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Purpose: High-dose SABR for prostate cancer offers the radiobiologic potency of the most intensified radiation therapy regimens but was associated with >90% rates of ulceration of the anterior rectal wall on endoscopic assessment; this infrequently progressed to severe rectal toxicity in prior prospective series. A multi-institutional phase 2 prospective trial was conducted to assess whether placement of a perirectal hydrogel spacer would reduce acute periprostatic rectal ulcer events after high-dose (>40 Gy) SABR., Methods and Materials: Eligible patients included men with stage ≤T2c localized grade group 1 to 3 prostate cancer, a prostate-specific antigen (PSA) level ≤15 ng/mL, American Urological Association Symptom Index = AUA-SI scores ≤18, and a gland volume ≤80 cm 3 . Patients underwent perirectal hydrogel spacer placement, followed by SABR of 45 Gy in 5 fractions every other day to the prostate only. Androgen deprivation was not allowed except for cytoreduction. The rectal wall was directly assessed by serial anoscopy during follow-up to determine whether the spacer would reduce acute periprostatic rectal ulcer events from >90% to <70% within 9 months of treatment., Results: Forty-four men were enrolled and 43 were eligible for protocol analysis. The median follow-up for surviving patients was 48 months. Acute periprostatic ulcers were observed in 6 of 42 patients (14.3%; 95% confidence interval, 6.0%-27%; P < .001) at a median of 2.9 months posttreatment (range, 1.7-5.6 months). All ulcers (grade 1, 5 ulcers; grade 2, 1 ulcer) resolved on repeat anoscopy within 8 months of incidence. There were no grade ≥3 late gastrointestinal toxicities; the incidence of late grade-2 gastrointestinal toxicities was 14.3%, with a prevalence at 3 years of 0%. No toxicities greater than grade 3 occurred in any domain. Four-year freedom from biochemical failure was 93.8% (95% CI, 85.2%-100.0%)., Conclusions: Temporary hydrogel spacer placement before high-dose SABR treatment for localized prostate cancer and use of strict dose constraints are associated with a significant reduction in the incidence of rectal ulcer events compared with prior phase 1/2 trial results., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To report early toxicity and tumor control outcomes of Pd-103 brachytherapy with ultrahypofractionated stereotactic radiation therapy (RT) for intermediate-risk prostate cancer., Methods and Materials: This prospective trial included 40 patients with intermediate-risk prostate cancer who underwent low-dose-rate (Pd-103) brachytherapy (prescription dose, 100 Gy), followed 1 month later with ultrahypofractionated stereotactic RT (25 Gy in 5 fractions) to the prostate and seminal vesicles. The primary endpoint was the rate of grade 2+ genitourinary toxicity at 12 months using Common Terminology Criteria for Adverse Events v 4.0. Secondary endpoints included patient-reported quality-of-life metrics (International Prostate Scoring System [IPSS], International Index of Erectile Function, and Expanded Prostate Cancer Index Composite-bowel). Biochemical failure was defined as prostate-specific antigen nadir +2 ng/mL. Posttreatment biopsies were performed at between 24 and 36 months; median follow-up was 36 months., Results: The rate of grade 2 urinary toxicity at 12 months was 25% with no grade 3 urinary toxicity noted. Mean IPSS at baseline and 12 and 24 months was 5, 10, and 6.2, respectively. Mean change in IPSS from baseline at 12 months was +5.5 (interquartile range, 1-9.75) and +1.05 (interquartile range, -3 to 3.25) at 24 months. Grade 2 bowel toxicity was 5% at 12 months with no grade 3 bowel toxicity noted. Mean Expanded Prostate Cancer Index Composite-bowel domain scores at baseline and 12 months were 92.8 and 90.3, respectively. Of patients who were potent (International Index of Erectile Function ≥21) at baseline, 75% remained potent at 12 months. Of 40 patients, 28 underwent posttreatment prostate biopsy (PPB), which was negative (n = 20) or demonstrated severe treatment effect (n = 8). No patient had a positive PPB or developed biochemical failure during the follow-up period. One patient without a PPB developed osseous metastases at 18 months posttreatment in the absence of biochemical failure., Conclusion: Low-dose-rate brachytherapy in combination with ultrahypofractionated stereotactic RT was safe and effective for intermediate-risk prostate cancer in early results of this trial., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer., Methods and Materials: A total of 136 patients were enrolled in a phase 1 dose-escalation study to determine the tolerance of escalating radiation dose levels of SBRT for the treatment of localized prostate cancer. The initial dose level was 32.5 Gy in 5 fractions, and doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy. Eligibility criteria included only patients with low and intermediate risk, and the maximum prostate volume was 60 cm 3 . Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5 years, respectively., Results: The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were 16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P = .013)., Conclusions: SBRT doses ranging from 32.5 to 40 Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the difference in prostate-specific antigen (PSA) recurrence-free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT)., Methods and Materials: During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75 Gy with ≥5 years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6 months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0 Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2 ng/mL. Median follow-up was 9.2 years (interquartile range, 6.9-11.3 years)., Results: One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6 months (interquartile range, 16.1-38.5 months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004)., Conclusions: Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have improved PSA recurrence-free survival, distant metastasis-free survival, overall survival, and cancer-specific survival outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To compare the potential benefits of continuous monitoring of prostate position and intervention (CMI) using 2-mm displacement thresholds during stereotactic body radiation therapy (SBRT) treatment to those of a conventional image-guided procedure involving single localization prior to treatment., Methods and Materials: Eighty-nine patients accrued to a prostate SBRT dose escalation protocol were implanted with radiofrequency transponder beacons. The planning target volume (PTV) margin was 5 mm in all directions, except for 3 mm in the posterior direction. The prostate was kept within 2 mm of its planned position by the therapists halting dose delivery and, if necessary, correcting the couch position. We computed the number, type, and time required for interventions and where the prostate would have been during dose delivery had there been, instead, a single image-guided setup procedure prior to each treatment. Distributions of prostate displacements were computed as a function of time., Results: After the initial setup, 1.7 interventions per fraction were required, with a concomitant increase in time for dose delivery of approximately 65 seconds. Small systematic drifts in prostate position in the posterior and inferior directions were observed in the study patients. Without CMI, intrafractional motion would have resulted in approximately 10% of patients having a delivered dose that did not meet our clinical coverage requirement, that is, a PTV D95 of >90%. The posterior PTV margin required for 95% of the dose to be delivered with the target positioned within the PTV was computed as a function of time. The margin necessary was found to increase by 2 mm every 5 minutes, starting from the time of the imaging procedure., Conclusions: CMI using a tight 2-mm displacement threshold was not only feasible but was found to deliver superior PTV coverage compared with the conventional image-guided procedure in the SBRT setting., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To identify an anatomic structure predictive for acute (AUT) and late (LUT) urinary toxicity in patients with prostate cancer treated with low-dose-rate brachytherapy (LDR) with or without external beam radiation therapy (EBRT)., Methods and Materials: From July 2002 to January 2013, 927 patients with prostate cancer (median age, 66 years) underwent LDR brachytherapy with Iodine 125 (n=753) or Palladium 103 (n=174) as definitive treatment (n=478) and as a boost (n=449) followed by supplemental EBRT (median dose, 50.4 Gy). Structures contoured on the computed tomographic (CT) scan on day 0 after implantation included prostate, urethra, bladder, and the bladder neck, defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. AUT and LUT were assessed with the