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Purpose: To investigate the use of radiation with radiosensitizing chemotherapy following repeated transurethral resection (trimodality therapy) as an alternative to radical cystectomy in T1 bladder cancer which has failed Bacillus Calmette-Guerin (BCG)., Patients and Methods: Patients with recurrent T1 bladders who had failed BCG and were recommended to undergo cystectomy were treated with trimodality therapy. The primary end point was 3-year freedom from cystectomy. Secondary end points were distant metastasis at 3 and 5 years, local recurrence, disease-specific and overall survival (OS), and safety., Results: This single-arm phase II study enrolled 37 patients. Efficacy and safety were evaluated in 34 patients after three exclusions. The median follow-up was 5.1 years. The 3-year freedom from cystectomy rate was 88% (lower one-sided 97.5% confidence limit [CI], 72%), meeting the primary study goal. OS at 3 and 5 years was 69% (95% CI, 54 to 85) and 56% (95% CI, 39 to 74), respectively. The distant metastasis rates at 3 and 5 years were 12% (95% CI, 4 to 26) and 19% (95% CI, 7 to 34), respectively. Eight patients died due to urothelial cancer, 12 exhibited local recurrence at 3 years (cumulative incidence: 32%; 95% CI, 17 to 48), 18 experienced grade 3 adverse events, mostly hematological, and one developed grade 4 neutropenia., Conclusion: Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder. At 3 years, 88% of the patients remained free of cystectomy.

Purpose: Women living with HIV (WLWH) experience decreased breast cancer survival. We sought to determine whether WLWH surviving breast cancer also experienced different quality of life (QOL) gain., Methods: Women who enrolled in the Thabatse Cancer Cohort across oncology centers in Botswana for the initial treatment of stage I-III breast cancer from October 2010 to February 2022 were included. Exclusion criteria were no documented definitive therapy and incomplete data at treatment end or 24 ± 3 months after treatment. QOL was measured quarterly using the SF-8 questionnaire. G methods using weighted exposure and outcome modules were used to mitigate potential bias from imbalances in demographic and cancer characteristics by HIV status. Primary analysis was change in physical component summary (PCS) and mental component summary (MCS) from treatment end to 24 months after treatment for WLWH compared with women without HIV., Results: Of 603 women enrolled, the final analysis included 298, comprising 85 WLWH and 213 women without HIV. Most common reasons for exclusion were no documented definitive treatment (n = 114) and death before 21 months after treatment (n = 137). WLWH were younger, were less wealthy, and had more estrogen receptor/progesterone receptor positive tumors. Overall, PCS and MCS significantly increased from treatment end to 24 months after treatment, from 50.8 to 52.8 and 51.8 to 53.7, respectively. There was no difference in the change of the PCS or MCS with HIV infection, 2.2 (95% CI, -0.4 to 4.9) and 0.6 (95% CI, -1.7 to 2.9), respectively., Conclusion: HIV infection did not impede QOL gain at 24 months after treatment in women surviving breast cancer. Further work is needed to clarify the role of HIV on specific treatment-related morbidities and in other malignancies.

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., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Scott Delacroix, Jared Foster, Francesca Khani, Joseph Liao, Abdul Tawab-Amiri Pamela West, Alex Wyatt: No conflicts. David McConkey: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Grants and contracts – Department of Defense, Mark Foundation, Commonwealth Foundation. Brian Baumann: Consulting fees – Boston Scientific, Varian, Novartis, Blue Earth; leadership or fiduciary role – Board of Directors, National Association for Proton Therapy. Stephanie Cooper Greenberg: Patient advocate, Johns Hopkins Greenberg Bladder Cancer Institute and NCI’s Bladder Cancer Task Force. David DeGraff: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review Grants and contracts – Bristol Myers Squibb, Department of Defense; receipt of material – Astra-Zeneca. Jason Efstathiou: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review Consulting fees – Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Astellas/Pfizer, Lantheus; payment or honoraria – IBA, Elekta, UpToDate; advisory boards – Merck, Roivant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Astellas, Gilead, Lantheus, Blue Earth Diagnostics, Angiodynamics; committee leadership – Vice-Chair, GU Committee, NRG; Board member (unpaid) – Massachusetts Prostate Cancer Coalition (MPCC) American College of Radiation Oncology (ACRO), Radiation Oncology Institute (ROI). Susan Groshen: Financial support from NCI/GUSC for attending a 2-day workshop that led to the CTPM. Edward Kadel: Patent, “PD-L1 PROMOTER METHYLATION IN CANCER”; stock or stock options, 89bio, Apple, Amazon, Alphabet, Eli Lilly & Co, Inspire Medical Systems, Merck & Co, Roche, SPDR S&P Biotech ETF, Teladoc; employee of Genentech/Roche. William Kim: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Grants or contracts – NIH R01-CA241810, Merck; consulting fees – Focal Medical (spouse); advisory board – OncoRev; stock or stock options – Abbvie, Amgen, Apellis, BeiGene, BMS, Lilly, ImmunityBio, Moderna, Natera, NovoNordisk, Revolution Medicines, Tango Therapeutics, Zentalis; other financial or non-financial interests – Focal Medical, ownership interest (spouse). Seth Lerner: Co-Editor-in-Chief of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Advisory board – FerGene, Pfizer. BMS, Incyte; consultant – Vaxiion, Verity, Protara, C2i Genomics, Ferring, Aura Bioscience, Surge Therapeutics; clinical trials – Genentech (SWOG), Vaxiion, Endo, FKD, JBL (SWOG), Merck (Alliance), Aura Bioscience, Surge Therapeutics, QED Therapeutics; honoraria – UroToday, co-editor bladder cancer section UpToDate, Grand Rounds Urology; compensated editorial responsibilities – IOS Press. Trevor Levin: Grants or contracts – NCI SBIR 5R44CA200174-05; patents issued or pending – WO/2017/056451, WO/2020/023630, WO/2020/243587, WO/2022/216865A1; leadership or fiduciary role – Convergent Genomics (Executive and Board roles); stock or stock options – Convergent Genomics. Matthew Milowski: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consulting: Loxo/Lilly; payments or honoraria, Medscape, Research to Practice; other financial or non-financial interests: Co-Editor in Chief, Clinical Genitourinary Cancer, Elsevier. Joshua Meeks: grants or contracts, VA, NIH, Department of Defense; consulting fees, Merck, AstraZeneca, Incyte, Janssen, BMS, UroGen, Prokarium, Imvax, Pfizer, Seagen/Astellas, Ferring; payments, Olympus, AUA, UroToday, OncLive; advisory boards, Astra-Zeneca, Medscape. David Miyamoto: grant support from NIH and the Radiation Oncology Institute. Kent Mouw: consulting fees, EMD Serono, Pfizer, UroGen, Riva Therapeutics. Eugene Pietzak: participation in a Data Safety Monitoring Committee or Advisory Board, QED Pharmaceuticals, Merck, Janssen, Urogen; society leadership, Chair of the Program Committtee, 2024 BCAN Think Tank. David Solit: consulting fees from Pfizer, Fog Pharma, PaigeAI, BridgeBio, Scorpion Therapeutics, FORE Therapeutics, Function Oncology, Pyramid, and Elsie Biotechnologies, Inc.; participation on a Data Safety Monitoring Board for Rain Therapeutics; stock or stock options from Scorpion Therapeutics, FORE Therapeutics, Function Oncology, Pyramid, Elsie Biotechnologies, Inc. Debashish Sundi: grants or contracts from Janssen, consulting fees from Janssen. Sara Wobker: royalties – Wolters Kluwer; honoraria – College of American Pathologists, American Society of Clinical Pathology, USCAP; travel reimbursement – Kidney Cancer Society. Andrea Apolo: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Peter Black: Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Consulting fees – AbbVie, AstraZeneca, Astellas, Bayer, BMS, Combat, EMD-Serono, Ferring, Janssen, Merck, Nonagen, Nanobot, NanOlogy, Pfizer, Photocure, Prokarium, Sumitomo, TerSera, Tolmar, Verity; payments – Janssen, TerSera, Bayer, Pfizer; patents issued or pending – Veracyte.

