Prospective evaluation of patient-reported outcomes of invisible ink tattoos for the delivery of external beam radiation therapy: the PREFER trial.

Introduction: Invisible ink tattoos (IITs) avoid cosmetic permanence of visible ink tattoos (VITs) while serving as more reliable landmarks for radiation setup than tattooless setups. This trial evaluated patient-reported preference and feasibility of IIT implementation. Methods and materials: In an IRB-approved, single institution, prospective trial, patients receiving proton therapy underwent IIT-based treatment setup. A survey tool assessed patient preference on tattoos using a Likert scale. Matched patients treated using our institutional standard tattooless setup were identified; treatment times and image guidance requirements were evaluated between tattooless and IIT-based alignment approaches. Distribution differences were estimated using Wilcoxon rank-sum tests or Chi-square tests. Results: Of 94 eligible patients enrolled, median age was 58 years, and 58.5% were female. Most common treatment sites were breast (18.1%), lung (17.0%) and pelvic (14.9%). Patients preferred to receive IITs versus VITs (79.8% pre-treatment and 75.5% post-treatment, respectively). Patients were willing to travel farther from home to avoid VITs versus IITs (p<0.01). Females were willing to travel (45.5% vs. 23.1%; p=0.04) and pay additional money to avoid VITs (34.5% vs. 5.1%; p<0.01). Per-fraction average +treatment time and time from on table/in room to first beam were shorter with IIT-based vs. tattooless setup (12.3min vs. 14.1min; p=0.04 and 24.1min vs. 26.2min; p=0.02, respectively). Discussion: In the largest prospective trial on IIT-based radiotherapy setup to date, we found that patients prefer IITs to VITs. Additionally, IIT-based alignment is an effective and efficient strategy in comparison with tattooless setup. Standard incorporation of IITs for patient setup should be strongly considered.

Advancing knowledge-based intensity modulated proton planning for adaptive treatment of high-risk prostate cancer.

To assess the performance of a knowledge-based planning (KBP) model for generating intensity-modulated proton therapy (IMPT) treatment plans as part of an adaptive radiotherapy (ART) strategy for patients with high-risk prostate cancer. A knowledge-based planning (KBP) model for proton adaptive treatment plan generation was developed based on thirty patient treatment plans utilizing RapidPlanTM PT (Varian Medical Systems, Palo Alto, CA). The model was subsequently validated using an additional eleven patient cases. All patients in the study were administered a prescribed dose of 70.2 Gy to the prostate and seminal vesicle (CTV70.2), along with 46.8 Gy to the pelvic lymph nodes (CTV46.8) through simultaneous integrated boost (SIB) technique. To assess the quality of the validation knowledge-based proton plans (KBPPs), target coverage and organ-at-risk (OAR) dose-volume constraints were compared against those of clinically used expert plans using paired t-tests. The KBP model training statistics (R2) (mean ± SD, 0.763 ± 0.167, range, 0.406 to 0.907) and χ² values (1.162 ± 0.0867, 1.039-1.253) indicate acceptable model training quality. Moreover, the average total treatment planning optimization and calculation time for adaptive plan generation is approximately 10 minutes. The CTV70.2 D98% for the KBPPs (mean ± SD, 69.1 ± 0.08 Gy) and expert plans (69.9 ± 0.04 Gy) shows a significant difference (p < 0.05) but are both within 1.1 Gy of the prescribed dose which is clinically acceptable. While the maximum dose for some organs-at-risk (OARs) such as the bladder and rectum is generally higher in the KBPPs, the doses still fall within clinical constraints. Among all the OARs, most of them received comparable results to the expert plan, except the cauda equina Dmax, which shows statistical significance and was lower in the KBPPs than in expert plans (48.5 ± 0.06 Gy vs 49.3 ± 0.05 Gy). The generated KBPPs were clinically comparable to manually crafted plans by expert treatment planners. The adaptive plan generation process was completed within an acceptable timeframe, offering a quick same-day adaptive treatment option. Our study supports the integration of KBP as a crucial component of an ART strategy, including maintaining plan consistency, improving quality, and enhancing efficiency. This advancement in speed and adaptability promises more precise treatment in proton ART.

Long-term Outcomes from a Phase 1 Dose Escalation Study Using Stereotactic Body Radiotherapy for Patients with Low- or Intermediate-risk Prostate Cancer.

