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There is an underutilization of potentially curative treatments for patients with muscle-invasive bladder cancer. Contemporary trimodality bladder-preservation therapy - which includes a maximally safe transurethral resection of the bladder tumor followed by concurrent chemoradiation and close cystoscopic surveillance with salvage cystectomy reserved for invasive tumor recurrence - can help fulfill this unmet need. Over the past few decades, cumulative published data from prospective clinical trials and large institutional series have established trimodality therapy (TMT) for select patients as a safe and effective alternative to upfront cystectomy. Indeed, TMT is now supported as an accepted option for muscle-invasive bladder cancer patients by numerous clinical guidelines. Following TMT, the vast majority of long-term survivors maintain their native bladders, which tend to function well with relatively low rates of long-term toxicity and good long-term quality of life. There is the potential to further improve outcomes by optimizing systemic therapy integration and by validating predictive biomarkers for improved patient and treatment selection. TMT offers a unique opportunity for urologic surgeons, radiation oncologists and medical oncologists to work hand-in-hand in a multidisciplinary effort to deliver such therapy optimally, to support its research, to promote informed decision-making and ultimately to preserve the autonomy of patients with bladder cancer. The third annual meeting of the Johns Hopkins Greenberg Bladder Cancer Institute/American Urological Association Translational Research Collaboration allowed bladder cancer experts to meet and advance this mission. [ABSTRACT FROM AUTHOR]

Men diagnosed with localized prostate cancer have many curative treatment options including several different radiotherapeutic approaches. Proton radiation is one such radiation treatment modality and, due to its unique physical properties, offers the appealing potential of reduced side effects without sacrificing cancer control. In this review, we examine the intriguing dosimetric rationale and theoretical benefit of proton radiation for prostate cancer and highlight the results of preclinical modeling studies. We then discuss the current state of the clinical evidence for proton efficacy and toxicity, derived from both large claim-based datasets and prospective patient-reported data. The result is that the data are mixed, and clinical equipoise persists in this area. We place these studies into context by summarizing the economics of proton therapy and the changing practice patterns of prostate proton irradiation. Finally, we await the results of a large prospective randomized clinical trial currently accruing and also a large prospective pragmatic comparative study which will provide more rigorous evidence regarding the clinical and comparative effectiveness of proton therapy for prostate cancer. [ABSTRACT FROM AUTHOR]

Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. We used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5 yr, and median follow-up time for patients without an event was 5.0 yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. Molecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. Gene expression profiling of TMT cases identified luminal (N = 40), luminal-infiltrated (N = 26), basal (N = 54), and claudin-low (N = 16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14–0.65], p = 0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p = 0.006), but not in the TMT cohort. This study is limited by its retrospective nature. Higher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. We used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer. Gene expression profiling of muscle-invasive bladder cancer reveals that immune infiltration is associated with improved disease-specific survival after bladder-sparing trimodality therapy, but not after radical cystectomy. Conversely, stromal infiltration is associated with worse outcomes after cystectomy, but not after trimodality therapy. [ABSTRACT FROM AUTHOR]

Purpose: Trimodality therapy with maximal transurethral resection of bladder tumor and definitive chemoradiation reserving cystectomy for salvage of local recurrence is an accepted treatment alternative to upfront cystectomy for selected patients with muscle-invasive bladder cancer. There is a need for molecular biomarkers to predict which patients will respond to bladder preservation therapy.Methods and Materials: We sought to identify biomarkers with the ability to predict response to chemoradiation and survival after selective bladder preservation therapy in a cohort of 40 patients using a microRNA profiling approach. In vitro experiments were performed using transitional cell carcinoma lines CRL1749, HTB5, and HTB4.Results: We identified a panel of microRNAs associated with overall survival in our bladder preservation cohort and in the TCGA cohort. We also identified several microRNAs, including miR-23a and miR-27a, microRNAs of the miR-23a cluster, to be suggestively associated with complete response to chemoradiation therapy. The microRNAs were significantly associated with overall survival in The Cancer Genome Atlas cohort. In vitro studies suggest that the functional roles of miR-23a and miR-27a involve targeting the SFRP1 protein, a negative regulator of the Wnt signaling pathway. The upregulation of β-catenin in the Wnt signaling pathway mediated proliferation, migration, invasion, and sensitivity to radiation and cisplatin treatment in bladder cancer cells.Conclusions: Our results indicate that miR-23a and miR-27a act as oncomirs, and once independently validated, they may help appropriately triage selected bladder cancer patients to individualize treatment. [ABSTRACT FROM AUTHOR]

The authors conducted a prospective longitudinal study from 2009 to 2016 to assess the short and long-term impact of a formal mentorship program on junior faculty satisfaction and productivity. Junior faculty mentees enrolled in the program and junior faculty without formal mentorship were administered surveys before and after the program to assess satisfaction with their mentoring experiences. Long-term retention, promotion, and funding data were also collected. Twenty-three junior faculty mentees and 91 junior faculty controls were included in the study. Mentees came from the Departments of Radiation Oncology and Anesthesia, Critical Care, and Pain Management. After participating in the mentorship program, mentees demonstrated an increase in satisfaction from baseline in five of seven domains related to mentoring, while controls experienced no significant change in satisfaction in six of the seven domains. At long-term follow up, mentees were more likely than controls to hold senior faculty positions (percent senior faculty: 47% vs. 13%, p = 0.030) despite no difference in initial administrative rank. When comparing the subset of faculty who were Instructors at baseline, mentees were more likely to be funded and/or promoted than controls (p = 0.030). A majority of mentees reported that the program strengthened their long-term success, and many maintained their original mentoring relationships and formed new ones, highlighting the strong culture of mentorship that was instilled. Several short-term and long-term benefits were fostered from this formal mentorship program. These findings highlight the potential impact of mentorship programs in propagating a culture of mentorship and excellence. [ABSTRACT FROM AUTHOR]