Purpose: Chemotherapy (CHT) or radiation therapy (RT) are first-line treatments for clinical stage II (CS-II) testicular seminoma. Historically, clinical stage I (CS-I) seminoma was also treated with CHT or RT, but in the past 2 decades practice has shifted toward active surveillance for CS-I with RT or CHT reserved for patients with progression to CS-II. Limited data exist on contemporary RT techniques and patient stratification (ie, de novo [CS-II at orchiectomy] vs relapsed [CS-II diagnosed during surveillance after orchiectomy for CS-I]). We investigated outcomes in CS-II patients treated with RT in the modern era across 2 institutions., Methods and Materials: A retrospective review identified 73 patients treated with RT for CS-II A or B seminoma between 2001 and 2022. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method and univariate analyses were performed with log-rank or Cox proportional hazard regression. Recurrence was defined as biopsy-proven metastatic seminoma after RT completion. Second malignancies were defined as a biopsy-proven malignancy originating in the prior RT field., Results: Thirty-eight (52%) patients presented with de novo CS-II and 35 (48%) patients had relapsed CS-II. Median follow-up was 4.8 years (IQR: 2.3-8.1). Five-year RFS was 82% overall (92% in relapsed patients and 73% in de novo patients). Relapsed CS-II disease had lower recurrence rates after RT compared with de novo CS-II disease. All recurrences occurred outside the prior RT field and were salvaged. Disease-specific survival was 100%. Two second malignancies occurred (prostate, colorectal cancer at 67 months and 119 months post-RT, respectively)., Conclusions: In patients with CS-II seminoma treated with modern RT, there were no in-field recurrences. Presentation with de novo CS-II is associated with out-of-field recurrence. Subject to further larger-scale validation, our results suggest that compared with CS-II at time of relapse, de novo CS-II may portend more aggressive or micrometastatic disease beyond the retroperitoneum, raising the possibility of benefit from CHT after radiation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Androgen deprivation therapy (ADT) has been associated with coronary heart disease and myocardial infarction (MI) in prostate cancer patients, but controversy persists regarding its effects on cardiovascular mortality (CVM)., Objective: We assessed the long-term relationship between ADT and CVM in a prostate cancer randomized trial (NRG Oncology/Radiation Therapy Oncology Group 9202)., Design, Setting, and Participants: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-T4, prostate-specific antigen <150 ng/ml) received radiotherapy with 4 mo (short-term [STADT]) versus 28 mo (longer-term [LTADT]) of ADT., Outcome Measurements and Statistical Analysis: Using the Fine-Gray and Cox regression models, the relationship between ADT and mortality was evaluated., Results and Limitations: With a median follow-up of 19.6 yr, LTADT was associated with improved overall survival (OS) versus STADT (adjusted hazard ratio [HR] 0.88; p = 0.03) and prostate cancer survival (subdistribution HR [sHR] 0.70, p = 0.003). Comparing LTADT with STADT, prostate cancer mortality improved by 6.0% (15.6% [95% confidence interval 13.0-18.3%] vs 21.6% [18.6-24.7%]) at 15 yr, while CVM increased by 2.2% (14.9% [12.4-17.6%] vs 12.7% [10.4-15.3%]). In multivariable analyses, LTADT was not associated with increased CVM versus STADT (sHR 1.22 [0.93-1.59]; p = 0.15). An association between LTADT and MI death was detected (sHR 1.58 [1.00-2.50]; p = 0.05), particularly in patients with prevalent cardiovascular disease (CVD; sHR 2.54 [1.16-5.58]; p = 0.02)., Conclusions: With 19.6 yr of follow-up, LTADT was not significantly associated with increased CVM in men with locally advanced prostate cancer. Patients may have increased MI mortality with LTADT, particularly those with baseline CVD. Overall, there remained a prostate cancer mortality benefit and no OS detriment with LTADT., Patient Summary: In a long-term analysis of a large randomized prostate cancer trial, radiation with 28 mo of hormone therapy did not increase the risk of cardiovascular death significantly versus 4 mo of hormone therapy. Future studies are needed for patients with pre-existing heart disease, who may have an increased risk of myocardial infarction death with longer hormone use., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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.

