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Purpose: Men with Gleason grade Group (GG) 4 and 5 prostate cancer have high failure rates when treated by conventional therapy. We investigated the effect of higher radiation doses on freedom from biochemical failure (FBF) and prostate cancer mortality (cause-specific survival [CSS]) in men treated with a combination of permanent implant and external beam irradiation (EBRT)., Methods and Materials: Three hundred twenty men with GG4 (n = 186) and 5 (n = 134) prostate cancer were treated with I-125 or Pd-103 implant followed by 45 Gy of EBRT. Radiation doses were converted to the biological equivalent dose (BED). The median age, prostate-specific antigen (PSA), time on hormone therapy, BED, and followup were 69 years, 9.0 ng/mL, 9 months, 210 Gy, and 6.5 years, respectively. FBF and CSS were calculated by Kaplan-Meier method with associations determined by log rank and Cox regression., Results: Ten-year FBF for GG4 vs. 5 was 77.8 vs. 61.3% (p = 0.015), and CSS was 94 vs. 79.3% (p = 0.001). Men with lower PSA had improved FBF and CSS (p < 0.001). Thirty-one of 320 died of prostate cancer of which 10/186 (5.4%) had GG4 and 21/134 (15.7%) GG5 (OR 3.3, p = 0.002). BED <200 Gy was associated with a 2.2× greater BF (p = 0.004) and 2.4× prostate cancer mortality (p = 0.020). Significant covariates on regression analysis for FBF and CSS were PSA (p = 0.014), GG (p = 0.007), BED (p = 0.009), and GG (p = 0.001)., Conclusions: Survival rates for high-grade prostate cancer are favorable when diagnosed in men with lower PSA and treated with doses of BED > 200 Gy. Higher BED is achieved with a combination of I-125 (110 Gy) or Pd-103 (100 Gy) and 45 Gy EBRT., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To 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 Materials: Three 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., Results: With 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)., Conclusions: Our 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., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate whether supplemental external beam radiotherapy (EBRT) is essential to maximize Pd-103 brachytherapy outcomes in patients with unfavorable intermediate-risk (IR) disease., Methods and Materials: A total of 630 patients were assessed from two prospective randomized brachytherapy trials evaluating the role of supplemental EBRT in patients with higher risk features. Patients were stratified into unfavorable IR (primary Gleason pattern 4, ≥50% positive biopsies, or ≥2 IR features), favorable IR, and high-risk (HR) cohorts. Median follow-up was 7.5 years. The brachytherapy prescription dose was prescribed to the prostate gland with generous periprostatic margins. Biochemical failure (BF) was defined as a prostate-specific antigen >0.40 ng/mL after nadir. Patients with metastatic prostate cancer or nonmetastatic castrate-resistant disease who died of any cause were classified as dead of prostate cancer. Multiple parameters were evaluated for effect on outcomes., Results: The 10-year BF for favorable IR, unfavorable IR, and HR was 1.7%, 6.6%, and 15.5% (p < 0.001). At 10 years, prostate cancer-specific mortality (PCSM) and overall mortality (OM) were 0% and 20.4%, 2.1% and 23.2%, and 4.3% and 42.4% for favorable IR, unfavorable IR, and HR. Although unfavorable IR patients had a greater incidence of BF, PCSM, and OM when compared with favorable IR, neither the addition nor dose of supplemental EBRT influenced outcome., Conclusions: Outcomes for favorable IR were superior to those with unfavorable IR. Within the confines of this study, neither the addition nor dose of supplemental EBRT influenced BF, PCSM, or OM in patients with IR disease., (Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the necessity and/or dose of supplemental external beam radiotherapy (EBRT) in conjunction with palladium-103 ((103)Pd) brachytherapy for high-risk prostate cancer patients., Methods and Materials: Trial 44/20 randomized patients to 44 Gy plus 90 Gy (103)Pd vs. 20 Gy with 115 Gy (103)Pd, and the subsequent trial randomized patients to the 20 Gy arm vs. 125 Gy (103)Pd without EBRT (20/0 trial). Eligibility criteria included clinically organ-confined disease with Gleason scores 7-9 and/or a pretreatment prostate-specific antigen (PSA) 10-20 ng/mL. The brachytherapy prescription dose was prescribed to the prostate gland with generous periprostatic margins. Biochemical failure (BF) was defined as a PSA >0.40 ng/mL after nadir. Median Day 0 minimum dose covering 90% of the prostate volume (D90) was >121.0% of the prescription dose. Multiple parameters were evaluated for effect on outcomes., Results: In 44/20 trial, 13-year BF, prostate cancer-specific mortality (PCSM), and overall mortality (OM) were 8.2%, 4.0%, and 42.8% vs. 8.0%, 1.0%. and 40.3% for the 44 and 20 Gy arms. In 20/0 trial, 8-year BF, PCSM, and OM were 2.1%, 0%, and 14.4% vs. 3.6%, 0%, and 16.1% in the 20 vs. 0 Gy arms. When stratified by either pretreatment PSA or by Gleason score, supplemental EBRT dose did not impact BF, PCSM, or OM. In multivariate analysis, BF was most closely related to percent positive biopsies and prostate volume. In both trials, patients with biochemically controlled disease had a median PSA of <0.02 ng/mL., Conclusions: With high-quality brachytherapy dose distributions, supplemental EBRT did not influence BF or PCSM for patients with intermediate-risk disease. The number of patients with Gleason score 8-9 was too small to determine the role of supplemental EBRT in that cohort., (Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine whether post-treatment prostate-specific antigen (ptPSA) values at 12 months and other clinical parameters predict long-term PSA relapse-free survival (PRFS) following prostate seed brachytherapy., Methods and Materials: Records of 204 hormone-naïve patients with localized adenocarcinoma of the prostate treated at St. Mary's Regional Medical Center in Reno, NV, and at Carson Tahoe Regional Medical Center in Carson City, NV, between 1998 and 2003, using I-125 or Pd-103 seed brachytherapy, were retrospectively analyzed. Treatment planning was done using a preplanned, modified peripheral loading technique. A total of 185 of 204 patients had PSA records at 12 months after implant. Variables included were age, initial pretreatment PSA, Gleason score, T stage, National Comprehensive Cancer Network (NCCN) risk group (RG), perineural invasion (PNI), external beam boost, dose, and ptPSA levels at 12 months with cutpoints at ≤1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml., Results: Median follow-up was 80 months, and median age was 69 years. The numbers of patients stratified by NCCN low, intermediate, and high RG were 110:65:10, respectively. Monotherapy and boost prescription doses were 145 Gy and 110 Gy for I-125, and 125 Gy and 100 Gy for Pd-103 seeds, respectively. The median dose (D90) was 95.4% of the prescribed dose. The 5-year PRFS at the 12-months ptPSA levels of ≤1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml were 98.5%, 85.7%, 61.5%, and 22.2%, respectively. The 10-year PRFS at the 12-months ptPSA levels of ≤1 and 1.01 to 2.00 ng/ml were 90.5% and 85.7%, respectively. In multivariate analysis, both ptPSA and PNI were significant independent predictors of PRFS. Hazard ratios (HR) for ptPSA levels at ≤1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml at 12 months were 1, 4.96, 27.57, and 65.10, respectively. PNI had an HR of 6.1 (p=0.009)., Conclusions: Presence of PNI and ptPSA values at 12 months are strong prognostic variables for long-term PRFS after definitive prostate brachytherapy seed implantation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To identify predictors of metastatic disease after brachytherapy treatment for prostate cancer., Methods and Materials: All patients who received either brachytherapy alone (implant) or brachytherapy in combination with external beam radiation therapy for treatment of localized prostate cancer at The Mount Sinai Hospital between June 1990 and March 2007 with a minimum follow-up of 2 years were included. Univariate and multivariable analyses were performed on the following variables: risk group, Gleason score (GS), clinical T stage, pretreatment prostate-specific antigen level, post-treatment prostate-specific antigen doubling time (PSA-DT), treatment type (implant vs. implant plus external beam radiation therapy), treatment era, total biological effective dose, use of androgen deprivation therapy, age at diagnosis, and race. PSA-DT was analyzed in the following ordinate groups: 0 to 90 days, 91 to 180 days, 180 to 360 days, and greater than 360 days., Results: We included 1,887 patients in this study. Metastases developed in 47 of these patients. The 10-year freedom from distant metastasis (FFDM) rate for the entire population was 95.1%. Median follow-up was 6 years (range, 2-15 years). The only two significant predictors of metastatic disease by multivariable analyses were GS and PSA-DT (p < 0.001 for both variables). Estimated 10-year FFDM rates for GS of 6 or less, GS of 7, and GS of 8 or greater were 97.9%, 94.3%, and 76.1%, respectively (p < 0.001). Estimated FFDM rates for PSA-DT of 0 to 90 days, 91 to 180 days, 181 to 360 days, and greater than 360 days were 17.5%, 67.9%, 74%, and 94.8%, respectively (p < 0.001). Estimated 10-year FFDM rates for the low-, intermediate-, and high-risk groups were 98.6%, 96.2%, and 86.7%, respectively. A demographic shift to patients presenting with higher-grade disease in more recent years was observed., Conclusions: GS and post-treatment PSA-DT are both statistically significant independent predictors of metastatic disease. Patients with a high GS and/or short PSA-DT have a higher likelihood of developing metastatic disease and should be considered for systemic therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Because limited information exists regarding whether the rate or magnitude of PSA decline following brachytherapy predicts long-term clinical outcomes, we evaluated whether achieving a prostate-specific antigen (PSA) nadir (nPSA) <0.5 ng/mL following brachytherapy is associated with decreased PSA failure and/or distant metastasis., Methods and Materials: We retrospectively analyzed our database of early-stage prostate adenocarcinoma patients who underwent brachytherapy, excluding those receiving androgen-deprivation therapy and those with <2 years follow-up. Median and mean pretreatment PSA were 6 ng/mL and 7.16 ng/mL, respectively. By clinical stage, 775 were low risk (≤ T2a), 126 were intermediate risk (T2b), and 20 were high risk (>T2b). By Gleason score, 840 were low risk (≤ 6), 71 were intermediate risk (7), and 10 were high risk (>7). Patients were treated with brachytherapy only (I-125, n = 779, or Pd-103, n = 47), or brachytherapy + external-beam radiation therapy (n = 95). Median follow-up was 6.3 years. We noted whether nPSA <0.5 ng/mL was achieved and the time to achieve this nadir and tested for associations with pretreatment risk factors. We also determined whether this PSA endpoint was associated with decreased PSA failure or distant metastasis., Results: Absence of high-risk factors in clinical stage (≤ T2b), Gleason score (≤ 7), and pretreatment PSA (≤ 20 ng/mL) was significantly associated with achieving nPSA <0.5 ng/mL. By Kaplan-Meier analysis, patients achieving nPSA <0.5 ng/mL had significantly higher long-term freedom from biochemical failure (FFBF) than nonresponders (5-year FFBF: 95.2 ± 0.8% vs. 71.5 ± 6.7%; p < 0.0005). Among responders, those who achieved nPSA <0.5 ng/mL in ≤ 5 years had higher FFBF than those requiring >5 years (5-year FFBF: 96.7 ± 0.7% vs. 80.8 ± 4.6%; p < 0.0005). On multivariate analysis, patients who achieved nPSA <0.5 ng/mL in ≤ 5 years had significantly higher FFBF than other patients., Conclusions: Pretreatment risk factors (clinical tumor stage, Gleason score, pretreatment PSA) strongly predict for patients achieving nPSA <0.5 ng/mL following brachytherapy, and this cohort had significantly higher long-term FFBF., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate temporal changes in testosterone after prostate brachytherapy and investigate the potential impact of these changes on response to treatment., Methods and Materials: Between January 2008 and March 2009, 221 consecutive patients underwent Pd-103 brachytherapy without androgen deprivation for clinically localized prostate cancer. Prebrachytherapy prostate-specific antigen (PSA) and serum testosterone were obtained for each patient. Repeat levels were obtained 3 months after brachytherapy and at least every 6 months thereafter. Multiple clinical, treatment, and dosimetric parameters were evaluated to determine an association with temporal testosterone changes. In addition, analysis was conducted to determine if there was an association between testosterone changes and treatment outcomes or the occurrence of a PSA spike., Results: There was no significant difference in serum testosterone over time after implant (p = 0.57). 29% of men experienced an increase ≥ 25%, 23% of men experienced a decrease ≥ 25%, and the remaining 48% of men had no notable change in testosterone over time. There was no difference in testosterone trends between men who received external beam radiotherapy and those who did not (p = 0.12). On multivariate analysis, preimplant testosterone was the only variable that consistently predicted for changes in testosterone over time. Men with higher than average testosterone tended to experience drop in testosterone (p < 0.001), whereas men with average or below average baseline testosterone had no significant change. There was no association between men who experienced PSA spike and testosterone temporal trends (p = 0.50) nor between initial PSA response and testosterone trends (p = 0.21)., Conclusion: Prostate brachytherapy does not appear to impact serum testosterone over time. Changes in serum testosterone do not appear to be associated with PSA spike phenomena nor with initial PSA response to treatment; therefore, PSA response does not seem related to temporal testosterone changes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate retrospectively the biochemical outcomes of young men treated with low-dose-rate brachytherapy for prostate cancer., Methods and Materials: From 1990 to 2005, 1,665 men with clinically localized prostate cancer were treated with low-dose-rate brachytherapy +/- hormone therapy (HT) +/- external beam radiotherapy and underwent > or = 2 years of follow-up. Patients were stratified on the basis of age: < or = 60 (n = 378) and >60 years (n = 1,287). Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/mL. Univariate and multivariate analyses were used to determine the association of variables with freedom from biochemical failure (FFbF)., Results: Median follow-up was 68 months (range, 24-180) for men < or = 60 years and 66 months (range, 24-200) for men >60. For the entire group, the actuarial 5- and 8-year FFbF rates were 94% and 88%, respectively. Men < or = 60 demonstrated similar 5- and 8-year FFbF (95% and 92%) compared with men >60 (93% and 87%; p = 0.071). A larger percent of young patients presented with low-risk disease; lower clinical stage, Gleason score (GS), and pretreatment PSA values; were treated after 1997; did not receive any HT; and had a high biologic effective dose (BED) of radiation (all ps <0.001). On multivariate analysis, PSA (p = 0.001), GS (p = 0.005), and BED (p < 0.001) were significantly associated with FFbF, but age was not (p = 0.665)., Conclusion: Young men achieve excellent 5- and 8-year biochemical control rates that are comparable to those of older men after prostate brachytherapy. Young age should not be a deterrent when considering brachytherapy as a primary treatment option for clinically localized prostate cancer., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To assess the correlation of postimplant dosimetric quantifiers with biochemical control of prostate cancer after low-dose rate brachytherapy., Methods and Materials: The biologically effective dose (BED), dose in Gray (Gy) to 90% of prostate (D(90)), and percent volume of the prostate receiving 100% of the prescription dose (V(100)) were calculated from the postimplant dose-volume histogram for 140 patients undergoing low-dose rate prostate brachytherapy from 1997 to 2003 at Durham Regional Hospital and the Durham VA Medical Center (Durham, NC)., Results: The median follow-up was 50 months. There was a 7% biochemical failure rate (10 of 140), and 91% of patients (127 of 140) were alive at last clinical follow-up. The median BED was 148 Gy (range, 46-218 Gy). The median D(90) was 139 Gy (range, 45-203 Gy). The median V(100) was 85% (range, 44-100%). The overall 5-year biochemical relapse-free survival (bRFS) rate was 90.1%. On univariate Cox proportional hazards modeling, no pretreatment characteristic (Gleason score sum, age, baseline prostate-specific antigen, or clinical stage) was predictive of bRFS. The BED, D(90), and V(100) were all highly correlated (Pearson coefficients >92%), and all were strongly correlated with bRFS. Using the Youden method, we identified the following cut points for predicting freedom from biochemical failure: D(90) >or= 110 Gy, V(100) >or= 74%, and BED >or= 115 Gy. None of the covariates significantly predicted overall survival., Conclusions: We observed significant correlation between BED, D(90), and V(100) with bRFS. The BED is at least as predictive of bRFS as D(90) or V(100). Dosimetric quantifiers that account for heterogeneity in tumor location and dose distribution, tumor repopulation, and survival probability of tumor clonogens should be investigated.

