Stage T3b prostate cancer diagnosed by seminal vesicle biopsy and treated with neoadjuvant hormone therapy, permanent brachytherapy and external beam radiotherapy.

OBJECTIVES: To report the long-term results of prostate brachytherapy followed by external beam radiotherapy (EBRT) in men with a positive seminal vesicle biopsy (+SVB). PATIENTS AND METHODS: In all, 1081 men with localised prostate cancer were treated with permanent brachytherapy, of which 615 had staging SVB and 53 (9.4%) were positive. Higher stage, Gleason score and PSA level were associated with a +SVB (P < 0.001). Patients with +SVB and negative laparoscopic pelvic lymph node dissection, bone and CT scans had 3 months of androgen-deprivation therapy (ADT) followed by 103 Pd implant to the prostate (dose 100 Gy) and proximal SVs, and 2 months later 45 Gy EBRT. ADT was continued for a median of 6 months (total ADT 9 months). The mean (range) follow-up was 9 (5-22) years. RESULTS: Biochemical freedom from failure (computed by the Phoenix definition), freedom from metastasis, and cause-specific survival (CSS) for patients with a negative SVB (-SVB) vs +SVB at 15 years, was 76.3% vs 60.6% (P = 0.001), 95.4% vs 78.2% (P < 0.001), and 95% vs 70.4% (P < 0.001), respectively. Prostate cancer death occurred in 45 of 590 (7.6%) men with a -SVB vs eight of 25 (32%) with a +SVB (odds ratio 5.7, 95% confidence interval 2.35-13.9, P < 0.001). Cox proportion hazard rates (HRs) demonstrated Gleason score (P < 0.001, HR 1.9), stage (P = 0.010, HR 1.42), RT dose (P = 0.013, HR 0.991), and +SVB (P = 0.001, HR 4.48), as significantly associated with CSS. CONCLUSIONS: Men with a +SVB have inferior CSS compared to those with a -SVB. However, a strategy that included a SVB in high-risk patients and implantation of the SVs in men undergoing combined therapy still yields favourable long-term results.

Outcomes and toxicities in patients with intermediate-risk prostate cancer treated with brachytherapy alone or brachytherapy and supplemental external beam radiation therapy.

OBJECTIVE: To evaluate the cancer control outcomes and long-term treatment-related morbidity of brachytherapy as well as combination brachytherapy and external beam radiation therapy (EBRT) in patients with intermediate-risk prostate cancer. MATERIALS AND METHODS: A retrospective review was conducted in a prospectively collected database of patients with intermediate-risk prostate cancer who were treated either with brachytherapy or brachytherapy and EBRT, with or without androgen deprivation therapy (ADT), in the period 1990-2014. Urinary and erectile dysfunction symptoms were measured using the International Prostate Symptom Score (IPSS), the Mount Sinai erectile function scale and the Sexual Health Inventory for Men (SHIM). Cancer control endpoints included biochemical failure and development of distant metastases. All statistical analyses were carried out using the Statistical Package for Social Science (SPSS). Survival curves were calculated using Kaplan-Meier actuarial methods and compared using log-rank tests. Cox regression multivariate analyses were used to test the effect of multiple variables on treatment outcomes. RESULTS: A total of 902 patients were identified, with a median follow-up of 91 months. Of these, 390 received brachytherapy and 512 received combination therapy with EBRT. In patients with one intermediate-risk factor, the addition of EBRT did not significantly affect freedom from biochemical failure or distant metastases. Among patients with two or three intermediate-risk factors, added EBRT did not improve freedom from biochemical failure. Significant differences in late toxicity between patients treated with brachytherapy vs combination brachytherapy and EBRT were identified including urge incontinence (P < 0.001), haematuria (P < 0.001), dysuria (P < 0.001), and change in quality-of-life IPSS (P = 0.002). These symptoms were reported by patients at any point during treatment follow-up. Analysis of patients who were potent before treatment using actuarial methods showed that patients receiving combination therapy more frequently experienced loss of potency, as measured by the Mount Sinai erectile function scale (P = 0.040). CONCLUSION: Brachytherapy monotherapy results in equal biochemical and distant control in both patients with one and more than one intermediate-risk features. While no significant benefit was shown, we believe that the addition of EBRT may prevent recurrence in patients with multiple intermediate-risk features and should be considered.

Low-dose-rate brachytherapy for prostate cancer: outcomes at >10 years of follow-up.

