Prostate-specific Antigen Failure-free Survival Research Articles

Comparison of hypofractionation and standard fractionation for post-prostatectomy salvage radiotherapy in patients with persistent PSA: single institution experience

BackgroundHypofractionated post-prostatectomy radiotherapy is emerging practice, however with no randomized evidence so far to support it’s use. Additionally, patients with persistent PSA after prostatectomy may have aggressive disease and respond less well on standard salvage treatment. Herein we report outcomes for conventionally fractionated (CFR) and hypofractionated radiotherapy (HFR) in patients with persistent postprostatectomy PSA who received salvage radiotherapy to prostate bed.MethodsSingle institution retrospective chart review was performed after Institutional Review Board approval. Between May 2012 and December 2016, 147 patients received salvage postprostatectomy radiotherapy. PSA failure-free and metastasis-free survival were calculated using Kaplan–Meier method. Cox regression analysis was performed to test association of fractionation regimen and other clinical factors with treatment outcomes. Early and late toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.ResultsSixty-nine patients who had persistent PSA (≥ 0.1 ng/mL) after prostatectomy were identified. Median follow-up was 67 months (95% CI 58–106 months, range, 8–106 months). Thirty-six patients (52.2%) received CFR, 66 Gy in 33 fractions, 2 Gy per fraction, and 33 patients (47.8%) received HFR, 52.5 Gy in 20 fractions, 2.63 Gy per fraction. Forty-seven (68%) patients received androgen deprivation therapy (ADT). 5-year PSA failure- and metastasis-free survival rate was 56.9% and 76.9%, respectively. Thirty patients (43%) experienced biochemical failure after salvage radiotherapy and 16 patients (23%) experienced metastatic relapse. Nine patients (13%) developed metastatic castration-resistant disease and died of advanced prostate cancer. Median PSA failure-free survival was 72 months (95% CI; 41–72 months), while median metastasis-free survival was not reached. Patients in HFR group were more likely to experience shorter PSA failure-free survival when compared to CFR group (HR 2.2; 95% CI 1.0–4.6, p = 0.04). On univariate analysis, factors significantly associated with PSA failure-free survival were radiotherapy schedule (CFR vs HFR, HR 2.2, 95% CI 1.0–4.6, p = 0.04), first postoperative PSA (HR 1.02, 95% CI 1.0–1.04, p = 0.03), and concomitant ADT (HR 3.3, 95% CI 1.2–8.6, p = 0.02). On multivariate analysis, factors significantly associated with PSA failure-free survival were radiotherapy schedule (HR 3.04, 95% CI 1.37–6.74, p = 0.006) and concomitant ADT (HR 4.41, 95% CI 1.6–12.12, p = 0.004). On univariate analysis, factors significantly associated with metastasis-free survival were the first postoperative PSA (HR 1.07, 95% CI 1.03–1.12, p = 0.002), seminal vesicle involvement (HR 3.48, 95% CI 1.26–9.6,p = 0.02), extracapsular extension (HR 7.02, 95% CI 1.96–25.07, p = 0.003), and surgical margin status (HR 2.86, 95% CI 1.03–7.97, p = 0.04). The first postoperative PSA (HR 1.04, 95% CI 1.00–1.08, p = 0.02) and extracapsular extension (HR 4.24, 95% CI 1.08–16.55, p = 0.04) remained significantly associated with metastasis-free survival on multivariate analysis.Three patients in CFR arm (8%) experienced late genitourinary grade 3 toxicity.ConclusionsIn our experience, commonly used hypofractionated radiotherapy regimen was associated with lower biochemical control compared to standard fractionation in patients with persistent PSA receiving salvage radiotherapy. Reason for this might be lower biological dose in HFR compared to CFR group. However, this observation is limited due to baseline imbalances in ADT use, ADT duration and Grade Group distribution between two radiotherapy cohorts. In patients with persistent PSA post-prostatectomy, the first postoperative PSA is an independent risk factor for treatment failure. Additional studies are needed to corroborate our observations.

Vesico‐urethral anastomosis sampling: a forgotten tool for guiding salvage radiation after radical prostatectomy