Biochemical recurrence (BCR) occurs in 20-50% of patients with prostate cancer (PCa) undergoing primary definitive treatment. Patients with high-risk BCR have an increased risk of metastatic progression and subsequent PCa-specific mortality, and thus could benefit from treatment intensification. Given the increasing complexity of diagnostic and therapeutic modalities, multidisciplinary care (MDC) can play a crucial role in the individualized management of this patient population. This review explores the role for MDC when evaluating the clinical evidence for the evolving definition of high-risk BCR and the emerging therapeutic strategies, especially with novel hormone therapies (NHTs), for patients with either high-risk BCR or oligometastatic PCa. Clinical studies have used different characteristics to define high-risk BCR and there is no consensus regarding the definition of high-risk BCR nor for management strategies. Next-generation imaging and multigene panels offer potential enhanced patient identification and precision-based decision-making, respectively. Treatment intensification with NHTs, either alone or combined with radiotherapy or metastasis-directed therapy, has been promising in clinical trials in patients with high-risk BCR or oligometastases. As novel risk-stratification and treatment options as well as evidence-based literature evolve, it is important to involve a multidisciplinary team to identify patients with high-risk features at an earlier stage, and make informed decisions on the treatments that could optimize their care and long-term outcomes. Nevertheless, MDC data are scarce in the BCR or oligometastatic setting. Efforts to integrate MDC into the standard management of this patient population are needed, and will likely improve outcomes across this heterogeneous PCa patient population., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jason A. Efstathiou reports consulting roles for Blue Earth Diagnostics, Boston Scientific, AstraZeneca, and Genentech; honoraria from IBA; advisory boards for Merck, Roviant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Inc., Genentech, Gilead, Blue Earth Diagnostics, and Lantheus Medical Imaging. Alicia K. Morgans reports grant support from Bayer, Sanofi, Myovant Sciences, Pfizer, Inc., Astellas Scientific and Medical Affairs Inc., and Dendreon Pharmaceuticals; honoraria from AstraZeneca, Advanced Accelerator Applications, Novartis, and Pfizer, Inc.; consulting or advisory roles for AstraZeneca, Sanofi, Bayer, Astellas Pharma, Janssen, Advanced Accelerator Applications, Myovant Sciences, Blue Earth Diagnostics, Exelixis, Novartis, Myriad Genetics, Lantheus Medical Imaging, Merck, and Gilead. Christopher S. Bland reports being an employee and shareholder of Pfizer, Inc. Neal D. Shore reports grant support from AbbVie, Amgen, Astellas Pharma, Bayer, Dendreon Pharmaceuticals, Ferring Pharmaceuticals, Janssen Oncology, Pfizer, Inc., Sanofi–Genzyme, and Tolmar Pharmaceuticals; consulting or advocacy roles for AbbVie, Akido, Alessa Therapeutics, Amgen, Arquer, Asieris, Astellas Pharma, Inc., Astra Zeneca, Bayer, BMS, Boston Scientific, Clarity, Clovis, Cold Genesys, Dendreon Pharmaceuticals, Exact Images, Exact Sciences, FerGene, Ferring Pharmaceuticals, Foundation Medicine, FIZE Medical, GConcology, GenesisCare, Genetech, Guardant, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX, Merck, Minomic, Myovant, Myriad, NGM, Nonagen, Novartis, NYMOX, Pacific Edge, Pfizer, Inc., Photocure, PlatformQ, Profound, Promaxo, Propella, Protara, Sanofi, SesenBio, Speciality Networks, Telix, Tolmar Pharmaceuticals, Urogen, Vaxiion, and Vessi., (Copyright © 2023. Published by Elsevier Ltd.)

Context: We present an overview of the updated 2023 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC)., Objective: To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment., Evidence Acquisition: 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., Evidence Synthesis: 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., Conclusions: This summary of the 2023 EAU guidelines provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice., Patient Summary: 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., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood., Experimental Design: We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of patients with MIBC homogeneously treated with TMT. Pretreatment tumors from 76 patients with MIBC underwent whole-exome sequencing; 67 underwent matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation., Results: With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS [HR, 0.15; 95% confidence interval (CI), 0.06-0.37; P = 0.030] and improved BI-EFS, an endpoint that includes all-cause mortality (HR, 0.33; 95% CI, 0.15-0.68; P = 0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wild-type cells., Conclusions: Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Bladder cancer is the tenth leading cause of cancer death in the United States (US). Advances in diagnosis, imaging, and treatments have led to improvements in bladder cancer management., Objective: To evaluate longitudinal bladder cancer mortality trends from 1999-2020 in the US by gender, race, ethnicity, age, geographic region, and urbanization category., Methods: Age-adjusted bladder cancer death and incidence rates of individuals in the US of all ages between 1999-2020 were obtained using the CDC WONDER and NAACCR databases. Trends and average annual percent changes (AAPC) in age-adjusted Bladder Cancer-Specific Mortality (BCSM) and incidence rates were estimated. Data were analyzed from May 2023 to October 2023., Results: From 1999-2020, overall BCSM decreased by 0.4% annually, with a dramatic decrease in deaths between 2015-2020 (AAPC: -2.0% [95% CI: -2.6,-1.3]). However, BCSM rates and metastatic malignant bladder cancer incidence rates from 1999-2020 increased for individuals≥85 years old (AAPC for BCSM: 0.8% [95% CI:0.5,1.1]; AAPC for metastatic malignant incidence: 2.5% [95% CI: 2.0,2.9]). Increases in BCSM were found for certain years in the South, in rural areas, and for Non-Hispanic White and Asian or Pacific Islander individuals., Conclusions: Overall mortality from bladder cancer has been decreasing in the US over two decades. Upon disaggregation, increasing trends were found for BCSM and for metastatic malignant bladder cancer incidence for individuals≥85 years old from 1999-2020. Further evaluation of these trends is essential to understand how to target specific populations to improve patient outcomes., Competing Interests: Dr. Jason A. Efstathiou is an Editorial Board Member of this journal but was not involved in the peer-review process nor had access to any information regarding its peer-review. Dr. Efstathiou reports consulting fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, and Genentech. Dr. Efstathiou reports participation on a Data Safety Monitoring Board or Advisory Board at Merck, Roivant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Astellas, Gilead, Lantheus, Blue Earth Diagnostics, and Angiodynamics. Dr. Efstathiou reports board membership at Massachusetts Prostate Cancer Coalition (MPCC), American College of Radiation Oncology (ACRO), and Radiation Oncology Institute (ROI). Isabella R. Pompa, David Qi, Anushka Ghosh, Saveli I. Goldberg, and Dr. Sophia C. Kamran have no conflicts of interest to report., (© 2023 – The authors. Published by IOS Press.)