BACKGROUND: Ultrahypofractionated stereotactic body radiation therapy (SBRT) has become a standard treatment intervention for localized prostate cancer. OBJECTIVE: To report final long-term tumor control outcomes and late gastrointestinal (GI) and genitourinary (GU) toxicities from a single-center phase 1 dose escalation study using SBRT for patients with low- or intermediate-risk prostate cancer. DESIGN, SETTING AND PARTICIPANTS: Between 2009 and 2012, 136 patients were enrolled and treated. The initial dose level was 32.5 Gy in five fractions. Doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy in five fractions delivered every other day. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was late treatment-related toxicity. Secondary endpoints included prostate-specific antigen (PSA) failure. RESULTS AND LIMITATIONS: The median follow-up was 10.5 yr for the 32.5-Gy group, 9.9 yr for the 35-Gy group, 8.2 yr for the 37.5-Gy group, and 7.3 yr for the 40-Gy group. The 8-yr cumulative incidence of PSA failure was 26% for 32.5 Gy, 15% for 35 Gy, 3.4% for 37.5 Gy, and 6.6% for 40 Gy. Higher radiation dose (37.5-40 Gy) and favorable intermediate risk (vs unfavorable intermediate risk) were associated with better PSA recurrence rates (p = 0.011 and 0.002, respectively). The 8-yr actuarial probability rates for survival free from late grade ≥2 toxicity were 94% for GI toxicity and 86% for GU toxicity. No grade 4 events were recorded. Higher dose levels were not associated with higher rates of late grade ≥2 GI (p = 0.2) or GU (p > 0.9) toxicity. CONCLUSIONS: SBRT doses ranging from 32.5 to 40 Gy were associated with low incidence of moderate or severe toxicities. Higher doses resulted in superior disease control outcomes 8 yr after treatment. PATIENT SUMMARY: We investigated the association between the radiotherapy dose used and the rate of control of prostate cancer. We found that higher doses resulted in more favorable outcomes without excess toxicity. This trial is registered on ClinicalTrials.gov as NCT00911118.

Quality Metric to Assess Adequacy of Hydrogel Rectal Spacer Placement for Prostate Radiation Therapy and Association of Metric Score With Rectal Toxicity Outcomes.

Purpose: Although hydrogel spacer placement (HSP) minimizes rectal dose during prostate cancer radiation therapy, its potential benefit for modulating rectal toxicity could depend on the achieved prostate-rectal separation. We therefore developed a quality metric associated with rectal dose reduction and late rectal toxicity among patients treated with prostate stereotactic body radiation therapy (SBRT). Methods and Materials: A quality metric consisting of prostate-rectal interspace measurements from axial T2-weighted magnetic resonance imaging simulation images was applied to 42 men enrolled in a multi-institutional phase 2 study using HSP with prostate SBRT (45 Gy in 5 fractions). A score of 0, 1, or 2 was assigned to a prostate-rectal interspace measurement of <0.3 cm, 0.3 to 0.9 cm, or ≥1 cm, respectively. An overall spacer quality score (SQS) was computed from individual scores at rectal midline and ±1 cm laterally, located at the prostate base, midgland, and apex. Associations of SQS with rectal dosimetry and late toxicity were evaluated. Results: The majority of the analyzed cohort had an SQS of 1 (n = 17; 41%) or 2 (n = 18; 43%). SQS was associated with maximum rectal point dose (rectal Dmax; P = .002), maximum dose to 1 cc of rectum (D1cc; P = .004), and volume of rectum receiving ≥100% of prescription dose (V45; P = .046) and ≥40 Gy (V40; P = .005). SQS was also associated with a higher incidence of (P = .01) and highest-graded late rectal toxicity (P = .01). Among the 20 men who developed late grade ≥1 rectal toxicity, 57%, 71%, and 22% had an SQS of 0, 1, and 2, respectively. Men with an SQS of 0 or 1 compared with 2 had 4.67-fold (95% CI, 0.72-30.11) or 8.40-fold (95% CI, 1.83-38.57) greater odds, respectively, of developing late rectal toxicity. Conclusions: We developed a reliable and informative metric for assessing HSP, which appears to be associated with rectal dosimetry and late rectal toxicity after prostate SBRT.

Proton therapy for high-risk prostate cancer: Results from the Proton Collaborative Group PCG 001-09 prospective registry trial.

