Interpreting Testosterone and Concomitant Prostate Specific Antigen Values during Androgen Deprivation Therapy for Recurrent Prostate Cancer.

PURPOSE: Measurement of testosterone levels during androgen deprivation therapy (ADT) is broadly recommended, but how therapy should be altered in response to testosterone values during ADT remains controversial. Our objective was therefore to evaluate the relation between testosterone and concomitant prostate specific antigen (PSA) levels during ADT on clinical outcomes. MATERIALS AND METHODS: Patients from the continuous androgen deprivation arm of the PR.7 trial of intermittent ADT for biochemically recurrent prostate cancer following radiotherapy were included. Statistical analyses evaluated the prognostic importance of testosterone levels during ADT relative to concomitant PSA levels. We similarly evaluated whether the number of testosterone breakthroughs >1.7 nmol/l predicted the time to castrate-resistant prostate cancer (CRPC), cancer specific survival (CSS) or overall survival (OS) with Kaplan-Meier and Cox regression analyses. RESULTS: Overall, the prognostic importance of testosterone on outcomes was eclipsed by the prognostic value of concomitant PSA values. The occurrence of testosterone values >0.7 nmol/l in the first year of therapy was associated with subsequent rises >1.7 nmol/l, but the number of testosterone breakthroughs per patient had no relationship to the risk of CRPC, CSS or OS. A time-dependent adjusted analysis indicated as expected that PSA values were prognostic, but there was no association of relative cumulative testosterone exposure with outcomes. CONCLUSIONS: In this large-scale trial with long followup, breakthrough testosterone was unrelated to time to CRPC, CSS or OS. Castrate testosterone values during ADT for recurrent prostate cancer provides prognostic information that must be considered alongside the time since ADT initiation and concomitant PSA values.

Intermittent androgen suppression for rising PSA level after radiotherapy.

BACKGROUND: Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial. METHODS: We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals. RESULTS: Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24). CONCLUSIONS: Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).

Mortality reduction and cumulative excess incidence (CEI) in the prostate-specific antigen (PSA) screening era.

The extent to which PSA screening is related to prostate cancer mortality reduction in the United States (US) is controversial. US Surveillance, Epidemiology, and End Results Program (SEER) data from 1980 to 2016 were examined to assess the relationship between prostate cancer mortality and cumulative excess incidence (CEI) in the PSA screening era and to clarify the impact of race on this relationship. CEI was considered as a surrogate for the intensity of prostate cancer screening with PSA testing and subsequent biopsy as appropriate. Data from 163,982,733 person-years diagnosed with 544,058 prostate cancers (9 registries, 9% of US population) were examined. Strong inverse linear relationships were noted between CEI and prostate cancer mortality, and 317,356 prostate cancer deaths were avoided. Eight regions of the US demonstrated prostate cancer mortality reduction of 46.0-63.7%. On a per population basis, the lives of more black men than white men were saved in three of four registries with sufficient black populations for comparison. Factor(s) independent of CEI (potential effects of treatment advances) explained 14.6% of the mortality benefit (p-value = 0.3357) while there was a significant main effect of CEI (effect = -0.0064; CI: [-0.0088, -0.0040]; p-value < 0.0001). Therefore, there is a strong relationship between CEI and prostate cancer mortality reduction that was not related to factors independent of screening utilization. Minority populations have experienced large mortality reductions in the context of PSA mass utilization.

Outcomes after PD-103 versus I-125 for low dose rate prostate brachytherapy monotherapy: An international, multi-institutional study.