Purpose: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel., Methods: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually)., Results: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text., Conclusion: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

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 hypothesis-generating. The NRG is currently developing a phase II randomized clinical trial comparing CRT to other novel, bladder preservation strategies., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BCB declares consulting work for Varian Medical Systems and Boston Scientific, outside of the scope of thesubmitted work. The others have no conflicts of interest that are relevant to the submitted work., (Copyright © 2023. Published by Elsevier Inc.)

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.

Purpose: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods., Materials and Methods: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R 2 ). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed., Results: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R 2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively., Conclusion: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways depending on whether the disease is non-muscle invasive or muscle invasive. The mutational burden is higher in muscle-invasive than in non-muscle-invasive disease. Commonly mutated genes include TERT, FGFR3, TP53, PIK3CA, STAG2 and genes involved in chromatin modification. Subtyping of both forms of bladder cancer is likely to change considerably with the advent of single-cell analysis methods. Early detection signifies a better disease prognosis; thus, minimally invasive diagnostic options are needed to improve patient outcomes. Urine-based tests are available for disease diagnosis and surveillance, and analysis of blood-based cell-free DNA is a promising tool for the detection of minimal residual disease and metastatic relapse. Transurethral resection is the cornerstone treatment for non-muscle-invasive bladder cancer and intravesical therapy can further improve oncological outcomes. For muscle-invasive bladder cancer, radical cystectomy with neoadjuvant chemotherapy is the standard of care with evidence supporting trimodality therapy. Immune-checkpoint inhibitors have demonstrated benefit in non-muscle-invasive, muscle-invasive and metastatic bladder cancer. Effective management requires a multidisciplinary approach that considers patient characteristics and molecular disease characteristics., (© 2023. Springer Nature Limited.)

Purpose: 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., Methods and Materials: 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., Results: 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)., Conclusions: 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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Testicular cancer (TC) mortality rates have decreased over time, however it is unclear whether these improvements are consistent across all communities., Aims: The aim of this study was to analyze trends in TC incidence, mortality, and place of death (PoD) in the United States between 1999-2020 and identify disparities across race, ethnicity, and geographic location., Methods and Results: This cross-sectional study used CDC WONDER and NAACCR, to calculate age-adjusted rates of TC incidence and mortality, respectively. PoD data for individuals who died of TC were collected from CDC WONDER. Using Joinpoint analysis, longitudinal mortality trends were evaluated by age, race, ethnicity, US census region, and urbanization category. TC stage (localized vs metastatic) trends were also evaluated. Univariate and multivariate regression analysis identified demographic disparities for PoD. A total of 8,456 patients died of TC from 1999-2020. Average annual percent change (AAPC) of testicular cancer-specific mortality (TCSM) remained largely stable (AAPC, 0.4; 95% CI -0.2 to 0.9; p = 0.215). Men ages 25-29 experienced a significant increase in TCSM (AAPC, 1.3, p = 0.003), consistent with increased metastatic testicular cancer-specific incidence (TCSI) trend for this age group (AAPC, 1.6; p < 0.01). Mortality increased for Hispanic men (AAPC, 1.7, p < 0.001), with increased metastatic TCSI (AAPC, 2.5; p < 0.001). Finally, younger (<45), single, and Hispanic or Black men were more likely to die in medical facilities (all p < 0.001). The retrospective study design is a limitation., Conclusion: Significant increases in metastatic TC were found for Hispanic men and men aged 25-29 potentially driving increasing testicular cancer specific mortality in these groups. Evidence of racial and ethnic differences in place of death may also highlight treatment disparities., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: 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., Methods and Materials: 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., Results: 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., Conclusions: 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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: 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., Methods and Materials: 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., Results: 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., Conclusions: 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bladder-sparing chemoradiation therapy (CRT) is a definitive first-line treatment for muscle-invasive bladder cancer. The optimal radiotherapy target volume, either bladder-only (BO) or bladder plus pelvic lymph nodes (BPN), remains unclear., Methods: We identified 2,104 patients in the National Cancer Database with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with CRT following maximal transurethral resection of bladder tumor from 2004 to 2016. The exposure of interest was BO vs. BPN treatment volume. The primary outcome was overall survival (OS), compared between groups using Kaplan-Meier and multivariable Cox proportional hazards. Sensitivity analysis tested an interaction term for clinical T stage (T2 vs. T3-4) and radiation modality (3-dimensional conformal radiotherapy vs. intensity modulated radiotherapy or proton therapy). Annual use of BO vs. BPN from 2004 to 2016 was compared using Cochran-Armitage test., Results: A total of 578 patients were treated with BO and 1,526 patients treated with BPN CRT. There was a significant increase in BPN use from 2004 to 2016 (66.9%-76.8%, P < 0.0001). With a median follow-up of 6.2 years, there was no survival difference between groups: 5- and 10-year OS 27.4% (95% CI 23.4%-31.4%) in the BO group vs. 31.9% (95% CI 29.3%-34.6%) in the BPN group, and 13.1% (95% CI 9.7%-17.1%) in the BO group vs. 13.2% (95% CI 10.6%-16.0%) in the BPN group, respectively (log-rank P = 0.10). On multivariable analysis, there was no significant association between BPN and OS (adjusted HR 0.90, 95% CI 0.81-1.02, P = 0.09). On sensitivity analysis, we found no differential effect by T stage or radiation modality., Conclusion: Use of pelvic lymph node radiation has risen in the US but may not impact long-term survival outcomes for patients with node-negative muscle-invasive bladder cancer (MIBC). Optimizing radiation treatment volumes for CRT for MIBC will be important to study under prospective trials, such as the SWOG/NRG 1806., Competing Interests: Conflict of interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identify 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic circulating tumor cells (CTCs). Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are enriched for immune-related genes; prominent among these is a single gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes implicated in innate immunity. The re-expression of CD1 or IFI16 murine orthologs in immuno-competent mice abrogates tumorigenesis, accompanied by the activation of anti-tumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs., Competing Interests: Declaration of interests Massachusetts General Hospital (MGH) has applied for patents regarding the CTC-iChip technology and CTC detection signatures. M.T., S.M., and D.A.H. are cofounders and have equity in Tell-Bio, which is not related to this work. The interests of these authors were reviewed and managed by MGH and Mass General Brigham (MGB) in accordance with their conflict of interest policies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: Declaration of interests ARZ reports participation on a data safety monitoring board or advisory board for Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase; and consulting fees from Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase. NEF reports grants or contracts from Janssen, Sanofi, Astellas, Nucleix, Bayer, and Progenix; consulting fees from Amgen, Sanofi, Janssen, AbbVie, Astellas, Ferring, and Bayer; stock or stock options in Verity Pharmaceuticals and POINT Biopharma; and is Chief Medical Officer for Verity Pharmaceuticals and Chief Medical Officer for POINT Biopharma. GSK reports grants or contracts from Janssen; and participation on a data safety monitoring board or advisory board for BMS, Pfizer, EMD Serono, Theralase, Verity Pharmaceuticals, Merck, Janssen, AstraZeneca, and Ferring. MASJ reports an honorarium from Pfizer; support for attending meetings or travel from the European Association of Urology; and is the Chair of the Board of Directors of the International Kidney Cancer Coalition. SSS reports grants or contracts from Bayer, Janssen, and Seagen; consulting fees from Astellas, AstraZeneca, Bayer, BMS, Eisai, EMD Serona, Hoffmann-LaRoche, Immunomedics, Ipsen, Janssen, Merck, Pfizer, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, EMD Serono, Seagen, and Bayer; and support for attending meetings or travel from EMD Serono. MDM reports participation on a data safety monitoring board or advisory board for Merck, Janssen, Eisai, and Exelixis. JAE reports consulting fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, and Genentech; and participation on a data safety monitoring board or advisory board for Merck, Roviant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Gilead, and Lantheus. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (© 2023 American Association of Physicists in Medicine.)