Common Terminology Criteria for Adverse Events, version4. Clinical and dosimetric factors associated with AUT and LUT were analyzed with Cox regression and receiver operating characteristic analysis to calculate area under the receiver operator curve (ROC) (AUC)., Results: Grade ≥2 AUT and grade ≥2 LUT occurred in 520 patients (56%) and 154 patients (20%), respectively. No grade 4 toxicities were observed. Bladder neck D2cc retained a significant association with AUT (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.03-1.04; P<.0001) and LUT (HR, 1.01; 95% CI, 1.00-1.03; P=.014) on multivariable analysis. In a comparison of bladder neck with the standard dosimetric variables by use of ROC analysis (prostate V100 >90%, D90 >100%, V150 >60%, urethra D20 >130%), bladder neck D2cc >50% was shown to have the strongest prognostic power for AUT (AUC, 0.697; P<.0001) and LUT (AUC, 0.620; P<.001)., Conclusions: Bladder neck D2cc >50% was the strongest predictor for grade ≥2 AUT and LUT in patients treated with LDR brachytherapy. These data support inclusion of bladder neck constraints into brachytherapy planning to decrease urinary toxicity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To determine the potential association between genitourinary (GU) toxicity and planning dose-volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients., Methods and Materials: A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose-volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analyses were done by the Kaplan-Meier method and Cox proportional hazard models, respectively., Results: Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19)., Conclusions: The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the bladder trigone seems to be associated with a reduction in late GU toxicity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To determine whether the response to neoadjuvant androgen deprivation therapy (ADT) defined by a decline in prostate-specific antigen (PSA) to nadir values is associated with improved survival outcomes after external beam radiation therapy (EBRT) for prostate cancer., Methods and Materials: One thousand forty-five patients with localized prostate cancer were treated with definitive EBRT in conjunction with neoadjuvant and concurrent ADT. A 6-month course of ADT was used (3 months during the neoadjuvant phase and 2 to 3 months concurrently with EBRT). The median EBRT prescription dose was 81 Gy using a conformal-based technique. The median follow-up time was 8.5 years., Results: The 10-year PSA relapse-free survival outcome among patients with pre-radiation therapy PSA nadirs of ≤0.3 ng/mL was 74.3%, compared with 57.7% for patients with higher PSA nadir values (P<.001). The 10-year distant metastases-free survival outcome among patients with pre-radiation therapy PSA nadirs of ≤0.3 ng/mL was 86.1%, compared with 78.6% for patients with higher PSA nadir values (P=.004). In a competing-risk analysis, prostate cancer-related deaths were also significantly reduced among patients with pre-radiation therapy PSA nadirs of <0.3 ng/mL compared with higher values (7.8% compared with 13.7%; P=.009). Multivariable analysis demonstrated that the pre-EBRT PSA nadir value was a significant predictor of long-term biochemical tumor control, distant metastases-free survival, and cause-specific survival outcomes., Conclusions: Pre-radiation therapy nadir PSA values of ≤0.3 ng/mL after neoadjuvant ADT were associated with improved long-term biochemical tumor control, reduction in distant metastases, and prostate cancer-related death. Patients with higher nadir values may require alternative adjuvant therapies to improve outcomes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To analyze the effect of primary Gleason (pG) grade among a large cohort of Gleason 7 prostate cancer patients treated with external beam radiation therapy (EBRT)., Methods and Materials: From May 1989 to January 2011, 1190 Gleason 7 patients with localized prostate cancer were treated with EBRT at a single institution. Of these patients, 613 had a Gleason 7 with a minimum of a sextant biopsy with nonfragmented cores and full biopsy core details available, including number of cores of cancer involved, percentage individual core involvement, location of disease, bilaterality, and presence of perineural invasion. Median follow-up was 6 years (range, 1-16 years). The prognostic implication for the following outcomes was analyzed: biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific mortality (PCSM)., Results: The 8-year bRFS rate for pG3 versus pG4 was 77.6% versus 61.3% (P<.0001), DMFS was 96.8% versus 84.3% (P<.0001), and PCSM was 3.7% versus 8.1% (P=.002). On multivariate analysis, pG4 predicted for significantly worse outcome in all parameters. Location of disease (apex, base, mid-gland), perineural involvement, maximum individual core involvement, and the number of Gleason 3+3, 3+4, or 4+3 cores did not predict for distant metastases., Conclusions: Primary Gleason grade 4 independently predicts for worse bRFS, DMFS, and PCSM among Gleason 7 patients. Using complete core information can allow clinicians to utilize pG grade as a prognostic factor, despite not having the full pathologic details from a prostatectomy specimen. Future staging and risk grouping should investigate the incorporation of primary Gleason grade when complete biopsy core information is used., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To report long-term survival and toxicity outcomes with the use of high-dose intensity modulated radiation therapy (IMRT) to 86.4 Gy for patients with localized prostate cancer., Methods and Materials: Between August 1997 and December 2008, 1002 patients were treated to a dose of 86.4 Gy using a 5-7 field IMRT technique. Patients were stratified by prognostic risk group based on National Comprehensive Cancer Network risk classification criteria. A total of 587 patients (59%) were treated with neoadjuvant and concurrent androgen deprivation therapy. The median follow-up for the entire cohort was 5.5 years (range, 1-14 years)., Results: For low-, intermediate-, and high-risk groups, 7-year biochemical relapse-free survival outcomes were 98.8%, 85.6%, and 67.9%, respectively (P<.001), and distant metastasis-free survival rates were 99.4%, 94.1%, and 82.0% (P<.001), respectively. On multivariate analysis, T stage (P<.001), Gleason score (P<.001), and >50% of initial biopsy positive core (P=.001) were predictive for distant mestastases. No prostate cancer-related deaths were observed in the low-risk group. The 7-year prostate cancer-specific mortality (PCSM) rates, using competing risk analysis for intermediate- and high-risk groups, were 3.3% and 8.1%, respectively (P=.008). On multivariate analysis, Gleason score (P=.004), percentage of biopsy core positivity (P=.003), and T-stage (P=.033) were predictive for PCSM. Actuarial 7-year grade 2 or higher late gastrointestinal and genitourinary toxicities were 4.4% and 21.1%, respectively. Late grade 3 gastrointestinal and genitourinary toxicity was experienced by 7 patients (0.7%) and 22 patients (2.2%), respectively. Of the 427 men with full potency at baseline, 317 men (74%) retained sexual function at time of last follow-up., Conclusions: This study represents the largest cohort of patients treated with high-dose radiation to 86.4 Gy, using IMRT for localized prostate cancer, with the longest follow-up to date. Our findings indicate that this treatment results in excellent clinical outcomes with acceptable toxicity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To investigate the utility of endorectal coil magenetic resonance imaging (eMRI) in predicting biochemical relapse in prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy., Methods and Materials: Between 2000 and 2008, 279 men with intermediate- or high-risk prostate cancer underwent eMRI of their prostate before receiving brachytherapy and supplemental intensity-modulated radiotherapy. Endorectal coil MRI was performed before treatment and retrospectively reviewed by two radiologists experienced in genitourinary MRI. Image-based variables, including tumor diameter, location, number of sextants involved, and the presence of extracapsular extension (ECE), were incorporated with other established clinical variables to predict biochemical control outcomes. The median follow-up was 49 months (range, 1-13 years)., Results: The 5-year biochemical relapse-free survival for the cohort was 92%. Clinical findings predicting recurrence on univariate analysis included Gleason score (hazard ratio [HR] 3.6, p = 0.001), PSA (HR 1.04, p = 0.005), and National Comprehensive Cancer Network risk group (HR 4.1, p = 0.002). Clinical T stage and the use of androgen deprivation therapy were not correlated with biochemical failure. Imaging findings on univariate analysis associated with relapse included ECE on MRI (HR 3.79, p = 0.003), tumor size (HR 