BACKGROUND AND PURPOSE: Pd-103 and I-125 are commonly used in low dose rate (LDR) brachytherapy for prostate cancer. Comparisons of outcomes by isotope type are limited, but Pd-103 has distinct radiobiologic advantages over I-125 despite its lesser availability outside the United States. We evaluated oncologic outcomes after Pd-103 vs I-125 LDR monotherapy for prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed databases at 8 institutions for men who received definitive LDR monotherapy with Pd-103 (n = 1,597) or I-125 (n = 7,504) for prostate cancer. Freedom from clinical failure (FFCF) and freedom from biochemical failure (FFBF) stratified by isotope were analyzed by Kaplan-Meier univariate and Cox multivariate analyses. Biochemical cure rates (prostate-specific antigen level ≤ 0.2 ng/mL between 3.5 and 4.5 years of follow-up) by isotype were calculated for men with at least 3.5 years of follow-up and compared by univariate and multivariate logistic regression. RESULTS: Compared with I-125, Pd-103 led to higher 7-year rates of FFBF (96.2% vs 87.6%, P < 0.001) and FFCF (96.5% vs 94.3%, P < 0.001). This difference held after multivariate adjustment for baseline factors (FFBF hazard ratio [HR] = 0.31, FFCF HR = 0.49, both P < 0.001). Pd-103 was also associated with higher cure rates on univariate (odds ratio [OR] = 5.9, P < 0.001) and multivariate (OR = 6.0, P < 0.001) analyses. Results retained significance in sensitivity analyses of data from the 4 institutions that used both isotopes (n = 2,971). CONCLUSIONS: Pd-103 monotherapy was associated with higher FFBF, FFCF, and biochemical cure rates, and suggests that Pd-103 LDR may lead to improved oncologic outcomes compared with I-125.

Effect of Brachytherapy With External Beam Radiation Therapy Versus Brachytherapy Alone for Intermediate-Risk Prostate Cancer: NRG Oncology RTOG 0232 Randomized Clinical Trial.

PURPOSE: To determine whether addition of external beam radiation therapy (EBRT) to brachytherapy (BT) (COMBO) compared with BT alone would improve 5-year freedom from progression (FFP) in intermediate-risk prostate cancer. METHODS: Men with prostate cancer stage cT1c-T2bN0M0, Gleason Score (GS) 2-6 and prostate-specific antigen (PSA) 10-20 or GS 7, and PSA < 10 were eligible. The COMBO arm was EBRT (45 Gy in 25 fractions) to prostate and seminal vesicles followed by BT prostate boost (110 Gy if 125-Iodine, 100 Gy if 103-Pd). BT arm was delivered to prostate only (145 Gy if 125-Iodine, 125 Gy if 103-Pd). The primary end point was FFP: PSA failure (American Society for Therapeutic Radiology and Oncology [ASTRO] or Phoenix definitions), local failure, distant failure, or death. RESULTS: Five hundred eighty-eight men were randomly assigned; 579 were eligible: 287 and 292 in COMBO and BT arms, respectively. The median age was 67 years; 89.1% had PSA < 10 ng/mL, 89.1% had GS 7, and 66.7% had T1 disease. There were no differences in FFP. The 5-year FFP-ASTRO was 85.6% (95% CI, 81.4 to 89.7) with COMBO compared with 82.7% (95% CI, 78.3 to 87.1) with BT (odds ratio [OR], 0.80; 95% CI, 0.51 to 1.26; Greenwood T P = .18). The 5-year FFP-Phoenix was 88.0% (95% CI, 84.2 to 91.9) with COMBO compared with 85.5% (95% CI, 81.3 to 89.6) with BT (OR, 0.80; 95% CI, 0.49 to 1.30; Greenwood T P = .19). There were no differences in the rates of genitourinary (GU) or GI acute toxicities. The 5-year cumulative incidence for late GU/GI grade 2+ toxicity is 42.8% (95% CI, 37.0 to 48.6) for COMBO compared with 25.8% (95% CI, 20.9 to 31.0) for BT (P < .0001). The 5-year cumulative incidence for late GU/GI grade 3+ toxicity is 8.2% (95% CI, 5.4 to 11.8) compared with 3.8% (95% CI, 2.0 to 6.5; P = .006). CONCLUSION: Compared with BT, COMBO did not improve FFP for prostate cancer but caused greater toxicity. BT alone can be considered as a standard treatment for men with intermediate-risk prostate cancer.