To review the utility of vesicourethral anastomosis (VUA)-directed biopsy in the setting of biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer (PCa) in patients who have undergone evaluation by gallium-68 prostate-specific membrane antigen positron emission tomography with computed tomography (68 Ga-PSMA PET/CT). We completed a retrospective review of a prospectively maintained dataset from January 2015 to August 2020. Patient demographics were recorded for those who experienced BCR, as defined by a rise in prostate-specific antigen (PSA) level to above 0.2 ng/mL, who had a 68 Ga-PSMA PET/CT that did not demonstrate recurrence within the prostate bed, and who subsequently underwent a transperineal ultrasonography (TPUS)-guided biopsy directed at the VUA. Histological reporting of the biopsies was undertaken in order to determine whether the benefits of salvage radiation therapy (SRT) could be justified by the presence of cancer cells. Eighteen patients who had a 68 Ga-PSMA PET/CT and underwent VUA-directed biopsy were identified as having BCR. 68 Ga-PSMA PET/CT scans demonstrated avidity at the VUA in none of the patients, although two out of 18 patients showed avidity in the seminal vesicles and two out of 18 patients showed avidity within regional lymph nodes. Histology from the TPUS-guided, VUA-directed biopsies demonstrated no prostatic tissue in six out of 18 and presence of prostatic tissue in 12 out of 18 of patients, respectively. In 7 out of 18 cases, there was histological evidence of recurrent PCa at the VUA in the absence of a positive 68 Ga-PSMA PET/CT scan. This study highlights the potential value of VUA-directed biopsy. We are reminded that a negative 68 Ga-PSMA PET/CT does not exclude local recurrence and that the addition of a VUA-directed biopsy may aid in the decision-making process for patients with BCR following RP, especially when 68 Ga-PSMA PET/CT is locally negative. When the result of both 68 Ga-PSMA PET/CT and VUA-directed biopsy are negative, it should encourage clinicians to share decision-making in regard to undertaking SRT vs continuing BCR surveillance. This may delay the possible side effects associated with SRT, despite its excellent PSA failure-free survival rate.

Prostate-specific antigen dynamics after neoadjuvant androgen-deprivation therapy and carbon ion radiotherapy for prostate cancer.

This study aimed to explain the dynamics of prostate-specific antigen (PSA) levels in patients with prostate cancer who were treated with carbon ion radiotherapy (CIRT) and neoadjuvant androgen-deprivation therapy (ADT). Eighty-five patients with intermediate-risk prostate cancer who received CIRT and neoadjuvant ADT from December 2015 to December 2017 were analyzed in the present study. The total dose of CIRT was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. The PSA bounce was defined as a ≥0.4 ng/ml increase of PSA levels from the nadir, followed by any decrease. PSA failure was defined using the Phoenix criteria. The median patient age was 68 (range, 48-81) years. The median follow-up duration was 33 (range, 20-48) months. The clinical T stage was T1c, T2a, and T2b in 27, 44, and 14 patients, respectively. The Gleason score was 6 in 3 patients and 7 in 82 patients. The median pretreatment PSA level was 7.37 (range, 3.33-19.0) ng/ml. All patients received neoadjuvant ADT for a median of 6 (range, 2-117) months. PSA bounces were observed in 39 patients (45.9%), occurring a median of 12 (range, 6-30) months after CIRT. PSA failure was observed in eight patients (9.4%), occurring a median of 21 (range, 15-33) months after CIRT. The 3-year PSA failure-free survival rate was 88.5%. No clinical recurrence was observed during the follow-up period. Younger age and lower T stage were significant predictors of PSA bounce. Younger age was a significant predictor of PSA failure. In this study, we identified the significant predictors of the occurrence of PSA bounce and failure. Further follow-up is needed to reveal the clinical significance of PSA dynamics.

Kinetics of Prostate-Specific Antigen after Carbon Ion Radiotherapy for Prostate Cancer.

This study aimed to first elucidate prostate-specific antigen (PSA) kinetics in prostate cancer patients treated with carbon ion radiotherapy (CIRT). From 2010 to 2015, 131 patients with prostate adenocarcinoma treated with CIRT (57.6 Gy relative biological effectiveness (RBE) in 16 fractions) alone were recruited. PSA was measured at 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months post-CIRT. PSA bounce was defined as PSA increase over a cutoff followed by spontaneous decrease to or below the pre-bounce nadir. PSA failure was determined using the Phoenix criteria (nadir + 2.0 ng/mL). As a result, non-failure-associated temporary increase in PSA exhibited two distinct patterns, namely a classical bounce and a surge at one month. PSA bounce of ≥0.2 ng/mL was observed in 55.7% of the patients. Bounce amplitude was <2.0 ng/mL in 97.6% of cases. Bounce occurred significantly earlier than PSA failure. Younger age was a significant predictor of bounce occurrence. Bounce positivity was a significant predictor of favorable 5-year PSA failure-free survival. Meanwhile, a PSA surge of ≥0.2 ng/mL was observed in 67.9% of patients. Surge amplitude was significantly larger than bounce amplitude. Larger prostate volume was a significant predictor of PSA surge occurrence. PSA surge positivity did not significantly predict PSA failure. In summary, PSA bounce was distinguishable from PSA failure with regard to timing of occurrence and amplitude (earlier and lower for bounce, respectively). These data are useful for post-CIRT surveillance of prostate cancer patients.

Long-term results of intensity-modulated radiotherapy with three dose-fractionation regimens for localized prostate cancer.

