Search

Purpose of Review: This review sought to define the emerging roles of urinary tumor DNA (utDNA) for diagnosis, monitoring, and treatment of bladder cancer. Building from early landmark studies the focus is on recent studies, highlighting how utDNA could aid personalized care., Recent Findings: Recent research underscores the potential for utDNA to be the premiere biomarker in bladder cancer due to the constant interface between urine and tumor. Many studies find utDNA to be more informative than other biomarkers in bladder cancer, especially in early stages of disease. Points of emphasis include superior sensitivity over traditional urine cytology, broad genomic and epigenetic insights, and the potential for non-invasive, real-time analysis of tumor biology. utDNA shows promise for improving all phases of bladder cancer care, paving the way for personalized treatment strategies. Building from current research, future comprehensive clinical trials will validate utDNA's clinical utility, potentially revolutionizing bladder cancer management., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recent progresses in the use of immune checkpoint inhibitor (ICI) have challenged the therapeutic standards in patients with muscle-invasive urothelial bladder carcinoma (MIBC)., Objective: To compare neoadjuvant pembrolizumab followed by radical cystectomy (RC) versus neoadjuvant chemotherapy (NAC) and RC or upfront RC, according to cisplatin eligibility., Design, Setting, and Participants: We conducted two separate analyses for cisplatin-eligible and cisplatin-ineligible cT2-4N0M0 MIBC patients. We used a propensity score adjustment that relied on inverse probability of treatment-weighting (IPTW)., Intervention: Pembrolizumab within the PURE-01 trial, and NAC and RC or upfront RC from a high-volume tertiary care referral center., Outcome Measurements and Statistical Analysis: The primary endpoint in both analyses was event-free survival (EFS), defined as freedom from recurrence, and/or death from any cause indexed from the date of treatment initiation or RC. The secondary endpoints included EFS in propensity score-matched patients, pathologic response rate, and recurrence-free survival (RFS) after RC., Results and Limitations: A total of 458 patients who underwent RC, with or without NAC, at Moffitt Cancer Center between October 2005 and October 2020, and 146 patients enrolled in PURE-01 were analyzed. In cisplatin-ineligible patients, EFS was superior in those receiving pembrolizumab (p < 0.001). The estimated 3-yr EFS was 77.8% (95% confidence interval [CI]: 63.5-95.2) for pembrolizumab and RC, and 36.1% (95% CI: 28.6-45.5) for upfront RC. EFS remained superior in those receiving neoadjuvant ICI (NICI) following IPTW (p < 0.001). In cisplatin-eligible patients, EFS was superior in those receiving pembrolizumab and RC (p < 0.001). The estimated 3-yr EFS was 86.9% (95% CI: 80.9-93.3) for pembrolizumab and 63.5% (95% CI: 56.5-71.4) for NAC. EFS remained superior in those receiving NICI following IPTW (p < 0.001). Pathologic responses and RFS in pembrolizumab-treated patients were also superior to those in NAC-treated patients. Results are limited by the retrospective nature of the study., Conclusions: In the first ever reported comprehensive comparison of outcomes between neoadjuvant ICI and NAC, followed by RC, or upfront RC, we report increased responses and improved oncologic outcomes with neoadjuvant ICI in patients with MIBC., Patient Summary: We compared the results obtained from the use of pembrolizumab and radical cystectomy with standard-of-care treatments in patients with bladder carcinoma infiltrating the muscle layer. We reported increased response and survival rates possibilities with the use of immunotherapy, anticipating the possibility to set new therapeutic standards in these patients, pending the results of ongoing randomized studies., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in the density of immune effector cells in node-negative tumors and a progressive rise in inhibitory immune players such as type 2 macrophages and upregulation of the PD-L1 checkpoint in men with N1 and N2-3 disease. There were no differences in immune cell densities with HPV status.