Salvage prostate brachytherapy in radiorecurrent prostate cancer: An international Delphi consensus study.

BACKGROUND AND PURPOSE: Local recurrences after previous radiotherapy (RT) are increasingly being identified in biochemically recurrent prostate cancer. Salvage prostate brachytherapy (BT) is an effective and well tolerated treatment option. We sought to generate international consensus statements on the use and preferred technical considerations for salvage prostate BT. MATERIALS AND METHODS: International experts in salvage prostate BT were invited (n = 34) to participate. A three-round modified Delphi technique was utilized, with questions focused on patient- and cancer-specific criteria, type and technique of BT, and follow-up. An a priori threshold for consensus of ≥ 75% was set, with a majority opinion being ≥ 50%. RESULTS: Thirty international experts agreed to participate. Consensus was achieved for 56% (18/32) of statements. Consensus was achieved in several areas of patient selection: 1) A minimum of 2-3 years from initial RT to salvage BT; 2) MRI and PSMA PET should be obtained; and 3) Both targeted and systematic biopsies should be performed. Several areas did not reach consensus: 1) Maximum T stage/PSA at time of salvage; 2) Utilization/duration of ADT; 3) Appropriateness of combining local salvage with SABR for oligometastatic disease and 4) Repeating a second course of salvage BT. A majority opinion preferred High Dose-Rate salvage BT, and indicated that both focal and whole gland techniques could be appropriate. There was no single preferred dose/fractionation. CONCLUSION: Areas of consensus within our Delphi study may serve as practical advice for salvage prostate BT. Future research in salvage BT should address areas of controversy identified in our study.

MRI-defined treatment margins, urinary toxicity, and PSA response in LDR prostate brachytherapy.

PURPOSE: Implant quality metrics as measured by D90 and V100 do not address the adequacy of periprostatic margins. Relative margin deficiencies may relate to efficacy and margin excesses to post-implant toxicity. Our purpose is to determine MRI-defined treatment margins on prostate achieved with LDR brachytherapy. METHODS AND MATERIALS: Post implant CT and MR images from 487 consecutive patients who received LDR brachytherapy from 2010 to 14 were co-registered. Four prostate quadrants were defined; anterior-superior (AS), posterior-superior (PS), anterior-inferior (AI), posterior-inferior (PI). Dosimetric variables were measured for prostate, and for each quadrant with a 0-, 2-, 3-, and 5-mm margin, as well as for the membranous urethra defined on MRI. RESULTS: Prostate D90 (no margin) was associated with D90 to the volume enclosed by 2 mm, 3 mm and 5 mm margins (R2 = 0.9 - 1.0) with an average 7.1% decrease in dose per mm of margin. Mean D90 for PS, AI and PI quadrants were > 110% of prescription dose for margins of 2-, 3-, and 5-mm. AS quadrant mean D90s were generally lower (83.2% for 2 mm, 76.4% for 3 mm and 62.2% for 5 mm). Urethral strictures (n = 9) were associated with higher doses in the AI quadrant, and higher membranous urethral V125 (51 vs. 32%, p 0.013) and V150 (34.5 vs. 17.6%, p 0.01). CONCLUSIONS: Using MR-CT post implant dosimetry, margin coverage up to 5 mm was excellent with less margin coverage in the AS quadrant. Late ≥ grade 2 toxicity and urinary strictures are more likely to occur with relative margin excess in the anterior-inferior quadrant and higher doses caudal to the prostate apex. Within this analysis, there was no relationship between treatment margins, and PSA outcome.

Raman spectroscopy and supervised learning as a potential tool to identify high-dose-rate-brachytherapy induced biochemical profiles of prostate cancer.