We evaluated long-term outcomes of three protocols of intensity-modulated radiation therapy (IMRT) for localized prostate cancer. Between 2005 and 2014, 348 patients were treated with 5-field IMRT. The first 74 patients were treated with a daily fraction of 2.0 Gy to 74 Gy (low-risk prostate cancer) or 78 Gy (intermediate- or high-risk prostate cancer); then 101 patients were treated with 2.1-Gy daily fractions to 73.5 or 77.7 Gy. More recently, 173 patients were treated with 2.2-Gy fractions to 72.6 or 74.8 Gy. The median age of all patients was 70 years and the median follow-up period was 82 months. The median follow-up periods were 124 months in the 2.0-Gy group, 98 months in the 2.1-Gy group, and 69 months in the 2.2-Gy group. The overall and prostate-specific antigen (PSA) failure-free survival (PSA-FFS) rates were, respectively, 89 and 68% at 10 years for the 2.0-Gy group, 91 and 84% at 8 years for the 2.1-Gy group, and 93 and 92% at 6 years for the 2.2-Gy group. The PSA-FFS rate for high-risk patients in all groups was 80% at 7 years. The cumulative incidences of Grade ≥2 late genitourinary (GU) and gastrointestinal (GI) toxicity were, respectively, 7.2 and 12.4% at 10 years for the 2.0-Gy group, 7.4 and 14.1% at 8 years for the 2.1-Gy group, and 7.1 and 7.9% at 6 years for the 2.2-Gy group. All three fractionation schedules yielded good tumor control with acceptable toxicities.

Biochemical control and toxicity for favorable- and intermediate-risk patients using real-time intraoperative inverse optimization prostate seed implant: Less is more!

PurposeTo report the biochemical control rate and clinical outcomes with real-time inverse planning (inverse optimization prostate seed implant [IO-PSI]) for favorable-risk (FR) and intermediate-risk (IR) prostate adenocarcinoma in a community practice setting. This analysis is an extended followup of our initial report, with favorable early biochemical control rate (biochemical nonevidence of disease) of 97% at 4 years. Methods and MaterialsThree hundred fifty-seven evaluable patients with FR and IR prostate cancer underwent real-time IO-PSI (iodine-125/145 Gy or palladium-103/120 Gy) between 2001 and 2013. ResultsWith a median followup of 54 months (range, 24–110 months), the absolute biochemical failure free survival of disease was 96%. The 8-year actuarial probability of prostate-specific antigen failure-free survival for FR and IR cohorts was 92.4% and 87%, respectively. Late genitourinary and gastrointestinal toxicity remained low. Late Grade 2 and Grade 3 genitourinary toxicity was 19% and 1%, respectively. Late Grade 2 and 3 rectal bleeding rates were 1% and 0%, respectively. No difference in biochemical control was observed with preimplant short course androgen deprivation or between Gleason score 3 + 4 vs. 4 + 3 patients. No dosimetric parameter was predictive of biochemical failure. Patients with FR had a significantly decreased risk of failure (hazard ratio = 0.26; 95% confidence interval = 0.09–0.78; p = 0.02) compared with those with IR. Patients with a prostate-specific antigen nadir >0.4 ng/mL had an increased risk of failure (hazard ratio = 1.37; 95% confidence interval = 1.27–1.47; p < 0.0001). ConclusionsOur initial biochemical and clinical outcomes using real-time IO-PSI persisted with extended followup and support our original hypothesis for use of a reduced number of sources, needles, and total activity, suggesting that with IO, less is more.

End-of-radiation PSA as a novel prognostic factor in patients undergoing definitive radiation and androgen deprivation therapy for prostate cancer.

BackgroundIn men undergoing definitive radiation for prostate cancer, it is unclear whether early biochemical response can provide additional prognostic value beyond pre-treatment risk stratification.MethodsProstate cancer patients consecutively treated with definitive radiation at our institution by a single provider from 1993–2006 and who had an EOR PSA (n=688, median follow-up 11.2 years). We analyzed the association of an end-of-radiation (EOR) prostate-specific antigen (PSA) level, obtained during the last week of radiation, with survival outcomes. Multivariable-adjusted cox proportional hazards models were constructed to assess associations between a detectable EOR PSA (defined as ≥0.1 ng ml−1) and biochemical failure-free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Kaplan-Meier survival curves were constructed, with stratification by EOR PSA.ResultsAt the end of radiation, the PSA level was undetectable in 30% of patients. Men with a detectable EOR PSA experienced inferior 10-year BFFS (49.7% vs. 64.4%, p<0.001), 10-year MFS (84.8% vs. 92.0%, p=0.003), 10-year PCSS (94.3% vs. 98.2%, p=0.007), and 10-year OS (75.8% vs. 82.5%, p=0.01), as compared to men with an undetectable EOR PSA. Among NCCN intermediate- and high-risk men who were treated with definitive radiation and androgen deprivation therapy (ADT), a detectable EOR PSA was more strongly associated with PCSS than initial NCCN risk level (EOR PSA: HR 5.89, 95% CI 2.37–14.65, p<0.001; NCCN risk level: HR 2.01, 95% CI 0.74–5.42, p=0.168). Main study limitations are retrospective study design and associated biases.ConclusionsEOR PSA was significantly associated with survival endpoints in men who received treated with definitive radiation and ADT. Whether the EOR PSA can be used to modulate treatment intensity merits further investigation.