Purpose: To evaluate the influence of patient- and treatment-related factors on freedom from biochemical failure (FFbF) in patients with intermediate-risk prostate cancer., Methods and Materials: From a prospectively collected database of 2250 men treated at Mount Sinai Hospital from 1990 to 2004 with low-dose-rate brachytherapy for prostate cancer, 558 men with either one or more intermediate-risk features (prostate-specific antigen [PSA] level 10-20 ng/mL, Gleason score 7, or Stage T2b) were identified who had a minimum follow-up of 24 months and postimplant CT-based dosimetric analysis. Biologically effective dose (BED) values were calculated to compare doses from different isotopes and treatment regimens. Patients were treated with brachytherapy with or without hormone therapy and/or external-beam radiotherapy. Patient- and treatment-related factors were analyzed with respect to FFbF. The median follow-up was 60 months (range, 24-167 months). Biochemical failure was defined according to the Phoenix definition. Univariate analyses were used to determine whether any variable was predictive of FFbF. A two-sided p value of <0.05 was considered significant., Results: Overall, the actuarial FFbF at 10 years was 86%. Dose (BED <150 Gy(2) vs. >or=150 Gy(2)) was the only significant predictor of FFbF (p < 0.001). None of the other variables (PSA, external-beam radiotherapy, Gleason score, treatment type, hormones, stage, and number of risk factors) was found to be a statistically significant predictor of 10-year FFbF., Conclusions: Radiation dose is an important predictor of FFbF in intermediate-risk prostate cancer. Treatment should continue to be individualized according to presenting disease characteristics until results from Radiation Therapy Oncology Group trial 0232 become available.