Prostate cancer treatment with definitive radiation therapy (RT) has evolved dramatically in the past 2 decades. From the initial 2-dimensional planning using X-rays, advances in technology led to 3-dimensional conformal RT, which used computerized tomography-based planning. This has allowed delivery of higher doses of radiation to the prostate while reducing dose to the surrounding organs, resulting in improved cancer control. Today, intensity-modulated RT (IMRT) is considered standard, where radiation beams of different shapes and intensities can be delivered from a wide range of angles, thus further decreasing doses to normal organs and likely reducing treatment-related toxicity. In addition, image guidance ascertains the location of the prostate before daily treatment delivery. Brachytherapy is the placement of radioactive seeds directly in the prostate, and has a long track record as a monotherapy for low-risk prostate cancer patients with excellent long-term cancer control and quality of life outcomes. Recent studies including several randomized trials support the use of brachytherapy in combination with external beam RT for higher-risk patients. RT for prostate cancer continues to evolve. Proton therapy has a theoretical advantage over photons as it deposits most of the dose at a prescribed depth with a rapid dose fall-off thereafter; therefore it reduces some doses delivered to the bladder and rectum. Prospective studies have shown the safety and efficacy of proton therapy for prostate cancer, but whether it leads to improved patient outcomes compared to IMRT is unknown. Hypofractionated RT delivers a larger dose of daily radiation compared to conventional IMRT, and thus reduces the overall treatment time and possibly cost. An extreme form of hypofractionation is stereotactic body radiation therapy where highly precise radiation is used and treatment is completed in a total of 4 to 5 sessions. These techniques take advantage of the biological characteristic of prostate cancer, which is more sensitive to larger radiation doses per fraction, and therefore could be more effective than conventional IMRT. Multiple randomized trials have demonstrated noninferiority of moderately hypofractionated RT compared to conventional fractionation. There is also a growing body of data demonstrating the safety and efficacy of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: The study aimed to investigate oncological outcomes of patients with concomitant bladder cancer (BC) and urethral carcinoma. Methods: This is a multicenter series of 110 patients (74 men, 36 women) diagnosed with urethral carcinoma at 10 referral centers between 1993 and 2012. Kaplan- Meier analysis was used to investigate the impact of BC on survival, and Cox regression multivariable analysis was performed to identify predictors of recurrence. Results: Syn-chronous BC was diagnosed in 13 (12%) patients, and the median follow-up was 21 months (interquartile range 4-48). Urethral cancers were of higher grade in patients with synchronous BC compared to patients with non-synchronous BC (p = 0.020). Patients with synchronous BC exhibited significantly inferior 3-year recurrence-free survival (RFS) compared to patients with non-synchronous BC (63.2 vs. 34.4%; p = 0.026). In multivariable analysis, inferior RFS was associated with clinically advanced nodal stage (p < 0.001), proximal tumor location (p < 0.001) and synchronous BC (p = 0.020). Conclusion: The synchronous presence of BC in patients diagnosed with urethral carcinoma has a significant adverse impact on RFS and should be an impetus for a multimodal approach. [ABSTRACT FROM AUTHOR]

Intravenous anti–PD-L1 durvalumab therapy can safely be combined with intravesical bacillus Calmette-Guerin (BCG) treatments or a short-course of bladder-focused external beam radiation therapy (6 Gy × 3) in BCG-unresponsive non–muscle-invasive bladder cancer patients. Encouraging preliminary efficacy requires validation. Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients. To evaluate the safety and preliminary efficacy of anti–PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). A multicenter phase 1 trial was conducted at community and academic sites. Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). Post-treatment cystoscopy and urine cytology were performed at 3 and 6 –mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. Durvalumab combination therapy can be safely administered to non–muscle-invasive bladder cancer patients with the goal of increasing durable response rates. [ABSTRACT FROM AUTHOR]

Botswana has experienced a dramatic increase in HIV-related malignancies over the past decade. The BOTSOGO collaboration sought to establish a sustainable partnership with the Botswana oncology community to improve cancer care. This collaboration is anchored by regular tumor boards and on-site visits that have resulted in the introduction of new approaches to treatment and perceived improvements in care, providing a model for partnership between academic oncology centers and high-burden countries with limited resources. [ABSTRACT FROM AUTHOR]

Botswana has experienced a dramatic increase in HIV-related malignancies over the past decade. The BOTSOGO collaboration sought to establish a sustainable partnership with the Botswana oncology community to improve cancer care. This collaboration is anchored by regular tumor boards and on-site visits that have resulted in the introduction of new approaches to treatment and perceived improvements in care, providing a model for partnership between academic oncology centers and high-burden countries with limited resources. [Copyright &y& Elsevier]

The National Radiation Oncology Registry (NROR), sponsored by the Radiation Oncology Institute and the American Society for Radiation Oncology, is designed to collect standardizedinformation on cancer care delivery among patients treated with radiotherapy in the United States and will focus on patients with prostate cancer. Stakeholders were engaged through a forum that emphasized the need for patientcenteredoutcomes, minimal data burden, and maximal connectivity to existing registries and databases. An electronicinfrastructure is under development to provide connectivity across radiation oncology and hospital information systems. The NROR Gateway features automatic abstraction as well as aggregation of treatment and outcome data. The prostate cancer data dictionary provides standardized elements in four domains: facility, physician, patient, and treatment.The pilot phase will consist of clinical centers chosen to provide a representative mix of radiation treatment modalities,facility types, population-based settings, and regional locations. The initial set of radiation practice metrics includes physician board certification and maintenance,ordering of staging scans, active surveillance discussion,dose prescriptions for low-risk/high-risk disease, radiation fields for low-risk/high-risk disease, image-guided radiation therapy use, androgen deprivation therapy use, postbrachytherapyimplant computed tomography dosimetry,collection of toxicity assessments, and longitudinal patient follow-up. The NROR pilot study will provide the framework for expansion to a nationwide electronic registry for radiation oncology. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To analyze the location of metastatic lymph nodes in seminoma patients relative to vascular and bony anatomy and conventional radiation fields. Materials and methods: Cross-sectional scans of 90 seminoma patients with infradiaphragmatic adenopathy were analyzed. The position of each node respective to vascular anatomy was transferred to a standardized template. Conventional radiation fields were overlaid on the template and locations of metastatic nodes were assessed. Results: One hundred and forty-five nodes were radiographically positive. Eighty-four percent, 9%, and 7% of nodes were located in the para-aortic, common iliac, and pelvic regions, respectively. Ninety-nine percent of nodes were within a 2.5cm lateral and 2.1cm anterior expansion of the aorta inferior to T12/L1. No radiographically positive nodes were identified within the renal hilum or superior to L1 in left-sided seminomas. For right-sided seminomas, no radiographically positive nodes were superior to L2. Three percent of all radiographically positive nodes would have been located outside of conventional and modified fields. Conclusions: Infradiaphragmatic nodal metastases from a contemporary cohort of seminoma patients localized to a smaller area than is targeted by conventional radiation fields. Modified treatment fields based on vascular, rather than bony, anatomy are smaller and may allow for a significant decrease in normal tissue irradiation and toxicity. [Copyright &y& Elsevier]