OBJECTIVE: To examine biochemical control, survival, and late morbidity with definitive low-dose-rate brachytherapy (LDR-BT) for patients with prostate cancer surviving for >10 years after treatment. PATIENTS AND METHODS: We identified 757 men with localised prostate cancer who underwent definitive LDR-BT in the period 1990-2006 and were followed for >10 years at our institution. Biochemical failure-free survival (BFFS), distant metastases-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were selected as study endpoints. Survival was examined using the log-rank test, Kaplan-Meier method, and Cox regression modelling. Urinary, quality of life (QoL), and potency scores at baseline and last follow-up were recorded. RESULTS: The median follow-up was 12.5 years (range, 10.1-21.8 years). At the time of analysis, 88.6% of patients were alive, 1.5% died from prostate cancer and 13.9% developed biochemical failure, with 82% of failures occurring in the first decade of follow-up. Overall, 2.3% developed distant metastases. On multivariate analyses, stage T3a-T3b, prostate-specific antigen level of >20 ng/mL, intermediate- and high-risk disease predicted worse BFFS; whereas age >70 years at diagnosis and stage T3a-T3b predicted worse OS. A total biologically effective dose of ≥150 Gy and androgen-deprivation therapy were associated with improved BFFS, but not OS. The overall 17-year rates for BFFS, DMFS, PCSS, and OS were 79, 97, 97, and 72%, respectively. Respective 17-year BFFS rates for low-, intermediate- and high-risk patients were 86, 80, and 65% (P < 0.001), whereas OS rates for the same groups were 82, 73, and 60%, respectively (P = 0.09). Amongst those patients who were potent at baseline, 25% remained potent at the last follow-up. Urinary function and QoL were mainly unaffected. CONCLUSIONS: LDR-BT yields excellent survival rates, with a 17-year PCSS rate of 97%. In all, 18% of patients with biochemical relapse failed at >10 years after implantation, which justifies their continued follow-up.

Factors influencing long-term urinary symptoms after prostate brachytherapy.

OBJECTIVES: To determine which patient and treatment-related factors are associated with increased American Urological Association symptom score (AUASS) in men who presented with minimal symptoms before treatment for prostate cancer by permanent seed implantation. PATIENTS AND METHODS: Of 1842 men with a minimum follow-up of 5 years (mean 9.4), 1110 (60.3%) had an initial AUASS of 0-7 and were treated with brachytherapy (BT) alone (n = 491) or BT with neoadjuvant hormone therapy (NHT) and/or external beam radiation therapy (EBRT, n = 619). The median prostate volume was 37 mL. Data were prospectively collected on comorbidities. Initial AUASS was compared to last using a Student's t-test (two-tailed). Freedom from increasing from minimal to moderate or severe symptoms was determined by the Kaplan-Meier method with comparisons by log-rank and Cox hazard rates (HRs). RESULTS: The change from pre-treatment score for the minimal, moderate and severe symptom groups was: 3.6-7.3 (P < 0.001), 11.6-11.3 (P = 0.426), and 24.1-16.9 (P < 0.001). For those with minimal symptoms the 10- and 15-year estimates for freedom from worse symptoms were 72.9% and 39.1%, respectively. Cox HRs were significant for EBRT boost (HR 1.45, P = 0.004), RT dose >200 Gy2 (HR 1.25, P = 0.024), hypertension (HR 1.37, P = 0.006), and alcohol use (HR 1.46, P = 0.001). CONCLUSION: A substantial number of men with initial low AUASS treated by BT experience worsening urinary symptoms with long-term follow-up. Use of EBRT, RT dose, hypertension and alcohol use are risk factors for an increase in urinary symptom score.

Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer.

Importance: The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective: To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. Design, Setting, and Participants: Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results: Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance: Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

15-year cause specific and all-cause survival following brachytherapy for prostate cancer: negative impact of long-term hormonal therapy.

