specific survival of 92% and 82%, and a PSA recurrence-free follow-up at 5 years of 31%. Using univariable analysis, preoperative PSA level, pathological Gleason score, pathological stage, surgical margin status and tumour volume were found to significantly affect the PSA recurrence-free follow-up. No variables were significant on multivariable analysis. Cancer-related symptoms were reported by only 14 patients, with a median time from surgery to first symptom of 43 months. High-grade prostate cancer can be treated with RP as initial monotherapy with an acceptable 10-year cancer-specific survival (82%). The PSA recurrence-free follow-up is poor (31% at 5 years). However, few patients progress to symptomatic recurrence after PSA relapse within the first 5 years.

Does a tertiary Gleason pattern 4 or 5 influence the risk of biochemical relapse after radical prostatectomy for clinically localized prostate cancer?

The presence of a tertiary Gleason grade (TGG) pattern 4 or 5 in radical prostatectomy (RP) specimens has been reported with adverse pathology and a higher biochemical relapse rate after RP. This study investigated the impact of a TGG pattern 4 or 5 on biochemical and pathological outcome in men operated with RP. The study reviewed 151 consecutive cases treated at the hospital between 1985 and 2006; 148 were included in the study. All prostatectomy specimens were re-examined by a genitourinary pathologist and among others parameters the presence of TGG pattern 4 or 5 was recorded. The hospital files were examined retrospectively for clinical follow-up data. Prostate-specific antigen (PSA) relapse was defined as two subsequent rising measurements above 0.20 ng/ml. The influence of a TGG pattern 4 or 5 on prognosis was assessed in a Cox proportional hazards regression model controlling for pathological stage, surgical margin (SM) status, seminal vesicle invasion (SVI) and extraprostatic extension (EPE). Fifty-six patients (38%) experienced PSA relapse during follow-up. Twenty-one patients (58%) with a TGG pattern 4 or 5 had a biochemical relapse compared with 35 patients (31%) without TGG pattern 4 or 5. In the Cox regression model, TGG pattern 4 or 5 was an independent predictor of biochemical failure (p = 0.020). In patients undergoing RP the presence of a TGG pattern 4 or 5 is an independent predictor for biochemical relapse. Consequently, the RP specimens should routinely be investigated for TGG pattern 4 or 5.

Predicting Post–External Beam Radiation Therapy PSA Relapse of Prostate Cancer Using Pretreatment MRI

To investigate whether pretreatment endorectal magnetic resonance imaging (MRI) findings can predict biochemical relapse in patients with clinically localized prostate cancer treated with external beam radiation therapy (EBRT). Between January 2000 and January 2002, 224 patients (median age, 69 years; age range, 45-82 years) with biopsy-proven prostate cancer underwent endorectal MRI before high-dose (≥81Gy) EBRT. The value of multiple clinical and MRI variables in predicting prostate-specific antigen (PSA) relapse at 5 years was determined by use of univariate and multivariate stepwise Cox regression. Clinical variables included pretreatment PSA, clinical T stage, Gleason score, use of neoadjuvant hormonal therapy, and radiation dose. Magnetic resonance imaging variables, derived from retrospective consensus readings by two radiologists, were used to measure intraprostatic and extraprostatic tumor burden. After a median follow-up of 67 months, PSA relapse developed in 37 patients (16.5%). The significant predictors of PSA relapse on univariate analysis were pretreatment PSA, clinical T stage, and multiple MRI variables, including MRI TN stage score; extracapsular extension (ECE) status; number of sextants involved by ECE, all lesions, or index (dominant) lesion; apical involvement; and diameter and volume of index lesion. Pretreatment PSA and ECE status were the only significant independent predictors on multivariate analysis (p < 0.05 for both). Extracapsular extension status was associated with the highest hazard ratio, 3.04; 5-year PSA relapse rates were 7% for no ECE, 20% for unilateral ECE, and 48% for bilateral ECE. Magnetic resonance imaging findings can be used to predict post-EBRT PSA relapse, with ECE status on MRI and pretreatment PSA being significant independent predictors of this endpoint.