Purpose: While dose escalation is associated with improved local control (LC) for adrenal gland metastases (AGMs), the proximity of gastrointestinal (GI) organs-at-risk (OARs) limits the dose that can be safely prescribed via CT-based stereotactic body radiation therapy (SBRT). The advantages of magnetic resonance-guided SBRT (MRgSBRT), including tumor tracking and online plan adaptation, facilitate safe dose escalation., Methods: This is a multi-institutional review of 57 consecutive patients who received MRgSBRT on a 0.35-T MR linac to 61 AGMs from 2019 to 2021. The Kaplan-Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and LC, and the Cox proportional hazards model was utilized for univariate analysis (UVA)., Results: Median follow up from MRgSBRT was 16.4 months (range [R]: 1.1-39 months). Median age was 67 years (R: 28-84 years). Primary histologies included non-small cell lung cancer (N = 38), renal cell carcinoma (N = 6), and melanoma (N = 5), amongst others. The median maximum diameter was 2.7 cm (R: 0.6-7.6 cm), and most AGMs were left-sided (N = 32). The median dose was 50 Gy (R: 30-60 Gy) in 5-10 fractions with a median BED 10 of 100 Gy (R: 48-132 Gy). 45 cases (74 %) required adaptation for at least 1 fraction (median: 4 fractions, R: 0-10). Left-sided AGMs required adaptation in at least 1 fraction more frequently than right-sided AGMs (88 % vs 59 %, p  = 0.018). There were 3 cases of reirradiation, including 60 Gy in 10 fractions (N = 1) and 40 Gy in 5 fractions (N = 2). One-year LC, PFS, and OS were 92 %, 52 %, and 78 %, respectively. On UVA, melanoma histology predicted for inferior 1-year LC (80 % vs 93 %, p  = 0.012). There were no instances of grade 3+ toxicity., Conclusions: We demonstrate that MRgSBRT achieves favorable early LC and no grade 3 + toxicity despite prescribing a median BED 10 of 100 Gy to targets near GI OARs., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rupesh Kotecha has received personal fees from Accuray Inc., Elekta AB, ViewRay Inc., Novocure Inc., Elsevier Inc., Brainlab, Kazia Therapeutics, Castle Biosciences, and institutional research funding from Medtronic Inc., Blue Earth Diagnostics Ltd., Novocure Inc., GT Medical Technologies, AstraZeneca, Exelixis, ViewRay Inc., Brainlab, Cantex Pharmaceuticals, and Kazia Therapeutics. Tugce Kutuk has received a travel stipend from GT Medical Technologies, Inc. Sarah Hoffe has received research funding from ViewRay, Inc, and Galera Pharmaceuticals. Jessica Frakes has received consulting fees from ViewRay, Inc, and a speaker bureau role for Boston Scientific. Evan Wuthrick has received consulting fees from ViewRay, Inc, AlphaTau, Castle, and Varian. Michael Chuong has received personal fees from ViewRay, Sirtex, IBA and institutional research funding from Novocure, ViewRay, and StratPharma. Stephen Rosenberg has received consulting fees and research support from Viewray, Inc., as well as consulting fees and speaker’s honoraria from Novocure, Inc., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Objectives: Stereotactic body radiotherapy (SBRT) is widely used for localized prostate cancer and implementation of MR-guided radiotherapy has the advantage of tighter margins and improved sparing of organs at risk. Here we evaluate outcomes and time required to treat using non-adaptive MR-guided SBRT (MRgSBRT) for localized prostate cancer at our institution., Methods: From 9/2019 to 11/2021 we conducted a retrospective review of 80 consecutive patients who were treated with MRgSBRT to the prostate. Patients included low (LR) (5%), favorable intermediate (FIR) (40%), unfavorable intermediate (UIR) (49%), and high risk (HR) (6%). Short-term androgen deprivation therapy was used in 32% of patients. Target volumes included prostate gland and proximal seminal vesicles with an isotropic 3 mm margin. Treatment was prescribed to 36.25 Gy in 5 fractions every other day with urethral sparing. Hydrogel spacer was used in 18% of patients. Time on the linac was recorded as beam on time (BOT) plus total treatment time (TTT) including gating. Analyzed outcomes included PSA response and patient reported outcomes scored by the American Urological Association (AUA) questionnaire and toxicity per CTCAE v5. General linear regression model was used to analyze factors affecting PSA and AUA in longitudinal follow up, and chi-square test was used to assess factors affecting toxicity., Results: Median follow up was 19.3 months (3.8 - 36.6). Median BOT was 4.6 min (2.6 - 7.2) with a median TTT of 11 min (7.6 - 15.8). Pre-treatment vs post-RT median PSA was 6.36 (2.20 - 19.6) vs 0.85 (0.19 - 3.6), respectively ( P < 0.001). PSA decrease differed significantly when patients were stratified by risk category, favoring LR/FIR vs UIF/HR group ( P = 0.019). Four (5%) patients experienced a biochemical failure (BCF), with a median time to BCF of 20.4 months (7.9 - 34.5). Median biochemical failure free survival (BCFFS) was not reached, with 2-yr and 4-yr BCFFS of 97.1% and 72.1%, respectively. Patients with LR/FIR disease had 100% 2-yr and 4-yr BCFFS, whereas patients with UIF/HR had 95% and 41% 2-yr and 4-yr BCFFS ( P = 0.05). Mean pre-treatment AUA was 7.3 (1 - 25) vs 11.3 (1 - 26) at first follow-up; however, AUA normalized to baseline over time. Urethral Dmax ≥35 Gy trended to lower AUA score at all follow-ups ( P = 0.07). Forty-one (51%) patients reported grade 1-2 genitourinary toxicities at the 1 month follow up. Grade 3 toxicity (proctitis) was noted in 1 patient. There was no decrease in any grade rectal toxicity with use of hydrogel spacer (3 vs 6, P = 0.2). No grade ≥4 toxicities was observed., Conclusions: MRgSBRT has the potential for treatment adaptation but this comes at the cost of increased resource utilization. Our experience with non-adaptive MRgSBRT of the prostate highlights its short treatment times as well as efficacy with good PSA control and low toxicity profile., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Yamoah receives grant funding from NCI and American Cancer Society, consulting fees from Janssen R&D. Dr. Latifi receives consulting fees from ViewRay. Dr. Rosenberg receives grant funding and consulting fees from ViewRay. The remaining authors have no disclosures.

Background: Despite abundant evidence supporting the use of perioperative chemotherapy from clinical trials, no study to date has comprehensively evaluated its use in the treatment of muscle-invasive bladder cancer (MIBC) in the real-world setting. Little is known regarding the impact of pretreatment disease stage and real-world factors such as patient comorbidities preventing timely completion of therapy on its effectiveness. This study aims to assess the usage of perioperative chemotherapy and examines its impact on pathologic downstaging rates and recurrence free survival in patients undergoing radical cystectomy., Methods: A retrospective review was conducted in 805 patients with muscle invasive bladder cancer undergoing radical cystectomy with no perioperative chemotherapy, 761 with presurgical chemotherapy followed by radical cystectomy, and 134 radical cystectomy followed by adjuvant chemotherapy. Relevant clinicopathologic features were reviewed. Recurrence-free survival and Overall Survival probability estimates were calculated using the Kaplan-Meier method and compared using the Log-rank or Gehan-Breslow tests. The prognostic effects of presurgical chemotherapy and adjuvant chemotherapy regimens were evaluated by estimating hazard ratio and 95% confidence interval from an adjusted Cox proportional hazards model. Statistical tests were 2-sided, and significance was defined as P-value < 0.05., Results: In this contemporary, real-world cohort, 5-yr RFS was found to be 65.6% in pT0, 59.1%in pT2, and 10.8% in pN+ patients. Presurgical chemotherapy increased pathologic downstaging rates from 27.5% to 41.1% in patients with ≥cT2 BCa. Stratified by clinical T-stage, only cT2 patients derived recurrence-free survival (Median 45.3 months vs. 29.0 months, P < 0.01) and overall survival (Median 62.3 months vs. 41.9 months, P < 0.001) benefits.  In patients with adverse pathologic features (≥pT3 or pN+), adjuvant chemotherapy improved recurrence-free survival (Median 22.8 months vs. 10.0 months, P < 0.0001) and overall survival (Median OS 32.4 months vs. 16.3 months, P < 0.0001)., Conclusions: We report real-world outcomes from a large cohort of muscle-invasive bladder cancer patients undergoing surgical treatment with/out perioperative chemotherapy. Pathologic response rates to pre-surgical chemotherapy were modest and led to clinical benefit only in cT2 patients. Adjuvant chemotherapy provided survival benefit for pathologically advanced MIBC patients irrespective of pT/N staging., Competing Interests: Declaration of Competing Interest There are no conflicts of interest pertaining to this study. RL: Research support: Predicine, Veracyte, CG Oncology, Valar Labs; Clinical trial protocol committee – CG Oncology; Scientific advisor/consultant – BMS, Merck, Ferring, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence; Honoraria – SAI MedPartners, Solstice Health Communications. JZ: Scientific advisor/consultant — Seagen. PS: COI — Vice Chair, NCCN Bladder and Penile Panel. WS: Consultant/ Advisory Board — Urogen Pharmaceuticals, Pacific Edge Diagnostics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Guideline recommendations disagree on template boundaries for pelvic lymph node dissection (PLND) in conventional urothelial carcinoma. Less is known about PLND in variant histology. We aimed to analyze the role of LND in plasmacytoid urothelial carcinoma (PUC)., Methods: A retrospective review of patients with cTanyNanyM0 PUC who underwent radical cystectomy (RC) with PLND was performed from 2012 to 2022. Lymph node count (LNC) was a surrogate for extent of lymph node dissection and dichotomized based on maximally selected rank statistics. Multivariable cox hazard regression analysis (MVA) for overall survival (OS) corrected for age, perioperative chemotherapy, soft tissue margin status, and stage ≥pT3 and/or pN+ was performed. Disease free survival (DFS) and OS were estimated using Kaplan-Meier (KM) analysis., Results: Sixty-seven patients with median age of 71, who were 79.1% male were included. Neoadjuvant and adjuvant chemotherapy were administered in 61.2% and 19.4% of patients, respectively. At RC, 70.1% were ≥pT3. Median LNC was 22 (IQR 14-27) with 43.3% of patients being pN+. Calculated optimal-LNC cut point for DFS and OS was 19. Grouping by optimal (≥20) vs. suboptimal-LNC (<20), no significant clinicodemographic differences were found. Optimal-LNC provided improved DFS (P = 0.05) and OS (P = 0.02). Optimal-LNC (HR 0.47, 0.24-0.93 CI 95%, P = 0.03) and negative soft tissue margin (HR 0.38, 0.19-0.76 CI 95%, P = 0.01) was associated with improved OS on MVA. Receipt of perioperative chemotherapy did not improve OS (P = 0.46)., Conclusion: In PUC, complete surgical extirpation achieving negative soft tissue margins and removing ≥20 lymph should be prioritized if operative intervention is pursued., (Copyright © 2023 Elsevier Inc. All rights reserved.)