Abstract: Context: New guidelines of the International Consultation on Urological Diseases for the treatment of muscle-invasive bladder cancer (MIBC) have recently been published. Objective: To provide a comprehensive overview of the current role of radical cystectomy (RC) in MIBC. Evidence acquisition: A detailed Medline analysis was performed for original articles addressing the role of RC with regard to indication, timing, surgical extent, perioperative morbidity, oncologic outcome, and follow-up. The analysis also included radiation-based bladder-preserving strategies. Evidence synthesis: The major findings are presented in an evidence-based fashion and are based on large retrospective unicenter and multicenter series with some prospective data. Conclusions: Open RC is the standard treatment for locoregional control of MIBC. Delay of RC is associated with reduced cancer-specific survival. In males, standard RC includes the removal of the bladder, prostate, seminal vesicles, and distal ureters; in females, RC includes an anterior pelvic exenteration including the bladder, entire urethra and adjacent vagina, uterus, and distal ureters. A procedure sparing the urethra and the urethra-supplying autonomous nerves can be performed in case of a planned orthotopic neobladder. Further technical variations (ie, seminal-sparing or vaginal-sparing techniques) aimed at improving functional outcomes must be weighed against the risk of a positive margin. Laparoscopic surgery is promising, but long-term data are required prior to accepting it as an option equivalent to the open procedure. Lymphadenectomy should remove all lymphatic tissue around the common iliac, external iliac, internal iliac, and obturator region bilaterally. Complications after RC should be reported according to the modified Clavien grading system. In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC. [Copyright &y& Elsevier]

Abstract: Purpose: Given concerns of excess malignancies following adjuvant radiation for seminoma, we evaluated photon and proton beam therapy (PBT) treatment plans to assess dose distributions to organs at risk and model rates of second cancers. Materials and methods: Ten stage I seminoma patients who were treated with conventional para-aortic AP–PA photon radiation to 25.5Gy at Massachusetts General Hospital had PBT plans generated (AP–PA, PA alone). Dose differences to critical organs were examined. Risks of second primary malignancies were calculated. Results: PBT plans were superior to photons in limiting dose to organs at risk. PBT decreased dose by 46% (8.2Gy) and 64% (10.2Gy) to the stomach and large bowel, respectively (p <0.01). Notably, PBT was found to avert 300 excess second cancers among 10,000 men treated at a median age of 39 and surviving to 75 (p <0.01). Conclusions: In this study, the use of protons provided a favorable dose distribution with an ability to limit unnecessary exposure to critical normal structures in the treatment of early-stage seminoma. It is expected that this will translate into decreased acute toxicity and reduced risk of second cancers, for which prospective studies are warranted. [Copyright &y& Elsevier]

Abstract: Background: Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) is largely unknown. Objective: Report long-term outcomes of patients with muscle-invasive BCa treated by CMT. Design, setting, and participants: We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2–4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr. Interventions: Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC—60 for less than CR and 42 for recurrent invasive tumors. Measurements: Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method. Results and limitations: Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2=74%, 67%, and 63%; T3–4=53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3–4=41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p <0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity. Conclusions: CMT achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients. [Copyright &y& Elsevier]

Purpose: To quantify interfractional anatomical variations and their dosimetric impact during the course of fractionated proton therapy (PT) of prostate cancer and to assess the robustness of the current treatment planning techniques. Methods: Simulation and daily in-room CT scans from ten prostate carcinoma patients were analyzed. PT treatment plans (78 Gy in 39 fractions of 2 Gy) were created on the simulation CT, delivering 25 fractions to PTV1 (expanded from prostate and seminal vesicles), followed by 14 boost fractions to PTV2 (expanded from prostate). Plans were subsequently applied to daily CT, with beams aligned to the prostate center in the sagittal plane. For five patients having a sufficiently large daily imaging volume, structure contours were manually drawn, and plans were evaluated for all CT sets. For the other five patients, the plans were evaluated for six selected fractions. The daily CT was matched to the simulation CT through deformable registration. The registration accuracy was validated for each fraction, and the three patients with a large number of accurately registered fractions were used for dose accumulation. Results: In individual fractions, the coverage of the prostate, seminal vesicles, and PTV1 was generally maintained at the corresponding prescription dose. For PTV2, the volume covered by the fractional prescription dose of 2 Gy (i.e., V2) was, on average, reduced by less than 3% compared to the simulation plan. Among the 225 (39 × 5 + 6 × 5) fractions examined, 15 showed a V2 reduction larger than 5%, of which ten were caused by a large variation in rectal gas, and five were due to a prostate shift in the craniocaudal direction. The fractional dose to the anterior rectal wall was found to increase for one patient who had large rectal gas volume in 25 of the 39 fractions, and another who experienced significant prostate volume reduction during the treatment. The fractional bladder dose generally increased with decreasing fullness. In the total accumulated dose for the three patients after excluding a few fractions with inaccurate registration due to a large amount of rectal gas (a condition inconsistent with RTOG protocol), 98.5%, 96.6%, and 98.2% of the PTV2 received the prescription dose of 78 Gy. The V75 and V70 of the anterior rectal wall and bladder both remained within tolerance. Conclusions: The results confirm that the PT planning techniques and dose constraints used at our institution ensure that target coverage to the prescription dose is maintained in the presence of interfractional anatomical variations. Dose coverage in individual fractions can be compromised, and normal tissue dose increased, due to deviations in the bladder and rectal volume compared to the simulation plans or progressive changes in the prostate volume during the treatment. Deviations from the plan can be reduced with efforts aimed at maintaining consistent daily patient anatomy. [ABSTRACT FROM AUTHOR]