PURPOSE: We analyzed factors influencing 15-year cause specific and all-cause survival in men treated with prostate brachytherapy. MATERIALS AND METHODS: A total of 1,669 men with a median age of 66 years who had T1-T3 prostate cancer were treated with prostate brachytherapy and followed a mean of 10 years. Treatments were implant alone, implant plus hormone therapy, or external beam irradiation or implant plus hormone therapy plus external beam irradiation. Hormone therapy was administered in 898 men (53.8%) for a median of 6 months. Cause specific and all-cause survival were estimated by the Kaplan-Meier method with comparisons made by logistic regression and Cox proportions hazard rates. RESULTS: The 15-year cause specific survival rate was 94.1%. Cause specific survival in the 3 NCCN® risk groups was 96.3%, 97.5% and 85.2% (p <0.001). Hormone therapy did not positively impact cause specific survival. The 15-year all-cause survival rate was 57%. Cox regression revealed age (HR 1.09, p <0.001), hormone therapy (HR 1.04, p = 0.032), diabetes (HR 1.86, p = 0.013), atrial fibrillation (HR 2.90, p = 0.041), smoking (HR 1.42, p = 0.030) and emphysema (HR 8.20, p = 0.040) as significant associations. At 15 years hormone therapy decreased all-cause survival from 60.3% to 54.9% (p = 0.009). All-cause survival was not reduced when hormone therapy was limited to 6 months or less (p = 0.005). This difference was present in men 66 years old or younger (p = 0.017) and in older men (p = 0.05). CONCLUSIONS: Prostate brachytherapy yields favorable 15-year cause specific survival, especially in patients at high risk. All-cause survival is less in patients with preexisting diabetes, atrial fibrillation and emphysema. Hormone therapy for longer than 6 months has a negative effect on all-cause survival even in younger patients without an apparent beneficial effect on cause specific survival.

A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of urinary symptoms after radiotherapy for prostate cancer.

PURPOSE: We identified single nucleotide polymorphisms associated with change in the AUA Symptom Score after radiotherapy for prostate cancer. MATERIALS AND METHODS: A total of 723 patients treated with brachytherapy with or without external beam radiation therapy were assessed at baseline and annually after radiotherapy using the AUA Symptom Score. A 2-stage genome-wide association study was performed with the primary end point of change in AUA Symptom Score from baseline at each of 4 followup periods. Single nucleotide polymorphism associations were assessed using multivariable linear regression adjusting for pre-radiotherapy AUA Symptom Score severity category and clinical variables. Fisher's trend method was used to calculate combined p values from the discovery and replication cohorts. RESULTS: A region on chromosome 9p21.2 containing 8 single nucleotide polymorphisms showed the strongest association with change in AUA Symptom Score (combined p values 8.8×10(-6) to 6.5×10(-7) at 2 to 3 years after radiotherapy). These single nucleotide polymorphisms form a haplotype block that encompasses the inflammation signaling gene IFNK. These single nucleotide polymorphisms were independently associated with change in AUA Symptom Score after adjusting for clinical predictors including smoking history, hypertension, α-blocker use and pre-radiotherapy AUA Symptom Score. An additional 24 single nucleotide polymorphisms showed moderate significance for association with change in AUA Symptom Score. Several of these single nucleotide polymorphisms were more strongly associated with change in specific AUA Symptom Score items, including rs13035033 in the MYO3B gene, which was associated with straining (beta coefficient 0.9, 95% CI 0.6-1.2, p = 5.0×10(-9)). CONCLUSIONS: If validated, these single nucleotide polymorphisms could provide insight into the biology underlying urinary symptoms following radiotherapy and could lead to development of an assay to identify patients at risk for experiencing these effects.

Risk of urinary incontinence following post-brachytherapy transurethral resection of the prostate and correlation with clinical and treatment parameters.

PURPOSE: We assess the risk of urinary incontinence after transurethral prostate resection in patients previously treated with prostate brachytherapy. MATERIALS AND METHODS: A total of 2,495 patients underwent brachytherapy with or without external beam radiation therapy for the diagnosis of prostate cancer between June 1990 and December 2009. Patients who underwent transurethral prostate resection before implantation were excluded from study. Overall 79 patients (3.3%) underwent channel transurethral resection of the prostate due to urinary retention or refractory obstructive urinary symptoms. Correlation analyses were performed using the chi-square (Pearson) test. Estimates for time to urinary incontinence were determined using the Kaplan-Meier method with comparisons using logistic regression and Cox proportional hazard rates. RESULTS: Median followup after implantation was 7.2 years. Median time to first transurethral prostate resection after implantation was 14.8 months. Of the 79 patients who underwent transurethral prostate resection after implantation 20 (25.3%) had urinary incontinence compared with 3.1% of those who underwent implantation only (OR 10.4, 95% CI 6-18, p<0.001). Of the 15 patients who required more than 1 transurethral prostate resection, urinary incontinence developed in 8 (53%) compared with 19% of patients who underwent only 1 resection (OR 4.9, 95% CI 1.5-16, p=0.006). Exclusion of patients who underwent multiple transurethral prostate resections still demonstrated significant differences (18.8% vs 3.1%, OR 7.1, 95% CI 3.6-13.9, p<0.001). Median time from last transurethral prostate resection to urinary incontinence was 24 months. On linear regression analysis, hormone use and transurethral prostate resection after implantation were associated with urinary incontinence (p<0.05). There was no correlation between the timing of transurethral prostate resection after implantation and the risk of incontinence. CONCLUSIONS: Urinary incontinence developed in 25.3% of patients who underwent transurethral prostate resection after prostate brachytherapy. The risk of urinary incontinence correlates with the number of transurethral prostate resections. Patients should be counseled thoroughly before undergoing transurethral prostate resection after implantation.

