Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Prognostic Significance of Immune Cell Infiltration in Muscle-invasive Bladder Cancer Treated with Definitive Chemoradiation: A Secondary Analysis of RTOG 0524 and RTOG 0712.

Chemoradiation therapy (CRT) is a treatment for muscle-invasive bladder cancer (MIBC). Using a novel transcriptomic profiling panel, we validated prognostic immune biomarkers to CRT using 70 pretreatment tumor samples from prospective trials of MIBC (NRG/RTOG 0524 and 0712). Disease-free survival (DFS) and overall survival (OS) were estimated via the Kaplan-Meier method and stratified by genes correlated with immune cell activation. Cox proportional-hazards models were used to assess group differences. Clustering of gene expression profiles revealed that the cluster with high immune cell content was associated with longer DFS (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.26-1.10; p = 0.071) and OS (HR 0.48, 95% CI 0.24-0.97; p = 0.040) than the cluster with low immune cell content. Higher expression of T-cell infiltration genes (CD8A and ICOS) was associated with longer DFS (HR 0.40, 95% CI 0.21-0.75; p = 0.005) and OS (HR 0.49, 95% CI 0.25-0.94; p = 0.033). Higher IDO1 expression (IFNγ signature) was also associated with longer DFS (HR 0.44, 95% CI 0.24-0.88; p = 0.021) and OS (HR 0.49, 95% CI 0.24-0.99; p = 0.048). These findings should be validated in prospective CRT trials that include biomarkers, particularly for trials incorporating immunotherapy for MIBC. PATIENT SUMMARY: We analyzed patient samples from two clinical trials (NRG/RTOG 0524 and 0712) of chemoradiation for muscle-invasive bladder cancer using a novel method to assess immune cells in the tumor microenvironment. Higher expression of genes associated with immune activation and high overall immune-cell content were associated with better disease-free survival and overall survival for patients treated with chemoradiation.

A Multi-Institutional Survey of Radiation Oncology Professionals' Knowledge, Attitudes, and Practice Behaviors Toward Sexual and Gender Minority Patients With Cancer.

Purpose: Sexual and gender minority (SGM) individuals have an increased risk of poor health outcomes, in part due to knowledge and training gaps in health care education. This study sought to evaluate the knowledge, attitudes, and practice behaviors of various health care role groups within radiation oncology toward SGM patients. Methods and Materials: A 38-item web-based survey was emailed to 1045 staff across 2 large radiation oncology departments. The survey assessed demographics, attitudes, knowledge, and practice behaviors. χ2 tests were performed to explore differences in survey responses by age, political affiliation, religious identity, year since graduation, and role groups. One-way analysis of variance tests were conducted to determine differences between respondents' confidence in knowledge and performance on the knowledge section of the survey. Thematic analysis was applied to the open discussion section. Results: Of the 223 respondents, 103 clinicians (physicians/advanced practice providers/nurses) and 120 nonclinicians (administrative staff, medical assistants, and other nonmedical staff) participated in the survey (21.3% response rate): 72.6% answered the knowledge questions; 93.5% stated they were comfortable treating sexual minorities, or lesbian, gay, bisexual, and queer + patients; 88% indicated comfort in treating transgender patients; 36.6% stated they were confident in their knowledge of the health needs of transgender patients; and 50.3% expressed confidence in treating lesbian, gay, bisexual, and queer + patients. Fewer nonclinicians than clinicians thought that gender identity, sexual orientation, and sex assigned at birth were important to provide the best care (P < .05). The open comments section identified key themes, including the belief that current educational tools are not helpful, desire for more educational formats (lectures, case-based learning, seminars), and an overall interest in SGM health education. Conclusions: Most staff feel comfortable in treating SGM patients but are less confident in the distinct needs of this population. Knowledge gaps persist for both clinicians and nonclinicians, indicating a need for further training specific to oncology care.

Recent Trends in "Manels" and Gender Representation Among Panelists at North American Annual Radiation Oncology Meetings.