Purpose: To investigate the biochemical control rate in patients undergoing permanent prostate brachytherapy as a function of the biologically effective dose (BED) and risk group., Methods and Materials: Six centers provided data on 3,928 permanent brachytherapy patients with postimplant dosimetry results. The mean prostate-specific antigen level was 8.9 ng/mL. (125)I was used in 2,293 (58%), (103)Pd in 1,635, and supplemental external beam radiotherapy in 882 (22.5%) patients. The patients were stratified into low- (n = 2,188), intermediate- (n = 1,188), and high- (n = 552) risk groups and into three BED groups of < 140 Gy (n = 524), 140-200 Gy (n = 2284), and >200 Gy (n = 1,115). Freedom from biochemical disease progression (biochemical freedom from failure [bFFF]) was determined using the American Society for Therapeutic Radiology Oncology and Phoenix definitions and calculated using the Kaplan-Meier method, with factors compared using the log-rank test., Results: The 10-year prostate-specific antigen bFFF rate for the American Society for Therapeutic Radiology Oncology and Phoenix definitions was 79.2% and 70%, respectively. The corresponding bFFF rates for the low-, intermediate-, and high-risk groups was 84.1% and 78.1%, 76.8% and 63.6%, and 64.4% and 58.2%, respectively (p < 0.0001). The corresponding bFFF rate for the three BED groups was 56.1% and 41.4%, 80% and 77.9%, and 91.1% and 82.9% (p < 0.0001). The corresponding bFFF rate for the low-risk patients by dose group was 69.8% and 49.8%, 86% and 85.2%, and 88.1% and 88.3% for the low-, intermediate, and high-dose group, respectively (p <0.0001). The corresponding bFFF rate for the intermediate-risk patients by dose group was 52.9% and 23.1%, 74.1% and 77.7%, and 94.3% and 88.8% for the low-, intermediate-, and high-dose group, respectively (p < 0.0001). The corresponding bFFF rate for high-risk patients by dose group was 19.2% and 41.7%, 61.8% and 53.2%, and 90% and 69.6% for the low-, intermediate-, and high-dose group, respectively (p < 0.0001)., Conclusions: These data suggest that permanent brachytherapy dose prescriptions can be customized to risk status. In low-risk patients, achieving a BED of >or=140 Gy might be adequate for prostate-specific antigen control. However, high-risk disease might require a BED dose of >or=200 Gy.

Purpose: To evaluate prostate-specific antigen (PSA) spikes after permanent prostate brachytherapy in low-risk patients., Methods and Materials: The study population consisted of 164 prostate cancer patients who were part of a prospective randomized trial comparing (103)Pd and (125)I for low-risk disease. Of the 164 patients, 61 (37.2%) received short-course androgen deprivation therapy. The median follow-up was 5.4 years. On average, 11.1 post-treatment PSA measurements were obtained per patient. Biochemical disease-free survival was defined as a PSA level of < or =0.40 ng/mL after nadir. A PSA spike was defined as an increase of > or =0.2 ng/mL, followed by a durable decline to prespike levels. Multiple parameters were evaluated as predictors for a PSA spike., Results: Of the 164 patients, 44 (26.9%) developed a PSA spike. Of the 46 hormone-naive (125)I patients and 57 hormone-naive (103)Pd patients, 21 (45.7%) and 8 (14.0%) developed a PSA spike. In the hormone-naive patients, the mean time between implantation and the spike was 22.6 months and 18.7 months for (125)I and (103)Pd, respectively. In patients receiving neoadjuvant androgen deprivation therapy, the incidence of spikes was comparable between isotopes ((125)I 28.1% and (103)Pd 20.7%). The incidence of spikes was substantially different in patients <65 years vs. > or =65 years old (38.5% vs. 16.3%). On multivariate Cox regression analysis, patient age (p < 0.001) and isotope (p = 0.002) were significant predictors for spike., Conclusion: In low-risk prostate cancer, PSA spikes are most common in patients implanted with (125)I and/or <65 years of age. Differences in isotope-related spikes are most pronounced in hormone-naive patients.

Purpose: To assess long-term prostate-specific antigen (PSA) outcome after permanent prostate brachytherapy (BT) and identify predictors of improved disease-free survival., Methods and Materials: Eleven institutions combined data on 2,693 patients treated with permanent interstitial BT monotherapy for T1-T2 prostate cancer. Of these patients, 1,831 (68%) were treated with I-125 (median dose, 144 Gy) and 862 (32%) were treated with Pd-103 (median dose, 130 Gy). Criteria for inclusion were: available pre-BT PSA, BT > or =5 years before data submission, BT between 1988-1998, and no androgen deprivation before failure. The median follow-up was 63 months., Results: Among patients where the I-125 dose to 90% of the prostate (D90) was > or =130 Gy, the 8-year PSA relapse-free survival (PRFS) was 93% compared with 76% for those with lower D90 dose levels (p < 0.001). A multivariable analysis identified tumor stage (p = 0.002), Gleason score (p < 0.001), pretreatment PSA level (p < 0.001), treatment year (p = 0.001), and the isotope used (p = 0.004) as pretreatment and treatment variables associated with PRFS. When restricted to patients with available postimplantation dosimetric information, D90 emerged as a significant predictor of biochemical outcome (p = 0.01), and isotope was not significant. The 8-year PRFS was 92%, 86%, 79%, and 67%, respectively, for patients with PSA nadir values of 0-0.49, 0.5-0.99, 1.0-1.99, and >2.0 ng/mL (p < 0.001). Among patients free of biochemical relapse at 8 years, the median nadir level was 0.1 ng/mL, and 90% of these patients achieved a nadir PSA level <0.6 ng/mL., Conclusions: Outcome after permanent BT for prostatic cancer relates to tumor stage, Gleason score, pretreatment PSA, BT year, and post-BT dosimetric quality. PSA nadir < or =0.5 ng/mL was particularly associated with durable long-term PSA disease-free survival. The only controllable factor to impact on long-term outcome was the D90 which is a reflection of implant quality.

Purpose: To analyze the role of dosimetric quality parameters in maximizing cancer eradication in higher risk prostate cancer patients treated with palladium (Pd)-103 and supplemental beam radiation., Methods: One-hundred-seventy-nine patients treated with Pd-103 and supplemental beam radiation, with minimum 2 years follow-up prostate-specific antigen (PSA) values and posttreatment computed tomography scans were analyzed. Dosimetric parameters included the V100 (percent of the postimplant volume covered by the prescription dose), the D90 (the minimum dose that covered 90% of the post implant volume), and the treatment margins (the radial distance between the prostatic edge and the prescription isodose). Treatment margins (TMs) were calculated using premarket software., Results: Freedom from biochemical failure was 79% at 3 years, with 92 of the 179 patients (51%) followed beyond 3 years. In comparing patients who did or did not achieve biochemical control, the most striking differences were in biologic factors of pretreatment PSA and Gleason score. The V100, D90, and average TM all showed nonsignificant trends to higher values in patients with biochemical control. In multivariate analysis of each of the three dosimetric parameters against PSA and Gleason score, TM showed the strongest correlation with biochemical control (p = 0.19)., Conclusions: For patients with intermediate and high-risk prostate cancer treated with Pd-103 brachytherapy and external beam radiation, biologic factors (PSA and Gleason score) were the most important determinants of cancer eradication. However, there is a trend to better outcomes among patients with higher quality implant parameters, suggesting that attention to implant quality will maximize the likelihood of cure.