2.58, p = 0.04), and T stage (HR 1.71, p = 0.004). On multivariate analysis incorporating both clinical and imaging findings, only ECE on MRI and Gleason score were independent predictors of recurrence., Conclusions: Pretreatment eMRI findings predict for biochemical recurrence in intermediate- and high-risk prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Gleason score and the presence of ECE on MRI were the only significant predictors of biochemical relapse in this group of patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To compare toxicity profiles and biochemical tumor control outcomes between patients treated with high-dose image-guided radiotherapy (IGRT) and high-dose intensity-modulated radiotherapy (IMRT) for clinically localized prostate cancer., Materials and Methods: Between 2008 and 2009, 186 patients with prostate cancer were treated with IGRT to a dose of 86.4 Gy with daily correction of the target position based on kilovoltage imaging of implanted prostatic fiducial markers. This group of patients was retrospectively compared with a similar cohort of 190 patients who were treated between 2006 and 2007 with IMRT to the same prescription dose without, however, implanted fiducial markers in place (non-IGRT). The median follow-up time was 2.8 years (range, 2-6 years)., Results: A significant reduction in late urinary toxicity was observed for IGRT patients compared with the non-IGRT patients. The 3-year likelihood of grade 2 and higher urinary toxicity for the IGRT and non-IGRT cohorts were 10.4% and 20.0%, respectively (p = 0.02). Multivariate analysis identifying predictors for grade 2 or higher late urinary toxicity demonstrated that, in addition to the baseline Internatinoal Prostate Symptom Score, IGRT was associated with significantly less late urinary toxicity compared with non-IGRT. The incidence of grade 2 and higher rectal toxicity was low for both treatment groups (1.0% and 1.6%, respectively; p = 0.81). No differences in prostate-specific antigen relapse-free survival outcomes were observed for low- and intermediate-risk patients when treated with IGRT and non-IGRT. For high-risk patients, a significant improvement was observed at 3 years for patients treated with IGRT compared with non-IGRT., Conclusions: IGRT is associated with an improvement in biochemical tumor control among high-risk patients and a lower rate of late urinary toxicity compared with high-dose IMRT. These data suggest that, for definitive radiotherapy, the placement of fiducial markers and daily tracking of target positioning may represent the preferred mode of external-beam radiotherapy delivery for the treatment of prostate cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To review the impact of high-dose radiotherapy (RT) in the postprostatectomy salvage setting on long-term biochemical control and distant metastases-free survival, and to identify clinical and pathologic predictors of outcomes., Methods and Materials: During 1988-2007, 285 consecutive patients were treated with salvage RT (SRT) after radical prostatectomy. All patients were treated with either three-dimensional conformal RT or intensity-modulated RT. Two hundred seventy patients (95%) were treated to a dose ≥66 Gy, of whom 205 (72%) received doses ≥70 Gy. Eighty-seven patients (31%) received androgen-deprivation therapy as a component of their salvage treatment. All clinical and pathologic records were reviewed to identify treatment risk factors and response., Results: The median follow-up time after SRT was 60 months. Seven-year actuarial prostate-specific antigen (PSA) relapse-free survival and distant metastases-free survival were 37% and 77%, respectively. Independent predictors of biochemical recurrence were vascular invasion (p < 0.01), negative surgical margins (p < 0.01), presalvage PSA level >0.4 ng/mL (p < 0.01), androgen-deprivation therapy (p = 0.03), Gleason score ≥7 (p = 0.02), and seminal vesicle involvement (p = 0.05). Salvage RT dose ≥70 Gy was not associated with improvement in biochemical control. A doubling time <3 months was the only independent predictor of metastatic disease (p < 0.01). There was a trend suggesting benefit of SRT dose ≥70 Gy in preventing clinical local failure in patients with radiographically visible local disease at time of SRT (7 years: 90% vs. 79.1%, p = 0.07)., Conclusion: Salvage RT provides effective long-term biochemical control and freedom from metastasis in selected patients presenting with