BACKGROUND: Data for proton therapy in high-risk prostate cancer (HRPC) are limited. Using the Proton Collaborative Group prospective registry, we evaluated outcomes for HRPC patients treated with proton therapy. METHODS: A totsl of 605 men with localized HRPC treated with proton therapy from 8/2009 to 3/2019 at nine institutions were selected. Outcomes examined included freedom from progression (FFP), metastasis free survival (MFS), overall survival (OS), and toxicity. Multivariable cox/binomial regression models were used to assess predictors of FFP and toxicity. RESULTS: Median age was 71 years. Gleason grade groups 4 (49.4%) and 5 (31.7%) were most common, as were clinical stage T1c (46.1%) and cT2 (41.3%). The median pretreatment prostate specific antigen (PSA) was 9.18 and median International Prostate Symptom Score (IPSS) was 6. Androgen deprivation therapy was given in 63.6%. Median dose was 79.2 GyE in 44 fractions. Pelvic lymph nodes were treated in 58.2% of cases. Pencil beam scanning was used in 54.5%, uniform scanning in 38.8%, and a rectal spacer in 14.2%. At a median followup of 22 months, the 3- and 5-year FFP were 90.7% and 81.4%, respectively. Five-year MFS and OS were 92.8% and 95.9%, respectively. Independent correlates of FFP included Gleason ≥8, PSA > 10, and cT2 (all p < 0.05). No grade 4 or 5 adverse events were reported. There were 23 (5%) grade 2 and 0 grade 3 gastrointestinal events. Prevalence of late grade 3, late grade 2, acute grade 3, and acute grade 2 genitourinary toxicity was 1.7%, 5.8%, 0%, and 21.8%, respectively. Prevalence of grade 2 and 3 erectile dysfunction at 2 years was 48.4% and 8.4%, respectively. CONCLUSIONS: In the largest series published to date, our results suggest early outcomes using proton therapy for HRPC are encouraging for both safety and efficacy. Further evaluation is needed to determine if an advantage exists to use protons over other radiation techniques in this population.

Racial inequity and other social disparities in the diagnosis and management of bladder cancer.

BACKGROUND: We investigate the impact of gender, race, and socioeconomic status on the diagnosis and management of bladder cancer in the United States. METHODS: We utilized the National Cancer Database to stratify cases of urothelial cell carcinoma of the bladder as early (Tis, Ta, T1), muscle invasive (T2-T3, N0), locally advanced (T4, N1-3), and metastatic. Multivariate binomial and multinomial logistic regression analyses identified demographic characteristics associated with stage at diagnosis and receipt of cancer-directed therapies. Odds ratios (OR) are reported with 95% confidence intervals. RESULTS: After exclusions, we identified 331,714 early, 72,154 muscle invasive, 15,579 locally advanced, and 15,161 metastatic cases from 2004-2016. Relative to diagnosis at early stage, the strongest independent predictors of diagnosis at muscle invasive, locally advanced, and metastatic disease included Black race (OR = 1.19 [1.15-1.23], OR = 1.49 [1.40-1.59], OR = 1.66 [1.56-1.76], respectively), female gender (OR = 1.21 [1.18-1.21], OR = 1.16 [1.12-1.20], and OR = 1.34 [1.29-1.38], respectively), and uninsured status (OR = 1.22 [1.15-1.29], OR = 2.09 [1.94-2.25], OR = 2.57 [2.39-2.75], respectively). Additional demographic factors associated with delayed diagnosis included older age, treatment at an academic center, Medicaid insurance and patients from lower income/less educated/more rural areas (all p < 0.01). Treatment at a non-academic center, older age, women, Hispanic and Black patients, lower income and rural areas were all less likely to receive cancer-directed therapies in early stage disease (all p < 0.01). Women, older patients, and Black patients remained less likely to receive treatment in muscle invasive, locally advanced, and metastatic disease (all p < 0.01). CONCLUSION: Black race was the strongest independent predictor of delayed diagnosis and substandard treatment of bladder cancer.

Local Failure after Prostate SBRT Predominantly Occurs in the PI-RADS 4 or 5 Dominant Intraprostatic Lesion.

BACKGROUND: A positive post-treatment prostate biopsy following definitive radiotherapy carries significant prognostic implications. OBJECTIVE: To determine whether local recurrences after prostate stereotactic body radiation therapy (SBRT) are associated with the presence of and occur more commonly within the region of a PI-RADS 4 or 5 dominant intra-prostatic lesion (DIL) identified on pre-treatment multi-parametric magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: 247 patients with localized prostate cancer treated with SBRT at our institution from 2009-2018 underwent post-treatment biopsies (median time to biopsy: 2.2 years) to evaluate local control. INTERVENTIONS: Prostate SBRT (median 40 Gy in 5 fractions). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MRIs were read by a single diagnostic radiologist blinded to other patient characteristics and treatment outcomes. The DIL presence, size, location, and extent were then analyzed to determine associations with the post-treatment biopsy outcomes. RESULTS AND LIMITATIONS: Among patients who underwent post-treatment biopsies, 39/247 (15.8%) were positive for Gleason-gradable prostate adenocarcinoma, of which 35/39 (90%) had a DIL initially present and 29/39 (74.4%) had a positive biopsy within the DIL. Factors independently associated with post-treatment biopsy outcomes included the presence of a DIL (OR 6.95; p = 0.001), radiographic T3 disease (OR 5.23, p < 0.001), SBRT dose ≥40 Gy (OR 0.26, p = 0.003), and use of androgen deprivation therapy (ADT; OR 0.28, p = 0.027). Among patients with a DIL (N = 149), the only factors associated with post-treatment biopsy outcomes included ≥50% percent cores positive (OR 2.4, p = 0.037), radiographic T3 disease (OR 4.04, p = 0.001), SBRT dose ≥40 Gy (OR 0.22, p < 0.001), and use of ADT (OR 0.21, p = 0.014). CONCLUSIONS: Our results suggest that men with PI-RADS 4 or 5 DILs have a higher risk of local recurrence after prostate SBRT and that most recurrences are located within the DIL. PATIENT SUMMARY: We found the presence of a dominant tumor on pre-treatment MRI was strongly associated with residual cancer within the prostate after SBRT and that most recurrences were within the dominant tumor.