Study Type – Prognosis (risk model) Level of Evidence 2a OBJECTIVE To design a decision-support tool to facilitate evidence-based treatment decisions in clinically localized prostate cancer, as individualized risk assessment and shared decision-making can decrease distress and decisional regret in patients with prostate cancer, but current individual models vary or only predict one outcome of interest. METHODS We searched Medline for previous reports and identified peer-reviewed articles providing pretreatment predictive models that estimated pathological stage and treatment outcomes in men with biopsy-confirmed, clinical T1-3 prostate cancer. Each model was entered into a spreadsheet to provide calculated estimates of extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymph node involvement (LNI). Estimates of the prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) or radiotherapy (RT), and clinical outcomes after RT, were also entered. The data are available at . RESULTS Entering a patient’s 2002 clinical T stage, Gleason score and pretreatment PSA level, and details from core biopsy findings, into the CaP Calculator provides estimates from predictive models of pathological extent of disease, four models for ECE, four for SVI and eight for LNI. The 5-year estimates of PSA relapse-free survival after RT and 10-year estimates after RP were available. A printout can be generated with individualized results for clinicians to review with each patient. CONCLUSIONS The CaP Calculator is a free, online ‘clearing house’ of several predictive models for prostate cancer, available in an accessible, user-friendly format. With further development and testing with patients, the CaP Calculator might be a useful decision-support tool to help doctors promote evidence-based shared decision-making in prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Gonadotropin-releasing hormone agonists (GnRHa) are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about their potential effects on cardiovascular mortality. We assessed the relationship between duration of GnRHa therapy and cardiovascular mortality in a large randomized trial of men treated with short-term versus longer-term adjuvant goserelin and radiation therapy (RT) for locally advanced prostate cancer. Methods: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c–4, prostate-specific antigen [PSA] <150ng/ml) received RT and 4 mo of goserelin and then were randomized to no additional therapy (arm 1) or 24 mo adjuvant goserelin (arm 2) in a phase 3 trial (Radiation Therapy Oncology Group [RTOG] 92-02). Cox regression analyses were performed to evaluate the relationship between treatment arm and cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes (DM), race, PSA, Gleason score, and stage. Results: After median follow-up of 8.1 yr, 185 cardiovascular-related deaths had occurred. No increase in cardiovascular mortality occurred for men receiving a longer duration of goserelin. At 5 yr, cardiovascular mortality for men receiving longer-term adjuvant goserelin was 5.9% versus 4.8% with short-term goserelin (Gray''s p =0.16). In multivariate analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR]=1.09; 95% confidence interval [CI], 0.81–1.47; p =0.58; when censoring at time of salvage goserelin, HR=1.02, 95%CI, 0.73–1.43; p =0.9). Traditional cardiac risk factors, including age, prevalent CVD, and DM, were significantly associated with greater cardiovascular mortality. Conclusions: Longer duration of adjuvant GnRHa therapy does not appear to increase cardiovascular mortality in men with locally advanced prostate cancer. [Copyright &y& Elsevier]

Purpose: Increasing body mass index (BMI) is associated with prostate-specific antigen (PSA) failure after radical prostatectomy and external beam radiation therapy (EBRT). We investigated whether BMI is associated with PSA failure in men treated with brachytherapy for clinically localized prostate cancer. Patients and Methods: Retrospective analyses were conducted on 374 patients undergoing brachytherapy for stage T1c–T2cNXM0 prostate cancer from 1996–2001. Forty-nine patients (13%) received supplemental EBRT and 131 (35%) received androgen deprivation therapy (ADT). Height and weight data were available for 353 (94%). Cox regression analyses were performed to evaluate the relationship between BMI and PSA failure (nadir + 2 ng/ml definition). Covariates included age, race, preimplantation PSA, Gleason score, T category, percent of prescription dose to 90% of the prostate, use of supplemental EBRT, and ADT. Results: Median age, PSA, and BMI were 66 years (range, 42–80 years), 5.7 ng/ml (range, 0.4–22.6 ng/ml), and 27.1 kg/m2 (range, 18.2–53.6 kg/m2), respectively. After a median follow-up of 6.0 years (range, 3.0–10.2 years), there were 76 PSA recurrences. The BMI was not associated with PSA failure. Six-year PSA failure rates were 30.2% for men with BMI less than 25 kg/m2, 19.5% for BMI of 25 or greater to less than 30 kg/m2, and 14.4% for BMI of 30 kg/m2 or greater (p = 0.19). Results were similar when BMI was analyzed as a continuous variable, using alternative definitions of PSA failure, and excluding patients treated with EBRT and/or ADT. In multivariate analyses, only baseline PSA was significantly associated with shorter time to PSA failure (adjusted hazard ratio, 1.12; 95% confidence interval, 1.05–1.20; p = 0.0006). Conclusions: Unlike after surgery or EBRT, BMI is not associated with PSA failure in men treated with brachytherapy for prostate cancer. This raises the possibility that brachytherapy may be a preferred treatment strategy in obese patients. [Copyright &y& Elsevier]

Background: Greater body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure following radical prostatectomy and radiation therapy (RT). Whether BMI is associated with prostate cancer-specific mortality (PCSM) was investigated in a large randomized trial of men treated with RT and androgen deprivation therapy (ADT) for locally advanced prostate cancer.Methods: Between 1987 and 1992, 945 eligible men with locally advanced prostate cancer were enrolled in a phase 3 trial (RTOG 85-31) and randomized to RT and immediate goserelin or RT alone followed by goserelin at recurrence. Height and weight data were available at baseline for 788 (83%) subjects. Cox regression analyses were performed to evaluate the relations between BMI and all-cause mortality, PCSM, and nonprostate cancer mortality. Covariates included age, race, treatment arm, history of prostatectomy, nodal involvement, Gleason score, clinical stage, and BMI.Results: The 5-year PCSM rate for men with BMI <25 kg/m(2) was 6.5%, compared with 13.1% and 12.2% in men with BMI > or =25 to <30 and BMI > or =30, respectively (Gray's P = .005). In multivariate analyses, greater BMI was significantly associated with higher PCSM (for BMI > or =25 to <30, hazard ratio [HR] 1.52, 95% confidence interval [CI], 1.02-2.27, P = .04; for BMI > or =30, HR 1.64, 95% CI, 1.01-2.66, P = .04). BMI was not associated with nonprostate cancer or all-cause mortality.Conclusions: Greater baseline BMI is independently associated with higher PCSM in men with locally advanced prostate cancer. Further studies are warranted to evaluate the mechanism(s) for increased cancer-specific mortality and to assess whether weight loss after prostate cancer diagnosis alters disease course. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated whether body mass index (BMI) is associated with time to prostate-specific antigen (PSA) failure in men treated with androgen suppression therapy (AST) and radiation therapy (RT) for clinically localized prostate cancer. Cox regression analyses were performed in the study to analyze whether BMI was associated with time to PSA failure.