Relationship of Positive Resection Margin, Cancer Location and Learning Curve after Laparoscopic Radical Prostatectomy

Background: One of surgical goals is decreasing of positive resection margin (PRM). In radical prostatectomy, PRM is important because of prognostic factor. We examine the relationship of PRM, cancer location and learning curve after laparoscopic radical prostatectomy (LRP). Methods: Between May, 2009 and May, 2015, 331 consecutive patients were treated with LRP. The resection margin status, Gleason score, pathological stage, cancer location and diameter were assessed in each surgical specimen, and the independent factors for PRM and prostate-specific antigen (PSA) failure were identified. The learning curve for PRM was calculated and the number of cases until the plateau was obtained. Results: PRM was found in 30.5% of all patients, with 27.7% in the pT2 patients and 39.0% in the pT3 patients. The most common site of PRM was in the apex-anterior. The 5-year PSA failure-free survival rate was 73.9%. In patients with a negative resection margin, the 5-year PSA failure-free survival rate was 81.6%, and in patients with PRM, it was 57.4%. The factors associated with PSA failure-free survival were PRM and elevated PSA. The tumor location was not associated with PSA failure-free survival. The factors associated with PRM were tumor location, nerve sparing procedure, and tumor diameter. When the tumor was localized in the apex-anterior, the rate of PRM was elevated 3-fold comparing the tumor in apex-posterior. The learning curve of all surgeons for obtaining a negative resection margin plateaus after 167 cases. The curve of a single surgeon was more improved than all surgeons and the rate of PRM was 16.7%. Conclusions: PRM was associated with both cancer location and diameter. The learning curve of PRM reached a plateau in about 170 cases. However, PRM can be further reduced. These findings related to LRP outcomes are useful for improvement in surgical techniques and for determining prognosis.

Biochemical failure after radical prostatectomy in intermediate-risk group men increases with the number of risk factors.

Introduction:We aimed to determine whether the number and type of risk factors are associated with biochemical recurrence-free survival after radical prostatectomy in men with D’Amico intermediate-risk prostate cancer.Materials and Methods:Between August 1998 and May 2013, 481 Japanese patients underwent antegrade radical prostatectomy. The relationships between the rate of PSA failure after radical prostatectomy and the number and type of risk factors were examined in the intermediate-risk group.Results:According to the D’Amico criteria, the low-, intermediate-, and high-risk groups comprised 107, 222, and 152 patients, respectively. The median follow-up period after surgery was 54.1 months. The 5-year PSA failure-free rates in the low-, intermediate-, and high-risk groups were 96.5%, 88.9%, and 72.6%, respectively (P < 0.001). The 5-year PSA failure-free rate in the intermediate-risk group with one, two, and three intermediate risk factors was 94.9%, 88.4%, and 49.0%, respectively (P < 0.001). The difference between the high- and intermediate-risk group with three intermediate risk factors was statistically significant based on the log-rank test (P = 0.039).Conclusion:The number of intermediate risk factors is significantly associated with the PSA failure-free survival rate after radical prostatectomy in the intermediate-risk group. Patients classified into the intermediate-risk group based on all three intermediate risk factors are less likely to achieve a complete cure through surgery alone.

Patients treated with radical prostatectomy with positive digital rectal examination findings in the intermediate-risk group are prone to PSA recurrence.

The present study aimed to evaluate the possibility of performing radical prostatectomy (RP) alone to achieve a radical cure for prostate cancer in the intermediate-risk group. Samples were collected from 638 Japanese patients who underwent antegrade RP between August 1998 and May 2013; subsequently, 157 patients were excluded. According to the D'Amico criteria, the low-, intermediate- and high-risk groups comprised 107, 222 and 152 patients, respectively. The 5-year prostate-specific antigen (PSA) failure-free survival rates in the low-, intermediate-, and high-risk groups were 96.5, 88.9 and 72.6%, respectively (P<0.001; degrees of freedom=2). In the intermediate-risk group, the difference in PSA failure-free survival between the 0<PSA≤10 and 10<PSA≤20 ng/ml, and the biopsy Gleason score 6 and 7 groups were not statistically significant, according to the log-rank test (P=0.2266 and P=0.1329, respectively). However, the difference in PSA failure-free survival between the clinical tumor stage (cT)1c and cT2a/b groups was statistically significant based on the log-rank test (P<0.0001). The results of the multivariate analysis revealed that, of the preoperative characteristics, only the cT was a significant predictor in patients with and without PSA failure (P<0.001). Therefore, patients classified into the intermediate-risk group with cT2a/b stage, according to positive digital rectal examination findings, and are not considered to be likely to achieve a complete cure with RP surgery alone. In summary, for patients meeting these criteria in the intermediate-risk group, RP surgery alone is likely to be insufficient, and other additional treatments may be considered subsequent to RP.