Purpose: To analyze the effect of biologically effective dose (BED) values on prostate-specific antigen (PSA) failure and posttreatment biopsy., Methods and Materials: From 1990 to 2003, 1,377 patients had prostate brachytherapy alone (I-125 or Pd-103) (571), hormonal and brachytherapy (371), and trimodality therapy (hormonal, implant, and external beam) (435). Dose was defined as the D90 (dose delivered to 90% of the gland from the dose-volume histogram)., Results: Freedom from PSA failure (FFPF) at 10 years was 87%. The 10-year FFPF for BED<100, >100-120, >120-140, >140-160, <160-180, >180-200, and >200 were 46%, 68%, 81%, 85.5%, 90%, 90%, and 92%, respectively (p<0.0001). BED and Gleason score had the greatest effect, with p values of p<0.0001 in multivariate analysis. Posttreatment positive biopsy rate was 7% (31/446). The positive biopsy rates for BED100-120, >120-140, >140-160, >160-180, >180-200, and >200 were 24% (8/33), 15% (3/20), 6% (2/33), 6% (3/52), 7% (6/82), 1% (1/72), and 3% (4/131), respectively (p<0.0001). BED was the most significant predictor of biopsy outcome in multivariate analysis (p=0.006)., Conclusions: Biologically effective dose equations provide a method of comparing different isotopes and combined therapies in the brachytherapy management of prostate cancer. The effects of BED on FFPF and posttreatment biopsy demonstrate a strong dose-response relationship.

Background: The concept of a prostate-specific antigen (PSA) "nadir" has been used as a predictive marker for treatment success in patients treated with radiotherapy for localized prostate carcinoma. However, this approach is not applicable in patients who are concomitantly treated with short-term hormonal therapies. To address this, the authors sought to develop a new predictive marker in such patients after prostate brachytherapy (BT)., Methods: Between March 1997 and November 2002, 194 men with clinical Stage T1A-T3N0M0 prostate carcinoma (according to the 1992 International Union Against Cancer/American Joint Committee on Cancer TNM classification system) were treated with interstitial palladium (103Pd3) BT and androgen ablation therapy with or without external beam radiotherapy (EBRT). Based on tumor characteristics, 127 patients received an antiandrogen, finasteride, and BT whereas 67 received an antiandrogen, leuprolide, and EBRT followed by a BT boost. Hormonal therapy was initiated 2-3 months before any radiotherapy for a total duration of 8-9 months. Follow-up included physical examination and determining the PSA level at 3-month intervals. Postoperative serum testosterone was evaluated in preoperatively potent patients with erectile dysfunction > 6 months after therapy. A PSA level < or = 0.06 ng/mL or < or = 0.20 ng/mL detected during a 6-12-month window after the implant were evaluated as predictors of biochemically disease-free survival (DFS), defined as the time to a PSA level > or = 1.0 ng/mL., Results: Of the 194 patients, 163 were available for analysis. The median length of follow-up was 48 months. In those patients with a PSA level < or = 0.20 ng/mL at 6-12 months, the DFS at 48 months after the implant was 96% (95% confidence interval [95% CI], 91-99%) compared with the remainder of the patients, whose DFS decreased to 80% (95% CI, 65-89%) (P < 0.001). When a PSA level < or = 0.06 ng/mL was used as an indicator, the 48-month DFS was 99% (95% CI, 91-100%) compared with that for patients with a PSA level > 0.06 ng/mL, in whom the DFS was 85% (95% CI, 74-92%) (P = 0.004). Furthermore, because testosterone levels may occasionally remain low after the cessation of luteinizing hormone-releasing hormone agonist therapy and result in erectile dysfunction and an artificially low PSA level, the authors reviewed the serum testosterone levels in 23 patients who were so treated and were experiencing erectile dysfunction. None had PSA values below the lower limit of normal., Conclusions: A PSA level < or = 0.20 ng/mL or < or = 0.06 ng/mL measured at 6-12 months after BT appears to be a useful predictive marker for detecting early success in patients with prostate carcinoma who are treated with neoadjuvant androgen ablation and BT. These markers may be used to identify those patients who are at an increased risk of biochemical failure and may be useful in stratifying patients for closer follow-up, long-term adjuvant therapies, or clinical trials. A longer follow-up period will be needed to verify whether these are predictive of long-term cancer control., (Copyright 2005 American Cancer Society.)

Purpose: To analyze the effect of high-dose regions on biochemical cancer control rates after prostate brachytherapy., Methods and Materials: Patients with 1997 American Joint Committee on Cancer clinical Stage T1c-T2a prostate carcinoma (Gleason grade 5-6, prostate-specific antigen level 4-10 ng/mL) were randomized to implantation with 125I (144 Gy) vs. 103Pd (125 Gy, National Institute of Standards and Technology 1999). Isotope implantation was performed by standard techniques, using a modified peripheral loading pattern. Of the 313 patients entered in the protocol, 270 were included in this analysis. The 125I source strength ranged from 0.4 to 0.89 mCi (median, 0.55 mCi), and the 103Pd source strength ranged from 1.3 to 1.6 mCi (median, 1.5 mCi). CT was performed within 4 h after implantation. The dosimetric parameters analyzed included the percentage of the postimplant prostate volume covered by the 100%, 150%, 200%, and 300% prescription dose (V100, V150, V200, and V300, respectively). The median time to the last follow-up for patients without failure was 2.7 years. Freedom from biochemical failure was defined as a serum prostate-specific antigen level of < or =0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum prostate-specific antigen level was still decreasing., Results: The mean V100, V150, V200, and V300 value was 90% (+/-8%), 63% (+/-14), 35% (+/-13%), and 14% (+/-7%), respectively. Patients with a V100 of > or =90% had a 3-year freedom from biochemical failure rate of 96% vs. 87% for those with a V100 of <90% (p=0.0029). Overall, patients with more high-dose regions had a greater chance of biochemical control. However, when only patients with a V100 of > or =90% were analyzed, no relationship was found between higher dose regions and the likelihood of cancer control. This lack of effect on biochemical control was apparent for both isotopes., Conclusion: High-dose regions do not appear to affect cancer control rates, as long as >90% of the prostate volume is covered by the prescription dose.

Purpose: To evaluate the impact of supplemental external beam radiotherapy (EBRT) and/or androgen deprivation therapy (ADT) on 8-year biochemical outcome after permanent prostate brachytherapy., Methods and Materials: Between April 1995 and January 2001, 668 consecutive patients underwent brachytherapy using either (103)Pd or (125)I for clinical Stage T1b-T3aNxM0 (2002 American Joint Committee on Cancer) adenocarcinoma of the prostate gland. No patient underwent seminal vesicle biopsy or pathologic lymph node staging. The median follow-up was 58.6 months. Biochemical progression-free survival was defined by the American Society for Therapeutic Radiology and Oncology consensus definition. The clinical, treatment, and dosimetric parameters evaluated for biochemical progression-free survival included supplemental EBRT, ADT, patient age, clinical stage, Gleason score, preimplant prostate specific antigen (PSA), risk group, percentage of positive biopsies, isotope used, prostate volume, planning volume, percentage of target volume receiving 100%, 150%, and 200% of prescribed dose, minimal percentage of dose covering 90% of target volume, tobacco status, hypertension, and diabetes., Results: For the entire group, the actuarial 8-year biochemical progression-free survival rate was 98.2%, 98.4%, and 88.2% for low-, intermediate-, and high-risk patients, respectively, with a median PSA level of <0.1 ng/mL for all risk groups and ADT and EBRT subgroups. At last follow-up, only 5 patients (0.8%) had died of metastatic prostate cancer. In multivariate analysis, Gleason score, percentage of positive biopsies, and ADT predicted for biochemical outcome in high-risk patients. In low- and intermediate-risk patients, none of the evaluated variables predicted for biochemical outcome. For the entire population, pretreatment PSA level, Gleason score, ADT, and clinical stage predicted for 8-year biochemical progression-free survival, with the percentage of positive biopsies approaching statistical significance., Conclusion: Prostate brachytherapy results in a high probability of 8-year biochemical progression-free survival for low-, intermediate-, and high-risk patients. Although the role of supplemental EBRT could not be adequately evaluated in high-risk patients, it did not improve biochemical outcome in low- and intermediate-risk patients. However, ADT resulted in a statistically significant improvement in progression-free survival for high-risk patients.