Although immediate radical cystectomy remains the standard of care for invasive bladder cancer, a large body of international experience from single institutions and cooperative groups has accumulated, suggesting favorable results with bladder-sparing approaches in appropriately selected patients. Modern selective bladder preservation with trimodality therapy, consisting of transurethral resection of the bladder tumor, radiation, and chemotherapy, can achieve complete response rates of 60–80%, 5-year survival rates of 50–60%, and survival rates with an intact bladder of 40–45%. Although no randomized comparisons between cystectomy and trimodality therapy exist, long-term data confirm that the 10-year overall and disease-specific survival rates for patients in bladder-sparing protocols are comparable to outcomes reported in contemporary cystectomy series. In addition, quality of life studies have demonstrated that the retained native bladder functions well. Thus, trimodality therapy with careful cystoscopic surveillance and with prompt cystectomy for invasive recurrences has emerged as a legitimate alternative to extirpative surgery. Future work will continue to optimize the bladder-sparing regimen while limiting toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To compare the preoperative characteristics, postoperative prostate-specific antigen (PSA) doubling time (DT), and prostate cancer-specific mortality (PCSM) estimates after PSA failure in men diagnosed during a screening study versus a community referral population. A PSA-DT of less than 3 months is a surrogate endpoint for PCSM. Methods: From 1988 to 2002, 1492 of 9637 patients with clinically localized prostate cancer underwent radical prostatectomy and experienced PSA failure. They were either participating in a screening study (n = 841) or attended 1 of 44 community-based practices (n = 611). The distributions of PSA, Gleason score, tumor stage, and PSA-DT were compared using chi-square metric. The estimates of PCSM after PSA failure were compared using Gray’s P value. Results: Compared with the community population, the annually screened men experiencing PSA failure had a lower PSA level at diagnosis (5.1 versus 9.5 ng/mL, P <0.0001), were less likely to have Gleason score 7 to 10 cancer (25.1% versus 42.1%, P <0.0001), and were more likely to have low-risk disease (64.5% versus 23.8%, P <0.0001). Furthermore, the screened cohort had a reduction (P <0.0001) in the proportion with a PSA-DT of less than 3, 3 to 5.99, and 6 to 11.99 months and a significant increase in the proportion with a PSA-DT of 12 months or longer. After a median follow-up of 4.5 and 4.1 years after PSA failure in the screened and community cohorts, respectively, the PCSM estimates were lower (P = 0.0002) in the screened cohort (10-year estimate 3.6% [95% confidence interval 1.3 to 5.8] versus 11.3% [95% confidence interval 5.9 to 17.4]). Conclusions: Patients diagnosed by annual prostate cancer screening appeared more likely to experience an indolent PSA recurrence and less likely to die of prostate cancer after PSA recurrence compared with patients referred from the community. [Copyright &y& Elsevier]

Objective: To determine whether nonsteroidal antiinflammatory drugs (NSAIDs) affect the establishment and progression of endometriotic lesions in a murine model. Design: Pharmacologic intervention in a surgically induced murine model of abdominal/peritoneal endometriosis. Setting: Animal research facility. Patient(s): Eight-week-old, female C57BL/6 mice. Intervention(s): After implantation of autologous endometrium, mice were randomized into groups and treated with one of several NSAIDs or the vehicle-matched control for 4 weeks. Main outcome measure(s): Establishment, growth, and total burden of endometriotic lesions. Result(s): The NSAIDs differentially inhibited lesion establishment and growth, resulting in significantly reduced disease burden. Compared with controls (5.7 ± 2.3 mm2), lesion burden was reduced by celecoxib (1.3 ± 1.2 mm2), indomethacin (1.4 ± 1.4 mm2), naproxen (2.7 ± 1.2 mm2), sulindac (3.1 ± 1.5 mm2), rofecoxib (3.4 ± 3.0 mm2), and ibuprofen (4.1 ± 1.4 mm2). In contrast, aspirin (5.9 ± 1.2 mm2) had no statistically significant effect. Uninterrupted estrus cycling was confirmed by vaginal exams and smears in celecoxib-treated mice. Conclusion(s): Chronic administration of certain NSAIDs limits the progression of endometriosis in this murine model. The data suggest that NSAID selection in the treatment of endometriosis should be extended beyond pain management to maximize the inhibitory effect on disease burden. [Copyright &y& Elsevier]

Presents information on a study which investigated whether mutations in type II transforming growth factor (TGF)-beta receptor gene (TGFBR2) actually give rise to resistance to TGF-beta1. Materials and methods; Results and discussion.

The article presents a commentary on the use of postoperative radiation in the treatment of prostate cancer. The European Organisation for Research and Treatment of Cancer (EORTC) trial 22911 showed an improvement in biochemical progression-free survival among patients with prostate cancer. The effect of the increased use of salvage therapy in the trial is indicated. The use of adjuvant therapy against prostate cancer is also discussed.

Simple Summary: Radiation therapy is an effective treatment for stage IIA and select stage IIB testicular seminoma patients. However, given the young age and long life expectancy of these patients, there are concerns about the risk of secondary cancers from radiation therapy. This study assessed the expected differences in secondary cancer risk for stage II seminoma patients receiving proton pencil-beam scanning (PBS) and photon VMAT compared to 3D conformal photon treatment plans. For 10 seminoma patients treated at our institution, 3D, VMAT, and PBS plans were generated. The percentage increase in the lifetime risk of developing cancers secondary to the radiation was modeled for each plan. On average, PBS reduced the mean radiation dose to critical organs by 60% and reduced the increase in lifetime secondary cancer risk by 55% compared to photons. Proton therapy should be considered for this patient population as it shows the potential to reduce late side effects. Radiation therapy (RT) is an effective treatment for stage IIA and select stage IIB seminomas. However, given the long life expectancy of seminoma patients, there are concerns about the risk of secondary cancers from RT. This study assessed differences in secondary cancer risk for stage II seminoma patients following proton pencil-beam scanning (PBS) and photon VMAT, compared to 3D conformal photon RT. Ten seminoma patients, five with a IIA staging who received 30 GyRBE and five with a IIB staging who received 36 GyRBE, had three RT plans generated. Doses to organs at risk (OAR) were evaluated, and secondary cancer risks were calculated as the Excess Absolute Risk (EAR) and Lifetime Attributable Risk (LAR). PBS reduced the mean OAR dose by 60% on average compared to 3D, and reduced the EAR and LAR for all OAR, with the greatest reductions seen for the bowel, liver, and stomach. VMAT reduced high doses but increased the low-dose bath, leading to an increased EAR and LAR for some OAR. PBS provided superior dosimetric sparing of OAR compared to 3D and VMAT in stage II seminoma cases, with models demonstrating that this may reduce secondary cancer risk. Therefore, proton therapy shows the potential to reduce acute and late side effects of RT for this population. [ABSTRACT FROM AUTHOR]