PD03-06 RADICAL PROSTATECTOMY FOLLOWING ACTIVE SURVEILLANCE IS ASSOCIATED WITH INCREASED RATES OF UNFAVOURABLE PATHOLOGY

You have accessJournal of UrologyProstate Cancer: Localized: Active Surveillance I1 Apr 2016PD03-06 RADICAL PROSTATECTOMY FOLLOWING ACTIVE SURVEILLANCE IS ASSOCIATED WITH INCREASED RATES OF UNFAVOURABLE PATHOLOGY Richard Savdie, Robert Bell, Jonathan Anning, Alan So, Martin Gleave, Peter Black, and Larry Goldenberg Richard SavdieRichard Savdie More articles by this author , Robert BellRobert Bell More articles by this author , Jonathan AnningJonathan Anning More articles by this author , Alan SoAlan So More articles by this author , Martin GleaveMartin Gleave More articles by this author , Peter BlackPeter Black More articles by this author , and Larry GoldenbergLarry Goldenberg More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2094AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Our centre has offered AS to men with very low to low-tier intermediate risk PCa based on patient and physician accepted balance of competing risks. We aimed to analyse the rates of unfavourable pathology in those undergoing radical prostatectomy (RP) following AS and compare these with a contemporary immediate RP group. METHODS Patients were stratified into very low risk (Epstein), low and intermediate NCCN risk groups. Rates of unfavourable pathology (predominant Gleason pattern 4 or ≥pT3 disease) and PSA failure following radical prostatectomy were analysed. A 2:1 propensity score matched analysis was performed using age, pre-treatment PSA, biopsy Gleason score and clinical T stage with a cohort of immediate RP patients from the same time period. RESULTS 651 men had AS (including 144 Intermediate Risk) with a median follow-up of 4.5 years (range 0.6-19.1). 203 patients had radical prostatectomy after AS (AS+RP) with an overall rate of unfavourable pathology of 34.9%. 195 AS+RP were matched to 390 immediate RP (IRP) with excellent correlation between covariates. The median time to surgery was 1.59 years for the AS+RP group vs 0.3 years for the IRP group ( p<0.001). There were slightly higher rates of EPE in AS+RP vs IRP group but this was not statistically significant (20% v 17%, p=0.5). Predominant Gleason pattern 4 was seen in significantly more men who had delayed RP compared to their matched counterparts (24.6% vs 12%, p<0.001). There was no difference in unfavourable pathology in the very low risk AS+RP vs IRP group (p=0.17). Despite differences in unfavourable pathology, there was no difference in the PSA failure free survival between the two groups at 3 years (Log Rank, p=0.47). CONCLUSIONS Active surveillance carries an increased risk of unfavourable pathology at the time of delayed RP in low and intermediate but not very low risk groups. Early data suggests that PSA recurrence rates are similar following RP despite delay in treatment. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e58 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Richard Savdie More articles by this author Robert Bell More articles by this author Jonathan Anning More articles by this author Alan So More articles by this author Martin Gleave More articles by this author Peter Black More articles by this author Larry Goldenberg More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Ten-year outcomes of intensity-modulated radiation therapy combined with neoadjuvant hormonal therapy for intermediate- and high-risk patients with T1c-T2N0M0 prostate cancer.

We aimed to analyze the 10-year outcomes of intensity-modulated radiation therapy (IMRT) combined with neoadjuvant hormonal therapy (HT) for patients with intermediate- and high-risk T1c-T2N0M0 prostate cancer. Fifty patients with T1c-T2N0M0 prostate cancer, who were treated with high-dose IMRT combined with neoadjuvant HT, were evaluated. Of these patients, 19 and 31 were classified into the intermediate- and high-risk groups, respectively. Neoadjuvant HT was administered over a median duration of 6months; 74 and 78 Gy in 2Gy per fraction were essentially delivered to the intermediate- and high-risk cases, respectively. Adjuvant HT was not administered to any of the patients after the completion of IMRT. Over a median follow-up period of 118months, the 10-year prostate-specific antigen failure-free survival, prostate-specific antigen failure-free, salvage hormonal therapy-free, prostate cancer-specific survival, and overall survival rates were 70.2%, 78.7%, 89.2%, 100%, and 88.8%, respectively. No grade 3 or higher acute or late toxicities were observed. The 10-year likelihoods of developing grade 2 late urinary and rectal toxicities were 13.7% and 4.2%, respectively. Compared with the outcomes of a cohort of historical controls who were locally irradiated with 70Gy by three-dimensional conformal radiotherapy, the prostate-specific antigen failure-free rate was significantly better in the IMRT groups (78.7% vs. 53.4% at 10years; p=0.027). High-dose IMRT combined with neoadjuvant HT achieved not only high prostate-specific antigen control, but also excellent survival outcomes with acceptable morbidities, for a Japanese cohort of intermediate- and high-risk T1c-T2N0M0 prostate cancer patients, and these results warrant further investigation.