Salvage Radiotherapy for Patients with PSA Relapse Following Radical Prostatectomy: Issues and Challenges

A progressively rising level of serum prostate specific antigen (PSA) after radical prostatectomy (RP) invariably indicates the recurrence of prostate cancer. The optimal management of patients with post-RP PSA relapse has remained uncertain due to a wide variability in the natural course of post-RP PSA relapse and the inability to separate a recurrent disease confined to the prostate bed from that with occult distant metastasis. Management uncertainty is further compounded by the lack of phase III clinical studies demonstrating which therapeutic approach, if any, would prolong life with no significant morbidity. Radiotherapy has been the main therapeutic modality with a curative potential for patients with post-RP PSA relapse. This review article depicts issues and challenges in the management of patients with post-RP PSA relapse, presents the literature data for the efficacy of salvage radiotherapy, either alone or in combination of androgen ablation therapy, and discusses future directions that can optimize treatment strategies.

Detection of Local, Regional, and Distant Recurrence in Patients With PSA Relapse After External-Beam Radiotherapy Using 11C-Choline Positron Emission Tomography

An elevated serum prostate-specific antigen (PSA) level cannot distinguish between local-regional recurrences and the presence of distant metastases after treatment with curative intent for prostate cancer. With the advent of salvage treatment such as cryotherapy, it has become important to localize the site of recurrence (local or distant). In this study, the potential of (11)C-choline positron emission tomography (PET) to identify site of recurrence was investigated in patients with rising PSA after external-beam radiotherapy (EBRT). Seventy patients with histologically proven prostate cancer treated with EBRT and showing biochemical recurrence as defined by American Society for Therapeutic Radiology and Oncology consensus statement and 10 patients without recurrence underwent a PET scan using 400 MBq (11)C-choline intravenously. Biopsy-proven histology from the site of suspicion, findings with other imaging modalities, clinical follow-up and/or response to adjuvant therapy were used as comparative references. None of the 10 patients without biochemical recurrence had a positive PET scan. Fifty-seven of 70 patients with biochemical recurrence (median PSA 9.1 ng/mL; mean PSA 12.3 ng/mL) showed an abnormal uptake pattern (sensitivity 81%). The site of recurrence was only local in 41 of 57 patients (mean PSA 11.1 ng/mL at scan), locoregionally and/or distant in 16 of 57 patients (mean PSA 17.7 ng/mL). Overall the positive predictive value and negative predictive value for (11)C-choline PET scan were 1.0 and 0.44 respectively. Accuracy was 84%. (11)C-choline PET scan is a sensitive technique to identify the site of recurrence in patients with PSA relapse after EBRT for prostate cancer.

Hormonal treatment for progression

A rise of the prostate specific antigen (PSA) following radical prostatectomy (RP) or radiotherapy (RT) with curative intent is the earliest sign of tumour progression. The current definition of tumour progression after RP is a PSA of at least 0.4 ng/mL. Many still consider two consecutive levels of 0.2 ng/mL or greater (EAU guidelines) and further rising; after RT it is defined as a rise of 2 ng/mL or greater above the post-treatment nadir. The prognosis of these patients is very heterogeneous, the relevant prognostic parameters being Gleason score, time to PSA progression and PSA doubling time (PSA DT). Imaging studies are of limited value for the decision on salvage radiotherapy (following RP) as the decision must be taken very early in the course (PSA <0.5 ng/mL) to get acceptable results. Before a local salvage therapy (salvage RP, cryo-surgery, high intensity focused ultrasound [HIFU]) is persued after RT, a biopsy is necessary to confirm local tumour progression and distant metastases should be excluded. Androgen deprivation is widely applied if curative treatment fails primarily, or if local salvage treatment fails secondarily. However, side effects (osteoporosis, anaemia, cardio-vascular diseases) of long-term hormonal therapy are now increasingly recognised. This has to be taken into account as well as the fact that there is a long interval (median 8 years) from PSA progression to clinical progression after radical prostatectomy, if patients are left untreated [1]. Only about 30% of patients with rising PSA following RP and no further therapy reach the stage of clinical metastases [2]. This seems to be more common after RT (up to 75%). Patients after radical prostatectomy with good prognostic factors (long PSA DT, late PSA relapse, Gleason score <8) have a low risk of dying from prostate cancer within 15 years [3]. These figures must be taken into account when hormonal therapy is decided upon. When hormonal therapy is considered in this situation, several questions arise: early versus late treatment, continuous versus intermittent treatment, combined androgen blockade versus monotherapy, and luteinising hormone releasing hormone (LHRH) analogues versus anti-androgens