Failure Patterns by PSMA PET for Recurrent Prostate Cancer after Prostatectomy and Salvage Radiation.

OBJECTIVE: To characterize patterns of failure using prostate-specific membrane antigen positron emission tomography (PSMA PET) after radical prostatectomy (RP) and salvage radiotherapy (SRT). METHODS: Patients with rising PSA post-RP+SRT underwent 68Ga-HBED-iPSMA PET/CT on a single-arm, prospective imaging trial (NCT03204123). Scans were centrally reviewed with pattern-of-failure analysis by involved site. Positive scans were classified using 3 failure categories: pelvic nodal, extra-pelvic nodal or distant non-nodal. Associations with failure categories were analyzed using cumulative incidence and generalized logits regression. RESULTS: We included 133 men who received SRT a median of 20 months post-RP; 56% received SRT to the prostatic fossa alone, while 44% received pelvic SRT. PSMA PET/CT was performed a median of 48 months post-SRT. Overall, 31% of PSMA PET/CT scans were negative, 2% equivocal and 67% had at least 1 positive site. Scan detection was significantly associated with PSA level prior to PSMA PET/CT. Analysis of 89 positive scans demonstrated pelvic nodal (53%) was the most common relapse and fossa relapse was low (9%). Overall, positive scans were pelvic (n = 35, 26%), extra-pelvic nodal (n = 26, 20%) or distant non-nodal failure (n = 28, 21%), and 70% of positive scans were oligorecurrent. We observed similar cumulative incidence for all failure categories and relatively few clinicodemographic associations. Men treated with pelvic SRT had reduced odds of pelvic failure versus exclusive fossa treatment. CONCLUSION: Pelvic, extra-pelvic nodal, and distant non-nodal failures occur with similar incidence post-SRT. Regional nodal relapse is relatively common, especially with fossa-only SRT. A high oligorecurrence rate suggests a potentially important role for PSMA-guided focal therapies.

Combined brachytherapy and ultra-hypofractionated radiotherapy for intermediate-risk prostate cancer: Comparison of toxicity outcomes using a high-dose-rate (HDR) versus low-dose-rate (LDR) brachytherapy boost.

PURPOSE/OBJECTIVE: To compare toxicity profiles of low-dose rate (LDR) and high-dose rate (HDR) brachytherapy boost combined with ultra-hypofractionated external beam radiation therapy (UH-EBRT). MATERIALS/METHODS: 99 patients with intermediate-risk prostate cancer underwent an HDR (n = 59) or LDR (n = 40) boost combined with UH-EBRT (5 Gy x 5) . HDR (Ir-192) was delivered a single dose (15 Gy) and LDR (Pd-103) prescription dose was 100 Gy. Median baseline IPSS was 5 for both cohorts. Median follow-up was 29.3mos. Cumulative incidences were calculated for toxicity. Fisher exact tests were used to evaluate associations. RESULTS: Overall incidence of grade 2 genitourinary toxicity for the entire cohort at 12 and 24 months was 21% and 29%, respectively. The incidence of grade 2 genitourinary toxicity at 12 and 24 months was higher for LDR cohort compared with HDR cohort (45% vs 5.1% and 55% vs 11%; p<0.001). On MVA, only treatment regimen (LDR versus HDR) was associated with grade 2+ genitourinary toxicity (p<0.001). Two patients experienced grade 2 rectal toxicity in each cohort. No grade > 3 toxicities were observed. CONCLUSIONS: Both LDR and HDR brachytherapy combined with UH-EBRT had favorable toxicity profiles, but significantly less grade 2+ genitourinary toxicity was observed in patients receiving HDR.

Influence of hydrogel spacer placement with prostate brachytherapy on rectal and urinary toxicity.