PURPOSE: Achieving gender equity in radiation oncology is an important goal, as a smaller proportion of women enter radiation oncology residency compared with those graduating from medical school. As invited speaking opportunities at academic medical conferences are vital for promotion/tenure, we investigated the prevalence of all-men panels ("manels") at American Society for Radiation Oncology (ASTRO) and Canadian Society of Radiation Oncology (CARO) annual meetings. METHODS AND MATERIALS: Using ASTRO and CARO online meeting programs, 2018 to 2021 faculty information was obtained, including gender, panel role (chair vs nonchair), type of session, and topic. Primary outcomes included percentage of manels and proportion of female panelists over time. Representation of women among chairs was also evaluated. RESULTS: Over the 4-year study period across both conferences, a total of 765 panel sessions were held with 2973 faculty members, of whom 1287 (43.3%) were women. Of these sessions, 127 of 765 (16.6%) were manels. ASTRO meetings had 1169 of 2742 (42.6%) female faculty members and held 107 of 680 (15.7%) manels, whereas CARO meetings had 118 of 231 (51.1%) female faculty and held 20 of 85 manels (23.5%). From 2018 to 2021, the proportion of manels decreased at ASTRO and CARO meetings from 25.6% to 8.2% (P < .001) and from 29.6% to 15.0% (P = .130), respectively. The role of chair was majority male in every year from 2018 to 2021 at ASTRO meetings (58.6% overall), but more balanced at CARO meetings (48.0% overall). Among session types, the highest proportion of manels was observed for scientific sessions (19.1%, P = .011) at ASTRO meetings and leadership sessions (29.4%, P = .533) at CARO meetings. The lowest proportion of female panelists was on genitourinary cancer topics at ASTRO meetings (31.9%, P = .018) and physics topics at CARO meetings (40.4%, P = .085). CONCLUSIONS: During the study period, the proportion of female panelists increased with a corresponding decrease in manels. ASTRO and CARO should strive for further involvement of women and the elimination of manels whenever possible.

Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524-A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation.

BACKGROUND: Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil-based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered. OBJECTIVE: To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study. DESIGN, SETTING, AND PARTICIPANTS: Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival. RESULTS AND LIMITATIONS: Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2. CONCLUSIONS: In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy. PATIENT SUMMARY: Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate.

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis.

BACKGROUND: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy. METHODS: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW). FINDINGS: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11). INTERPRETATION: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option. FUNDING: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.

Gender-Affirming Surgery and Cancer: Considerations for Radiation Oncologists for Pelvic Radiation in Transfeminine Patients.

Access to gender-affirming surgery is increasing for many transgender and nonbinary people in the United States, and radiation oncologists must be equipped to care for patients who have undergone such surgery in the region of their planned radiation treatment field. There are no guidelines for radiation treatment planning after gender-affirming surgery, and most oncologists do not receive training in the unique needs of transgender people with cancer. We review common gender-affirming genitopelvic surgeries for transfeminine people, including vaginoplasty, labiaplasty, and orchiectomy, and summarize the existing literature on the treatment of cancers of the neovagina, anus, rectum, prostate, and bladder in these patients. We also describe our systematic treatment approach and rationale for pelvic radiation treatment planning.

Impact of a negative confirmatory biopsy on risk of disease progression among men on active surveillance for prostate cancer.

OBJECTIVE: Most prostate cancer active surveillance (AS) protocols suggest a confirmatory biopsy within 12 to 18 months of diagnosis to mitigate the risk of unsampled high-grade disease. We investigate whether the results of confirmatory biopsy impact AS outcomes and could be used to tailor surveillance intensity. METHODS: We retrospectively reviewed our institutional database of prostate cancer patients managed by AS from 1997 to 2019 who underwent confirmatory biopsy and ≥3 biopsies overall. Biopsy progression was defined as either an increase in grade group or an increase in the proportion of positive biopsy cores to >34% and was compared between patients with a negative vs positive confirmatory biopsy using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: We identified 452 patients meeting inclusion criteria for this analysis, of whom 169 (37%) had a negative confirmatory biopsy. With a median follow-up of 6.8 years, 37% of patients progressed to treatment, most commonly due to biopsy progression. A negative confirmatory biopsy was significantly associated with biopsy progression-free survival in multivariable analysis (HR 0.54, 95% CI 0.34-0.88, P = 0.013), adjusting for known clinical and pathologic factors, including use of mpMRI prior to confirmatory biopsy. Negative confirmatory biopsy was also associated with an increased risk of adverse pathologic features at prostatectomy but not with biochemical recurrence among men who ultimately underwent definitive treatment. CONCLUSIONS: A negative confirmatory biopsy is associated with a lower risk of biopsy progression. While the increased risk of adverse pathology at time of definitive treatment sounds a small cautionary note regarding decreasing surveillance intensity, the majority of such patients have a favorable outcome on AS.