Simple Summary: As proton therapy evolves and becomes more accessible, it is important to explore its potential value for all patient cases to enable more informed treatment individualization. Currently, external beam radiotherapy for prostate cancer patients with hip prosthesis is limited to photons because traditional proton therapy beams interfere with the implanted hardware. The goal of this study was to investigate the dosimetric feasibility and robustness of novel proton therapy techniques, i.e., proton arc therapy and anterior beam directions for prostate cancer patients with unilateral hip prosthesis. It was demonstrated that proton therapy for prostate cancer in the setting of hip prosthesis is feasible and could potentially reduce the dose to some critical organs and hence reduce toxicities. Purpose: Given that the current standard of proton therapy (PT) for prostate cancer is through bilateral beams, this modality is typically avoided when it comes to treatment of patients with hip prosthesis. The purpose of this study was to evaluate whether novel PT methods, i.e., anterior proton beams and proton arc therapy (PArc), could be feasible options to treat this patient subpopulation. We evaluate PT methods in the context of dosimetry and robustness and compare with standard of practice volumetric modulated arc therapy (VMAT) to explore any potential benefits. Methods: Two PT and one VMAT treatment plans were retrospectively created for 10 patients who participated in a clinical trial with a weekly repeat CT (rCT) imaging component. All plans were robustly optimized and featured: (1) combination anterior oblique and lateral proton beams (AoL), (2) PArc, and (3) VMAT. All patients had hydrogel spacers in place, which enabled safe application of anterior proton beams. The planned dose was 70 Gy (RBE) to the entire prostate gland and 50 Gy (RBE) to the proximal seminal vesicles in 28 fractions. Along with plan dose–volume metrics, robustness to setup and interfractional variations were evaluated using the weekly rCT images. The linear energy transfer (LET)-weighted dose was evaluated for PArc plans to ensure urethra sparing given the typical high-LET region at the end of range. Results: Both PT methods were dosimetrically feasible and provided reduction of some key OAR metrics compared to VMAT except for penile bulb, while providing equally good target coverage. Significant differences in median rectum V35 (22–25%), penile bulb Dmean (5 Gy), rectum V61 (2%), right femoral head Dmean (5 Gy), and bladder V39 (4%) were found between PT and VMAT. All plans were equally robust to variations. LET-weighted dose in urethra was equivalent to the physical dose for PArc plans and hence no added urethral toxicity was expected. Conclusions: PT for treatment of prostate cancer patients with hip prosthesis is feasible and equivalent or potentially superior to VMAT in quality in some cases. The choice of radiotherapy regimen can be personalized based on patient characteristics to achieve the best treatment outcome. [ABSTRACT FROM AUTHOR]

The objective of the European Association of Urology guidelines is to provide practical evidence-based recommendations and consensus statements on the clinical management of urological conditions, with a focus on diagnosis and treatment. In this context the summary of the 2023 guideline on muscle-invasive and metastatic bladder cancer provides updated information on the diagnosis and treatment of this disease for incorporation in clinical practice. We present an overview of the updated 2023 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC). To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment. A broad and comprehensive scoping exercise covering all areas of the MMIBC guidelines has been performed annually since 2017. Searches cover the Medline, EMBASE, and Cochrane Libraries databases for yearly guideline updates. A level of evidence and strength of recommendation are assigned. The evidence cutoff date for the 2023 MIBC guidelines was May 4, 2022. Patients should be counselled regarding risk factors for bladder cancer. Pathologists should describe tumour and lymph nodes in detail, including the presence of histological subtypes. The importance of the presence or absence of urothelial carcinoma (UC) in the prostatic urethra is emphasised. Magnetic resonance imaging (MRI) of the bladder is superior to computed tomography (CT) for disease staging, specifically in differentiating T1 from T2 disease, and may lead to a change in treatment approach in patients at high risk of an invasive tumour. Imaging of the upper urinary tract, lymph nodes, and distant metastasis is performed with CT or MRI; the additional value of flurodeoxyglucose positron emission tomography/CT still needs to be determined. Frail and comorbid patients should be evaluated by a multidisciplinary team. Postoperative histology remains the most important prognostic variable, while circulating tumour DNA appears to be an interesting predictive marker. Neoadjuvant systemic therapy remains cisplatin-based. In motivated and selected women and men, sexual organ–preserving cystectomy results in better functional outcomes without compromising oncological outcomes. Robotic and open cystectomy have comparable outcomes and should be combined with (extended) lymph node dissection. The diversion type is an individual choice after taking patient and tumour characteristics into account. Radical cystectomy remains a highly complex procedure with considerable morbidity and risk of mortality, although lower rates are observed for higher hospital volumes (>20 cases/yr). With proper patient selection, trimodal therapy (chemoradiation) has comparable outcomes to radical cystectomy. Adjuvant chemotherapy after surgery improves disease-specific survival and overall survival (OS) in patients with high-risk disease who did not receive neoadjuvant treatment, and is strongly recommended. There is a weak recommendation for adjuvant nivolumab, as OS data are not yet available. Health-related quality of life should be assessed using validated questionnaires at baseline and after treatment. Surveillance is needed to monitor for recurrent cancer and functional outcomes. Recurrences detected on follow-up seem to have better prognosis than symptomatic recurrences. This summary of the 2023 EAU guidelines provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice. The European Association of Urology guidelines panel on muscle-invasive and metastatic bladder cancer has released an updated version of the guideline containing information on diagnosis and treatment of this disease. Recommendations are based on studies published up to May 4, 2022. Surgical removal of the bladder and bladder preservation are discussed, as well as updates on the use of chemotherapy and immunotherapy in localised and metastatic disease. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on changes in management strategies in patients with low, intermediate, and high-risk prostate cancer in a previous issue.