OBJECTIVE: To determine the influence of rectal hydrogel spacer placement (HSP) on late rectal toxicity outcomes in prostate cancer patients treated with low-dose-rate (LDR) brachytherapy, with or without supplemental external beam radiotherapy (EBRT). PATIENTS AND METHODS: A total of 224 patients underwent LDR brachytherapy with HSP, as monotherapy or combined with EBRT, between January 2016 and December 2019. Dosimetric variables reflecting the extent of rectal sparing and late rectal toxicity outcomes were evaluated. This spacer cohort was retrospectively compared to a similar patient group (n = 139) in whom HSP was not used. RESULTS: Hydrogel spacer placement was associated with significantly reduced rectal doses for all dosimetric variables; the median percentage rectal dose to 1 cc of rectum and rectal dose to 2 cc of rectum of the spacer cohort were all significantly lower compared to the non-spacer cohort. The incidence rates of overall (any grade) and grade ≥2 rectal toxicity were lower in patients with HSP compared to patients who did not undergo HSP: 12% and 1.8% vs 31% and 5.8%, respectively. The 3-year cumulative incidence of overall rectal toxicity was significantly lower with HSP than without (15% vs 33%; P < 0.001), corresponding to an overall rectal toxicity reduction on univariable analysis (hazard ratio 0.45, 95% confidence interval 0.28-0.73; P = 0.001). In this patient cohort treated with prostate brachytherapy, none of the urethral dosimetric variables or the presence or absence of HSP was associated with late urinary toxicity. CONCLUSION: Hydrogel rectal spacer placement is a safe procedure, associated with significantly reduced rectal dose. HSP translates to a decrease in overall late rectal toxicity in patients receiving dose-escalated brachytherapy-based procedures.

Early outcomes of high-dose-rate brachytherapy combined with ultra-hypofractionated radiation in higher-risk prostate cancer.

PURPOSE: This study evaluated outcomes associated with a high-dose-rate (HDR) brachytherapy boost combined with stereotactic body radiation therapy (SBRT) for patients with higher-risk localized prostate cancer. MATERIALS AND METHODS: We identified 101 patients with National Comprehensive Cancer Network high-risk, unfavorable intermediate-risk, or favorable intermediate-risk with probable extra-prostatic extension treated with HDR brachytherapy (15 Gy x 1 fraction) followed by SBRT (5 Gy x 5 daily fractions to the prostate and/or seminal vesicles and/or pelvic lymph nodes). Androgen deprivation therapy was used in 55.4% of all patients (90% of high-risk, 33% of intermediate-risk). Toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and International Prostate Symptom Scores were prospectively documented at each followup visit. Biochemical relapse was defined as PSA nadir +2ng/mL. RESULTS: The median follow-up time after SBRT was 24.1 months. No grade ≥3 toxicities were observed. The incidence of acute and late grade 2 gastrointestinal toxicities was both 0.99%. Acute and late grade 2 genitourinary (GU) toxicities were observed in 5.9% and 9.9%, respectively. Median time to a grade 2 GU toxicity was 6 months with a 14% 2-year actuarial rate of grade 2 GU toxicity. Median International Prostate Symptom Scores at 24 months was not significantly different than baseline (6 vs. 5; p = 0.24). Inclusion of pelvic lymph nodes and absence of a rectal spacer were significantly associated with more frequent grade ≥1 GU toxicity, but not grade ≥2 GU or gastrointestinal toxicity. The 2-year biochemical relapse free survival was 97%. CONCLUSIONS: HDR brachytherapy combined with SBRT was associated with a favorable early toxicity profile and encouraging cancer control outcomes.

Quantifying clinical severity of physics errors in high-dose rate prostate brachytherapy using simulations.

PURPOSE: To quantitatively evaluate through automated simulations the clinical significance of potential high-dose rate (HDR) prostate brachytherapy (HDRPB) physics errors selected from our internal failure-modes and effect analysis (FMEA). METHODS AND MATERIALS: A list of failure modes was compiled and scored independently by 8 brachytherapy physicists on a one-to-ten scale for severity (S), occurrence (O), and detectability (D), with risk priority number (RPN) = SxOxD. Variability of RPNs across observers (standard deviation/average) was calculated. Six idealized HDRPB plans were generated, and error simulations were performed: single (N = 1722) and systematic (N = 126) catheter shifts (craniocaudal; -1cm:1 cm); single catheter digitization errors (tip and connector needle-tips displaced independently in random directions; 0.1 cm:0.5 cm; N = 44,318); and swaps (two catheters swapped during digitization or connection; N = 528). The deviations due to each error in prostate D90%, urethra D20%, and rectum D1cm3 were analyzed using two thresholds: 5-20% (possible clinical impact) and >20% (potentially reportable events). RESULTS: Twenty-nine relevant failure modes were described. Overall, RPNs ranged from 6 to 108 (average ± 1 standard deviation, 46 ± 23), with responder variability ranging from 19% to 184% (average 75% ± 30%). Potentially reportable events were observed in the simulations for systematic shifts >0.4 cm for prostate and digitization errors >0.3 cm for the urethra and >0.4 cm for rectum. Possible clinical impact was observed for catheter swaps (all organs), systematic shifts >0.2 cm for prostate and >0.4 cm for rectum, and digitization errors >0.2 cm for prostate and >0.1 cm for urethra and rectum. CONCLUSIONS: A high variability in RPN scores was observed. Systematic simulations can provide insight in the severity scoring of multiple failure modes, supplementing typical FMEA approaches.