PSCC is a rare cancer, with approximately half of all cases related to HPV. While HPV and p16 IHC testing have proven their prognostic value for oropharyngeal cancer, this is not yet established for PSCC. The current level of evidence exploring the relation between PSCC and HPV is moderate, so we conducted a systematic review following PRISMA guidelines to evaluate the prognostic role of HPV and p16 IHC in PSCC clinical outcomes. We searched the PubMed, Embase, and Cochrane databases and identified 34 relevant studies that met our inclusion criteria. Of these, 33 were retrospective cohort studies, and one was a cross-sectional study. Nine studies reported that HPV-positive and p16-positive PSCC had better overall survival (OS) and disease-free survival (DFS). This study highlights the need for a meta-analysis to determine the role of routine HPV status or p16 staining testing as part of the initial diagnosis and staging of PSCC patients worldwide.

Purpose: Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes., Methods and Materials: We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes., Results: Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified., Conclusions: This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Penile squamous cell carcinoma (PSCC) is a rare malignancy in most parts of the world and the underlying mechanisms of this disease have not been fully investigated. About 30-50% of cases are associated with high-risk human papillomavirus (HPV) infection, which may have prognostic value. When PSCC becomes resistant to upfront therapies there are limited options, thus further research is needed in this venue. The extracellular domain-facing protein profile on the cell surface (i.e., the surfaceome) is a key area for biomarker and drug target discovery. This research employs computational methods combined with cell line translatomic (n = 5) and RNA-seq transcriptomic data from patient-derived tumors (n = 18) to characterize the PSCC surfaceome, evaluate the composition dependency on HPV infection, and explore the prognostic impact of identified surfaceome candidates. Immunohistochemistry (IHC) was used to validate the localization of select surfaceome markers. This analysis characterized a diverse surfaceome within patient tumors with 25% and 18% of the surfaceome represented by the functional classes of receptors and transporters, respectively. Significant differences in protein classes were noted by HPV status, with the most change being seen in transporter proteins (25%). IHC confirmed the robust surface expression of select surfaceome targets in the top 85% of expression and a superfamily immunoglobulin protein called BSG /CD147 was prognostic of survival. This study provides the first description of the PSCC surfaceome and its relation to HPV infection and sets a foundation for novel biomarker and drug target discovery in this rare cancer.

Precision medicine has transformed the way urothelial carcinoma is managed. However, current practices are limited by the availability of tissue samples for genomic profiling and the spatial and temporal molecular heterogeneity observed in many studies. Among rapidly advancing genomic sequencing technologies, non-invasive liquid biopsy has emerged as a promising diagnostic tool to reproduce tumour genomics, and has shown potential to be integrated in several aspects of clinical care. In urothelial carcinoma, liquid biopsies such as plasma circulating tumour DNA (ctDNA) and urinary tumour DNA (utDNA) have been investigated as a surrogates for tumour biopsies and might bridge many shortfalls currently faced by clinicians. Both ctDNA and utDNA seem really promising in urothelial carcinoma diagnosis, staging and prognosis, response to therapy monitoring, detection of minimal residual disease and surveillance. The use of liquid biopsies in patients with urothelial carcinoma could further advance precision medicine in this population, facilitating personalized patient monitoring through non-invasive assays., (© 2023. Springer Nature Limited.)

The genomic era has significantly changed the practice of clinical oncology. The use of genomic-based molecular diagnostics including prognostic genomic signatures and new-generation sequencing has become routine for clinical decisions regarding cytotoxic chemotherapy, targeted agents and immunotherapy. In contrast, clinical decisions regarding radiation therapy (RT) remain uninformed about the genomic heterogeneity of tumors. In this review, we discuss the clinical opportunity to utilize genomics to optimize RT dose. Although from the technical perspective, RT has been moving towards a data-driven approach, RT prescription dose is still based on a one-size-fits all approach, with most RT dose based on cancer diagnosis and stage. This approach is in direct conflict with the realization that tumors are biologically heterogeneous, and that cancer is not a single disease. Here, we discuss how genomics can be integrated into RT prescription dose, the clinical potential for this approach and how genomic-optimization of RT dose could lead to new understanding of the clinical benefit of RT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions., (© 2023. The Author(s).)