Purpose: Recent studies have suggested that cigarette smoking may be associated with an increased risk of death from prostate cancer. In this study, we evaluated the effect of cigarette smoking on the presentation and biochemical outcome after permanent prostate brachytherapy for prostate cancer., Methods and Materials: A total of 582 patients underwent brachytherapy with generous periprostatic margins using either (103)Pd or (125)I with or without supplemental external beam radiotherapy between April 1995 and September 2000. Of the 582 patients, 178 (30.6%) had never smoked, 306 (52.6%) were former smokers, and 98 (16.8%) were current smokers. The median patient age was 67.9 years, and the median follow-up was 54.5 months. No patient was lost to follow-up. No patient underwent routine seminal vesicle biopsy or pathologic lymph node staging. The clinical, treatment, and dosimetric parameters evaluated included tobacco status, age, clinical stage, Gleason score, pretreatment prostate-specific antigen level, risk group, percentage of positive biopsies, ultrasound volume, isotope used, planning volume, hormonal status, use of external beam radiotherapy, and postimplant dosimetry (percentage of target volume receiving 100%, 150%, and 200% of the prescribed dose and percentage of prescribed dose covering 90% of the target volume). Biochemical outcome was determined using the American Society for Therapeutic Radiology and Oncology consensus definition., Results: No differences in the clinical, treatment, or dosimetric parameters were identified, except that current smokers were statistically younger than those who had never smoked or former smokers (65.9 vs. 67.8 vs. 68.3 years, respectively, p = 0.016). Specifically, no relationship was discerned between tobacco history and risk group, supplemental external beam radiotherapy, choice of isotope, or use of hormonal therapy. The overall biochemical freedom from progression survival rate at 7 years was 96.2%, 95.6%, and 91.6% for patients who had never smoked, former smokers, and current smokers, respectively (p = 0.126). When stratified by risk group and hormonal status, tobacco consumption did not predict outcome, although a trend for poorer biochemical progression-free survival was noted in current smokers. The median prostate-specific antigen level for hormone-naive and hormonally manipulated disease-free patients was <0.1 ng/mL. In multivariate Cox regression analysis, Gleason score, pretreatment prostate-specific antigen level, risk group, and hormonal status were predictors of biochemical outcome., Conclusion: In this prostate brachytherapy cohort, tobacco consumption did not predict for risk group stratification or treatment approach. Although no statistically significant difference was found in biochemical progression-free survival, a trend for poorer biochemical outcome was demonstrated in current smokers.

Purpose: We described the temporarily increase phenomenon in prostate-specific antigen level (PSA bounce) after transperineal interstitial permanent prostate brachytherapy (TIPPB) for localized prostate cancer., Materials and Methods: From December 1998 to May 2003, 500 consecutive patients with localized prostate cancer were treated with TIPPB using iodine-125 or palladium-103. We examined 200 patients who have more than 2-year PSA follow-up. Median follow-up length was 1,069 days (range, 712-1,411 days). No patient received neoadjuvant or adjuvant hormone therapy. PSA determinations were performed every 3 months for the first 2 years after procedure, and every 6 months hereafter. PSA bounce was defined as an increase of 0.1 ng/ml or greater above the preceding PSA level after implant followed by a subsequent decrease below that level. The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel criteria 1996 were used to define biochemical failure., Results: PSA bounce was observed in 40% (80/200) of the cases receiving TIPPB. The median time to PSA bounce was 13 months from the day of implant. The median magnitude of the PSA bounce was 0.3 ng/ml from the pre-bounce level. Twelve cases demonstrated biochemical failure according to the ASTRO consensus guidelines of three consecutive rises in PSA. Ten of these subsequently showed a drop in PSA, consistent with biologic control of their disease. Two cases remain classified as apparent biochemical failures., Conclusions: A transient rise in the PSA following TIPPB, the so-called "bounce" is a common occurrence. The apparent PSA control of ten of twelve cases failing by the ASTRO criteria raises some concern. Further observation will be necessary to determine ways to discriminate these from true disease progression.

Purpose: To compare prostate cancer control rates in patients who received (125)I vs. (103)Pd., Materials and Methods: Of a planned total of 600 patients with 1997 American Joint Committee on Cancer clinical Stage T1c-T2a prostate carcinoma (Gleason score 5-6, prostate-specific antigen [PSA] 4-10 ng/mL), 126 were randomized to implantation with (125)I (144 Gy) vs. (103)Pd (125 Gy). The prostate biopsies were reviewed for Gleason score by one of us (L.T.). A single manufacturer of (125)I sources (Model 6711, Amersham, Chicago, IL) and (103)Pd sources (Theraseed, Theragenics, Buford, Georgia) was used. Isotope implantation was performed with standard techniques, using a modified peripheral loading pattern. Of a total of 126 patients randomized, 11 were excluded, leaving 115 randomized patients for this analysis. Twenty patients received a short course of preimplant hormonal therapy, none of whom continued hormonal therapy after their implant procedure. Postimplant CT was obtained 2-4 hours after implantation. The dosimetric parameters analyzed included the percentage of the postimplant prostate or rectal volume covered by the prescription dose (V(100)) and the dose that covered 90% of the postimplant prostate volume (D(90)). Freedom from biochemical failure was defined as a serum PSA level < or =0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum PSA level was still decreasing. Patients whose serum PSA had reached a nadir at a value >0.5 ng/mL were scored as having failure at the time at which their PSA had reached a nadir. The follow-up period for patients without failure ranged from 2.0 to 4.9 years (median 2.9). Freedom-from-failure curves were calculated by the Kaplan-Meier method. Differences between groups were determined by the log-rank method., Results: The actuarial biochemical freedom-from-failure rate at 3 years was 89% for (125)I patients vs. 91% for (103)Pd patients (p = 0.76). The 3-year biochemical freedom-from-failure rate for patients with a D(90) <100% of the prescription dose was 82% vs. 97% for patients with a D(90) > or =100% of the prescription dose (p = 0.01). Similarly, the 3-year biochemical freedom-from-failure rate for patients with a V(100) <90% of the prescription dose was 87% vs. 97% for patients with a V(100) > or =90% of the prescription dose (p = 0.01). The effect of the dosimetric parameters on biochemical control was most pronounced for (125)I, but also apparent for (103)Pd., Conclusions: The 3-year actuarial biochemical control rates for low early-stage prostate cancer are similar after (125)I and (103)Pd.

Purpose: The role of external beam radiation therapy in addition to brachytherapy continues to be scrutinized for long term control of PSA levels after prostate cancer diagnosis., Methods and Materials: We report 10-year biochemical relapse-free survival (BRFS) on 232 patients presenting with localized prostate cancer and consecutively treated with iodine(125) (I(125)) or palladium(103) (Pd(103)) brachytherapy and neoadjuvant external beam radiation therapy. Multivariate regression analysis was used to create a pretreatment clinical prognostic risk model using a modified ASTRO consensus definition (two consecutive rises in serum PSA) as the outcome. Gleason scoring was performed by pathologists at a small community hospital. Derived risk categories are the following: low = PSA 10 ng/mL or Gleason Score >or=7 or stage >or=T2c (1 intermediate risk factor); and high = 2 or more intermediate risk factors. Time to PSA failure (local, distant, or biochemical) was calculated and compared using Kaplan-Meier plots., Results: Ten-year BRFS for the entire treatment group was 70%. Biochemical control rates by risk cohort analysis (95% confidence interval): low risk, 85% (83.3-90.7%); intermediate risk, 77% (73.0-84.5%); and high risk, 45% (45.4-57.2%). Using a risk grouping proposed by the Mt. Sinai group, the BRFS was: low risk, 84%; intermediate risk, 93%; and high risk, 57%. Grouping by the risk classification used by D'Amico, the BRFS was: low risk, 86%; intermediate risk, 90%; and high risk, 48%., Conclusions: I(125) or Pd(103) brachytherapy, as a boost combined with EBRT, continues to result in high rates of biochemical control at 10 years. Different risk group classification schemes lead to different BRFS results.