Haematuria after prostate brachytherapy.

OBJECTIVE: To characterize the incidence and clinical history of gross haematuria after prostate brachytherapy. To identify treatment risk factors for the development of gross haematuria in this setting. PATIENTS AND METHODS: We reviewed haematuria outcomes collected prospectively in 2454 patients treated with transperineal prostate brachytherapy over a 20-year period at a single institution. Patients were followed for a median of 5.9 years. The association of haematuria with age, pretreatment PSA, ethnicity, clinical tumour stage, Gleason score, prostate volume, isotope (iodine 125 or palladium 103), biologically effective dose (BED), external beam radiation, androgen deprivation, development of urinary retention and occurrence of biochemical failure was investigated. RESULTS: A total of 218 men (8.9%) reported gross haematuria at a median time of 772.2 days after implantation. Haematuria was associated with prostate volume >40 cm(3) (P < 0.01), use of external beam radiation (P < 0.01), Gleason score >7 (P = 0.037), Asian ethnicity (P < 0.001), BED >200 Gy (P = 0.01), and freedom from biochemical failure (P = 0.004). On multivariate analysis, prostate volume >40 cm(3) (P = 0.002), external beam radiation, (P = 0.001), and freedom from biochemical failure (P = 0.035) were predictors of haematuria. CONCLUSIONS: Late gross haematuria was observed in a small proportion of men after brachytherapy and may occur with considerable latency. Larger prostate glands, freedom from biochemical failure and external beam radiation are risk factors.

Temporal patterns of selected late toxicities in patients treated with brachytherapy or brachytherapy plus external beam radiation for prostate adenocarcinoma.

UNLABELLED: What's known on the subject? and What does the study add? While the frequencies and severity of late toxicities following prostate brachytherapy are well known, less has been published with regard to time to first onset. Several series with limited median follow-up have published time to onset. An extensive analysis of timing to late toxicity following brachytherapy for cervical cancer has also been published. This study is the largest of its kind with the longest median follow-up to capture very late events. It can provide a basis for physician and patient education about when late toxicities can reasonably be expected to occur. The study also shows that a significant amount of erectile dysfunction might be more age related than radiation induced. OBJECTIVES: • To assess the timing of first onset of late rectal bleeding, late haematuria and erectile dysfunction (ED) following brachytherapy with or without external beam radiation therapy (EBRT) for prostate adenocarcinoma. • To identify treatment factors and patient characteristics that affect the time to first onset. PATIENTS AND METHODS: • In all, 2046 patients were definitively treated for prostate adenocarcinoma with a full (125) I or (103) Pd implant or a partial (103) Pd implant followed by EBRT with 6 years median follow-up (range 2-17 years). • Patients were selected for an event of Radiation Therapy Oncology Group (RTOG) grade 2 or greater rectal bleeding, ≥RTOG grade 2 haematuria, or a drop in the Mount Sinai Erectile Dysfunction Score from potent to impotent (excluding patients who received androgen deprivation therapy). • Life tables were generated to calculate actuarial incidence rates of toxicity. • Wilcoxon rank sum and Cox regression were utilized to identify treatment factors affecting time to onset. RESULTS: • The incidence rate per 1000 patients for 0-2 years, 2-5 years and 5-10 years following radiation for rectal bleeding is 14.3, 15.9 and 6.5, respectively; for haematuria, 14.0, 8.2 and 1.3, respectively; and for ED, 82.4, 48.2 and 42.2, respectively. • Just 5% of rectal bleeding occurs after 5 years from radiation vs 18% of haematuria cases and 22% of ED. • On multivariate analysis, time to first onset of rectal bleeding was affected by the addition of EBRT only whereas the time to onset of haematuria was affected by the biological effective dose of the radiation and the addition of EBRT. • The only factor on multivariate analysis to affect time to onset of ED was the age of the patient at treatment, independent of radiation dose or technique. CONCLUSIONS: • Unique temporality to first onset of selected toxicities was observed in patients after radioactive implant for prostate adenocarcinoma with or without EBRT. • Clinicians and patients should be counselled when to expect late toxicities. • The only factor to affect time to onset of ED is the age of the patient, suggesting possible over-reporting of radiation-induced ED in the light of normal age-related events.