A pair of deep learning auto-contouring models for prostate cancer patients injected with a radio-transparent versus radiopaque hydrogel spacer.

BACKGROUND: Absorbable hydrogel spacer injected between prostate and rectum is gaining popularity for rectal sparing. The spacer alters patient anatomy and thus requires new auto-contouring models. PURPOSE: To report the development and comprehensive evaluation of two deep-learning models for patients injected with a radio-transparent (model I) versus radiopaque (model II) spacer. METHODS AND MATERIALS: Model I was trained and cross-validated by 135 cases with transparent spacer and tested on 24 cases. Using refined training methods, model II was trained and cross-validated by the same dataset, but with the Hounsfield Unit distribution in the spacer overridden by that obtained from ten cases with opaque spacer. Model II was tested on 64 cases. The models auto-contour eight regions of interest (ROIs): spacer, prostate, proximal seminal vesicles (SVs), left and right femurs, bladder, rectum, and penile bulb. Qualitatively, each auto contour (AC), as well as the composite set, was assessed against manual contour (MC), by a radiation oncologist using a 1 (accepted directly or after minor editing), 2 (accepted after moderate editing), 3 (accepted after major editing), and 4 (rejected) scoring scale. The efficiency gain was characterized by the mean score as nearly complete [1-1.75], substantial (1.75-2.5], meaningful (2.5-3.25], and no (3.25-4.00]. Quantitatively, the geometric similarity between AC and MC was evaluated by dice similarity coefficient (DSC) and mean distance to agreement (MDA), using tolerance recommended by AAPM TG-132 Report. The results by the two models were compared to examine the outcome of the refined training methods. The large number of testing cases for model II allowed further investigation of inter-observer variability in clinical dataset. The correlation between score and DSC/MDA was studied on the ROIs with 10 or more counts of each acceptable score (1, 2, 3). RESULTS: For model I/model II: the mean score was 3.63/1.30 for transparent/opaque spacer, 2.71/2.16 for prostate, 3.25/2.44 for proximal SVs, 1.13/1.02 for both femurs, 2.25/1.25 for bladder, 3.00/2.06 for rectum, 3.38/2.42 for penile bulb, and 2.79/2.20 for the composite set; the mean DSC was 0.52/0.84 for spacer, 0.84/0.85 for prostate, 0.60/0.62 for proximal SVs, 0.94/0.96 for left femur, 0.95/0.96 for right femur, 0.91/0.95 for bladder, 0.81/0.84 for rectum, and 0.65/0.65 for penile bulb; and the mean MDA was 2.9/0.9 mm for spacer, 1.9/1.7 mm for prostate, 2.4/2.3 mm for proximal SVs, 0.8/0.5 mm for left femur, 0.7/0.5 mm for right femur, 1.5/0.9 mm for bladder, 2.3/1.9 mm for rectum, and 2.2/2.2 mm for penile bulb. Model II showed significantly improved scores for all ROIs, and metrics for spacer, femurs, bladder, and rectum. Significant inter-observer variability was only found for prostate. Highly linear correlation between the score and DSC was found for the two qualified ROIs (prostate and rectum). CONCLUSIONS: The overall efficiency gain was meaningful for model I and substantial for model II. The ROIs meeting the clinical deployment criteria (mean score below 3.25, DSC above 0.8, and MDA below 2.5 mm) included prostate, both femurs, bladder and rectum for both models, and spacer for model II.

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

PURPOSE: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. MATERIALS AND METHODS: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. RESULTS: Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. CONCLUSIONS: An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.

Analysis of MRE11 and Mortality Among Adults With Muscle-Invasive Bladder Cancer Managed With Trimodality Therapy.