Urinary Outcomes for Men With High Baseline International Prostate Symptom Scores Treated With Prostate SBRT.

PURPOSE: There are limited data regarding high-dose stereotactic body radiation therapy (SBRT) for prostate cancer in patients with poor baseline urinary function. The purpose of this study was to evaluate genitourinary (GU) toxicity and changes in patient-reported symptom severity scores after prostate SBRT in men with a high pretreatment International Prostate Symptom Score (IPSS). METHODS AND MATERIALS: Seven hundred fifty-three patients treated with prostate SBRT at our institution from 2012 to 2019 were identified, of whom 72 consecutive patients with baseline IPSS ≥15 were selected for this study. GU toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and IPSS were prospectively documented at each follow-up visit. Univariable logistic regression was used to evaluate for potential predictors of GU toxicity. RESULTS: Median follow-up in survivors was 26.8 months. The rates of acute grade 2 and 3 GU toxicity were 20.8% and 1.4%, respectively. The rates of late grade 2 and 3 GU toxicity were 37.5% and 5.6%, respectively. The majority of grade 2+ toxicities resolved by last follow-up, and when toxicities were regraded per CTCAE v5.0, there were no longer any grade 3 adverse events. Total IPSS and individual symptom subscores improved over time. Compared with baseline, median total IPSS at 24 ± 6 months was significantly lower (18 vs 12; P < .001) and the proportion of patients with severe scores (IPSS ≥20) decreased from 29.2% to 13.9%. Pretreatment urinary urgency was associated with late grade 2+ GU toxicity (odds ratio, 2.10; 95% confidence interval, 1.33-3.31; P = .001). CONCLUSIONS: In men with baseline IPSS ≥15 managed with prostate SBRT, the rate of severe GU toxicity was low and patient-reported symptoms generally improved over time. Thus, high pretreatment IPSS should not deter clinicians from offering prostate SBRT.

Clinical implementation of deep learning contour autosegmentation for prostate radiotherapy.

BACKGROUND AND PURPOSE: Artificial intelligence advances have stimulated a new generation of autosegmentation, however clinical evaluations of these algorithms are lacking. This study assesses the clinical utility of deep learning-based autosegmentation for MR-based prostate radiotherapy planning. MATERIALS AND METHODS: Data was collected prospectively for patients undergoing prostate-only radiation at our institution from June to December 2019. Geometric indices (volumetric Dice-Sørensen Coefficient, VDSC; surface Dice-Sørensen Coefficient, SDSC; added path length, APL) compared automated to final contours. Physicians reported contouring time and rated autocontours on 3-point protocol deviation scales. Descriptive statistics and univariable analyses evaluated relationships between the aforementioned metrics. RESULTS: Among 173 patients, 85% received SBRT. The CTV was available for 167 (97%) with median VDSC, SDSC, and APL for CTV (prostate and SV) 0.89 (IQR 0.83-0.95), 0.91 (IQR 0.75-0.96), and 1801 mm (IQR 1140-2703), respectively. Physicians completed surveys for 43/55 patients (RR 78%). 33% of autocontours (14/43) required major "clinically significant" edits. Physicians spent a median of 28 min contouring (IQR 20-30), representing a 12-minute (30%) time savings compared to historic controls (median 40, IQR 25-68, n = 21, p < 0.01). Geometric indices correlated weakly with contouring time, and had no relationship with quality scores. CONCLUSION: Deep learning-based autosegmentation was implemented successfully and improved efficiency. Major "clinically significant" edits are uncommon and do not correlate with geometric indices. APL was supported as a clinically meaningful quantitative metric. Efforts are needed to educate and generate consensus among physicians, and develop mechanisms to flag cases for quality assurance.

Predictors for post-treatment biopsy outcomes after prostate stereotactic body radiotherapy.

PURPOSE: To investigate predictors associated with post-treatment biopsy outcomes after stereotactic body radiotherapy (SBRT) for localized prostate cancer. MATERIALS AND METHODS: 257 patients treated with prostate SBRT to dose levels of 32.5 Gy to >40 Gy in 5-6 fractions underwent a post-treatment biopsy performed approximately two years after treatment to evaluate local control status. 73 had% intermediate-risk disease (n = 187) and the remaining 17% (n = 43) and 10% (n = 27) had low-risk and high-risk disease, respectively. RESULTS: The incidence of positive, negative, and treatment-effect post-treatment biopsies were 15.6%, 57.6%, and 26.8%, respectively. The incidence of a positive biopsy according to dose was 37.5% (n = 9/24), 21.4% (n = 6/28), 19.4% (n = 6/31), and 10.9% (n = 19/174) for 32.5 Gy, 35 Gy, 37.5 Gy, and >40 Gy, respectively. In a multivariable model, patients treated with SBRT doses of <40 Gy and those with unfavorable-intermediate-risk or high-risk disease had higher likelihood of a positive post-treatment biopsy. A positive post-SBRT biopsy was associated with a significantly higher likelihood of subsequent PSA relapse at five years (Positive biopsy: 57%, 95% CI: 29-77% compared to negative biopsy: 7%, 95% CI: 3-14%; p < 0.001). CONCLUSION: Based on two-year post-SBRT biopsies, excellent tumor control was achieved when dose levels of 40 Gy or higher were used. Standard SBRT dose levels of 35-37.5 Gy were associated with a higher likelihood of a positive post-treatment biopsy. Two-year positive post-treatment biopsies pre-dated the development of PSA failure in the majority of patients.