The relative importance of hormonal therapy and biological effective dose in optimizing prostate brachytherapy treatment outcomes.

OBJECTIVES: To compare the relative importance of radiation dose escalation vs androgen deprivation therapy (ADT) in the definitive treatment of prostate adenocarcinoma. PATIENTS AND METHODS: In total, 2427 patients with prostate adenocarcinoma were treated with definitive brachytherapy or brachytherapy with external beam radiation with or without ADT. Over the 20-year period of the present study (median follow-up of 78 months), patients were treated with a range of doses that were converted to the biological effective dose (BED) and/or ADT as the treatment paradigms were optimized. Using univariate and multivariate analysis, the relative impact on the biochemical control and post-treatment prostate biopsy results of BED vs ADT was determined. RESULTS: The 10-year freedom from biochemical failure (FBF) was significantly affected by BED group: ≤150 Gy2 (64%), >150-200 Gy2 (88%), >200-220 Gy2 (89%) and >220 Gy2 (89.5%) (P < 0.001). When stratified into dose groups, ADT improved FPF on multivariate analysis for the BED group (<150 Gy2 , hazard ratio = 0.55; >150-200 Gy2 , hazard ratio = 0.39) but not for the higher BED groups. Among patients receiving ADT, a significant difference in 10-year FBF was seen when stratifying BED into groups ≤150 Gy2 (78%) vs >150 Gy2 (87%) (P = 0.01). On logistic regression, ADT had a significant impact on obtaining a negative biopsy (hazard ratio = 0.21) with BED <200 Gy2 , although there was no difference with BED >200 Gy2 . CONCLUSIONS: When treated with brachytherapy with or without EBT, ADT improves FBF only in the setting of lower doses. The benefit of ADT may be primarily as an enhancer of local control, explaining why high radiation doses can compensate for its absence.

Clinical and treatment characteristics of secondary bladder malignancies following low dose rate brachytherapy for prostate cancer.

PURPOSE/OBJECTIVES: To characterize the clinical course and prognosis of bladder malignancies associated with prior prostate brachytherapy SUBJECTS/PATIENTS AND METHODS: We queried our institutional database for patients with bladder cancer (BC) diagnosed between January 2005 and April 2019 who had previously undergone low dose rate (LDR) prostate brachytherapy. Patients diagnosed with BC at least 1 year following LDR prostate brachytherapy with or without external beam radiation therapy were included. Clinical and disease-specific characteristics were abstracted from chart review and survival outcomes were estimated using Kaplan-Meier estimates. We compared the pathologic characteristics and prognosis of secondary BCs in our study cohort to those of BCs diagnosed after prostate cancer managed without radiation reported by the Surveillance, Epidemiology, and End Results (SEER) populational database from 2005 to 2018. RESULTS: Three hundred seventy-five patients were identified with combined diagnosis of prostate cancer and BC, 51 of whom met inclusion criteria in the study cohort. Median times from brachytherapy to BC diagnosis for the study and SEER cohort were 9.5 ± 4.5 and 6.3 ± 4.1 years, respectively. Compared to the SEER cohort, significantly greater proportion of BC from the study cohort presented with high-grade (study: 78.4%, SEER: 52.3%, P = 0.0008) and with MIBC (Study BC 35.3%, SEER BC: 17.5%, P = 0.0009). The study and the SEER cohort had similar 5-year overall survival (study: 67.9%, SEER: 58.0%, P = 0.1099), and 5-year cancer-specific survival (study: 81.0%, SEER: 82.8%, P = 0.5559). The 5-year progression-free survival for the study cohort was 43.7% (95% CI: 28.8-57.7). CONCLUSION: Compared to bladder cancers following prostate cancer managed without radiation, bladder malignancies following prostate LDR brachytherapy present with higher grade and are more likely to be muscle invasive. Despite the aggressive presenting features of postprostate brachytherapy BC, there were no differences in overall and cancer-specific survival between the groups.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Factors influencing urinary symptoms 10 years after permanent prostate seed implantation.