High-dose-rate-brachytherapy (HDR-BT) is an increasingly attractive alternative to external beam radiation-therapy for patients with intermediate risk prostate cancer. Despite this, no bio-marker based method currently exists to monitor treatment response, and the changes which take place at the biochemical level in hypo-fractionated HDR-BT remain poorly understood. The aim of this pilot study is to assess the capability of Raman spectroscopy (RS) combined with principal component analysis (PCA) and random-forest classification (RF) to identify radiation response profiles after a single dose of 13.5 Gy in a cohort of nine patients. We here demonstrate, as a proof-of-concept, how RS-PCA-RF could be utilised as an effective tool in radiation response monitoring, specifically assessing the importance of low variance PCs in complex sample sets. As RS provides information on the biochemical composition of tissue samples, this technique could provide insight into the changes which take place on the biochemical level, as result of HDR-BT treatment.

Prediction of disease progression indicators in prostate cancer patients receiving HDR-brachytherapy using Raman spectroscopy and semi-supervised learning: a pilot study.

This work combines Raman spectroscopy (RS) with supervised learning methods-group and basis restricted non-negative matrix factorisation (GBR-NMF) and linear discriminant analysis (LDA)-to aid in the prediction of clinical indicators of disease progression in a cohort of 9 patients receiving high dose rate brachytherapy (HDR-BT) as the primary treatment for intermediate risk (D'Amico) prostate adenocarcinoma. The combination of Raman spectroscopy and GBR-NMF-sparseLDA modelling allowed for the prediction of the following clinical information; Gleason score, cancer of the prostate risk assessment (CAPRA) score of pre-treatment biopsies and a Ki67 score of < 3.5% or > 3.5% in post treatment biopsies. The three clinical indicators of disease progression investigated in this study were predicted using a single set of Raman spectral data acquired from each individual biopsy, obtained pre HDR-BT treatment. This work highlights the potential of RS, combined with supervised learning, as a tool for the prediction of multiple types of clinically relevant information to be acquired simultaneously using pre-treatment biopsies, therefore opening up the potential for avoiding the need for multiple immunohistochemistry (IHC) staining procedures (H&E, Ki67) and blood sample analysis (PSA) to aid in CAPRA scoring.

Recent Advances in the Management of Penile Cancer: A Contemporary Review of the Literature.

Penile cancer is a rare condition, which mostly affects men in their sixth decade of life. The most common histology is squamous cell carcinoma (SCC), with about half of the cases linked to human papilloma virus (HPV) infection. The lack of awareness and significant social and psychological stigma associated with penile cancer often leads to delays in presentation, diagnosis and management. Timely multidisciplinary care at experienced centers is therefore critical for improving outcomes. For patients with advanced disease, treatment options are limited and prognosis remains poor. Large international efforts are underway to further define the optimal standards of care. Targeted therapies and immune checkpoint inhibitors could potentially play a role in advanced disease and are under evaluation in clinical trials. In this review, we discuss the current management of penile cancer and future directions.

The Association Between Statin Use and Outcomes in Patients Initiating Androgen Deprivation Therapy.

BACKGROUND: Studies have conflicting results regarding the association between statin use and biochemical recurrence for prostate cancer (PCa). A limited number of studies examining statins in advanced stages report positive results, with a few specifically examining statins and androgen deprivation therapy (ADT). OBJECTIVE: To perform a post hoc secondary analysis of a randomised controlled trial (RCT) of men initiating ADT to examine the association between statin use and outcomes. DESIGN, SETTING, AND PARTICIPANTS: Patients with prostate-specific antigen (PSA) >3 ng/ml >1 yr following primary/salvage radiotherapy were enrolled in an RCT of intermittent androgen deprivation (IAD) versus continuous ADT (NCT00003653). Baseline and on-study statin use was modelled as a time-dependent covariate. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was overall survival. Models were adjusted for age, time from radiotherapy to ADT, baseline PSA, and prior ADT. RESULTS AND LIMITATIONS: Of 1364 patients, statin users (585; 43%) were younger (72.7 vs 73.8 yr, p = 0.001) and less likely to have PSA >15 ng/ml (20% vs 25%, p = 0.04). After a median follow-up of 6.9 yr, statin use was associated with reduced overall (hazard ratio [HR]: 0.64; 95% confidence interval [CI] 0.53-0.78, p < 0.001) and PCa-specific (HR: 0.65, 95% CI 0.48-0.87, p = 0.004) mortality. Statin users had 13% longer time to castration resistance, but this did not reach statistical significance (p = 0.15). As an exploratory endpoint, in the IAD arm, statin users had longer time off treatment (median: 0.85 vs 0.64 yr, p = 0.06). Limitations include potential for residual confounding between statin users and nonusers, and confounding by indication. CONCLUSIONS: In men treated with ADT following primary or salvage radiotherapy, statin use was associated with improved overall and PCa-specific survival. In patients treated with IAD, statin use was associated with a trend towards longer time off treatment. A prospective trial of statins in men commencing ADT is warranted. PATIENT SUMMARY: We found a favourable association between statin use and survival outcomes in patients initiating androgen deprivation therapy.