Importance: Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches. Objective: To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis. Design, Setting, and Participants: This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020. Exposures: Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy. Main Outcomes and Measures: MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio. Results: Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44). Conclusions and Relevance: Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.

Mucinous adenocarcinoma of the prostatic urethra after brachytherapy for prostatic adenocarcinoma: a case series.

Mucinous adenocarcinoma of the urethra is extremely rare, even more so in a setting of postradiation therapy, with only 3 cases reported up to date including the first case published by our group in 2011. In the present study, we included the long-term follow-up on our previously reported case and report 3 additional cases. This is the first case series to date of this rare disease entity. The aim of this study is to review the clinicopathologic features of mucinous adenocarcinoma of the prostatic urethra in patients after receiving brachytherapy for prostatic adenocarcinoma. We identified 4 patients with a mean age of 72 years, and a mean interval of 14.8 years from brachytherapy for prostate carcinoma (grade group 1). Patients presented with hematuria or urinary retention. A colonoscopy was performed in three-fourth of patients and was within normal limits. Three patients underwent cystoprostatectomy and 1 had a transurethral resection of the prostate. On gross examination, only tumor formed a 3.5 cm tan-gray, ulcerated, friable, and necrotic mass and 2 displayed either irregular red granular or thickened areas within the prostatic urethra. Abundant extracellular mucin pools dissecting the prostatic stroma were present in all tumors, with clusters of tumor cells floating in the mucin. The mucin pools were lined by pleomorphic pseudostratified columnar mucinous epithelium. Tumors were diffusely positive for CK20, CDX2 (4/4), and AMACR (2/2); they focally expressed CK7 (2/4), and lacked nuclear ß-catenin expression (3/3). PSA, PSAP, NKX3.1, p63, and GATA3 were negative in the tumors tested. Among the 3 patients who underwent radical surgery, 2 had stage 2 tumors (confined to the prostatic urethra and prostate), and 1 had a stage 3 tumor, with seminal vesicle involvement. All 4 patients were alive without disease with a mean follow-up of 4.9 years. In conclusion, brachytherapy-associated mucinous adenocarcinoma of the prostatic urethra displays intestinal-type features as its non-radiation-related counterpart. It appears to lack a villous adenoma component, displays a different immunohistochemical profile with diffuse CK20 and CDX2 positivity, and is associated with lower stage and less aggressive behavior.

Biochemical Failure Is Not a Surrogate End Point for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601.

PURPOSE: Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer. MATERIALS AND METHODS: NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; [BF1]) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; [BF2]), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average R2 between treatment hazard ratios for ICE and OS). RESULTS: BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated (R2 = 0.67), but this was not true for BF1 (R2 = 0.09), BF2 (R2 = 0.12), or DM (R2 = 0.18) and OS. CONCLUSION: MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.

Adding Short-Term Androgen Deprivation Therapy to Radiation Therapy in Men With Localized Prostate Cancer: Long-Term Update of the NRG/RTOG 9408 Randomized Clinical Trial.

PURPOSE: For men with localized prostate cancer, NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 demonstrated that adding short-term androgen deprivation therapy (ADT) to radiation therapy (RT) improved the primary endpoint of overall survival (OS) and improved disease-specific mortality (DSM), biochemical failure (BF), local progression, and freedom from distant metastases (DM). This study was performed to determine whether the short-term ADT continued to improve OS, DSM, BF, and freedom from DM with longer follow-up. METHODS AND MATERIALS: From 1994 to 2001, NRG/RTOG 9408 randomized 2028 men from 212 North American institutions with T1b-T2b, N0 prostate adenocarcinoma and prostate-specific antigen (PSA) ≤20ng/mL to RT alone or RT plus short-term ADT. Patients were stratified by PSA, tumor grade, and surgical versus clinical nodal staging. ADT was flutamide with either goserelin or leuprolide for 4 months. Prostate RT (66.6 Gy) was started after 2 months. OS was calculated at the date of death from any cause or at last follow-up. Secondary endpoints were DSM, BF, local progression, and DM. Acute and late toxic effects were assessed using RTOG toxicity scales. RESULTS: Median follow-up in surviving patients was 14.8 years (range, 0.16-21.98). The 10-year and 18-year OS was 56% and 23%, respectively, with RT alone versus 63% and 23% with combined therapy (HR 0.94; 95% confidence interval [CI], 0.85-1.05; P = .94). The hazards were not proportional (P = .003). Estimated restricted mean survival time at 18 years was 11.8 years (95% CI, 11.4-12.1) with combined therapy versus 11.3 years with RT alone (95% CI, 10.9-11.6; P = .05). The 10-year and 18-year DSM was 7% and 14%, respectively, with RT alone versus 3% and 8% with combined therapy (HR 0.56; 95% CI, 0.41-0.75; P < .01). DM and BF favored combined therapy at 18 years. Rates of late grade ≥3 hepatic, gastrointestinal, and genitourinary toxicity were ≤1%, 3%, and 8%, respectively, with combined therapy versus ≤1%, 2%, and 5% with RT alone. CONCLUSIONS: Further follow-up demonstrates that OS converges at approximately 15 years, by which point the administration of 4 months of ADT had conferred an estimated additional 6 months of life.