Feasibility of brachytherapy as monotherapy for high-volume, low-risk prostate cancer.

We sought to determine whether patients with high-volume, low-risk prostate cancer are suitable candidates for ultrasound-guided brachytherapy, monotherapy alone, without supplemental external beam radiation. The study cohort comprised 200 consecutive patients who received ultrasound.guided monotherapy from November 02, 1998 to March 26, 2010. Real.time intraoperative treatment planning was performed for all patients. 145. Gy with I125 was prescribed to the prostate with no margin. The primary endpoint was time to prostate-specific antigen. (PSA) failure using the phoenix definition. Cox multivariable regression analysis was used to determine the factors significantly associated with time to PSA failure. Median follow-up was 59 months (range 1.2-146.8 months). The median PSA was 5.0 ng/ml. For the overall cohort, both 5- and 8-year PSA failure-free survival was 92.3% (95% confidence interval [95% CI]: 86.5-95.7%). Low-risk patients per the NCCN criteria had 5- and 8-year PSA failure-free survival of 93.6%. On cox multivariable analysis, only baseline PSA (adjusted hazard ratio: 1.29 [95% CI: 1.02-1.65], P = 0.036) was associated with outcome. Among patients with Conclusions: Our analysis indicates that patients with a high number of cores positive for cancer can be adequately treated with modern brachytherapy as monotherapy and be spared the additional morbidity and cost of supplemental external beam radiation or androgen deprivation therapy.

Combination external beam and brachytherapy for intermediate- to high-risk prostate cancer: Comparison of high-dose rate (HDR) and seed (LDR) implant methods.

90 Background: Maximizing the therapeutic ratio for intermediate to high risk localized prostate cancer may be accomplished by using a combination of external beam radiotherapy (EBRT) and radiation implant. Differences in implant methods could be expected to influence mortality. We compared outcomes for patients treated using combination EBRT and high dose rate (HDR) versus EBRT and low dose rate (LDR) seed implant methods. Methods: Between 12/1993 and 05/2010 there were 307 cases of combination therapy with analyzable data: 227 HDR + EBRT (HDRe) and 81 LDR + EBRT (LDRe) Intermediate risk patients had 1+ risk factors: PSA ≥ 10, Gleason score (GS) ≥ 7, or AJCC clinical stage ≥ T2b. High risk patients exhibited either 2+ of these risk factors or PSA ≥ 20, GS ≥ 8, or AJCC clinical stage ≥ T3. External beam radiation was 45 Gy in 1.8 Gy daily fractions using 3D conformal or IMRT methods. The prostate, seminal vesicles, and (in some patients) pelvic lymph nodes were treated. HDR brachytherapy was delivered one week prior to beginning EBRT. Afterloading HDR catheter needles were surgically implanted into the prostate. HDR dose was 21 Gy in three equal fractions of 7 Gy peripheral dose given over two days. LDR was performed 2-3 weeks after EBRT using I-125 or Pd-103 seeds and 109 or 90 Gy respectively. PSA failure was defined as “nadir plus two.” Results: HDRe and LDRe cases were well matched for pretreatment risk factors. There were 18 PSA failures in the HDRe group (7.9%) and 6 PSA failures in the LDRe group (7.4%). Adjusted Cox proportional hazard models showed no statistically significant difference between the treatment groups with regard to PSA failure. Hazard ratio for LDRe compared to HDRe was 0.82 (95% CI 0.28, 2.46; p=0.73). There were 26 deaths from any cause (11.45%) in the HDRe group and 11 deaths from any cause (13.58%) in the LDRe group. Adjusted Cox models showed no statistically significant difference between the treatment groups for survival. Hazard ratio for LDRe compared to HDRe was 1.49 (95% CI 0.68, 3.25; p=0.32). Conclusions: There were no statistically significant differences in PSA failure free survival or overall survival detected in LDRe versus HDRe patient groups.

Ganglioside disialosyl globopentaosylceramide is an independent predictor of PSA recurrence-free survival following radical prostatectomy

Disialosyl globopentaosylceramide (DSGb5) is a ganglioside originally isolated from renal cell carcinoma (RCC) tissue that has been associated with RCC metastasis. However, in prostate cancer, the expression of DSGb5 has not yet been fully assessed. In this study, we investigated DSGb5 expression in prostate tissues and the relationship between DSGb5 expression and clinicopathological characteristics of prostate cancer patients. A total of 130 patients who underwent radical prostatectomy (RP) at our hospital between January 2005 and December 2007 were analyzed in this study. The expression of DSGb5 in prostatectomy specimens was examined by immunohistochemical analysis with monoclonal antibody 5F3 (anti-DSGb5). Associations between 5F3 expression and clinicopathological findings were investigated and the factors that affected PSA failure-free survival were assessed by Kaplan-Meier analysis and a Cox regression model. When immunoreactivities of 5F3 were measured, negative to strong staining was observed in prostate cancer tissue, whereas strong staining was observed in benign prostate glands. These expression patterns suggest that DSGb5 may act as a differentiation antigen in cancerization. The PSA failure-free survival was significantly higher in the 5F3 intact expression group than in the 5F3 reduced expression group (log-rank P=0.0220). On multivariate analysis, 5F3 intact expression showed significantly worse PSA failure-free survival following RP. 5F3 expression reflects the clinical and pathological features of prostate cancer and is correlated with the outcomes following RP. Further studies are necessary to clarify the functional roles of DSGb5 and establish a novel biomarker for prostate cancer.