There is a lack of accepted consensus on what should constitute appropriate quality-of-care indicators for bladder cancer. To evaluate the optimal management of bladder cancer and propose quality indicators (QIs). A systematic review was performed to identify literature on current optimal management and potential quality indicators for both non–muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer. A panel of experts was convened to select a recommended list of QIs. For NMIBC, preoperative QIs include tobacco cessation counselling and appropriate imaging before initial transurethral resection of bladder tumour (TURBT). Intraoperative QIs include administration of antibiotics, proper safe conduct of TURBT using a checklist, and performing restaging TURBT with biopsy of the prostatic urethra in appropriate cases. Postoperative QIs include appropriate receipt of perioperative adjuvant therapy, risk-stratified surveillance, and appropriate decision to change therapy when indicated (eg, bacillus Calmette-Guerin [BCG] unresponsive). For MIBC, preoperative QIs include multidisciplinary care, selection for candidates for continent urinary diversion, receipt of neoadjuvant cisplatin-based chemotherapy, time to commencing radical treatment, consideration of trimodal therapy as a bladder-sparing alternative in select patients, preoperative counselling with stoma marking, surgical volume of radical cystectomy, and enhanced recovery after surgery protocols. Intraoperative QIs include adequacy of lymphadenectomy, blood loss, and operative time. Postoperative QIs include prospective standardised monitoring of morbidity and mortality, negative surgical margins for pT2 disease, appropriate surveillance after primary treatment, and adjuvant cisplatin-based chemotherapy in appropriate cases. Participation in clinical trials was highlighted as an important component indicating high quality of care. We propose a set of QIs for both NMIBC and MIBC based on established clinical guidelines and the available literature. Although there is currently a lack of level 1 evidence for the benefit of implementing these QIs, we believe that the measurement of these QIs could aid in the improvement and benchmarking of optimal care for bladder cancer. After a systematic review of existing guidelines and literature, a panel of experts has recommended a set of quality indicators that can help providers and patients measure and strive towards optimal outcomes for bladder cancer care. The measurement of quality indicators in bladder cancer services based on established clinical guidelines and available literature can help improve and benchmark optimal care for bladder cancer patients. [ABSTRACT FROM AUTHOR]

Previous studies have reported significant variation in prostate cancer rates and trends mainly due to differences in detection practices, availability of treatment, and underlying genetic susceptibility. To assess recent worldwide prostate cancer incidence, mortality rates, and trends using up-to-date incidence and mortality data. We present estimated age-standardized prostate cancer incidence and mortality rates by country and world regions for 2018 based on the GLOBOCAN database. We also examined rates and temporal trends for incidence (44 countries) and mortality (76 countries) based on data series from population-based registries. The highest estimated incidence rates were found in Australia/New Zealand, Northern America, Western and Northern Europe, and the Caribbean, and the lowest rates were found in South-Central Asia, Northern Africa, and South-Eastern and Eastern Asia. The highest estimated mortality rates were found in the Caribbean (Barbados, Trinidad and Tobago, and Cuba), sub-Saharan Africa (South Africa), parts of former Soviet Union (Lithuania, Estonia, and Latvia), whereas the lowest rates were found in Asia (Thailand and Turkmenistan). Prostate cancer incidence rates during the most recent 5 yr declined (five countries) or stabilized (35 countries), after increasing for many years; in contrast, rates continued to increase for four countries in Eastern Europe and Asia. During the most recent 5 data years, mortality rates among the 76 countries examined increased (three countries), remained stable (59 countries), or decreased (14 countries). As evident from available data, prostate cancer incidence and mortality rates have been on the decline or have stabilized recently in many countries, with decreases more pronounced in high-income countries. These trends may reflect a decline in prostate-specific antigen testing (incidence) and improvements in treatment (mortality). We examined recent trends in prostate cancer incidence and mortality rates in 44 and 76 countries, respectively, and found that rates in most countries stabilized or decreased. We examined recent trends in prostate cancer incidence and mortality rates in 44 and 76 countries, respectively, and found that rates mostly stabilized or decreased. These trends may reflect declines in prostate-specific antigen testing (incidence) and improvements in treatment (mortality). [ABSTRACT FROM AUTHOR]

Currently, there is limited data on the comparative effectiveness of radiation therapy (RT) vs. chemoradiation (CHT) for high-grade T1 (HGT1) non-muscle invasive bladder cancer (non-MIBC). Patients diagnosed with HGT1 non-MIBC, and treated with transurethral resection of bladder tumor followed by either treatment with RT alone or CRT, were identified in the National Cancer Database. A total of 259 patients with HGT1 UC were treated with: (i) RT alone (n = 123) or (ii) CRT (n = 136). Propensity-weighted MVA showed that combined modality treatment with CRT was associated with improved OS relative to radiation alone (Hazard Ratio (HR): 0.62, 95% Confidence Interval (95% CI): 0.44-0.88, P = .007). Background: Non-muscle invasive bladder cancer (non-MIBC) that is high-grade and confined to the lamina propria (HGT1) often has an aggressive clinical course. Currently, there is limited data on the comparative effectiveness of RT vs. CRT for HGT1 non-MIBC. We hypothesized that CRT would be associated with improved overall survival (OS) vs. RT in HGT1 bladder cancer. Methods: Patients diagnosed with HGT1 non-MIBC, and treated with transurethral resection of bladder tumor followed by either treatment with RT alone or CRT, were identified in the National Cancer Database. Inverse probability of treatment weighting (IPTW) was employed and weight-adjusted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) hazard ratios. OS was the primary endpoint, and was estimated using the Kaplan-Meier method and log-rank tests. Results: A total of 259 patients with HGT1 UC were treated with: (i) RT alone (n = 123) or (ii) CRT (n = 136). Propensity-weighted MVA showed that combined modality treatment with CRT was associated with improved OS relative to radiation alone (Hazard Ratio [HR]: 0.62, 95% Confidence Interval (95% CI): 0.44-0.88, P = .007). Four-year OS for the CRT vs. RT alone was 36% and 19%, respectively (log-rank P < .008). Conclusion: For patients with HGT1 bladder cancer, concurrent CRT was associated with improved OS compared with radiation alone in a retrospective cohort. These results are hypothesisgenerating. The NRG is currently developing a phase II randomized clinical trial comparing CRT to other novel, bladder preservation strategies. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer. [ABSTRACT FROM AUTHOR]