Sildenafil Citrate and Risk of Biochemical Recurrence in Prostate Cancer Patients Treated with Radiation Therapy: Post-Hoc Analysis of a Randomized Controlled Trial.

BACKGROUND: Sildenafil citrate has been shown to be protective of sexual function when given concurrently and following prostate radiation therapy (RT), but some evidence suggests an increased biochemical recurrence (BCR) risk in patients taking sildenafil after radical prostatectomy. AIM: To evaluate whether sildenafil use is associated with increased risk of BCR in patients receiving prostate RT, we performed a secondary analysis of a randomized placebo-controlled trial (RPCT) that compared sildenafil citrate to placebo during and after prostate RT. METHODS: The study population consisted of prostate cancer patients who initiated radiation treatment at our institution and participated in our multi-institutional RPCT that compared 6 months of sildenafil 50 mg once a day to placebo with a 24-month follow-up. Androgen deprivation therapy (ADT) was allowed. Prostate cancer prognostic risk grouping was not an exclusion criterion, but most study participants had low- or intermediate-risk prostate cancer. Statistical analysis was performed using Kaplan-Meier plots and log-rank testing. OUTCOMES: The primary outcomes of this report were biochemical recurrence and overall survival rates, where BCR was defined according to the Phoenix definition. RESULTS: Data of 162 men were analyzed. Nine men had inadequate PSA follow-up and the remaining 153 men were included in the final report. Median age was 61 years. At a median follow-up of 8.3 years (range: 3.0-12.2), 5/94 (5.3%) and 2/59 (3.4%) patients developed BCR in the sildenafil and placebo groups, respectively. The 6-year BCR-free survival was 98.8% for all patients, 98.1% for the sildenafil cohort, and 100% for the placebo cohort. The 10-year BCR-free survival was 94.4% for all patients, 95.6% for the sildenafil cohort, and 92.9% for the placebo cohort. There was no difference in BCR-free survival between the sildenafil and placebo groups by log-rank comparison (p = 0.36). CLINICAL IMPLICATIONS: This analysis informs clinical decision making about the safety of using sildenafil during and after prostate RT. STRENGTHS AND LIMITATIONS: This study included patients who were treated in the setting of a prospective, randomized placebo-controlled trial, and who attained high medication compliance. However, the study was limited by the post-hoc nature of the analysis, use of ADT in some patients, inadequate study power to detect a difference in BCR between sildenafil and placebo groups. CONCLUSION: Prophylactic sildenafil citrate was not associated with biochemical recurrence risk in prostate cancer patients treated with radiation. However, the study was inadequately powered to definitively conclude a negative finding.

Optimal timing of radiotherapy in high risk prostate cancer: Do missed days matter?

INTRODUCTION: High-risk prostate cancer is associated with poorer overall survival (OS) and biochemical control compared to more favorable risk groups. External beam radiation therapy (EBRT) is widely used; however, outcomes data are limited with respect to time elapsed between diagnosis and initiation of EBRT. METHODS: The National Cancer Database was queried from 2004 to 2015 for patients diagnosed with high-risk adenocarcinoma of the prostate who received androgen deprivation therapy (ADT) and definitive EBRT. Logistic regression was utilized to determine covariates associated with missing EBRT treatments. OS was analyzed using multivariate cox proportional hazards models and propensity score matching. RESULTS: 9,610 patients met inclusion criteria with median follow-up of 40.6 months and median age of 72 years. Median PSA was 8.7 and median EBRT dose was 78 Gy. ADT was initiated at a median of 36 days and EBRT at a median of 63 days post-diagnosis. Median number of prolonged treatment days was 2.2. Black race (OR: 1.40; p < 0.01), treatment at a community clinic (OR: 1.32; p < 0.01), and living in an urban/densely populated area were associated with prolonged treatment. Time elapsed between ADT and EBRT > 74 days (HR: 1.20; p = 0.01) and prolonged treatment>3 days of EBRT (HR: 1.26; p = 0.005) were associated with an increased hazard of death. The 5-year OS was 79.6% and 82.9% for patients with prolonged treatment of 3 days or more of EBRT and those missing 3 days or less, respectively (p = 0.0006). CONCLUSION: In this hypothesis-generating study, prolonged treatment delays and missing three or more EBRT treatments was associated with poorer OS in patients with high-risk adenocarcinoma of the prostate.