Purpose: Bladder preservation with trimodal therapy (TMT; maximal tumor resection followed by chemoradiation) is an effective paradigm for select patients with muscle invasive bladder cancer. We report our institutional experience of a TMT protocol using nonadaptive magnetic resonance imaging-guided radiation therapy (MRgRT) for partial bladder boost (PBB)., Methods and Materials: A retrospective analysis was performed on consecutive patients with nonmetastatic muscle invasive bladder cancer who were treated with TMT using MRgRT between 2019 and 2022. Patients underwent intensity modulated RT-based nonadaptive MRgRT PBB contoured on True fast imaging with steady state precession (FISP) images (full bladder) followed sequentially by computed tomography-based RT to the whole empty bladder and pelvic lymph nodes with concurrent chemotherapy. MRgRT treatment time, table shifts, and dosimetric parameters of target coverage and normal tissue exposure were described. Prospectively assessed acute and late genitourinary and gastrointestinal (GI) toxicity were reported. Two-year local control was assessed with Kaplan-Meier methods., Results: Seventeen patients were identified for analysis. PBB planning target volume margins were ≤8 mm in 94% (n = 16) of cases. Dosimetric target coverage parameters were favorable and all normal tissue dose constraints were met. For MRgRT PBB fractions, median table shifts were 0.4 cm (range, 0-3.15), 0.45 cm (0-2.65), and 0.75 cm (0-4.8) in the X, Y, and Z planes, respectively. Median treatment time for MRgRT PBB fractions was 9 minutes (range, 6.9-17.4). We identified 32 out of 100 total MRgRT fractions that may have benefitted from online adaptation based on changes in organ position relative to planning target volume, predominantly because of small bowel (13/32, 41%) or rectum (8/32, 25%). Two patients discontinued RT prematurely. The incidence of highest-grade acute genitourinary toxicity was 1 to 2 (69%) and 3 (6%), whereas the incidence of acute GI toxicity was 1 to 2 (81%) and 3 (6%). There were no late grade 3 events; 17.6% had late grade 2 cystitis and none had late GI toxicity. With median follow-up of 18.2 months (95% CI, 12.4-22.5), the local control rate was 92%, and no patient has required salvage cystectomy., Conclusions: Nonadaptive MRgRT PBB is feasible with favorable dosimetry and low resource utilization. Larger studies are needed to evaluate for potential benefits in toxicity and local control associated with this approach in comparison to standard treatment techniques., Competing Interests: Kujtim Latifi reports consulting fees with ViewRay Inc. Stephen A. Rosenberg reports research funding from ViewRay Inc and serves on the ViewRay Lung Research Consortium. G. Daniel Grass reports consulting fees for MyCareGorithm., (© 2023 The Authors.)

Introduction and Objective: Muscle invasive bladder cancer with extravesical extension is an aggressive disease entity that requires multimodal therapy. The benefits of adjuvant chemotherapy (AC) in patients with a positive soft-tissue surgical margin (STSM), however, are relatively unknown due to exclusion of this population in randomized controlled trials of AC. We sought to define survival benefits in this patient population through our institutional bladder cancer database., Methods: Retrospective review of all patients undergoing radical cystectomy for urothelial carcinoma of the bladder from 2004-2020 with ≥pT3b disease irrespective of neoadjuvant chemotherapy (NAC) use was conducted. Progression-free survival (PFS) and overall survival (OS) estimates were obtained using the Kaplan-Meier method with log-rank test, and the Cox-proportional hazards model was used to identify predictors of improved PFS and OS. AC was defined by any chemotherapy use within 90 days of cystectomy, regardless of STSM status., Results: 476 patients with pT3b disease or worse were identified. Median follow-up was 12.3 months. An amount of 21% of patients were treated with AC. An amount of 24% of patients had positive STSM. Median OS for patients with positive STSM was 8.4 months [95% CI 7-11.5] and 18.3 months [95% CI 15.6-20.8] ( p < 0.001) for patients with negative STSM. In the overall cohort, positive STSM (HR 1.93, 95% CI 1.45-2.57, p < 0.001), AC use (HR 0.68, 95% CI 0.51-0.90, p = 0.007), and pN1-3 disease (HR 1.47, 95% CI 1.16-1.87, p = 0.002) were independent predictors of OS when adjusted for performance status, pT-stage, and neoadjuvant chemotherapy use. In patients with positive STSM, median survival was seven months [95% CI 5.2-8.4] without AC, compared to 16.2 months [95% CI 11.5-52.5] with AC ( p = 0.0038). For patients with negative STSM, median survival was 17.4 months [95% CI 14-20.1] without AC compared to 22.3 months [95% CI 17.2-36.9] with AC ( p = 0.23). In patients with positive STSM, AC use was the only factor associated with an OS benefit with a HR of 0.41 (95% CI 0.21-0.78, p = 0.007). In patients with negative STSM, pT4 and pN1-3 disease were the only factors associated with worse overall survival with a HR of 1.32 (95% CI 1.00-1.74, p = 0.050) and 1.97 (95% CI 1.49-2.60, p < 0.001), respectively., Conclusions: Administration of adjuvant chemotherapy is of particular benefit in patients with positive STSM following radical cystectomy for gross extravesical disease. Positive STSM may be a representative of "early metastatic" or micrometastatic disease.

Penile squamous cell carcinoma (PSCC) remains a worldwide healthcare concern with poor outcomes and inadequate therapeutic options. Molecular characterization continues to describe the intricacies of PSCC biology, which vary by human papillomavirus (HPV) infection. Despite these advancements in our understanding, utilization of targeted therapies remains limited and underexplored. In this study, we evaluated the transcript and protein expression of Nectin-4 (PVRL4) in PSCC tumors and evaluated whether this is related to tumor features or clinical outcomes. Using two separate PSCC cohorts, we demonstrate that the majority of tumors have active transcription of Nectin-4. We then validated our findings using immunohistochemistry in a tissue microarray representing 57 patients with PSCC. We identified that Nectin-4 was expressed at higher levels in patients with high-risk HPV infection. No significant differences were identified in tumor characteristics or various clinical endpoints when comparing tumors with high and low Nectin-4 expression. This study demonstrates that Nectin-4 is expressed in PSCC and may represent a novel therapeutic target., Patient Summary: In this study, we evaluated the expression of Nectin-4, a cell surface protein, in tumors from patients with nonmetastatic penile squamous cell carcinoma (PSCC). To our knowledge, this is the first study to describe elevated expression of Nectin-4 in PSCC, which may suggest its utility as a therapeutic target., (© 2023 The Author(s).)

Background: Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting., Methods: This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non-African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score., Results: The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non-African American men). A higher proportion of African American men with National Comprehensive Cancer Network-classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non-African American men. Self-identified African American men were twice more likely than non-African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes., Conclusions: Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions., (Published by Oxford University Press 2022.)