Prostate cancer: Prognostic significance of the association of heterogeneous nuclear ribonucleoprotein K and androgen receptor expression

The management of prostate cancer (PCa) remains challenging because to date, there has been no way to distinguish between indolent and aggressive tumors. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is implicated in the network of mechanisms that control androgen receptor (AR) expression. We studied the expression of the two proteins in PCa to evaluate their prognostic potential and elucidate the hnRNP K function in PCa progression. HnRNP K and AR expression were analyzed immunohistochemically in 105 patients who had undergone radical prostatectomy. The association between the expression of hnRNP K and/or AR and PSA progression or death was evaluated by univariate and multivariate analyses. The expression of hnRNP K was also investigated in vitro using the BPH-1 cell line and two different LNCaP populations that recapitulate the progression of PCa towards a more aggressive disease. AR and hnRNP K were differentially expressed between cancer and normal prostate tissues. A strong association with a good prognosis was evident in PCa exhibiting high percentage of AR-positive cells (>75%) (p≤0.005) and more interestingly, the combination of high AR and low cytoplasmic hnRNP K expression emerged as the most significant independent prognostic marker for PSA failure-free survival, in a multivariate analysis (p≤0.001). In vitro, a higher expression of hnRNP K and pERK was associated with higher PSA levels, suggesting a relationship between hnRNP K phosphorylation and AR-regulated genes. These results indicate that the interaction between the AR and hnRNP K has an important role in the progression of PCa. Changes of the expression of the two proteins are strongly associated with the clinical outcome and may be a potential prognostic marker.

Current status and outcomes of salvage radiotherapy for patients with PSA recurrence after prostatectomy: A JROSG surveillance study.

207 Background: Salvage radiotherapy (S-RT) for patients with prostate cancer who developed PSA failure after radical prostatectomy is widely applied. However, current status of this approach in Japan has not been surveyed so far. The aim of this study was to reveal the present conditions and outcomes of S-RT for Japanese patients with biochemically recurrent prostate cancer. Methods: Clinical data of the S-RT was gathered by sending a questionnaire to participating facilities to the Japanese Radiation Oncology Study Group (JROSG). The S-RT was defined as external-beam radiotherapy delivered to the prostate bed to patients with prostate cancer who eventually developed PSA failure, although their PSA value had once reached &lt;0.2 ng/ml after prostatectomy. In addition, the interval between prostatectomy and the S-RT should essentially be six months or longer. PSA failure-free survival (PFFS) and clinical failure-free survival (CFFS) was calculated by the Kaplan-Meier estimation. Results: 371 cases were registered from 38 facilities. Among them, hormonal therapy was combined with S-RT in 151 patients. In 3 cases, chemotherapy was combined before or after the S-RT. The rests of the cases were treated by S-RT alone. However, prognostic information was insufficient in 28 cases, and PSA nadir was &gt;0.2 ng/ml in 3 cases. Therefore, outcome studies were conducted in the remaining 186 cases. The median age was 67 years old. The nadir value of the PSA after prostatectomy and the PSA value at the initiation of S-RT were 0.0135 ng/ml and 0.292 ng/ml, respectively. The median period between prostatectomy and the S-RT was 18.6 months. Median follow-up period was 58 months. The 5-year PFFS and CFFS were 50.1% (95%CI: 42.8 – 57.9) and 90.1% (95%CI: 86.4 – 95.7), respectively. PFFS was significantly superior in patients with PSA values &lt;= 0.3 ng/ml at the initiation of S-RT than those of PSA values &gt; 0.3. (57.5% vs. 40.5%, p = 0.027) Conclusions: In Japan, hormonal therapy was combined with S-RT in about 40% of the cases. The 5-year PFFS and CFFS rates of cases treated by S-RT alone were 50.1% and 90.1%, respectively. A PSA value of 0.3 was significant cut-off point for predicting PFFS.