Low dose rate brachytherapy for primary treatment of localized prostate cancer: A systemic review and executive summary of an evidence-based consensus statement.

PURPOSE: The purpose of this guideline is to present evidence-based consensus recommendations for low dose rate (LDR) permanent seed brachytherapy for the primary treatment of prostate cancer. METHODS AND MATERIALS: The American Brachytherapy Society convened a task force for addressing key questions concerning ultrasound-based LDR prostate brachytherapy for the primary treatment of prostate cancer. A comprehensive literature search was conducted to identify prospective and multi-institutional retrospective studies involving LDR brachytherapy as monotherapy or boost in combination with external beam radiation therapy with or without adjuvant androgen deprivation therapy. Outcomes included disease control, toxicity, and quality of life. RESULTS: LDR prostate brachytherapy monotherapy is an appropriate treatment option for low risk and favorable intermediate risk disease. LDR brachytherapy boost in combination with external beam radiation therapy is appropriate for unfavorable intermediate risk and high-risk disease. Androgen deprivation therapy is recommended in unfavorable intermediate risk and high-risk disease. Acceptable radionuclides for LDR brachytherapy include iodine-125, palladium-103, and cesium-131. Although brachytherapy monotherapy is associated with increased urinary obstructive and irritative symptoms that peak within the first 3 months after treatment, the median time toward symptom resolution is approximately 1 year for iodine-125 and 6 months for palladium-103. Such symptoms can be mitigated with short-term use of alpha blockers. Combination therapy is associated with worse urinary, bowel, and sexual symptoms than monotherapy. A prostate specific antigen <= 0.2 ng/mL at 4 years after LDR brachytherapy may be considered a biochemical definition of cure. CONCLUSIONS: LDR brachytherapy is a convenient, effective, and well-tolerated treatment for prostate cancer.

A biochemical definition of cure after brachytherapy for prostate cancer.

BACKGROUND AND PURPOSE: To identify a PSA threshold value at an intermediate follow-up time after low dose rate (LDR) prostate brachytherapy associated with cure, defined as long-term (10-15 year) freedom from prostate cancer. MATERIALS AND METHODS: Data from 7 institutions for 14,220 patients with localized prostate cancer treated with LDR brachytherapy, either alone (8552) or with external beam radiotherapy (n = 1175), androgen deprivation (n = 3165), or both (n = 1328), were analyzed. Risk distribution was 42.4% favorable, 49.2% intermediate, and 8.4% high-risk. Patients with clinical failure before 3.5 years were excluded. Kaplan-Meier analysis was used with clinical failure (local, distant, regional or biochemical triggering salvage) as an endpoint for each of four PSA categories: PSA ≤ 0.2, >0.2 to ≤0.5, >0.5 to ≤1.0, and >1.0 ng/mL. PSA levels at 4 years (±6 months) in 8746 patients without clinical failure were correlated with disease status at 10-15 years. RESULTS: For the 77.1% of patients with 4-year PSA ≤ 0.2, the freedom-from-recurrence (FFR) rates were 98.7% (95% CI 98.3-99.0) at 10 years and 96.1% (95% CI 94.8-97.2) at 15 years. Three independent validation cohorts confirmed 97-99% 10-year FFR rates with 4-year PSA ≤ 0.2. Successive PSA categories were associated with diminished disease-free rates at 10 and 15 years. PSA category was strongly associated with treatment success (p < 0.0005). CONCLUSIONS: Since 98.7% of patients with PSA ≤ 0.2 ng/mL at 4 years after LDR prostate brachytherapy were disease-free beyond 10 years, we suggest adopting this biochemical definition of cure for patients with ≥4 years' follow-up after LDR brachytherapy.