Background: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients., Objective: 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)., Design, Setting, and Participants: A multicenter phase 1 trial was conducted at community and academic sites., Intervention: 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)., Outcome Measurements and Statistical Analysis: 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., Results and Limitations: 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., Conclusions: 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., Patient Summary: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Rurality and neighborhood deprivation can contribute to poor patient-reported outcomes, which have not been systematically evaluated in patients with specific cancers in national trials. Our objective was to examine the effect of rurality and neighborhood socioeconomic and environmental deprivation on patient-reported outcomes and survival in men with prostate cancer in NRG Oncology RTOG 0415., Methods and Materials: Data from men with prostate cancer in trial NRG Oncology RTOG 0415 were analyzed; 1,092 men were randomized to receive conventional radiation therapy or hypofractionated radiation therapy. Rurality was categorized as urban or rural. Neighborhood deprivation was assessed using the area deprivation index and air pollution indicators (nitrogen dioxide and particulate matter with a diameter less than 2.5 micrometers) via patient ZIP codes. Expanded Prostate Cancer Index Composite measured cancer-specific quality of life. The Hopkins symptom checklist measured anxiety and depression. EuroQoL-5 Dimension assessed general health., Results: We analyzed 751 patients in trial NRG Oncology RTOG 0415. At baseline, patients from the most deprived neighborhoods had worse bowel (P = .011), worse sexual (P = .042), and worse hormonal (P = .015) scores; patients from the most deprived areas had worse self-care (P = .04) and more pain (P = .047); and patients from rural areas had worse urinary (P = .03) and sexual (P = .003) scores versus patients from urban areas. Longitudinal analyses showed that the 25% most deprived areas (P = .004) and rural areas (P = .002) were associated with worse EuroQoL-5 Dimension visual analog scale score. Patients from urban areas (hazard ratio, 1.81; P = .033) and the 75% less-deprived neighborhoods (hazard ratio, 0.68; P = .053) showed relative decrease in risk of recurrence or death (disease-free survival)., Conclusions: Patients with prostate cancer from the most deprived neighborhoods and rural areas had low quality of life at baseline, poor general health longitudinally, and worse disease-free survival. Interventions should screen populations from deprived neighborhoods and rural areas to improve patient access to supportive care services., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT)., Materials and Methods: Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality., Results: Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points ( P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT., Conclusion: ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

For muscle-invasive bladder cancer, the historical, gold standard treatment was radical cystectomy. However, the notion of organ preservation using trimodality therapy (TMT, consisting of maximal transurethral resection of bladder tumor followed by chemoradiation) has been established as a viable treatment alternative to complete removal of the bladder. Despite the lack of direct head-to-head randomized comparisons of TMT to radical cystectomy, the Radiation Therapy Oncology Group (RTOG)/NRG has spearheaded the use of radiation therapy as part of bladder preservation for years, with prospective data demonstrating similar long-term clinical outcomes to cystectomy series, particularly with contemporary treatment. We summarize these trials and discuss the evolution of bladder preservation throughout the decades, culminating in our current TMT protocols. We further discuss the future of organ-preservation therapy in MIBC, with continued improvement in radiation techniques, incorporation of novel therapies, and personalization of treatment to optimize benefit for bladder cancer patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There are limited data regarding the optimal management of patients with pelvic node-positive, but non-metastatic, bladder cancer. Increasing data demonstrate that this is a distinct clinical entity with outcomes bridging between bladder-confined muscle-invasive bladder cancer and metastatic advanced bladder cancer. Guidelines and staging systems have formalized the need to incorporate the unique considerations of management of pelvic node-positive bladder cancer. However, there remains an absence of a definite standard of care. Treatment options include systemic therapy alone, neoadjuvant chemotherapy followed by radical cystectomy, or bladder-preserving trimodality therapy. Furthermore, ongoing studies aim to determine the benefit of incorporating immunotherapy into these treatment paradigms. In this review article, we will discuss the key considerations for management of patients with pelvic node-positive bladder cancer., (Published by Elsevier Inc.)