The Role of F‐18 Choline PET and PET/CT in Prostate Cancer

SummaryF‐18 fluorocholine [fluoromethyl‐dimethyl‐2‐hydroxyethyl‐ammonium (FCH)] is a choline analogue that shows great structural similarity to natural choline. The pathophysiological basis for the use of choline and its derivates for prostate cancer (PC) imaging are the elevation of choline levels and the up‐regulation of choline kinase activity in malignant cells. In order to allow rapid tumour growth, malignant cells are able to trap choline to produce phosphatidylcholine, part of the cellular membrane. As shown in recent studies, F‐18 choline PET and PET/CT might be a valuable tool in detecting the primary tumour in case of elevated prostate‐specific antigen (PSA) serum levels. However, data are not consistent, and further research is necessary before general recommendations concerning F‐18 choline PET and PET/CT can be given in this setting. Furthermore, some studies investigated the accuracy of F‐18 choline PET and PET/CT in detecting lymph node or bone metastases and local recurrences in case of PSA relapse in patients with a history of PC.

Commentary on Prospective assessment of gastrointestinal and genitourinary toxicity of salvage radiotherapy for patients with prostate-specific antigen relapse or local recurrence after radical prostatectomy: Pearse M, Choo R, Danjoux C, Gardner S, Morton G, Szumacher E, Loblaw A, Cheung P, Department of Radiation Oncology, Auckland Hospital, Auckland, New Zealand

To assess the acute and late gastrointestinal (GI) and genitourinary (GU) toxicity of salvage radiotherapy (RT). A total of 75 patients with prostate-specific antigen relapse or clinically isolated local recurrence after radical prostatectomy were accrued between 1998 and 2002 for a Phase II study to evaluate the efficacy of salvage RT plus 2-year androgen suppression. Acute and late GI and GU toxicity were prospectively assessed using the National Cancer Institute Expanded Common Toxicity Criteria version 2. For acute toxicity, prevalence was examined. For late toxicity, cumulative incidences of Grade 2 or higher and Grade 3 toxicity were calculated. Median age was 67 years at the time of salvage RT. Median time from radical prostatectomy to RT was 36.2 months. Median follow-up was 45.1 months. Seventy-five patients were available for acute toxicity analysis, and 72 for late toxicity. Twelve percent and 40% had pre-existing GI and GU dysfunction before RT, respectively. Sixty-eight percent, 21%, and 5% experienced Grades 1, 2, and 3 acute GI or GU toxicity, respectively. Cumulative incidences of Grade 2 or higher late GI and GU toxicity at 36 months were 8.7% and 22.6%, and Grade 3 late GI and GU toxicity, 1.6% and 2.8%, respectively. None had Grade 4 late toxicity. The severity of acute GU toxicity (Grade < 2 vs. >/= 2) was a significant predictor factor for Grade 2 or higher late GU toxicity after adjusting for pre-existing GU dysfunction. Salvage RT generally was well tolerated. Grade 3 or higher late GI or GU toxicity was uncommon.

Urokinase‐plasminogen‐activator receptor expression in disseminated tumour cells in the bone marrow and peripheral blood of patients with clinically localized prostate cancer