PURPOSE: We investigated the factors that influenced urinary symptoms in the first 10 years after prostate brachytherapy. MATERIALS AND METHODS: A total of 1,932 men were treated with prostate brachytherapy alone or with external beam irradiation and followed a mean of 6.8 years. The influence of pretreatment American Urological Association symptom score (7 or less, 8 to 19, 20 or greater), external beam radiotherapy, (125)I or (103)Pd, biological effective dose, age, prostate size and hormone therapy on the change in American Urological Association symptom score (11,491) was compared. RESULTS: The mean change from initial score (7.4) was 11.4, 5.5, 3.3, 2.7, 1.5, 1.2, 1, 1, 1, 1, 1.3 and 1.4 points at 3, 6 months and 1 to 10 years, respectively (p <0.001). Factors that resulted in a greater increase in urinary symptoms at year 1 were low pretreatment score (p <0.001), no hormonal therapy (p <0.001), younger age (p = 0.046) and higher biological effective dose (p = 0.025). At 10 years patients with an initial score of 20 or greater had an average decrease of 11 points compared to a decrease of 0.9 for an initial score of 8 to 19 and an increase of 2.7 for an initial score of 7 or less (p <0.001). On linear regression the scores at 1 year were influenced by initial score (p <0.001), biological effective dose (p = 0.022), prostate size (p <0.001) and hormonal therapy (p = 0.009). At 10 years only the pretreatment score remained significant (p <0.001). CONCLUSIONS: There is minimal change in mean American Urological Association symptom score (1.4 points) 10 years after prostate brachytherapy. Patients presenting with high initial scores have the greatest improvement from baseline. Biological effective dose, external beam radiotherapy, hormonal therapy, isotope, patient age and prostate size do not appear to influence long-term urinary symptoms.

Gleason 7 prostate cancer treated with low-dose-rate brachytherapy: lack of impact of primary Gleason pattern on biochemical failure.

UNLABELLED: What's known on the subject? and What does the study add? There appears to be a clear difference in cancer control outcomes for patients with Gleason scores of 3+4 and those with scores of 4+3 after radical prostatectomy. It has been documented that patients with Gleason 4+3 prostate cancer have higher incidences of non-organ-confined disease than those with primary pattern 3. Higher rates of extracapsular extension, seminal vesicle invasion and positive margins have been found to be associated with primary pattern 4 over 3. These higher rates of non-organ-confined disease can lead to increased biochemical failure, which, in turn, can lead to higher mortality rates. This study provides information on the prognostic significance of primary Gleason pattern in the brachytherapy management of prostate cancer. Study Type - Prognosis (case series) Level of Evidence 4. OBJECTIVES: • To report the biochemical outcomes for Gleason 7 prostate cancer treated with brachytherapy. • To analyse the impact of the primary Gleason pattern as well as other disease- and treatment-related factors on outcome. PATIENTS AND METHODS: • A total of 560 patients with Gleason 7 prostate cancer were treated between 1990 and 2008 with brachytherapy, alone or in combination with hormonal therapy and/or external beam radiation therapy. • There were 352 patients with Gleason pattern 3+4 and 208 with Gleason pattern 4+3. • The mean (range) presenting PSA level was 11.2 (1-300) ng/mL, and the median was 7.8 ng/mL. • The presenting clinical stages were T1b in 1%, T1c in 33%, T2a in 16%, T2b in 32%, T2c in 16% and T3 in 2% of patients. RESULTS: • The actuarial freedom from biochemical failure rate at 10 years was 82%. • There was no significant difference between 10-year freedom from biochemical failure rates for patients with Gleason scores of 3+4 (79%) and those with scores of 4+3 (82%). • Biologically effective dose and presenting PSA level were both significant predictors of biochemical failure in multivariate analysis. CONCLUSIONS: • The primary Gleason pattern in Gleason 7 prostate cancer shows no significant effect on biochemical failure when treated with brachytherapy. • These results are different from those found after radical prostatectomy and are probably attributable to the enhanced local control afforded by a brachytherapy approach to this disease subset.