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.

Context: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear., Objective: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT., Evidence Acquisition: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states., Evidence Synthesis: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups., Conclusions: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis., Patient Summary: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 R 2 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 ( R 2 = 0.67), but this was not true for BF1 ( R 2 = 0.09), BF2 ( R 2 = 0.12), or DM ( R 2 = 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.

Purpose: Although mentorship has been associated with promotion, job satisfaction, and retention, data are limited on the mentorship experience of clinical- versus research-track physicians as well as feasibility and relative priority of formal program components., Methods and Materials: Within a single-institution, multi-site, academic network, we implemented a Radiation Oncology AcaDemic Mentorship Program (ROADMAP) for junior faculty. Validated surveys assessing mentee satisfaction were distributed at baseline and 1 year. The statistical analysis included Wilcoxon rank sum and signed tests. Mentees assessed the likelihood to recommend each program component (10-point Likert-type scale), and means with standard error (SE) are reported., Results: Among 42 eligible junior faculty, 36 (86%) opted into the program. The median time since residency was 2.5 years (interquartile range, 1.75-5.25) on the clinical track (n = 12) and 3 years (interquartile range, 2.75-5.00) on the research track (n = 24). At baseline, research-track physicians reported higher satisfaction with mentoring than physicians on the clinical track (2.92 vs 2.16; P = .02). Among 32 physicians completing 1 year, overall satisfaction with mentoring increased compared with baseline (2.72 vs 3.87; P < .001), which persisted on subset analysis for both clinical- (2.16 vs 4.03; P < .001) and research-track physicians (2.99 vs 3.77; P = .005). At 1 year, 28 mentees (88%) opted to continue the program. Program components were rated 8.25 (SE, 0.37) for mentor-mentee pairings, 7.22 (SE, 0.39) for goal setting, 6.84 (SE, 0.47) for administrative support, 6.69 (SE, 0.44) for peer mentoring, and 6.53 (SE, 0.45) for steering committee oversight. Ratings of peer mentoring were not associated with track (P = .59) or years in practice (P = .29)., Conclusions: Clinical-track physicians may be less satisfied with mentorship than research-track faculty. However, all junior faculty, regardless of track, appeared to benefit from formalizing dyadic mentor-mentee relationships, goal setting, and peer mentoring. Further work is needed to determine the role of mentorship in addressing physician burnout., (Copyright © 2022. Published by Elsevier Inc.)

Background: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown., Objective: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT., Design, Setting, and Participants: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT., Outcome Measurements and Statistical Analyses: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS)., Results and Limitations: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes., Conclusions: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT., Patient Summary: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Salvage radiotherapy (SRT) is an established treatment for men with biochemical recurrence following radical prostatectomy (RP). There are several risk factors associated with adverse outcomes; however, the value of postoperative prostate-specific antigen (PSA) kinetics is less clear in the ultrasensitive PSA era., Objective: To characterize the impact of PSA kinetics on outcomes following SRT and generate nomograms to aid in identifying patients with an increased risk of adverse clinical outcomes., Design, Setting, and Participants: A multi-institutional analysis was conducted of 1005 patients with prostate cancer treated with SRT after RP, with a median follow-up of 5 years., Outcome Measurements and Statistical Analysis: Variables examined include immediate postoperative PSA, postoperative PSA doubling time (DT), and pre-SRT PSA, in addition to previously identified predictive factors. Multivariable survival analyses were completed using Fine-Gray competing risk regression. Rates of biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM) were estimated by the cumulative incidence method. Nomograms were generated from multivariable competing risk regression with bootstrap cross-validation., Results and Limitations: Factors associated with BF after SRT include PSA DT <6 mo, initial postoperative PSA ≥0.2 ng/ml, higher pre-SRT PSA, lack of androgen deprivation therapy, a higher Gleason score (GS), negative margins, seminal vesicle invasion, lack of pelvic nodal radiation, radiation total dose <66 Gy, a longer RP to SRT interval, and older age (p < 0.05 for each). Factors associated with DM include PSA DT <6 mo, pre-SRT PSA, a higher GS, and negative margins. Factors associated with PCSM include PSA DT not calculable or <6 mo and a higher GS. Nomograms were generated to estimate the risks of BF (concordance index [CI] 0.74), DM (CI 0.77), and PCSM (CI 0.77). Limitations include retrospective nature, broad treatment eras, institutional variations, and multiple methods available for the estimation of PSA DT., Conclusions: Postoperative PSA kinetics, particularly pre-SRT PSA and PSA DT, are strongly associated with adverse oncologic outcomes following SRT and should be considered in management decisions., Patient Summary: In this report of men with prostate cancer who developed a prostate-specific antigen (PSA) recurrence after prostatectomy, we found that PSA levels after surgery and how quickly a PSA level doubles significantly impact the chance of prostate cancer recurrence after salvage radiation therapy. Based on this information, we created a tool to calculate a man's chance of cancer recurrence after salvage radiation therapy, and these estimations can be used to discuss whether additional treatment with radiation should be considered., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Importance: The 2012 US Preventive Services Task Force (USPSTF) Grade D recommendation against prostate-specific antigen (PSA) screening for all men has been controversial, with data documenting a shift to a higher stage of disease at diagnosis. The association between the Grade D recommendation and prostate cancer-specific mortality (PCSM) among contemporary cohorts, however, is unclear., Objective: To evaluate PCSM rates between 1999 and 2019, comparing trends in rates before and after the change in the 2012 USPSTF screening guideline to assess its association with PCSM., Exposure: The 2012 USPSTF Grade D recommendation against PSA screening for all men., Design, Setting, and Participants: This cross-sectional study used Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research maintained by the National Center for Health Statistics to collect data on cause of death for all individuals who died of prostate cancer in the US from 1999 to 2019. Analysis was performed from January to August 2021., Main Outcomes and Measures: Trends in PCSM rates were calculated from 1999 to 2012 and from 2014 to 2019, with a washout year of 2013, using linear regression, with year and binary indicator of pre-2013 and post-2013 status as interaction terms. Trends were further analyzed by age, race and ethnicity, urbanization category, and US Census region. Other measures included diagnosis of localized or metastatic prostate cancer and overall cancer mortality., Results: A total of 618 095 patients died of prostate cancer in the US from 1999 to 2019. Age-adjusted PCSM decreased linearly at a rate of -0.273 per 100 000 population per year from 1999 to 2012 and stalled at a rate of -0.009 per 100 000 per year from 2014 to 2019 (P < .001). This finding was significant among men aged 60 years or older, especially among men aged 60 to 69 years, men aged 80 years or older, and among Black men. Men aged 60 to 64 years had a decreasing, age-adjusted PCSM rate of -0.0088 per 100 000 population per year prior to 2013 followed by an increasing rate of 0.0014 per 100 000 per year. Men aged 65 to 69 years had a decreasing, age-adjusted PCSM rate of -0.024 per 100 000 population per year prior to 2013 followed by an increasing rate of 0.0011 per 100 000 population per year. Men aged 80 years or older had the largest absolute difference between rates before and after 2013 compared with all other age groups, with a difference of 0.06 for men aged 80 to 84 years and 0.07 for men 85 aged years or older. Black men had a decreasing, age-adjusted PCSM rate of -0.700 per 100 000 population per year prior to 2013 followed by a flattened rate of -0.091 per 100 000 population per year. Changes were observed across races and ethnicities, urbanization categories, and US Census regions and were accompanied by increased diagnoses of metastatic disease, which are inconsistent with mortality trends across all malignant neoplasms., Conclusions and Relevance: This cross-sectional study using comprehensive PCSM data through 2019 demonstrated decreasing PCSM rates that flattened or increased after the 2012 USPSTF Grade D recommendation, suggesting that decreased PSA screening may be a factor associated with this change. This change was seen across ages, races and ethnicities, urbanization categories, and US Census regions. The updated 2018 USPSTF guideline supporting shared decision-making may reverse these trends in the coming years.