Updated Results of Magnetic Resonance Imaging Guided Partial Prostate Brachytherapy for Favorable Risk Prostate Cancer: Implications for Focal Therapy

We report updated results of magnetic resonance imaging guided partial prostate brachytherapy and propose a definition of biochemical failure following focal therapy. From 1997 to 2007, 318 men with cT1c, prostate specific antigen less than 15 ng/ml, Gleason 3 + 4 or less prostate cancer received magnetic resonance imaging guided brachytherapy in which only the peripheral zone was targeted. To exclude benign prostate specific antigen increases due to prostatic hyperplasia, we investigated the usefulness of defining prostate specific antigen failure as nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year. Cox regression was used to determine the factors associated with prostate specific antigen failure. Median followup was 5.1 years (maximum 12.1). While 36 patients met the nadir +2 criteria, 16 of 17 biopsy proven local recurrences were among the 26 men who also had a prostate specific antigen velocity greater than 0.75 ng/ml per year (16 of 26 vs 1 of 10, p = 0.008). Using the nadir +2 definition, prostate specific antigen failure-free survival for low risk cases at 5 and 8 years was 95.1% (91.0-97.3) and 80.4% (70.7-87.1), respectively. This rate improved to 95.6% (91.6-97.7) and 90.0% (82.6-94.3) using nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year. For intermediate risk cases survival was 73.0% (55.0-84.8) at 5 years and 66.4% (44.8-81.1) at 8 years (the same values as using nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year). Requiring a prostate specific antigen velocity greater than 0.75 ng/ml per year in addition to nadir +2 appears to better predict clinical failure after therapies that target less than the whole gland. Further followup will determine whether magnetic resonance imaging guided brachytherapy targeting the peripheral zone produces comparable cancer control to whole gland treatment in men with low risk disease. However, at this time it does not appear adequate for men with even favorable intermediate risk disease.

Long-term Oncological Outcome and Risk Stratification in Men with High-risk Prostate Cancer Treated with Radical Prostatectomy

To evaluate the long-term oncological outcome of radical prostatectomy for patients with high-risk prostate cancer. Among 378 patients with prostate cancer who underwent radical prostatectomy at our hospital, 189 had high-risk prostate cancer defined as presenting with at least one of the following high-risk factors: prostate-specific antigen >20 ng/ml, clinical T3 and biopsy Gleason score ≥8. The median follow-up was 8.1 years. Of all patients, 106 and 61 had one and two high-risk factors, respectively, and the remaining 22 had all three high-risk factors. Pathological examination of the prostatectomy specimens revealed organ-confined disease, specimen-confined disease and lymph node metastasis in 80 (42%), 102 (54%) and 22 (12%), respectively. The 10-year prostate-specific antigen failure-free and local progression-free survival rates were 48.5 and 87.6%, respectively. The 10-year cancer-specific and overall survival rates were 94.1 and 88.7%, respectively. The 10-year prostate-specific antigen failure-free survivals of patients with one, two and all three high-risk factors were 58.5, 39.9 and 22.7%, respectively (P = 0.0001). Of the 106 patients with one high-risk factor only, the high Gleason score group had the best 10-year prostate-specific antigen failure-free survival (69.1%); in particular, that of patients without Gleason grade 5 was 100% (P= 0.032). Approximately half of patients with high-risk prostate cancer can be cured by radical prostatectomy without any adjuvant treatment. Radical prostatectomy for high-risk prostate cancer provides good long-term local cancer control and cancer-specific survival. In particular, radical prostatectomy for patients with only one high-risk factor can be considered a valuable therapeutic option as the first treatment.

Long-term results of MRI-guided partial prostate brachytherapy for favorable-risk prostate cancer: Implications for focal therapy.

114 Background: To report long-term results of MRI-guided partial prostate brachytherapy and propose a definition of biochemical failure following focal therapy Methods: From 1997-2007, 318 men with cT1c, PSA &lt; 15, Gleason ≤ 3 + 4 prostate cancer received MRI-guided brachtherapy in which only the peripheral zone was targeted. To exclude benign PSA increases due to prostatic hyperplasia, PSA failure was defined as nadir + 2 with PSA velocity &gt;0.75 ng/mL/year. Cox multivariable analysis was used to determine factors associated with PSA failure. Results: After a median follow-up of 5.1 years (interquartile range: 2.8 to 7.3, maximum 12.1), 26 men failed. While 36 patients met nadir+2 criteria, all eight biopsy-proven local recurrences were among the 26 men who also had a PSA velocity &gt;0.75 ng/mL/year. On multivariable analysis, having intermediate vs. low-risk disease (adjusted HR: 4.4 [95%CI: 1.3-5.5], p&lt;0.001) was the only factor significantly associated with an increased risk of PSA failure. PSA failure-free survival at 5 and 8 years was 95.6% and 90.0% for low risk, and was 73.0% and 66.4% for intermediate risk, respectively. Conclusions: MRI-guided brachytherapy targeting the peripheral zone produced comparable cancer control rates to whole-gland treatment in men with PSA-detected low-risk disease, but may not be adequate for men with “favorable” intermediate-risk disease. Requiring a PSA velocity&gt;0.75 in addition to nadir+2 may be a more appropriate way to define biochemical failure after therapies that target less than the whole gland.