Salvage Local Treatments After Focal Therapy for Prostate Cancer.

CONTEXT: Whether focal therapy (FT) for prostate cancer (PC) jeopardizes outcomes from salvage treatments is a matter of debate still to be resolved. OBJECTIVE: To review the literature on oncological and functional outcomes and complications for available treatment options for recurrent or residual PC after primary FT. EVIDENCE ACQUISITION: We performed a nonsystematic search of PubMed for articles assessing relevant outcomes for salvage local treatment after FT failure using a manual search. When no evidence could be extracted for the FT domain, records dealing with recurrence after whole-gland ablation were considered. EVIDENCE SYNTHESIS: Four retrospective series assessed salvage treatments after FT failure evaluating cases of radical prostatectomy (RP) and repeat ablation (sample size from 12 to 22 patients). The quality of the studies was low, with a high risk of bias. Other options are radiation therapy (RT) and whole-gland or focal repeat ablations, although these have only been described after whole-gland ablation. With some exceptions, including sexual function for RP, overall complications and oncological and functional outcomes do seem to be acceptable and are not much worse than those in the primary setting. Important limitations include the low level of the evidence and the absence of standardized criteria for FT, salvage treatment, and FT failure. CONCLUSIONS: Current evidence shows acceptable outcomes for post-FT salvage options, although this is based on retrospective data. While it seems that FT has a minimal impact on salvage treatment results, prospective controlled studies are needed to confirm these preliminary data. PATIENT SUMMARY: We performed a literature search to determine the treatment options available for prostate cancer after failure of focal therapy and their outcomes. Options include radical prostatectomy, repeat whole-gland ablation, focal ablation, and radiotherapy. Overall cancer control, impacts on urinary and sexual function, and complications seem slightly worse but not markedly different compared to primary treatments, but high-quality studies are awaited to confirm these findings.

A Prospective Phase 2 Trial of Transperineal Ultrasound-Guided Brachytherapy for Locally Recurrent Prostate Cancer After External Beam Radiation Therapy (NRG Oncology/RTOG-0526).

PURPOSE: Only retrospective data are available for low-dose-rate (LDR) salvage prostate brachytherapy for local recurrence after external beam radiation therapy (EBRT). The primary objective of this prospective phase 2 trial (NCT00450411) was to evaluate late gastrointestinal and genitourinary adverse events (AEs) after salvage LDR brachytherapy. METHODS AND MATERIALS: Eligible patients had low- or intermediate-risk prostate cancer before EBRT and biopsy-proven recurrence >30 months after EBRT, with prostate-specific antigen levels <10 ng/mL and no regional/distant disease. The primary endpoint was grade 3 or higher late treatment-related gastrointestinal or genitourinary AEs occurring 9 to 24 months after brachytherapy. These AEs were projected to be ≤10%, with ≥20% considered unacceptable. All events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Multivariate analyses investigated associations of pretreatment or treatment variables with AEs. RESULTS: One hundred patients from 20 centers were registered from May 2007 to January 2014. The 92 analyzable patients had a median follow-up of 54 months (range, 4-97) and a median age of 70 years (interquartile range [IQR], 65-74). The initial Gleason score was 7 in 48% of patients. The median dose of EBRT was 74 Gy (IQR, 70-76) at a median interval of 85 months previously (IQR, 60-119). Only 16% had androgen deprivation at study entry. Twelve patients (14%) had late grade 3 gastrointestinal/genitourinary AEs, with no treatment-related grade 4 or 5 AEs. No pretreatment variable predicted late AEs, including prior EBRT dose and elapsed interval. Higher V100 (percentage of prostate enclosed by prescription isodose) predicted both occurrence of late AEs (odds ratio, 1.24; 95% confidence interval, 1.02-1.52; P = .03) and earlier time to first occurrence (hazard ratio, 1.18; 95% CI, 1.03-1.34; P = .02). CONCLUSIONS: This prospective multicenter trial reports outcomes of salvage LDR brachytherapy for post-EBRT recurrence. The rate of late grade 3 AEs did not exceed the unacceptable threshold. The only factor predictive of late AEs was implant dosimetry reflected by V100. Efficacy outcomes will be reported at a minimum of 5-year follow-up.