Importance: Black patients are less likely than White patients to receive guideline-concordant cancer care in the US. Proton beam therapy (PBT) is a potentially superior technology to photon radiotherapy for tumors with complex anatomy, tumors surrounded by sensitive tissues, and childhood cancers., Objective: To evaluate whether there are racial disparities in the receipt of PBT among Black and White individuals diagnosed with all PBT-eligible cancers in the US., Design, Setting, and Participants: This cross-sectional study evaluated Black and White individuals diagnosed with PBT-eligible cancers between January 1, 2004, and December 31, 2018, in the National Cancer Database, a nationwide hospital-based cancer registry that collects data on radiation treatment, even when it is received outside the reporting facility. American Society of Radiation Oncology model policies were used to classify patients into those for whom PBT is the recommended radiation therapy modality (group 1) and those for whom evidence of PBT efficacy is still under investigation (group 2). Propensity score matching was used to ensure comparability of Black and White patients' clinical characteristics and regional availability of PBT according to the National Academy of Medicine's definition of disparities. Data analysis was performed from October 4, 2021, to February 22, 2022., Exposure: Patients' self-identified race was ascertained from medical records., Main Outcomes and Measures: The main outcome was receipt of PBT, with disparities in this therapy's use evaluated with logistic regression analysis., Results: Of the 5 225 929 patients who were eligible to receive PBT and included in the study, 13.6% were Black, 86.4% were White, and 54.3% were female. The mean (SD) age at diagnosis was 63.2 (12.4) years. Black patients were less likely to be treated with PBT than their White counterparts (0.3% vs 0.5%; odds ratio [OR], 0.67; 95% CI, 0.64-0.71). Racial disparities were greater for group 1 cancers (0.4% vs 0.8%; OR, 0.49; 95% CI, 0.44-0.55) than group 2 cancers (0.3% vs 0.4%; OR, 0.75; 95% CI, 0.70-0.80). Racial disparities in PBT receipt among group 1 cancers increased over time (annual percent change = 0.09, P < .001) and were greatest in 2018, the most recent year of available data., Conclusions and Relevance: In this cross-sectional study, Black patients were less likely to receive PBT than their White counterparts, and disparities were greatest for cancers for which PBT was the recommended radiation therapy modality. These findings suggest that efforts other than increasing the number of facilities that provide PBT will be needed to eliminate disparities.

Importance: Proton beam therapy (PBT) is a potentially superior technology to photon radiotherapy for tumors with complex anatomy, those surrounded by sensitive tissues, and childhood cancers., Objective: To assess patterns of use of PBT according to the present American Society of Radiation Oncology (ASTRO) clinical indications in the US., Design, Setting, and Participants: Individuals newly diagnosed with cancer between 2004 and 2018 were selected from the National Cancer Database. Data analysis was performed from October 4, 2021, to February 22, 2022. ASTRO's Model Policies (2017) were used to classify patients into group 1, for which health insurance coverage for PBT treatment is recommended, and group 2, for which coverage is recommended only if additional requirements are met., Main Outcomes and Measures: Use of PBT., Results: Of the 5 919 368 patients eligible to receive PBT included in the study, 3 206 902 were female (54.2%), and mean (SD) age at diagnosis was 62.6 (12.3) years. Use of PBT in the US increased from 0.4% in 2004 to 1.2% in 2018 (annual percent change [APC], 8.12%; P < .001) due to increases in group 1 from 0.4% in 2010 to 2.2% in 2018 (APC, 21.97; P < .001) and increases in group 2 from 0.03% in 2014 to 0.1% in 2018 (APC, 30.57; P < .001). From 2010 to 2018, among patients in group 2, PBT targeted to the breast increased from 0.0% to 0.9% (APC, 51.95%), and PBT targeted to the lung increased from 0.1% to 0.7% (APC, 28.06%) (P < .001 for both). Use of PBT targeted to the prostate decreased from 1.4% in 2011 to 0.8% in 2014 (APC, -16.48%; P = .03) then increased to 1.3% in 2018 (APC, 12.45; P < .001). Most patients in group 1 treated with PBT had private insurance coverage in 2018 (1039 [55.4%]); Medicare was the most common insurance type among those in group 2 (1973 [52.5%])., Conclusions and Relevance: The findings of this study show an increase in the use of PBT in the US between 2004 to 2018; prostate was the only cancer site for which PBT use decreased temporarily between 2011 and 2014, increasing again between 2014 and 2018. These findings may be especially relevant for Medicare radiation oncology coverage policies.