Purpose: A prostate brachytherapy program was initiated in 1990, when comparatively little was known of the relative importance of disease- and treatment-related factors on outcome. Patients treated during the first 6 years of the program were analyzed to determine the value of patient selection and implant quality on biochemical control., Methods and Materials: We treated 243 patients with clinically localized prostate cancer with radioactive seed implantation and underwent 1-month CT-based dosimetric analysis. Follow-up ranged from 61 to 135 months (median 75). The Gleason score was < or =6 in 78% (n = 189), 7 in 14% (n = 35), and 8-10 in 8% (n = 19). The initial prostate-specific antigen (PSA) level was < or =10 ng/mL in 61% (n = 149), 10.1-20 ng/mL in 26% (n = 63), and >20 ng/mL in 13% (n = 31). The disease stage was T2a or less in 49% (n = 120), and Stage T2b-T2c in 51% (n = 123). A real-time ultrasound-guided technique was used with (125)I (n = 138) and (103)Pd (n = 105) isotopes. No patient underwent external beam radiotherapy as part of their primary treatment. Of the 243 patients, 60% also received hormonal ablation for at least 3 months before and 2-3 months after seed implantation. All patients included underwent a 1-month CT-based dosimetric analysis. The implant dose was defined as the dose delivered to 90% of the prostate volume on postimplant dosimetry (D(90)). On the basis of prior dose-response analyses, patients were retrospectively grouped into optimal D(90) ((125)I > or =140 Gy Task Group 43 or (103)Pd >/=100 Gy) and suboptimal D(90) ( (125)I <140 Gy or (103)Pd <100 Gy) dose groups. Biochemical failure was defined using the American Society for Therapeutic Radiology Oncology definition., Results: Disease-related factors, including initial PSA level, Gleason score, and stage, were significant predictors of biochemical failure. The actuarial 8-year freedom from biochemical failure (bFFF) rate was 80% for those with a PSA level < or =10 ng/mL, 86% for PSA 10.1-20 ng/mL, and 45% for PSA >20 ng/mL (p = 0.0019). Patients with a Gleason score of < or =6 had an 8-year bFFF rate of 81% vs. 67% for those with Gleason score 7 and 53% for those with Gleason score 8-10 (p = 0.0003). Patients with Stage T2a or less had an 8-year bFFF rate of 85% compared with 69% for those with Stage T2b-T2c (p = 0.013). The 8-year bFFF rate was 88% for low-risk patients (Stage T2a or less, Gleason score < or =6, and initial PSA level < or =10 ng/mL; n = 75), 81% for moderate-risk patients (Stage T2b or Gleason score 7 or initial PSA level >10.1-20 ng/mL; n = 70), and 65% for high-risk patients (two or more moderate-risk features or Gleason score > or =8 or initial PSA level >20 ng/mL; n = 98; p = 0.0009). Patients with optimal dose implants (n = 145) had an 8-year bFFF rate of 82% compared with 68% for those with suboptimal dose implants (n = 98; p = 0.007). Hormonal therapy did not significantly affect biochemical failure (p = 0.27). In multivariate analysis, the statistically significant variables included initial PSA level (p <0.0001), Gleason score (p = 0.024), and dose group (p = 0.046). Because our current practice limits implantation alone to low-risk patients, an analysis of this subgroup was undertaken to validate the importance of dose. In the optimal dose group, low-risk patients had an 8-year bFFF rate of 94% vs. 75% for the low-risk patients in the suboptimal dose group (p = 0.02)., Conclusion: With minimal follow-up of 5 years, these data continue to support the use of implantation alone in low-risk prostate cancer patients and demonstrate the importance of implant quality (dose) in achieving optimal outcomes. Low-risk patients who receive an optimal dose implant have a 94% bFFF rate at 8 years.

Purpose: To evaluate 4-year biochemical outcomes for patients with prostate adenocarcinoma who underwent radioimmunoguided (Prostascint) permanent prostate brachytherapy., Methods and Materials: Eighty patients with clinical T1C-T3A NxM0 prostate cancer underwent ProstaScint-guided prostate brachytherapy using either (103)Pd or (125)I between February 1997 and December 2000. Sixty-seven patients underwent prostate brachytherapy alone, whereas 13 patients received neoadjuvant hormonal manipulation before implantation. Risk factors (RF) included PSA >10, Stage >or=T2b, and Gleason grade >or=7. Sixty patients had low-risk disease (0 RF), 17 were intermediate risk (1 RF), and 3 were high risk (2 RF). Biochemical disease-free survival (bDFS) was calculated using the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria, a PSA cutoff of 1.0 ng/mL, and a PSA cutoff of 0.5 ng/mL., Results: Four-year bDFS for the entire cohort was 97.4% using the ASTRO consensus criteria. Low-risk patients (60) had a 4-year bDFS of 100%; intermediate- and high-risk patients (20 patients) were 89.2%. The hormonally naïve group (67 patients) had a 4-year bDFS of 96.9% and a median PSA nadir of 0.2 ng/mL. Median time to nadir was 19.8 months (range: 1.9-53.2 months). For the neoadjuvant hormonal therapy group (13 patients), ASTRO-defined bDFS was 100%. Overall, 85.2% of patients had a posttreatment PSA

Purpose: To calculate the actuarial risk of developing a prostate-specific antigen (PSA) bounce after prostate brachytherapy alone, using three definitions of bounce mentioned in the literature, and to explore the relationship between disease and treatment variables and the risk of developing a bounce. The impact of PSA bounce on PSA failure was also explored., Methods and Materials: A total of 373 patients with T1-T2 prostate cancer underwent radioactive seed implant using 125I (n = 337) or 103Pd (n = 36) without hormonal therapy or external beam RT. All patients had a minimum of 1 year (median 4, maximum 11) of follow-up and at least three follow-up PSA values. PSA bounce was defined by a rise of one or two PSA values with a subsequent fall. Three definitions of bounce were used: definition 1, rise > or = 0.1 ng/mL; definition 2, rise > or = 0.4 ng/mL; and definition 3, rise >35% of previous value., Results: The actuarial likelihood of experiencing a PSA bounce at 5 years was 31% for definition 1, 17% for definition 2, and 20% for definition 3. The median time to develop a bounce was 19.5 months for definitions 1 and 2 and 20.5 months for definition 3. Gleason score, initial PSA level, and clinical stage did not predict for bounce using any definition. Using definition 1, younger patients (< or = 65 years) had a bounce rate at 5 years of 38% vs. 24% for older patients (p = 0.009). 125I patients receiving an implant dose of < or = 160 Gy had a bounce rate (definition 1) at 5 years of 24% vs. 38% for those receiving a dose delivered to 90% of the gland on the 1 month postimplant dose-volume histogram (D90) >160 Gy (p = 0.04). Using definition 2, prostate volume significantly affected the incidence of bounce. Patients with larger glands (>35 cm(3)) were more likely to experience a bounce (23% at 5 years) than those with smaller glands (< or = 35 cm(3)) who had a bounce rate of 11% at 5 years (p = 0.01). In a multivariate analysis of factors predicting for PSA failure, PSA bounce was not found to be significant., Conclusion: PSA bounce is a common phenomenon after prostate brachytherapy and occurs at a rate of 17-31%, depending on the definition used. It is more common in younger patients, those receiving higher implant doses, and those with larger glands. PSA bounce does not predict for future PSA failure.