Clinical Outcomes of Combined Prostate- and Metastasis-Directed Radiation Therapy for the Treatment of De Novo Oligometastatic Prostate Cancer.

PURPOSE: The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial reported overall survival benefits for prostate-directed radiation therapy (PDRT) in low-burden metastatic prostate cancer. Oligometastasis-directed radiation therapy (ORT) improves androgen deprivation therapy (ADT)-free and progression-free survivals. Comprehensive PDRT + ORT to all detectable metastases may offer benefit for de novo oligometastatic prostate cancer (DNOPC) and is under prospective study; given few available benchmarks, we reviewed our institutional experience. METHODS AND MATERIALS: Forty-seven patients with DNOPC with predominantly M1b disease received neoadjuvant, concurrent, and adjuvant ADT plus PDRT + ORT to 1 to 6 oligometastases. Gross pelvic (N1) nodes were not considered oligometastases unless focally targeted without broader nodal coverage. Outcomes were analyzed from radiation therapy (RT) start using Kaplan-Meier, competing risks, and Cox regression. Median follow-up was 27 (95% confidence interval, 16-42) months. RESULTS: At 1- and 2-years post-RT, cumulative incidence of distant metastatic progression (DMP) was 21% and 32%, whereas overall survival was 90% and 87%, respectively. Neuroendocrine/intraductal histology, prostate-specific antigen (PSA) < 20, and detectable PSA after PDRT + ORT were associated with increased DMP risk; number and location of oligometastases were not. Local failure was rare, with 3 prostate recurrences and progression of 10 treated oligometastases during follow-up. After neoadjuvant ADT, 9 (19%) patients had undetectable PSA (<0.05 ng/mL), which increased to 32 (68%) after PDRT + ORT. Overall 2-year incidence of biochemical recurrence (BCR) and development of castrate resistance were 23% and 36%, respectively. Undetectable PSA post-RT was associated with lower risk of BCR (hazard ratio, 0.19; P = .004) and DMP (hazard ratio, 0.26; P = .025). Overall, 23 (49%) patients were trialed off ADT; 16 (70%) had testosterone recovery (>150 ng/dL) and, of these, 5 had subsequent PSA rise and restarted ADT 2 to 21 months postrecovery. The remaining 11 were maintained off ADT without BCR. Median noncastrate duration was 8 months; 7 patients had normalized testosterone for >1 year. CONCLUSIONS: A comprehensive, radiotherapeutic-based treatment strategy has favorable clinical outcomes and can produce prolonged noncastrate remissions in a subset with DNOPC.

Strict bladder filling and rectal emptying during prostate SBRT: Does it make a dosimetric or clinical difference?

BACKGROUND: To evaluate inter-fractional variations in bladder and rectum during prostate stereotactic body radiation therapy (SBRT) and determine dosimetric and clinical consequences. METHODS: Eighty-five patients with 510 computed tomography (CT) images were analyzed. Median prescription dose was 40 Gy in 5 fractions. Patients were instructed to maintain a full bladder and empty rectum prior to simulation and each treatment. A single reviewer delineated organs at risk (OARs) on the simulation (Sim-CT) and Cone Beam CTs (CBCT) for analyses. RESULTS: Bladder and rectum volume reductions were observed throughout the course of SBRT, with largest mean reductions of 86.9 mL (19.0%) for bladder and 6.4 mL (8.7%) for rectum noted at fraction #5 compared to Sim-CT (P < 0.01). Higher initial Sim-CT bladder volumes were predictive for greater reduction in absolute bladder volume during treatment (ρ = - 0.69; P < 0.01). Over the course of SBRT, there was a small but significant increase in bladder mean dose (+ 4.5 ± 12.8%; P < 0.01) but no significant change in the D2cc (+ 0.8 ± 4.0%; P = 0.28). The mean bladder trigone displacement was in the anterior direction (+ 4.02 ± 6.59 mm) with a corresponding decrease in mean trigone dose (- 3.6 ± 9.6%; P < 0.01) and D2cc (- 6.2 ± 15.6%; P < 0.01). There was a small but significant increase in mean rectal dose (+ 7.0 ± 12.9%, P < 0.01) but a decrease in rectal D2cc (- 2.2 ± 10.1%; P = 0.04). No significant correlations were found between relative bladder volume changes, bladder trigone displacements, or rectum volume changes with rates of genitourinary or rectal toxicities. CONCLUSIONS: Despite smaller than expected bladder and rectal volumes at the time of treatment compared to the planning scans, dosimetric impact was minimal and not predictive of detrimental clinical outcomes. These results cast doubt on the need for excessively strict bladder filling and rectal emptying protocols in the context of image guided prostate SBRT and prospective studies are needed to determine its necessity.