Purpose: The use of prostate fiducial markers and perirectal hydrogel spacers can reduce the acute and late toxic effects associated with prostate radiation therapy. These procedures are usually performed days to weeks before simulation during a separate clinic visit to ensure resolution of procedure-related inflammation. The purpose of this study was to assess whether same-day intraprostatic fiducial marker placement, perirectal hydrogel injection, and computed tomography (CT) and magnetic resonance imaging (MRI) simulation were feasible without adversely affecting hydrogel volume, perirectal spacing, or rectal dose. If feasible, performing these procedures on the same day as simulation would expedite the start of radiation therapy, improve patient convenience, and reduce costs., Methods and Materials: Twenty-one patients with clinically localized prostate cancer who were enrolled on a prospective clinical trial (NCT01617161) underwent same-day marker placement, hydrogel injection, and CT and MRI simulation, then underwent T2 MRI verification scans 3 to 4 weeks later. The MRI scans were fused to the CT planning scans by clinical target volumes (CTVs) to generate comparison treatment plans (70 Gy in 28 fractions). Hydrogel volume and symmetry, perirectal spacing, CTV dose, and organ-at-risk dose were evaluated., Results: Verification scans occurred a mean of 24.9 ± 4.6 days after simulation and 9.3 ± 4.9 days after treatment start. Prostate volume did not change between scans (median, 67.3 ± 22.1 cm 3 vs 64.1 ± 21.8 cm 3 ; P = .64). The median hydrogel change between simulation and verification was - 1.8% ± 4.5% (P = .27). No significant differences in perirectal spacing (midgland: 1.33 ± 0.45 cm vs 1.3 ± 0.7 cm; 1 cm superior: 1.25 ± 0.95 cm vs 1.43 ± 0.91 cm; 1 cm inferior: 1.16 ± 0.28 cm vs 1.41 ± 0.49 cm) were identified. No significant differences in rectal V66 (median 2.3 ± 2.18% vs 2.3 ± 2.28%; P = .99), V35 (median 14.79 ± 7.61 vs 14.67 ± 8.4; P = .73), or D1cc (65.7 ± 9.2 Gy vs 68.2 ± 9.0 Gy; P = .80) were found. All plans met CTV and organ-at-risk constraints., Conclusion: Same-day placement of intraprostatic fiducial markers, perirectal hydrogel, and simulation scans was feasible and did not significantly affect hydrogel volume, position, CTV coverage, or rectal dose., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Conventional rectal spacers (nonI-SPs) are low-contrast on computed tomography (CT), often necessitating magnetic resonance imaging for accurate delineation. A new formulation of spacers (I-SPs) incorporates iodine to improve radiopacity and CT visualization. We characterized placement, stability, and plan quality of I-SPs compared to nonI-SPs., Methods and Materials: Patients with intact prostate cancer (n = 50) treated with I-SPs and photons were compared to randomly selected patients (n = 50) with nonI-SPs (photon or proton therapy). The I-SP was contoured on the planning CT and cone beam CTs at 3 timepoints: first, middle, and final treatment (n = 200 scans). I-SPs Hounsfield units (HU), volume, surface area (SA), centroid position relative to prostate centroid, and distance between prostate/rectum centroids were compared on the planning CTs between each cohort. I-SP changes were evaluated on cone beam CTs over courses of treatment. Dosimetric evaluations of plan quality and robustness were performed. I-SP was tested in a phantom to characterize its relative linear stopping power for protons., Results: I-SPs yielded a distinct visible contrast on planning CTs compared to nonI-SPs (HU 138 vs 12, P < .001), allowing delineation on CT alone. The delineated volume and SA of I-SPs were smaller than nonI-SPs (volume 8.9 vs 10.6 mL, P < .001; SA 28 vs 35 cm 2 , P < .001), yet relative spacer position and prostate-rectal separation were similar (P = .79). No significant change in HU, volume, SA, or relative position of the I-SPs hydrogel occurred over courses of treatment (all P > .1). Dosimetric analysis concluded there were no significant changes in plan quality or robustness for I-SPs compared to nonI-SPs. The I-SP relative linear stopping power was 1.018, necessitating HU override for proton planning., Conclusions: I-SPs provide a manifest CT contrast, allowing for delineation on planning CT alone with no magnetic resonance imaging necessary. I-SPs radiopacity, size, and relative position remained stable over courses of treatment from 28 to 44 fractions. No changes in plan quality or robustness were seen comparing I-SPs and nonI-SPs., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups., Methods: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855., Findings: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group., Interpretation: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended., Funding: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology., Competing Interests: Declaration of interests AUK reports personal fees from Varian Medical Systems, ViewRay, and Intelligent Automation; and research support from ViewRay, the American Society for Radiation Oncology, the Prostate Cancer Foundation, and the Jonsson Comprehensive Cancer Center, all outside the submitted work. FYF reports a consulting or advisory role for Astellas, Bayer, BlueEarth Diagnostics, Celgene, EMD Serono, Genentech, Janssen, Myovant, Ryovant, Bristol Myers Squibb, Exact Sciences, Varian, Bluestar Genomics, and Serimmun; and research funding from Zenth Epigenetics. AN reports personal fees from AstraZeneca, outside the submitted work. LS reports personal fees from Sanofi Canada and Varian Medical Systems, outside the submitted work. JAE reports personal fees from Blue Earth, Boston Scientific, AstraZeneca, Taris Biomedical, Merck, Roviant Pharma, and Myovant Sciences. HMS is a member of a clinical trial steering committee for Janssen and reports stock from Radiogel for an inactive role on medical advisory board, all outside of the submitted work. MBR reports personal fees from Amgen, Clovis, Janssen, Bayer, and Abrx; and research support from Janssen and Merck, outside the submitted work. NGN reports research funding from Janssen, Lantheus, and Bayer; and consulting fees from Oncolinea. DES declares personal fees from Janssen, AstraZeneca, and BlueEarth, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)