Long-term potency preservation following brachytherapy for prostate cancer.

UNLABELLED: Study Type - Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? Previously, rates of potency preservation with or without external beam radiation and/ or hormone therapy have been published with smaller series and limited follow-up. The study provides greater numbers and longer follow-up giving patients and clinicians a better appreciation of the true potency preservation rates in this population and how various factors such as age, hormone use and external beam affect those rates. OBJECTIVES: • To assess potency preservation in men following brachytherapy for prostate cancer with or without external beam radiation therapy (EBRT) and/or androgen deprivation therapy (ADT). • To evaluate the factors that significantly impact this rate. PATIENTS AND METHODS: • In all, 1063 potent men with T1-T3 prostate cancer were treated from 1990 to 2007 with seed implantation alone ((103) Pd or (125) I) (69.6%) or combined modality treatment consisting of a partial dose (103) Pd implant followed 6-8 weeks later by EBRT (45 Gy, prostate/seminal vesicles only) (30.4%). ADT was used in 49.1% of cases (range 1-27 months). • Patients were required to have a minimum of 2 years follow-up and to be off ADT for a minimum of 1 year. • Erectile function was assessed prior to seed implantation and at each follow-up visit using the physician-assigned Mount Sinai Erectile Function Score (MSEFS): 0, unable to have erections; 1, erections insufficient for intercourse; 2, suboptimal erections but sufficient for intercourse; 3, normal erectile function. Potent was defined as a score of greater than or equal to 2 with or without use of a phosphodiesterase type 5 inhibitor. • The potency rate was calculated using actuarial methods with comparisons tested by log-rank and Cox regression analysis. RESULTS: • The 5-year and 10-year actuarial rate of potency preservation was 68.0% and 57.9%, respectively, at last follow-up. • On multivariate analysis, 5- and 10-year potency was 87.6% (79.5%) for men younger than 60, 68.0% (57.5%) for age 60-70, and 42.2% (31.0%) for men older than 70 (P < 0.001). • Pretreatment MSEFS of 2 had a potency rate of 51.7% (37.2%) vs 74.2% (65.2%) for an MSEFS of 3 (P < 0.001). • There was a 75.8% (62.6%) potency rate without ADT vs 60.0% (53.0%) with ADT (P < 0.001). • Five-year potency was 76.4% for implant alone, 71.0% for implant with EBRT, 62.2% for implant with ADT, and 57.9% for implant with EBRT and ADT (P < 0.001). CONCLUSION: • Increasing initial age at implant, diminished pretreatment erectile function and the use of combination therapy with EBRT and/or ADT significantly increases erectile dysfunction following brachytherapy.

Radium-223 for Metastatic Castrate-Resistant Prostate Cancer.

Prostate cancer is a significant cause of morbidity and mortality among men worldwide. Although most patients present with localized or regional disease and experience excellent outcomes with treatment, approximately 10% to 20% of patients develop castrate-resistant prostate cancer (CRPC) within 5 years of diagnosis. Bone metastases, which can cause pain and adversely affect quality of life, are common among this population. Radium-223 has a relatively short half-life and decays via α-decay. Its daughter products, α-particles, have a short path length in tissue and exhibit high linear energy transfer. Together, these properties allow radium-223 to achieve relatively high cell kill in its target tissue while sparing the surrounding normal tissues. Administered in the clinic as radium-223 dichloride (Xofigo), radium-223 acts as a calcium mimetic in the human body, forming complexes with hydroxyapatite. In areas of high bone turnover, such as the osteoblastic bone metastases that are common in patients with CRPC, radium-223 is preferentially incorporated into the bone matrix, where it can exert an antitumor effect. In May 2013, the U.S. Food and Drug Administration approved Xofigo for use in patients with CRPC who have symptomatic bone metastases and no visceral metastases. In this topic discussion, we review the mechanism of action and clinical efficacy of radium-223 in patients with metastatic CRPC. We also discuss its administration and handling, distribution and elimination, and associated toxicities.

Ocular complications with the use of radium-223: a case series.