Loose seeds vs. stranded seeds: a comparison of critical organ dosimetry and acute toxicity in (125)I permanent implant for low-risk prostate cancer.

PURPOSE: To compare the critical organ dosimetry and toxicity of loose seeds (LS) with stranded seeds (SS) in (125)I permanent implant for low-risk prostate cancer. METHODS AND MATERIALS: Two cohorts of 20 patients each were treated in Institutional Review Board-approved protocols designed to assess prostate edema and seed stability using MR-CT fusion on Days 0, 7, and 30 after permanent implant. (125)I LS were used for one cohort and (125)I SS for the other. Rectal wall dosimetry was compared for the two cohorts using RV100 and RD1cc and urethral dosimetry using UD5, UD30, and UV150. Statistical comparisons were performed using unpaired Student's t test. RESULTS: At each time point (Days 0, 7, and 30), both the mean RD1 cc (SS: 123.1, 139.7, and 156.1 Gy vs. LS: 90.2, 104, and 129.4 Gy, respectively) and the mean RV100 (SS: 0.63, 1.0, and 1.4 cc vs. LS: 0.2, 0.4, and 0.73 cc, respectively) were significantly higher for strands (all p-values<0.01). Only 1 patient developed radiotherapy oncology group (RTOG) Grade 1 acute rectal toxicity in the loose seed cohort, whereas 3 patients had Grade 1 and 1 patient had Grade 2 toxicity with strands. The mean percentage increase of UD5 (7.7% LS vs. 24.6% SS; p=0.004) and UD30 (5% LS vs. 15.9% SS; p=0.02) from preplan to Day 30 was higher for strands. The increase in UV150 from baseline to Day 30 was significantly higher for strands (0.2 vs. 0.06 cc; p=0.01). Urinary toxicity was similar in both cohorts. CONCLUSIONS: SS resulted in higher dose to urethra and rectal wall compared with LS on postimplant dosimetry. A trend toward higher acute rectal toxicity rate was observed for SS.

Inter-institutional variation of implant activity for permanent prostate brachytherapy.

PURPOSE: Despite the existence of guidelines for permanent prostate brachytherapy, it is unclear whether there is interinstitutional consensus concerning the parameters of an ideal implant. METHODS AND MATERIAL: Three institutions with extensive prostate brachytherapy expertise submitted information regarding their implant philosophy and dosimetric constraints, as well as data on up to 50 radioiodine implants. Regression analyses were performed to reflect each institution's utilization of seeds and implanted activity. RESULTS: Despite almost identical implant philosophy, target volume, and dosimetric constraints, there were statistically significant interinstitutional differences in the number of seeds and total implant activity across the range of prostate volumes. For larger volumes, the variation in implanted activity was 25%; for smaller glands, it exceeded 40%. CONCLUSIONS: There remain wide variations in implanted activity between institutions espousing seemingly identical implant strategies, prescription, and dosimetry constraints. Brachytherapists should therefore be wary of using nomograms generated at other institutions.