Objective: Penile cancer is a rare malignancy in most developed countries, but may represent a significant oncologic challenge in certain African, Asian, and South American regions. Various treatment approaches have been described in penile cancer, including radiotherapy. This review aimed to provide a synopsis of radiotherapy use in penile cancer management and the associated toxicities. In addition, we aimed to discuss palliative radiation for metastases to the penis and provide a brief overview of how tumor biology may assist with treatment decision-making., Methods: Peer-reviewed manuscripts related to the treatment of penile cancer with radiotherapy were evaluated by a PubMed search (1960-2021) in order to assess its role in the definitive and adjuvant settings. Selected manuscripts were also evaluated for descriptions of radiation-related toxicity., Results: Though surgical resection of the primary is an excellent option for tumor control, select patients may be treated with organ-sparing radiotherapy by either external beam radiation or brachytherapy. Data from randomized controlled trials comparing radiotherapy and surgery are lacking, and thus management is frequently determined by institutional practice patterns and available expertise. Similarly, this lack of clinical trial data leads to divergence in opinion regarding lymph node management. This is further complicated in that many cited studies evaluating lymph node radiotherapy used non-modern radiotherapy delivery techniques. Groin toxicity from either surgery or radiotherapy remains a challenging problem and further risk assessment is needed to guide intensification with multi-modal therapy. Intrinsic differences in tumor biology, based on human papillomavirus infection, may help aid future prognostic and predictive models in patient risk stratification or treatment approach., Conclusion: Penile cancer is a rare disease with limited clinical trial data driving the majority of treatment decisions. As a result, the goal of management is to effectively treat the disease while balancing the importance of quality of life through integrated multidisciplinary discussions. More international collaborations and interrogations of penile cancer biology are needed to better understand this disease and improve patient outcomes., Competing Interests: Philippe E. Spiess is the President of Global Society of Rare Genitourinary Tumors, the vice-chair NCCN bladder and penile cancer, and a member of ASCO/EAU penile cancer panel. Other authors declare no other conflict of interest., (© 2022 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Purpose: Radiation therapy (RT) is a mainstay of cancer care, and accumulating evidence suggests the potential for synergism with components of the immune response. However, few data describe the tumor immune contexture in relation to RT sensitivity. To address this challenge, we used the radiation sensitivity index (RSI) gene signature to estimate the RT sensitivity of >10,000 primary tumors and characterized their immune microenvironments in relation to the RSI., Methods and Materials: We analyzed gene expression profiles of 10,469 primary tumors (31 types) within a prospective tissue collection protocol. The RT sensitivity of each tumor was estimated by the RSI and respective distributions were characterized. The tumor biology measured by the RSI was evaluated by differentially expressed genes combined with single sample gene set enrichment analysis. Differences in the expression of immune regulatory molecules were assessed and deconvolution algorithms were used to estimate immune cell infiltrates in relation to the RSI. A subset (n = 2368) of tumors underwent DNA sequencing for mutational frequency characterization., Results: We identified a wide range of RSI values within and across various tumor types, with several demonstrating nonunimodal distributions (eg, colon, renal, lung, prostate, esophagus, pancreas, and PAM50 breast subtypes; P < .05). Across all tumor types, stratifying RSI at a tumor type-specific median identified 7148 differentially expressed genes, of which 146 were coordinate in direction. Network topology analysis demonstrates RSI measures a coordinated STAT1, IRF1, and CCL4/MIP-1β transcriptional network. Tumors with an estimated high sensitivity to RT demonstrated distinct enrichment of interferon-associated signaling pathways and immune cell infiltrates (eg, CD8 + T cells, activated natural killer cells, M1-macrophages; q < 0.05), which was in the context of diverse expression patterns of various immunoregulatory molecules., Conclusions: This analysis describes the immune microenvironments of patient tumors in relation to the RSI gene expression signature., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Grade group 4 and 5 (GG-45) prostate cancer (PCa) patients are at the highest risk of lethal outcomes, yet lack genomic risk stratification for prognosis and treatment selection. Here, we assess whether transcriptomic interactions between tumor immune content score (ICS) and the Decipher genomic classifier can identify most lethal subsets of GG-45 PCa. We utilized whole transcriptome data from 8071 tumor tissue (6071 prostatectomy and 2000 treatment-naïve biopsy samples) to derive four immunogenomic subtypes using ICS and Decipher. When compared across all grade groups, GG-45 samples had the highest proportion of most aggressive subtype-ICS High /Decipher High . Subsequent analyses within the GG-45 patient samples (n = 1420) revealed that the ICS High /Decipher High subtype was associated with increased genomic radiosensitivity. Additionally, in a multivariable model (n = 335), ICS High /Decipher High subtype had a significantly higher risk of distant metastasis (hazard ratio [HR] = 5.41; 95% confidence interval [CI], 2.76-10.6; p ≤  0.0001) and PCa-specific mortality (HR = 10.6; 95% CI, 4.18-26.94; p ≤  0.0001) as compared with ICS Low /Decipher Low . The novel immunogenomic subtypes establish a very strong synergistic interaction between ICS and Decipher in identifying GG-45 patients who experience the most lethal outcomes. PATIENT SUMMARY: In this analysis, we identified a novel interaction between the total immune content of prostate tumors and genomic classifier to identify the most lethal subset of patients with grade groups 4 and 5. Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Understanding patterns of relapse for primary central nervous system lymphoma (PCNSL) may inform mechanisms of recurrence and optimal consolidation strategies. In this study, we report patterns of relapse among patients with PCNSL who achieved a complete response to high-dose methotrexate (HD-MTX)-based chemotherapy with or without consolidation radiation therapy (RT)., Methods and Materials: We conducted an institutional retrospective analysis of patients with PCNSL who received HD-MTX-based chemotherapy between November 2001 and May 2019. Relapses were characterized as in-field (within original T1 contrasted lesion), marginal (within T2 fluid-attenuated inversion recovery but not T1), local (in-field or marginal), distant brain (no overlap), or distant (distant brain, cerebrospinal fluid, vitreous or extra-axial) and further characterized with respect to periventricular location (≤10 mm of ventricles)., Results: Seventy-eight patients with PCNSL met inclusion criteria, of whom 29 (37%) underwent consolidation RT. Median progression-free survival and overall survival were 57.0 and 66.7 months, respectively. After a median follow-up of 38.9 months, a total of 32 patients (41%) experienced recurrence. Most patients (21 [65.6%]) had a periventricular failure. Surprisingly, local recurrences (n = 11) were exclusively observed within periventricular lesions, whereas distant recurrences (n = 21) were seen in both periventricular and nonperiventricular locations ( P  = .009). The median time to progression was shorter for locally recurrent lesions compared with distant recurrences (13.8 vs 26.1 months; P  = .03)., Conclusions: After complete response to HD-MTX, few failures occurred within initial T1 contrast-enhancing lesions and many of these may have been alternatively classified as periventricular failures. These observations argue against the use of purely focal RT consolidation for patients who achieve a complete response after HD-MTX-based chemotherapy and suggest that periventricular reseeding may have a central role in PCNSL recurrence., (© 2022 The Authors.)