BACKGROUND: Radium-223 is used for the treatment of osseous metastases in castrate-resistant prostate cancer, and has been shown to increase time to the first skeletal-related event, reduce the rate of hospitalization, and improve quality of life. It is well tolerated, with hematologic toxicity as the main adverse event. Thus far, no ocular complication has been reported in the literature after initial administration of radium-223 with a single case reported of ocular complications after a patient's second course of radium-223. CASE PRESENTATIONS: We present three cases of ocular complications after the use of radium-223 in patients with metastatic prostatic adenocarcinoma. Ocular complications presented as blurry vision, and formal diagnosis included uveitis and hyphema. CONCLUSIONS: Documentation of adverse events is exceedingly important due to the high incidence of metastatic prostate cancer and increasing interest for the use of radium-223 in other osteoblastic disease. The authors postulate that these ocular complications may be a result of radiation's potential effect on neovascularization, polypharmacy, or the biomolecular effects of radium-223 on integral signaling proteins, potentially coupled with poor underlying ocular health.

Factors associated with late local failure and its influence on survival in men undergoing prostate brachytherapy.

BACKGROUND AND PURPOSE: To determine the factors associated with a positive post-treatment prostate biopsy (PB) and the effects of local failure on biochemical control and cause-specific survival (CSS) in men receiving prostate brachytherapy. METHODS AND MATERIALS: Of 545 men with post-implant PB, 484 were routine (median 24 months) while 61 (median 55 months) were for cause. 114 had a repeat PB for rising PSA. Initial mean PSA was 10.5 ng/ml (±13.9) while 244 (44.8%), 202 (37.1%) and 99 (18.2%) had low, intermediate or high-risk disease. Treatments were implant only in 287 (52.7%), and implant with androgen deprivation therapy (ADT) ± external beam in 258. Radiation doses were converted to the biologically equivalent dose (BED). Final biopsy results were the last biopsy performed on that patient. Associations for the first and final biopsies with PSA, clinical stage (CS), Gleason grade group, time on hormone therapy (ADT) and BED were determined by ANOVA, chi-square and binary linear regression. Freedom from Phoenix failure (FFPF) and cause-specific survival were estimated by Kaplan Meier method and Cox proportions hazards. RESULTS: After a median of 11.4 years the first and final biopsy were positive in 10.8% and 8.8%, respectively. Significant linear regression associations with first positive PB were ADT (p = 0.005), CS (p = 0.044) and BED (p = 0.030) while only BED (p < 0.001) was significant for the final PB. Positive biopsy occurred in 21/112 (18.8%), 16/230 (7.0%) and 3/182 (1.6%) for BED ≤150, >150-200 and >200 Gy (p < 0.001), and in 29/261 (11.1%) for BED (median) ≤185 Gy vs. 5/263 (1.9%) for > 185 Gy (OR 4.2, p < 0.001). 15-year FFPF was 75.6 vs. 17.5% and cause-specific survival was 94.2 vs. 75.5% for negative vs. positive biopsy. CONCLUSIONS: Higher radiation doses are associated with 1.9% late local failure following prostate brachytherapy. A negative post-implant PB is associated with superior FFPF and decreased prostate cancer mortality.

Comparison of AUA and phoenix definitions of biochemical failure following permanent brachytherapy for prostate cancer.

PURPOSE: To compare biochemical recurrence free survival (BCRFS) and cancer-specific survival (CSS) after brachytherapy using the AUA and the Phoenix definitions. METHODS AND MATERIALS: 2634 men with T1-T4N0M0 prostate cancer were treated with brachytherapy with or without neoadjuvant hormonal therapy or external beam radiation therapy. Five, 10, and 15- year BCRFS and CSS were estimated with Kaplan-Meier estimates with log rank. Multivariate analysis of survival was performed with Cox regression analysis. RESULTS: Median age was 66, follow-up was 8.6 years, and prostate specific antigen was 6.9. Overall, 11.1% (n = 293) of patients experienced Phoenix BCR and 17.48% (n = 457) experienced AUA BCR. The rates of AUA BCR and Phoenix BCR were significantly different at 5 and 10-years but not at 15 years. Patients treated with BED ≤ 200 Gy were more likely to experience AUA BCR (22.5% vs. 12.4%, OR 1.44, p < 0.001) and Phoenix BCR (14.3% and 8.3%, OR 1.37, p < 0.001) than patients treated with a BED > 200 Gy. CONCLUSIONS: Compared to the Phoenix definition, the AUA definition of BCR after brachytherapy is associated with significantly worse BCRFS for the first 15 years after treatment. Receiving a BED > 200, which cannot be achieved without the addition of brachytherapy, is associated with better BCRFS and CSS. Our findings reaffirm the importance of dose in the management of prostate cancer.