detectable PSA after prostatectomy. Androgen-deprivation therapy was associated with improvement in biochemical progression-free survival. Clinical local failures were rare but occurred most commonly in patients with greater burden of disease at time of SRT as reflected by either radiographic imaging or a greater PSA level. Salvage radiation doses ≥70 Gy may ultimately be most beneficial in these patients, but this needs to be further studied., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To report the incidence and excess risk of second malignancy (SM) development compared with the general population after external beam radiotherapy (EBRT) and brachytherapy to treat prostate cancer., Methods and Materials: Between 1998 and 2001, 1,310 patients with localized prostate cancer were treated with EBRT (n = 897) or brachytherapy (n = 413). We compared the incidence of SMs in our patients with that of the general population extracted from the National Cancer Institute's Surveillance, Epidemiology, and End Results data set combined with the 2000 census data., Results: The 10-year likelihood of SM development was 25% after EBRT and 15% after brachytherapy (p = .02). The corresponding 10-year likelihood for in-field SM development in these groups was 4.9% and 1.6% (p = .24). Multivariate analysis showed that EBRT vs. brachytherapy and older age were the only significant predictors for the development of all SMs (p = .037 and p = .030), with a trend for older patients to develop a SM. The increased incidence of SM for EBRT patients was explained by the greater incidence of skin cancer outside the radiation field compared with that after brachytherapy (10.6% and 3.3%, respectively, p = .004). For the EBRT group, the 5- and 10-year mortality rate was 1.96% and 5.1% from out-of field cancer, respectively; for in-field SM, the corresponding mortality rates were 0.1% and 0.7%. Among the brachytherapy group, the 5- and 10-year mortality rate related to out-of field SM was 0.8% and 2.7%, respectively. Our observed SM rates after prostate RT were not significantly different from the cancer incidence rates in the general population., Conclusions: Using modern sophisticated treatment techniques, we report low rates of in-field bladder and rectal SM risks after prostate cancer RT. Furthermore, the likelihood of mortality secondary to a SM was unusual. The greater rate of SM observed with EBRT vs. brachytherapy was related to a small, but significantly increased, number of skin cancers in the EBRT patients compared with that of the general population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To investigate the association between 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and biochemical and survival outcomes after high-dose radiotherapy (RT) for prostate cancer., Methods and Materials: A total of 1711 men with clinical stage T1-T3 prostate cancer were treated with conformal RT to a median dose of 81 Gy during 1995-2007. Preradiotherapy medication data were available for 1681 patients. Three hundred eighty-two patients (23%) were taking a statin medication at diagnosis and throughout RT. Nine hundred forty-seven patients received a short-course of neoadjuvant and concurrent androgen-deprivation therapy (ADT) with RT. The median follow-up was 5.9 years., Results: The 5- and 8-year PSA relapse-free survival (PRFS) rates for statin patients were 89% and 80%, compared with 83% and 74% for those not taking statins (p=0.002). In a multivariate analysis, statin use (hazard ratio [HR] 0.69, p=0.03), National Comprehensive Cancer Network (NCCN) low-risk group, and ADT use were associated with improved PRFS. Only high-risk patients in the statin group demonstrated improvement in PRFS (HR 0.52, p=0.02). Across all groups, statin use was not associated with improved distant metastasis-free survival (DMFS) (p=0.51). On multivariate analysis, lower NCCN risk group (p=0.01) and ADT use (p=0.005) predicted improved DMFS., Conclusions: Statin use during high-dose RT for clinically localized prostate cancer was associated with a significant improvement in PRFS in high-risk patients. These data suggest that statins have anticancer activity and possibly provide radiosensitization when used in conjunction with RT in the treatment of prostate cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To report the influence of posttreatment prostate-specific antigen (PSA) nadir response at 2 years after external beam radiotherapy (RT) on distant metastases (DM) and cause-specific mortality (CSM)., Methods and Materials: Eight hundred forty-four patients with localized prostate cancer were treated with conformal RT. The median duration of follow-up was 9.1 years. A fixed landmark time point at 2 years was used to assess the influence of nadir PSA value as a time-dependent variable on long-term outcomes., Results: Multivariate analysis demonstrated that nadir PSA