Radiation treatment in prostate cancer: covering the waterfront.

OBJECTIVES: To present an overview of radiation therapy (RT) for prostate cancer over the past decade. METHODS: The literature on prostate cancer radiation therapy was reviewed and summarised. Radiation therapy (RT) for prostate cancer has dramatically evolved in the past decade, with superior techniques and exciting advances, pushing the role of the radiation oncologist to new frontiers. RESULTS: Innovations in imaging, treatment delivery, and a deeper understanding of biology has resulted in more tailored RT for individuals. In the present review, we summarise the changing landscape and broadly discuss new developments in prostate RT. CONCLUSIONS: Questions and challenges remain in the field, however there are multiple opportunities to further improve upon RT for our patients with prostate cancer.

Technical Giants But Biologic Infants: Defining a More Sophisticated Role for Local Therapy in Metastatic Disease.

The role of radiation therapy in metastatic cancer is rapidly evolving with increased understanding of the oligometastatic state and improved technologies to deliver higher doses of radiation with greater precision and avoidance of normal tissues than before. Recent data have demonstrated that the use of stereotactic ablative radiotherapy (SABR) in oligometastatic disease confers a survival benefit. Yet, the current enthusiasm must be balanced with caution. Here we summarize the evidence in favor of SABR for oligometastatic patients as well as the concerns regarding rapid adoption into clinical practice and outline broad principles to guide clinical trials evaluating the role of SABR in oligometastatic disease. As oncologists, we must exercise due diligence and gather the appropriate evidence necessary to 1) understand the oligometastatic disease state and 2) optimize benefit in those patients before broadly offering SABR to all. Any alternative path forward will do our field and our patients a great injustice.

Can Sex and Seniority Predict the Quality of a Journal Reviewer's Manuscript Critique?

PURPOSE: To evaluate reviewers' timeliness and review quality for the International Journal of Radiation Oncology, Biology, Physics (IJROBP) by sex and seniority. METHODS AND MATERIALS: The IJROBP editorial office provided data on 3962 individuals invited to review manuscripts from 2011 through 2014. We identified 1657 reviewers who had been invited to provide a review on at least 3 occasions during the study period and compared review timeliness and scoring between male and female reviewers. We confirmed the reviewers' sex after having unblinded their names based on our personal acquaintance with them and via an Internet search on their department websites. We then did a subset analysis of 124 US-based reviewers who had returned a "major revision" decision. We used the Review Quality Instrument (RQI) to rate their reviews. We used odds ratios and t tests to look for differences in mean RQI scores and factors that might be associated with quality-in particular, Hirsch indices (h indices) and year of first certification. RESULTS: Of the 1657 reviewers of interest, 1245 (75.1%) were men and 412 (24.9%) were women. We found no statistically significant differences between men and women in the time to respond to invitations. There were no statistically significant differences in timeliness or review reminders based on sex. Our subset analysis showed no difference in quality (RQI scores) based on the reviewers' sex, h index, or year of first certification. CONCLUSIONS: Women and men render reviews of equal quality regardless of seniority and h index, yet women have been invited less frequently to review. This is likely because of the underrepresentation of women in radiation oncology. A more balanced academic population is needed to address this continuing disparity of women's representation in academic publishing.