Radiation therapy (RT) has not been prominent in the treatment of penile cancer because of poorly reproducible results when used in the adjuvant setting. A genomic signature has recently been described that assays radiosensitivity of tumors and informs radiotherapy doses in these cases. Clinical validation in more than 1600 patients demonstrated associations with both overall survival and time to first recurrence. In addition, the signature predicted and quantified the therapeutic benefit of RT for each individual patient. Since penile cancer patients were not part of this analysis, we applied the model to patients with primary and nodal penile cancer tissue and clinical outcomes. Patient summary : Radiotherapy has not been widely used for treatment of penile cancer. New genetic data suggest that radiation doses commonly used to treat penile cancer are too low. This would explain prior poor results using radiation in this disease., (© 2021 The Author(s).)

Radiotherapy efficacy is the result of radiation-mediated cytotoxicity coupled with stimulation of antitumor immune responses. We develop an in silico 3-dimensional agent-based model of diverse tumor-immune ecosystems (TIES) represented as anti- or pro-tumor immune phenotypes. We validate the model in 10,469 patients across 31 tumor types by demonstrating that clinically detected tumors have pro-tumor TIES. We then quantify the likelihood radiation induces antitumor TIES shifts toward immune-mediated tumor elimination by developing the individual Radiation Immune Score (iRIS). We show iRIS distribution across 31 tumor types is consistent with the clinical effectiveness of radiotherapy, and in combination with a molecular radiosensitivity index (RSI) combines to predict pan-cancer radiocurability. We show that iRIS correlates with local control and survival in a separate cohort of 59 lung cancer patients treated with radiation. In combination, iRIS and RSI predict radiation-induced TIES shifts in individual patients and identify candidates for radiation de-escalation and treatment escalation. This is the first clinically and biologically validated computational model to simulate and predict pan-cancer response and outcomes via the perturbation of the TIES by radiotherapy., (Copyright © 2021. Published by Elsevier Inc.)

Background: Data on the impact of human papillomavirus (HPV) infection status and outcomes for perioperative treatments for patients with lymph node-involved penile squamous-cell carcinoma (PSCC) are lacking., Objective: To analyze the benefit from perioperative radiotherapy (RT) for PSCC according to HPV infection status., Design, Setting, and Participants: In an international multicenter database of 1254 patients with PSCC who received inguinal lymph node dissection (ILND), 507 had suitable clinical information., Intervention: ILND, with or without chemotherapy or RT for involved lymph nodes., Outcome Measurements and Statistical Analysis: Kaplan-Meier and restricted mean survival time (RMST) analyses for overall survival (OS) were performed for all patients and after propensity score-matching (PSM; n = 136), for which patient age, histology, type of penile surgical procedure, pathological tumor and nodal stage, ILND laterality, pelvic LND, and perioperative treatment were taken into account when assessing differences between HPV + and HPV- patients. Finally, we looked at genomic alterations in PSCC using data from the Foundation Medicine database (n = 199) to characterize HPV + PSCC., Results and Limitations: Patients with HPV + PSCC (n = 86; 17%) had lower clinical N stage (p < 0.001) and inguinal lymph node metastasis density (p < 0.001). Perioperative RT was delivered in 49 patients (9.7%), with the vast majority receiving adjuvant RT (n = 40). HPV + patients had similar median OS (p = 0.1) but longer RMST than HPV- patients at different time points. Nevertheless, HPV + patients treated with perioperative RT exhibited longer median OS (p = 0.015) and longer RMST compared to HPV- patients. In the PSM cohorts, HPV + status remained significantly associated with longer OS after RT. The HPV- PSCC group had a higher frequency of TP53 mutations compared to HPV + PSCC (75% vs 15%; p < 0.001). The results are limited by the retrospective nature of the data., Conclusions: Perioperative RT was more effective in the HPV + PSCC subgroup. Reasons for the enhanced radiosensitivity may be related to the lack of TP53 mutations., Patient Summary: We analyzed data from a large multicenter database for patients with penile cancer who had received inguinal lymph node dissection, with or without chemotherapy or radiotherapy. We found that for tumors positive for human papillomavirus (HPV), use of radiotherapy resulted in prolonged survival compared to HPV-negative tumors. On the basis of these results we are inspired to design studies on the use of radiotherapy in HPV-selected patients., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The use of stereotactic body radiation therapy (SBRT) is widely utilized for treatment of localized prostate cancer. Magnetic-resonance-guided radiotherapy (MRgRT) was introduced in 2014 and has recently been implemented in SBRT for prostate cancer as it provides an opportunity for smaller margins and adaptive daily planning. Currently, the only publications of MRgRT for prostate SBRT describe European clinical experiences which utilized adaptive planning. However, adaptive planning adds significantly to the time required for daily treatment., Objectives: Since prostate SBRT has demonstrated acceptable toxicity for several years, we did not consider daily adaptation critical to the process of prostate SBRT. After Institutional Review Board approval, we analyzed and now report our experience using MRgRT without adaptation., Methods: Between 25 September 2019 and 21 December 2020, 35 consecutive patients were treated with MRgRT prostate SBRT at our center. Patients treated with MRgRT included favorable intermediate risk (43%) and unfavorable intermediate risk (54%), and only one patient had low-risk prostate cancer. Nine patients (25%) received adjuvant leuprolide for a median of 4.5 months (range 4-6 m). Our clinical pathway allows for a maximum prostate gland volume of 60 cc; median prostate volume of this cohort was 35.0 cc (range 17-58.4 cc). Median pre-treatment PSA was 6.30 (range 2.55-16.77). Each patient was treated with 36.25 Gy delivered in five fractions over 2 weeks with urethral sparing to a maximal dose of 35 Gy. Target volumes included the prostate gland and proximal seminal vesicles with a 3 mm margin., Results: Median follow-up as of 26 May 2021 was 11.97 months (range 4.37-19.80). First follow-up data are available for all patients, with a median of 1.10 month from completion of treatment (0.63-3.40). The median PSA at first visit was 2.75 (range 0.02-9.00) with a median AUA symptom score of 9 (range 1-24). Second follow-up data are available for 34 patients at a median of 4.45 months (range 2.57-8.90). At second follow-up, the median PSA was 1.60 (range 0.02-5.40) with a median AUA symptom score of 6 (range 1-33). Seventeen patients had third follow-up data with a median of 9.77 months (range 4.70-12.33) after SBRT. The median PSA was 1.13 (range 0.02-4.73) with an AUA score of 9 (2-22) at the third follow-up. We observed a statistically significant decrease in PSA between pre-treatment and at first follow-up ( p < 0.005). The most common toxicity was grade 2 urethritis, managed in all cases by tamsulosin. One patient developed grade 2 tenesmus relieved by topical steroids. No cases of grade ≥ 3 toxicity were seen in our patient population., Conclusions: By avoiding the extra time required for plan adaptation, MRgRT without daily adaptation allows for successful prostate SBRT with manageable toxicity. We continue to reserve our limited adaptive treatment slots for preoperative pancreatic and ultra-central lung SBRT patients, which require time-intensive respiratory gating and adaptive planning.