Purpose: To examine whether the presence of sequence variants in the ATM (mutated in ataxia-telangiectasia) gene is predictive for the development of radiation-induced adverse responses resulting from (125)I prostate brachytherapy for early-stage prostate cancer., Materials and Methods: Thirty-seven patients with a minimum of 1-year follow-up who underwent (125)I prostate brachytherapy of early-stage prostate cancer were screened for DNA sequence variations in all 62 coding exons of the ATM gene using denaturing high-performance liquid chromatography. The clinical course and postimplant dosimetry for each genetically characterized patient were obtained from a database of 2,020 patients implanted at Mount Sinai Hospital after 1990., Results: Twenty-one ATM sequence alterations located within exons, or in short intronic regions flanking each exon, were found in 16 of the 37 patients screened. For this group, 10 of 16 (63%) exhibited at least one form of adverse response. In contrast, of the 21 patients who did not harbor an ATM sequence variation, only 3 of 21 (14%) manifested radiation-induced adverse responses (p = 0.005). Nine of the patients with sequence alterations specifically possessed missense mutations, which encode for amino acid substitutions and are therefore more likely to possess functional importance. For this group, 7 of 9 (78%) exhibited at least one form of adverse response. In contrast, of the 28 patients who did not have a missense alteration, only 6 of 28 (21%) manifested any form of adverse response to the radiotherapy (p = 0.004). Of the patients with missense variants, 5 of 9 (56%) exhibited late rectal bleeding vs. 1 of 28 (4%) without such alterations (p = 0.002). Of those patients who were at risk for developing erectile dysfunction, 5 of 8 (63%) patients with missense mutations developed prospectively evaluated erectile dysfunction as opposed to 2 of 20 (10%) without these sequence alterations (p = 0.009)., Conclusions: Possession of sequence variants in the ATM gene, particularly those that encode for an amino acid substitution, is predictive for the development of adverse radiotherapy responses among patients treated with (125)I prostate brachytherapy.

Purpose: The efficacy of a multimodality protocol using neoadjuvant and concomitant hormonal therapy, brachytherapy, and three-dimensional conformal external beam radiotherapy (RT) in high-risk prostate cancer was evaluated using biochemical outcomes and posttreatment biopsy results., Methods and Materials: Between February 1994 and November 1999, 132 high-risk patients were treated with combined hormonal therapy (9 months), permanent radioactive seed brachytherapy, and external beam RT, with follow-up ranging from 36 to 88 months (median, 50 months). The eligibility criteria were any of the following: Gleason score 8-10, initial prostate-specific antigen (PSA) level >20 ng/mL, clinical Stage T2c-T3, or positive seminal vesicle biopsy, or two or more of the following: Gleason score 7, PSA level >10-20 ng/mL, or Stage T2b. Twenty percent of patients had a positive seminal vesicle biopsy before therapy. Negative laparoscopic pelvic lymph node dissections were performed in 44% of patients., Results: The actuarial overall freedom from PSA failure rate was 86% at 5 years. The freedom from PSA failure rate at 5 years was 97% for those with a Gleason score of < or =6 (35 of 36), 85% for a Gleason score of 7 (50 of 59), and 76% for a Gleason score of 8-10 (28 of 37; p = 0.03). A trend was noted toward worse outcomes in seminal vesicle biopsy-positive patients, with a 5-year freedom from PSA failure rate of 74% vs. 89% for all other patients (p = 0.06). Posttreatment prostate biopsies were performed in 47 patients and were negative in 96% at the first biopsy and 100% at the last biopsy., Conclusion: Trimodality therapy with androgen suppression, brachytherapy, and external beam RT for high-risk prostate cancer results in excellent biochemical and pathologically confirmed local control.

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.