Purpose: To assess the difference in prostate-specific antigen (PSA) response kinetics in patients undergoing either (125)I or (103)Pd permanent prostate brachytherapy (PPB)., Methods and Materials: Between 1997 and 1999, 333 patients underwent PPB as monotherapy. Forty-eight patients received a (125)I implant, and 285 received a (103)Pd implant. Biochemical relapse-free survival was defined by the Kattan modification of the American Society for Therapeutic Radiology and Oncology consensus, based on three PSA increases. In addition, the time to reach a PSA threshold of

Objectives: To determine the effect of the dominant pattern in Gleason score 7 histologic findings on biochemical no evidence of disease survival for hormone-naive patients undergoing permanent prostate brachytherapy., Methods: A total of 114 hormone-naive patients with Gleason score 7 histologic findings underwent transperineal ultrasound-guided permanent prostate brachytherapy for clinical T1c-T3a NxM0 adenocarcinoma of the prostate gland from April 1995 to October 1999. No patient was lost to follow-up. No patient underwent seminal vesicle biopsy or pathologic lymph node staging. Sixty-four patients were diagnosed with Gleason score 3+4 and 50 with Gleason score 4+3 prostate cancer. Twenty-one patients were implanted with either palladium 103 or iodine 125 monotherapy, and 93 patients received supplemental external beam radiotherapy with a brachytherapy boost. The median patient age was 69 years (range 49 to 79). The median follow-up was 46.4 months (range 20 to 80). The American Society for Therapeutic Radiology and Oncology consensus definition was used to determine the biochemical disease-free survival., Results: The actuarial 5-year biochemical disease-free survival rate was 90.3%. No statistically significant difference in outcome was found when stratified by the dominant pattern in Gleason score 7 histologic features (89.4% versus 91.5% for 3+4 and 4+3, respectively, P = 0.700). The biochemical no evidence of disease survival analysis in terms of the Gleason cohorts revealed no difference in terms of the choice of isotope, use of supplemental external beam radiotherapy, or preimplant prostate-specific antigen level. The median and mean postimplant prostate-specific antigen level was less than 0.1 ng/mL and 0.12 +/- 0.20 ng/mL, respectively, without a significant difference between Gleason score 3+4 and 4+3., Conclusions: Our results indicate that the 5-year biochemical outcome with a hormone-naive prostate brachytherapy approach that uses multiple periprostatic seeds is not dependent on Gleason score 3+4 versus 4+3 histologic features.

Purpose: Recently, the percentage of positive prostate biopsies has been reported to be statistically significant in predicting the biochemical outcome after either radical prostatectomy or 3-dimensional conformal external beam radiotherapy. In this study, we evaluated the impact of the percentage of positive prostate biopsies in predicting the 5-year biochemical outcome for patients with clinically organ-confined prostate cancer undergoing permanent interstitial brachytherapy., Methods and Materials: Two hundred sixty-two hormone naive patients underwent transperineal ultrasound-guided permanent prostate brachytherapy with generous periprostatic margins, using either 103Pd or 125I for clinical T1b/T2b NXM0 (1997 AJCC) adenocarcinoma of the prostate gland from April 1995 to October 1999. No patient was lost to follow-up. The actual percentage of positive biopsies (number of positive biopsies/total number of biopsies) was determinable for 255 of the 262 patients. Of the evaluated cases, 133 patients were implanted with 103Pd and 122 patients with 125I. The median patient age was 68 years (range 48-81). The median follow-up was 38.6 months (range 6-73). Follow-up was calculated from the day of implantation. Patients were stratified by the percentage of positive biopsies into the following groups: <34%, 34-50%, and >50%. Additional clinical parameters evaluated included patient age, clinical T-stage, Gleason score, pretreatment prostate specific antigen (PSA), risk group, and prostate volume. Low-risk patients were staged as clinical T1c/T2a, Gleason score < or =6, and pretreatment PSA < or =10 ng/mL, intermediate-risk patients presented with one unfavorable prognostic parameter, and high-risk patients presented with two or more unfavorable prognostic parameters (clinical stage T2b, PSA >10 ng/mL, Gleason score > or =7). Treatment parameters included the use of supplemental external beam radiation and choice of isotope. Biochemical disease-free survival was defined by the American Society of Therapeutic Radiation and Oncology consensus definition., Results: For the 255 evaluated patients, the 5-year actuarial biochemical no evidence of disease survival rate was 92.5%. For patients with low, intermediate, and high-risk disease, 95.8%, 98.1%, and 79.4% of patients were free of biochemical failure, respectively. When each risk group was stratified into the percent positive biopsy categories of <34%, 34-50%, and >50%, no statistical difference was found in biochemical outcome for the biopsy subgroups. In multivariate analysis, none of the clinical or treatment parameters predicted for failure in the low-risk group; only Gleason score was predictive for intermediate-risk patients and only PSA for high-risk patients. In the overall population, PSA and Gleason score were both found to be predictors of biochemical failure, but not risk group, clinical stage, or percentage of positive biopsies. There was no significant dependence between the percent positive biopsy group and the Kaplan-Meier biochemical survival rates for any of the various subgroups of clinical and treatment parameters, except for clinical stage T1c-T2a (p = 0.006). The median postimplant PSA was 0.2 ng/mL for patients with either low-risk disease or <34% positive biopsies and 0.1 ng/mL for all other risk groups or percent positive biopsy subgroups., Conclusion: Although a significant trend was found for biochemical failure with increasing percent positive biopsies in the overall population, our results suggest that the percentage of positive biopsies is not statistically significant in predicting the 5-year biochemical disease-free outcome for patients with low, intermediate, and high-risk disease undergoing permanent prostate brachytherapy. Only the Gleason score in intermediate-risk patients and the pretreatment PSA level in high-risk patients was predictive of biochemical failure. We believe this relative lack of significance for the percentage of positive biopsies is a result of dose escalation far exceeding other radiotherapy modalities and the ability to aggressively treat the periprostatic region compared with radical prostatectomy by way of the accurate placement of periprostatic seeds.

Purpose: Standard therapies for locally advanced prostate cancer have resulted in suboptimal disease control rates. A Phase I/II trial was designed for patients with positive seminal vesicle biopsies, prostate-specific antigen (PSA) >15 ng/ml, Gleason score > or =8 or clinical classification T2c-T3 to improve local control and to test the tolerance of the prostate to high-dose radiation by using neoadjuvant hormonal therapy, 103Pd brachytherapy, and conformal three-dimensional external beam radiation therapy (EBRT). This article outlines treatment-related morbidity and PSA response to this regimen and analyzes the effect of escalating doses of brachytherapy., Methods and Materials: Forth-three patients with T1c-T3 prostate cancer were enrolled in a Phase I/II trial from March 1994 through September 1997. Follow-up ranged from 12 to 64 months (median, 32 months). Pretreatment PSA ranged from 2.1 to 202 ng/ml (median, 16 ng/ml). Seventy-seven percent (33 of 43) of patients had high-grade tumors (score > or =7). Seventy-four percent (32 of 43) had stage > or =T2c. A total of 21 (49%) patients had positive seminal vesicle biopsies. Treatment consisted of hormonal therapy for 3 months with leuprolide and flutamide followed by a 103Pd implant and, 2 months later, 59.4 Gy of three-dimensional EBRT. Hormonal therapy was continued for 9 months. The planned 103Pd dose was escalated from 57 Gy (13 patients) to 77 Gy (13 patients) to 86 Gy (17 patients)., Results: The actuarial freedom from PSA failure (PSA>0.5 ng/ml) at 4 years was 74%. There were no significant differences found when analyzing patients by presenting PSA or seminal vesicle status. There was a trend toward improved outcome with higher doses delivered to the prostate via the implant. Patients receiving doses > or =65 Gy (31 patients) had a freedom from PSA failure rate at 4 years of 89.5%, compared with 52.5% for those receiving doses <65 Gy (10 patients; p=0.08). The last PSA values for those patients free from PSA failure were < or =0.1 ng/ml in 25 (69%), >0.1-0.2 ng/ml in 5 (14%), and >0.2-0.5 ng/ml in 6 (17%). The actuarial freedom from developing Grade 2 proctitis was 75% at 4 years. There was a trend toward increased proctitis with increasing prostate implant doses. Patients with doses < or =70 Gy (n=12) had a 92% freedom from Grade 2 proctitis compared with 67.5% for those with doses delivered to 90% of the gland from a dose-volume histogram of >70 Gy (n=29) (p=0.15). There were no cases of Grade 3 or 4 proctitis. The 3-year actuarial preservation of sexual potency rate was 43%., Conclusions: The preliminary results from this regimen show an improvement in PSA control for this group of locally advanced prostate cancer patients over more standard therapies. To maximize control while minimizing toxicity, doses of 65-70 Gy of 103Pd should be used when 59.4 Gy of three-dimensional EBRT is delivered. Longer follow-up will be needed to further substantiate these findings.