Purpose: To assess the effectiveness and safety of prostatic artery embolization (PAE) on lower urinary tract symptoms (LUTS) in the setting of localized prostate cancer (PCa)., Materials and Methods: This was a retrospective, single-center, institutional review board-approved study from December 2016 to June 2020 of 21 patients (median age, 72; range, 63-83 years) with moderate LUTS and localized PCa. Clinical effectiveness was evaluated at 6 and 12 weeks using International Prostate Symptom Score (IPSS) and quality of life (QoL) improvement. Seventeen patients were scheduled to receive definitive radiotherapy (RT) after PAE; 13 patients completed RT. Short-term imaging signs of oncologic progression were evaluated at 6 and 12 weeks defined by at least one of the following on magnetic resonance imaging: increased Prostate Imaging-Reporting and Data System score of index lesion(s) to at least 4, new extracapsular extension, seminal vesicle involvement, or pelvic lymphadenopathy. Nonparametric Wilcoxon signed-rank test was used for analysis., Results: IPSS improved by a median of 12 (n = 19, P < .0001) and 14 (n = 14, P < .0001) at 6 and 12 weeks, respectively. QoL improved by a median of 2 (n = 19, P < .0001) and 3 (n = 3, P < .0001) at 6 and 12 weeks. Prostate volume decreased by a median of 24% (n = 19, P < .0001) and 36% (n = 12, P = .015) at 6 and 12 weeks. No patients demonstrated disease progression at 6 (n = 16) or 12 (n = 8) weeks by imaging. No patients experienced increased prostate-specific antigen after RT, grade ≥3 adverse events, or greater genitourinary toxicity., Conclusions: PAE is effective and safe for the treatment of men with LUTS from benign prostatic hyperplasia in the setting of concomitant, localized, non-obstructive PCa., (Copyright © 2021 SIR. Published by Elsevier Inc. All rights reserved.)

There is emerging evidence that the adaptive anti-tumor activity may be orchestrated by secondary lymphoid organ-like aggregates residing in the tumor microenvironment. Known as tertiary lymphoid structures, these lymphoid aggregates serve as key outposts for lymphocyte recruitment, priming and activation. They have been linked to favorable outcomes in many tumor types, and more recently, have been shown to be effective predictors of response to immune checkpoint blockade. We have previously described a 12-chemokine (12-CK) transcriptional score which recapitulates an overwhelming enrichment for immune-related and inflammation-related genes in colorectal carcinoma. Subsequently, the 12-CK score was found to prognosticate favorable survival in multiple tumors types including melanoma, breast cancer, and bladder cancer. In the current study, we summarize the discovery and validation of the 12-CK score in various tumor types, its relationship to TLSs found within the tumor microenvironment, and explore its potential role as both a prognostic and predictive marker in the treatment of various cancers., Competing Interests: RL: Clinical trial protocol committee - Cold Genesys, BMS; Scientific advisor/consultant – BMS, Fergene. JM: Associate Center Director at Moffitt Cancer Center, has ownership interest in Fulgent Genetics, Inc., Aleta Biotherapeutics, Inc., CG Oncology, Inc., Myst Pharma, Inc., Verseau Therapeutics, Inc., AffyImmune, Inc., and Tailored Therapeutics, Inc., and is a paid consultant/paid advisory board member for ONCoPEP, Inc., CG Oncology, Inc., Morphogenesis, Inc., Mersana Therapeutics, Inc., GammaDelta Therapeutics, Ltd., Myst Pharma, Inc., Tailored Therapeutics, Inc., Verseau Therapeutics, Inc., Iovance Biotherapeutics, Vault Pharma, Inc., Noble Life Sciences, and Fulgent Genetics, Inc., UbiVac, LLC, Vycellix, Inc., AffyImmune, Inc., and Aleta Biotherapeutics, Inc. A patent on the 12 chemokine gene expression signature in bladder cancer was issued on March 10, 2020, titled, “Immune Gene Signatures in Urothelial Carcinoma (UC)” (10,583,183). Inventors are: JM, Anthony M. Magliocco, and AB. A provisional patent application was filed on August 27, 2020, titled “Immune Gene Signature in Muscle Invasive Bladder Cancer” (Serial No. 63/071,320). Inventors are: RL, JM, and AB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Berglund, Zemp, Dhillon, Putney, Kim, Jain, Grass, Conejo-Garcia and Mulé.)

Background: To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa., Methods: Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189)., Results: Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders., Conclusion: Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.