OBJECTIVE To evaluate the expression of urokinase-plasminogen-activator receptor (uPA-R) in disseminated tumour cells (DTC) in bone marrow (BM) and peripheral blood (PB) of patients with clinically localized prostate cancer before radical prostatectomy (RP), and to assess the associations with pathological variables and prognosis. PATIENTS AND METHODS In all, 52 patients (47 with clinically localized cancer and five with benign prostatic hyperplasia, BPH, as controls) were prospectively enrolled. BM and PB samples were drawn before surgery. DTC were enriched using a commercial system, cytokeratin (CK) 8/18 was used to detect DTC, and uPA-R expression was detected by dual-immunostaining of the DTC. The final pathology of the RP specimen was compared with the results of immunostaining. Follow-up was initiated to detect tumour relapse (defined as a prostate-specific antigen (PSA) level of > or =0.2 ng/mL). RESULTS Overall, there was expression of 'CK + uPA-R' in 60% of the BM and in 19% of the PB specimens. Expression of this marker in BM was most significantly increased in those with unfavourable Gleason scores (P = 0.004), followed by high-risk cancer (P = 0.005). The relative risk for CK + uPA-R expression in the BM was 3.1 times higher in high-risk than in low-risk prostate cancer. No relevant expression rates were detected for PB. In the control group, no patient showed CK or uPA-R expression in BM or PB. The PSA-recurrence free survival was significantly lower in patients with CK + uPA-R-positive BM cells (P = 0.01). CONCLUSION In this pilot study, the preoperative detection rate of CK + uPAR expression in BM of patients with prostate cancer increased with Gleason score and in those with high-risk disease. All patients with a later PSA relapse had had uPA-R expression in their DTC from the BM. DTC with uPA-R expression was an adverse prognostic factor for prostate cancer.

Challenges in Clinical Prostate Cancer: Role of Imaging

This article reviews a recent 2-day workshop on prostate cancer and imaging technology that was conducted by the Cancer Imaging Program of the National Cancer Institute. The workshop dealt with research trends and avenues for improving imaging and applications across the clinical spectrum of the disease. After a summary of prostate cancer incidence and mortality, four main clinical challenges in prostate cancer treatment and management-diagnostic accuracy; risk stratification, initial staging, active surveillance, and focal therapy; prostate-specific antigen relapse after radiation therapy or radical prostatectomy; and assessing response to therapy in advanced disease-were discussed by the 55-member panel. The overarching issue in prostate cancer is distinguishing lethal from nonlethal disease. New technologies and fresh uses for established procedures make imaging effective in both assessing and treating prostate cancer.

Early salvage radiotherapy for patients with PSA relapse after radical prostatectomy

To assess the effectiveness of early salvage radiotherapy (RT) for patients with prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) retrospectively. Fifty-one patients underwent salvage RT for biochemical relapse of prostate cancer initially treated with RP. All patients had persistent or rising PSA >0.20 ng/ml at some point after surgery, or three successive PSA elevations after a postoperative nadir if PSA was < or =0.20 ng/ml. Most (96%) of pre-RT PSA were less or equal to 0.50 ng/ml, and median value was 0.25 ng/ml (range, 0.05-0.90 ng/ml). Median RT dose was 60 Gy (range, 50-66 Gy). Multivariate Cox regression analysis was performed for PSA before RP and salvage RT, margin status, seminal vesicle involvement, extracapsular invasion, Gleason score, PSA doubling time (PSADT), and RT dose to identify significant predictors of biochemical outcome. Median follow-up was 36 months. The 3-year biochemical no evidence of disease rate (bNED) was 55.1%. On multivariate analysis only the following factors were significantly associated with improved bNED: PSADT >3.0 months (P = 0.008), Gleason score < or =7 (P = 0.01), and RT dose > or =60 Gy (P = 0.028). Although a total dose of 60 Gy was effective at a low pre-RT PSA levels with short follow-up, an RT dose > or =60 Gy resulted in superior biochemical outcomes even in patients with a pre-RT PSA < or =0.50 ng/ml.

Persistence of expression of the TMPRSS2:ERG fusion gene after pre-surgery androgen ablation may be associated with early prostate specific antigen relapse of prostate cancer: Preliminary results