Purpose: The long-standing confusion regarding the clinical relevance of postimplant biopsies is complicated by the common occurrence of temporary PSA rises between 1 and 2 years after brachytherapy. We report here 4 patients with temporary, self-limited PSA rises and postimplant biopsies, for whom radical prostatectomy was strongly advised but for whom surgery would probably have been the wrong choice., Materials and Methods: Transperineal I-125 or Pd-103 implants were performed as previously described. After implantation, patients were followed routinely, with repeat PSA and physical examination at approximately every 4 to 6 months. Timing of postimplant PSAs was at the discretion of the patient and his doctors. Postimplant biopsies were performed in all cases out of concern for a persistently elevated serum PSA. Sections of fixed and embedded tissue were stained with standard hematoxylin and eosin., Results: All 4 patients presented here were advised to have a salvage prostatectomy based primarily on their PSA changes. However, all of the patients have subsequently had a dramatic PSA fall, consistent with long-term cancer control, despite the fact that 3 of the 4 had histologic evidence of persistent cancer on repeat prostate biopsy., Conclusions: It is crucial that clinicians be aware of the potential for the doubly confusing situation of temporary PSA rises and apparently positive rebiopsies and the pressure it puts on both patients and their physicians to go ahead with inappropriate salvage therapy.

Purpose: The evaluation of clinical variables that influence biochemical relapse-free survival in a cohort of patients treated by combined radiotherapy over a fixed interval., Methods and Materials: Three hundred forty-eight patients diagnosed with clinical Stage T1--T3a prostate cancer were treated with a course of (103)Pd or (125)I brachytherapy followed by a limited course of external beam radiation formed the basis for study. All censored patients had a minimum 2-year follow-up. Biochemical relapse-free survival (BRFS) was estimated using a modified American Society for Therapeutic Radiology and Oncology consensus definition. Discrete "risk groups" were developed based on BRFS as influenced by pretreatment parameters., Results: Significant risk factors contributing to biochemical failure were serum prostate-specific antigen (PSA) greater than 20 ng/mL, Gleason sum of 7 or greater, or clinical stage T2c or greater. Five-year biochemical control for those exhibiting no risk factor was 88%; one risk factor, 75%; two or more risk factors, 51%. The differences in BRFS among all three risk groups were statistically significant. Outcomes for patients presenting with PSA 10 to 20 ng/mL, but otherwise low-risk disease, fared no differently from those low risk patients presenting with PSA less than 10 ng/mL., Conclusions: Combined radiotherapy with (103)Pd or (125)I followed by external beam radiotherapy achieves a high rate of biochemical and clinical control in patients with low- to intermediate-risk clinically organ confined disease.

Purpose: A report of biochemical outcomes for patients treated with palladium-103 (Pd-103) brachytherapy over a fixed time interval., Methods and Materials: Two hundred thirty patients with clinical stage T1-T2 prostate cancer were treated with Pd-103 brachytherapy and followed with prostate-specific antigen (PSA) determinations. Kaplan-Meier estimates of biochemical failure on the basis of two consecutive elevations of PSA were utilized. Multivariate risk groups were constructed. Aggregate PSA response by time interval was assessed., Results: The overall biochemical control rate achieved at 9 years was 83.5%. Failures were local 3.0%; distant 6.1%; PSA progression only 4.3%. Significant risk factors contributing to failure were serum PSA greater than 10 ng/ml and Gleason sum of 7 or greater. Five-year biochemical control for those exhibiting neither risk factor was 94%; one risk factor, 82%; both risk factors, 65%. When all 1354 PSA determinations obtained for this cohort were considered, the patients with a proportion of PSAs < or = 0.5 ng/ml continued to increase until at least 48 months post-therapy. These data conformed to a median PSA half-life of 96.2 days., Conclusions: Prostate brachytherapy with Pd-103 achieves a high rate of biochemical and clinical control in patients with clinically organ-confined disease. PSA response following brachytherapy with low-dose-rate isotopes is protracted.

Purpose: Combined risk profiles are helpful in assessing the likelihood of prostate-specific antigen relapse-free survival (PSA-RFS) for patients with localized prostate cancer. This retrospective analysis reports the 5-year biochemical outcome of a large cohort of patients according to prognostic factors and risk profiles for patients undergoing ultrasound-guided transperineal interstitial permanent prostate brachytherapy (TIPPB)., Patients and Methods: Seven hundred seventeen consecutive patients with clinically localized prostate cancer treated between June 1992 and November 1997 underwent TIPPB. Palladium-103 (103Pd) (n = 539) or iodine-125 (125I) (n = 178) sources were utilized to a prescribed dose of 120 Gy and 144 Gy, respectively. One hundred eleven patients received combined external-beam irradiation (41.4 or 45 Gy) and TIPPB (103Pd, 90 Gy, and 125I, 108 Gy). One hundred twelve patients received androgen ablation therapy in advance of TIPPB. Patients were grouped into risk profiles based on pretreatment factors that consisted of PSA < or = 10 and Gleason score < or = 6. Patients meeting both criteria were classified as favorable (n = 334). Those not fulfilling one criteria were classified as intermediate risk (n = 261), and those not fulfilling two criteria were classified as unfavorable risk (n = 261). PSA-RFS was calculated based on the American Society of Therapeutic Radiology and Oncology consensus conference definition of PSA failure. The median follow-up was 41 months (range, 14-82 months)., Results: The actuarial PSA-RFS survival at 5 years was 82%. Multivariate Cox regression analysis identified PSA and Gleason score as highly significant factors predicting for biochemical outcome. Hazard risk ratios using a nadir definition of the PSA as < or = 1.0 ng/mL and < or = 0.5 ng/mL were each significant predictors of outcome with the 0.5 ng/mL nadir level only slightly better (risk ratio for nadir < or = 1.0 = 2.78; risk ratio for nadir < or = 0.5 = 3.57). Favorable-risk patients had a 5-year actuarial PSA-RFS of 93%, whereas intermediate-risk and unfavorable-risk groups had 5-year PSA-RFSs of 77% and 62%, respectively. Four hundred ninety-three patients underwent brachytherapy without external-beam irradiation or androgen ablation. From this group, the 5-year PSA-RFSs for the favorable-risk, intermediate-risk, and unfavorable-risk patients were 92%, 74%, and 55%, respectively., Discussion: This retrospective study examining TIPPB demonstrated excellent 5-year actuarial PSA-RFS rates. The assignment of risk profiles based on the results of multivariate analysis of prognostic factors identifies the expected PSA-RFS for patients undergoing TIPPB.

Background: Interactive, transrectal, ultrasound-guided transperineal implantation is a new technique for performing permanent brachytherapy implants of the prostate. Prostate specific antigen (PSA) findings, biopsy results, and morbidity are examined to demonstrate its efficacy and safety in treating early stage prostate carcinoma., Methods: Ninety-seven patients underwent permanent implants for classifications T1 to T2 adenocarcinoma of the prostate gland with a median follow-up of 18 months (range: 6-51 months). Seventy-nine patients had negative laparoscopic pelvic lymph node dissections prior to implantation. Patients with positive lymph nodes were not implanted. The radioactive isotope used was I-125 in 71 patients and Pd-103 in 26 patients., Results: PSA failure was defined as two consecutive increases in PSA above the nadir level. The actuarial freedom from PSA failure (FFPF) at 2 years was 76% for the entire group. Stage significantly affected FFPF. Patients classified as T1b to T2a (35) had a FFPF of 91% at 2 years compared with 68.5% for patients classified as T2b to T2c (62) (P = 0.04). The pre-treatment PSA also significantly affected FFPF. Patients with PSA values of < or = 10 ng/mL (44) had a FFPF of 83% at 2 years. A similar rate of 82% was found in patients with PSA values of 10.1 to 20 ng/mL (29). Patients with PSA values > 20 ng/mL (24) had a significantly poorer FFPF at 2 years of 58% (P = 0.02). The PSA values of patients free from a PSA failure (82) ranged from 0.1 to 12.9 ng/mL with a median of 0.8 ng/mL. Transrectal prostate biopsies were performed 18 to 36 months posttreatment in 39 patients. Negative biopsies were found in 74% (29/39) of cases. The procedure was associated with an actuarial preservation of erectile function rate and sexual potency at 2 years of 96% and 79%, respectively. There were no cases of urinary incontinence or radiation cystitis. Associated morbidity included urinary retention requiring catheterization in 4% of the patients, outlet obstruction requiring a transurethral resection of the prostate in 2% and Grade 2 rectal complications in 1%., Conclusions: Interactive, ultrasound-guided transperineal brachytherapy results in a low PSA failure rate, high negative biopsy rate, and is associated with low morbidity and preservation of erectile function.