The role of salvage brachytherapy for local relapse after external beam radiotherapy for prostate cancer.

Prostate cancer is the most prevalent cancer amongst men. For localized disease, there currently exist several reliable treatment modalities including surgery, radiotherapy and brachytherapy. Our growing understanding of this disease indicates that local control plays a very important role in prevention of subsequent dissemination. Many improvements to external beam radiotherapy over recent years have decreased toxicity and improved outcomes, but nonetheless, local relapse remains common. Many salvage options exist for locally recurrent prostate cancer, but are rarely offered, partly because of the fear of toxicity. Many men with isolated local recurrence therefore do not receive potentially curative second line treatment and are instead treated with palliative androgen suppression. Selection plays an important role in determining which individuals are likely to benefit from salvage. Those at high risk of pre-existing micro-metastatic disease despite negative staging scans are unlikely to benefit. Prostate brachytherapy has evolved over the more than 3 decades of experience. Modern techniques allow more precise tumor localization and dose delivery. Better understanding of dosimetric parameters can distinguish optimal from suboptimal implants. Salvage brachytherapy can be an effective treatment for locally recurrent prostate cancer after prior external beam radiotherapy. We review the literature pertaining to both low dose rate (LDR) and high dose rate (HDR) salvage brachytherapy and discuss patient selection, optimal dose, treatment volume and toxicity avoidance.

The nature and extent of urinary morbidity in relation to prostate brachytherapy urethral dosimetry.

PURPOSE: This study investigates whether the location and dose of urethral radiation received during transperineal interstitial permanent prostate brachytherapy determine the degree and type of urinary symptoms experienced subsequently. METHODS AND MATERIALS: Data from a prospectively acquired database of 219 men treated with transperineal interstitial permanent prostate brachytherapy using (125)I (prescribed dose 145Gy) between May 2001 and June 2003 were reviewed. To assess the effect of regional urethral dosimetry, the prostate was divided into equal thirds (proximal, mid, and apical) with doses beyond this considered distal. Mean and peak doses for each region were correlated with total International Prostate Symptom Score (IPSS) and the irritative and obstructive components of the score. IPSS values at 1 month postimplant, time to resolution of IPSS, and the need for catheterization were used as outcome variables and analyzed with respect to dose using logistic and linear regression. RESULTS: Peak and average doses with standard deviations to the proximal urethra were 168 (24) and 147 (24)Gy, mid prostatic urethra 192 (24) and 181 (21)Gy, and apical urethra 201 (28) and 192 (26)Gy. Catheterization was required for 28 men and was predicted by larger pretreatment transrectal ultrasound (TRUS) volume (OR 1.06 per unit change; 95% CI 1.03-1.10; p<0.001) and lower UV(150) (OR 0.30; 95% CI 0.13-0.68; p=0.004) in multivariate analysis. Greater IPSS at baseline (p<0.001) and preoperative TRUS volume (p=0.012) but conversely smaller D(30) doses (p=0.003) were predictive of IPSS outcomes at 1 month. IPSS returned to within two points of baseline for 72.2% of men by 1 year and 83.3% by 24 months. This was predicted by higher IPSS at baseline (OR 6.0; 95% CI 2.72-13.22; p<0.001), higher D(30) (OR 1.17; 95% CI 1.01-1.36; p=0.031), and lower V(100) (OR 0.39; 95% CI 0.22-0.70; p=0.002). Prostatic urethral segmental dosimetry failed to predict the need for catheterization, the nature of the urinary symptoms, or their time to resolution. CONCLUSIONS: Previously identified factors of importance for urinary morbidity such as pretreatment prostate volume and baseline urinary function were reemphasized in this study. Regional urethral dosimetry within contemporary practice does not seem to influence the nature or extent of urinary symptoms after prostate brachytherapy. Consequently, region sparing dosimetric modifications are not warranted to alter symptomatic outcomes.