Intermediate-risk prostate cancer is a heterogeneous disease state with diverse treatment options. The 22-gene Decipher genomic classifier (GC) retrospectively has shown to improve risk stratification in these patients. We assessed the performance of the GC in men with intermediate-risk disease enrolled in NRG Oncology/RTOG 01-26 with updated follow-up. After National Cancer Institute approval, biopsy slides were collected from NRG Oncology/RTOG 01-26, a randomized phase 3 trial of men with intermediate-risk prostate cancer randomized to 70.2 Gy versus 79.2 Gy of radiation therapy without androgen deprivation therapy. RNA was extracted from the highest-grade tumor foci to generate the locked 22-gene GC model. The primary endpoint for this ancillary project was disease progression (composite of biochemical failure, local failure, distant metastasis, prostate cancer-specific mortality, and use of salvage therapy). Individual endpoints were also assessed. Fine-Gray or cause-specific Cox multivariable models were constructed adjusting for randomization arm and trial stratification factors. Two-hundred fifteen patient samples passed quality control for analysis. The median follow-up was 12.8 years (range, 2.4-17.7). On multivariable analysis, the 22-gene GC (per 0.1 unit) was independently prognostic for disease progression (subdistribution hazard ratio [sHR], 1.12; 95% confidence interval [CI], 1.00-1.26; P =.04), biochemical failure (sHR, 1.22; 95% CI, 1.10-1.37; P <.001), distant metastasis (sHR, 1.28; 95% CI, 1.06-1.55; P =.01), and prostate cancer-specific mortality (sHR, 1.45; 95% CI, 1.20-1.76; P <.001). Ten-year distant metastasis in GC low-risk patients was 4% compared with 16% for GC high-risk patients. In patients with lower GC scores, the 10-year difference in metastasis-free survival rate between arms was –7%, compared with 21% for higher GC patients (P -interaction =.04). This study represents the first validation of a biopsy-based gene expression classifier, assessing both its prognostic and predictive value, using data from a randomized phase 3 trial of intermediate-risk prostate cancer. Decipher improves risk stratification and can aid in treatment decision-making in men with intermediate-risk disease. [ABSTRACT FROM AUTHOR]

There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 week and a day [twice a week]) or 12 fractions (4.3Gy in 2.5 weeks [5 times a week]). Secondary objectives assessed patient-reported toxicity at 5 years using the EPIC. Chi-square tests were used to assess the proportion of patients with a deterioration from baseline of >5 points for bowel, >2 points for urinary, and >11 points for sexual score. The study enrolled 127 patients to 5 fractions (121 eligible) and 128 patients to 12 fractions (125 eligible). The median follow-up for all patients at the time of analysis was 5.38 years. The 5-year frequency for >5 point change in bowel score were 38.4% (P =.27) and 23.4% (P = 0.98) for 5 and 12 fractions, respectively. The 5-year frequencies for >2 point change in urinary score were 46.6% (P =.15) and 36.4% (P =.70) for 5 and 12 fractions, respectively. For 5 fractions, 49.3% (P =.007) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points; for 12 fractions, 54% (P <.001) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points. Disease-free survival at 5 years is 89.6% (95% CI: 84.0-95.2) in the 5-fraction arm and 92.3% (95% CI: 87.4-97.1) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. This study confirms that, based on long-term changes in bowel and urinary domains and toxicity, the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens. [ABSTRACT FROM AUTHOR]

Decipher is a genomic classifier (GC) prospectively validated postprostatectomy. We validated the performance of the GC in pretreatment biopsy samples within the context of 3 randomized phase 3 high-risk definitive radiation therapy trials. A prespecified analysis plan (NRG-GU-TS006) was approved to obtain formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled in the NRG/Radiation Therapy Oncology Group (RTOG) 9202, 9413, and 9902 phase 3 randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability for the GC for distant metastases (DM), and secondary for prostate cancer–specific mortality (PCSM) and overall survival (OS) with Cox univariable and multivariable analyses. GC scores were obtained on 385 samples, of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9-13). In the pooled cohort, on univariable analysis, the GC was shown to be a prognostic factor for DM (per 0.1 unit; subdistribution hazard ratio [sHR], 1.29; 95% confidence interval [CI], 1.18-1.41; P <.001), PCSM (sHR, 1.28; 95% CI, 1.16-1.41; P <.001), and OS (hazard ratio [HR], 1.16; 95% CI, 1.08-1.22; P <.001). On multivariable analyses, the GC (per 0.1 unit) was independently associated with DM (sHR, 1.22; 95% CI, 1.09-1.36), PCSM (sHR, 1.23; 95% CI, 1.09-1.39), and OS (HR, 1.12; 95% CI, 1.05-1.20) after adjusting for age, Prostate Specific Antigen, Gleason score, cT stage, trial, and randomized treatment arm. GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy, but the absolute improvement in outcome varied by GC risk. This is the first validation of a gene expression biomarker on pretreatment prostate cancer biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state, and GC can improve risk stratification to help personalize shared decision making. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to demonstrate the feasibility of physician driven planning in intensity modulated radiotherapy (IMRT) with a multicriteria optimization (MCO) treatment planning system and template based plan optimization. Exploiting the full planning potential of MCO navigation, this alternative planning approach intends to improve planning efficiency and individual plan quality.Methods: Planning was retrospectively performed on 12 brain tumor and 10 post-prostatectomy prostate patients previously treated with MCO-IMRT. For each patient, physicians were provided with a template-based generated Pareto surface of optimal plans to navigate, using the beam angles from the original clinical plans. We compared physician generated plans to clinically delivered plans (created by dosimetrists) in terms of dosimetric differences, physician preferences and planning times.Results: Plan qualities were similar, however physician generated and clinical plans differed in the prioritization of clinical goals. Physician derived prostate plans showed significantly better sparing of the high dose rectum and bladder regions (p(D1) < 0.05; D1: dose received by 1% of the corresponding structure). Physicians' brain tumor plans indicated higher doses for targets and brainstem (p(D1) < 0.05). Within blinded plan comparisons physicians preferred the clinical plans more often (brain: 6:3 out of 12, prostate: 2:6 out of 10) (not statistically significant). While times of physician involvement were comparable for prostate planning, the new workflow reduced the average involved time for brain cases by 30%. Planner times were reduced for all cases. Subjective benefits, such as a better understanding of planning situations, were observed by clinicians through the insight into plan optimization and experiencing dosimetric trade-offs.Conclusions: We introduce physician driven planning with MCO for brain and prostate tumors as a feasible planning workflow. The proposed approach standardizes the planning process by utilizing site specific templates and integrates physicians more tightly into treatment planning. Physicians' navigated plan qualities were comparable to the clinical plans. Given the reduction of planning time of the planner and the equal or lower planning time of physicians, this approach has the potential to improve departmental efficiencies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]