The recently identified TMPRSS2: ERG fusion gene is a candidate oncogene for prostate cancer (PCa). We have tested for the presence of this gene in tumor samples from 84 patients who had radical prostatectomy in 1998-2000. Sixty patients (group A) had surgery only; 24 patients (group B) received androgen ablation therapy for 3 months before surgery. The occurrence of the rearrangement was evaluated by RT-PCR and by fluorescent in situ hybridization analysis. A TMPRSS2:ERG fusion gene was present and expressed, as demonstrated by RT-PCR, in 84% of patients in group A and in 54% of patients in group B (p=0.01). The presence of TMPRSS2:ERG transcripts and the levels of ERG RNA, measured by quantitative Real Time-PCR, did not correlate significantly with clinical and pathologic characteristics of the tumors. In patients of group A, but not in those of group B, ERG expression showed a negative correlation with the Gleason score (p=0.0001). Histochemical analysis showed that ERG expression is limited to tumor cells, and in group A patients (but not in group B patients) it is limited to those glands that express TMPRSS2:ERG. The lower proportion of patients expressing TMPRSS2: ERG in group B suggests that androgen ablation inhibits the expression of TMPRSS2:ERG. Moreover, in group B, but not in group A, patients with expression of the fusion gene had earlier prostate specific antigen recurrence (p=0.007). Although preliminary, the data indicate that tumors in which pre-surgery androgen ablation fails to suppress expression of the fusion gene have a higher risk of recurrence.

Efficacy of Salvage Radiotherapy Plus 2-Year Androgen Suppression for Postradical Prostatectomy Patients With PSA Relapse

To determine the efficacy of a combined approach of radiotherapy (RT) plus 2-year androgen suppression (AS) as salvage treatment for prostate-specific antigen (PSA) relapse after radical prostatectomy (RP). Seventy-five patients with PSA relapse after RP were treated with salvage RT plus 2-year AS, as per a pilot, prospective study. AS started within 1 month after completion of salvage RT and consisted of nilutamide for 4 weeks and buserelin acetate depot subcutaneously every 2 months for 2 years. Relapse-free rate including freedom from PSA relapse was estimated using the Kaplan-Meier method. PSA relapse was defined as a PSA rise above 0.2 ng/mL with two consecutive increases over a minimum of 3 months. A Cox regression analysis was performed to evaluate prognostic factors for relapse. Median age of the cohort was 63 years at the time of salvage RT. Median follow-up from salvage RT was 6.4 years. All achieved initially complete PSA response (< 0.2) with the protocol treatment. Relapse-free rate including the freedom from PSA relapse was 91.5% at 5 years and 78.6% at 7 years. Overall survival rate was 93.2% at both 5 and 7 years. On Cox regression analysis, pT3 stage and PSA relapse less than 2 years after RP were significant prognostic factors for relapse. The combined treatment of salvage RT plus 2-year AS yielded an encouraging result for patients with PSA relapse after RP and needs a confirmatory study.

Phase II Trial of Consolidation Docetaxel and Samarium-153 in Patients With Bone Metastases From Castration-Resistant Prostate Cancer

To assess docetaxel combined with samarium-153-ethylene diamine tetramethylene phosphonic acid (EDTMP), a radiopharmaceutical with a high affinity for bone, in patients with castration-resistant prostate cancer (CRPC). Patients with bone metastases from CRPC who achieved a response or stabilization after four cycles of docetaxel and estramustine were given consolidation docetaxel 20 mg/m(2)/wk for 6 weeks and samarium-153-EDTMP (37 MBq/kg) during week 1. Prostate-specific antigen (PSA) response was assessed by using consensus criteria, and pain was assessed by using a visual analog scale (VAS). This study used a Simon two-step design with PSA-progression-free survival (PFS) as the primary end point. Forty-three patients were included in the trial. A PSA response was obtained in 77% (95% CI, 61% to 82%). The pain response rate was 69% (95% CI, 49% to 85%). At least five of the six planned weekly injections of docetaxel were administered to 34 patients (81%). The consolidation docetaxel-samarium-153-EDTMP regimen was well tolerated; there was no febrile neutropenia, and only two episodes (5%) of rapidly reversible grade 3 thrombocytopenia occurred. Although a serum PSA relapse eventually occurred in all patient cases, this regimen resulted in pain control in the long-term. The median PSA-PFS was 6.4 months (95% CI, 6 to 7 months). The median survival was 29 months (95% CI, 22 to 31); the 1-year survival rate was 77% (62% to 87%); and the 2-year survival rate was 56% (41% to 70%). Combining docetaxel and samarium-153-EDTMP in patients with bone metastases from CRPC is well tolerated, and it yields major pain relief that persists long after treatment. Overall survival compares favorably with that expected in this population of patients, most of whom exhibit symptoms.