Introduction: Cancer sequencing efforts have revealed that cancer is the most complex and heterogeneous disease that affects humans. However, radiation therapy (RT), one of the most common cancer treatments, is prescribed on the basis of an empirical one-size-fits-all approach. We propose that the field of radiation oncology is operating under an outdated null hypothesis: that all patients are biologically similar and should uniformly respond to the same dose of radiation., Methods: We have previously developed the genomic-adjusted radiation dose, a method that accounts for biological heterogeneity and can be used to predict optimal RT dose for an individual patient. In this article, we use genomic-adjusted radiation dose to characterize the biological imprecision of one-size-fits-all RT dosing schemes that result in both over- and under-dosing for most patients treated with RT. To elucidate this inefficiency, and therefore the opportunity for improvement using a personalized dosing scheme, we develop a patient-specific competing hazards style mathematical model combining the canonical equations for tumor control probability and normal tissue complication probability. This model simultaneously optimizes tumor control and toxicity by personalizing RT dose using patient-specific genomics., Results: Using data from two prospectively collected cohorts of patients with NSCLC, we validate the competing hazards model by revealing that it predicts the results of RTOG 0617. We report how the failure of RTOG 0617 can be explained by the biological imprecision of empirical uniform dose escalation which results in 80% of patients being overexposed to normal tissue toxicity without potential tumor control benefit., Conclusions: Our data reveal a tapestry of radiosensitivity heterogeneity, provide a biological framework that explains the failure of empirical RT dose escalation, and quantify the opportunity to improve clinical outcomes in lung cancer by incorporating genomics into RT., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer., Methods and Materials: Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year., Results: The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval [CI], 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02)., Conclusions: Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Recurrent high-grade glioma (HGG) remains incurable with inevitable evolution of resistance and high inter-patient heterogeneity in time to progression (TTP). Here, we evaluate if early tumor volume response dynamics can calibrate a mathematical model to predict patient-specific resistance to develop opportunities for treatment adaptation for patients with a high risk of progression. A total of 95 T1-weighted contrast-enhanced (T1post) MRIs from 14 patients treated in a phase I clinical trial with hypo-fractionated stereotactic radiation (HFSRT; 6 Gy × 5) plus pembrolizumab (100 or 200 mg, every 3 weeks) and bevacizumab (10 mg/kg, every 2 weeks; NCT02313272) were delineated to derive longitudinal tumor volumes. We developed, calibrated, and validated a mathematical model that simulates and forecasts tumor volume dynamics with rate of resistance evolution as the single patient-specific parameter. Model prediction performance is evaluated based on how early progression is predicted and the number of false-negative predictions. The model with one patient-specific parameter describing the rate of evolution of resistance to therapy fits untrained data ( R 2 = 0.70 ). In a leave-one-out study, for the nine patients that had T1post tumor volumes ≥1 cm 3 , the model was able to predict progression on average two imaging cycles early, with a median of 9.3 (range: 3-39.3) weeks early (median progression-free survival was 27.4 weeks). Our results demonstrate that early tumor volume dynamics measured on T1post MRI has the potential to predict progression following the protocol therapy in select patients with recurrent HGG. Future work will include testing on an independent patient dataset and evaluation of the developed framework on T2/FLAIR-derived data.

Purpose: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) represents 90% of all chronic prostatitis cases and may occur after radiation therapy (RT) for localized prostate cancer. Medical therapy is effective in approximately 50% of cases, with no therapy demonstrating consistent efficacy in refractory cases. Prostatic artery embolization (PAE) is effective in men with lower urinary tract symptoms and benign prostatic hyperplasia. We report clinical improvement after PAE in a case series of men with CP/CPPS after RT., Methods and Materials: Nine men (median age 72 years; range, 61-83 years) with CP/CPPS after RT for prostate cancer underwent PAE. Baseline International Prostate Symptom Score was recorded in 5 patients (median 23; range, 4-26), Chronic Prostatitis Symptom Index score in 6 patients (median 22.5; range, 6-34), and quality of life (QoL) score in 8 patients (median 5; range, 2-6). Median baseline prostate volume was 49 cm 3 (range, 22-123 cm 3 ). Patients were followed up at 6 and 12 weeks with QoL, International Prostate Symptom Score, and/or Chronic Prostatitis Symptom Index score and magnetic resonance imaging., Results: Technical success (ie, bilateral embolization) was achieved in 78% (n = 7) of patients with the other 2 patients having undergone unilateral embolization with no major complications. Clinical success was seen in 89% (n = 8) of patients and QoL improved in 78% (n = 7) during the follow-up period., Conclusion: CP/CPPS after RT for localized prostate cancer is a highly morbid condition, with medical therapy successful in only 50% of cases. PAE may be a successful therapy for medically recalcitrant CP/CPPS, and further studies are necessary to understand the best patient selection and scenario for PAE in the setting of CP/CPPS., (© 2020 The Author(s).)

Background: Pseudoprogression (psPD) represents false radiologic evidence of tumor progression and is observed in some glioblastoma (GBM) patients after postoperative chemoradiation (CRT) with temozolomide (TMZ). The ambiguity of the psPD diagnosis confounds identification of true progression and may lead to unnecessary interventions. The association between psPD and isocitrate dehydrogenase 1 ( IDH1 ) mutational (mut) status is understudied, and its incidence may alter clinical decision making., Methods: We retrospectively evaluated 120 patients with IDH1 -mut (n = 60) and IDH1 -wild-type (IDH-WT; [n = 60]) GBMs who received postoperative CRT with TMZ at 4 academic institutions. Response Assessment in Neuro-Oncology criteria were used to identify psPD rates in routine brain MRIs performed up to 90 days after CRT completion., Results: Within 90 days of completing CRT, 9 GBM patients (1 [1.7%] IDH1 -mut and 8 [13.3%] IDH1 -WTs) demonstrated true progression, whereas 17 patients (3 [5%] IDH1 -muts and 14 [23.3%] IDH1 -WTs) demonstrated psPD ( P  =  .004). IDH1 -mut GBMs had a lower probability of psPD (hazard ratio: 0.173, 95% CI, 0.047-0.638, P = .008). Among the patients with radiologic signs suggestive of progression (n = 26), psPD was found to be the cause in 3 of 4 (75.0%) of the IDH1 -mut GBMs and 14 of 22 (63.6%) of the IDH1 -WT GBMs ( P = .496). Median overall survival for IDH1 -mut and IDH1 -WT GBM patients was 40.3 and 23.0 months, respectively ( P  < .001)., Conclusions: IDH1 -mut GBM patients demonstrate lower absolute rates of psPD expression. Irrespective of GBM subtype, psPD expression was more likely than true progression within 90 days of completing CRT. Continuing adjuvant treatment for IDH1 -mut GBMs is suggested if radiologic progression is suspected during this time interval., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The role of local disease control in the oligometastatic setting is evolving. Stereotactic body radiation therapy (SBRT) is a noninvasive treatment option for oligometastases; however, using ablative radiation doses for adrenal metastases raises concern given the proximity to radiosensitive organs. Novel treatment techniques may allow for selective dose escalation to improve local control (LC) while minimizing dose to nearby critical structures., Materials and Methods: We retrospectively reviewed patients with adrenal oligometastases treated with SBRT from 2013 to 2018. LC, disease-free survival, and overall survival were estimated using Kaplan-Meier methods. Predictors of outcomes were evaluated by log-rank and Cox proportional hazard analyses., Results: We identified 45 adrenal oligometastases in 41 patients treated with SBRT. The median age at treatment was 67 years (range, 40 to 80). The most common primary histologies were non-small cell lung cancer (51%), renal cell carcinoma (24%), and small cell lung cancer (10%). The median prescription dose was 50 Gy (range, 25 to 60 Gy), with 30 (67%) lesions receiving ≥50 Gy and 14 (31%) receiving 60 Gy. In total, 26 (58%) lesions received a simultaneous-integrated boost. Of the 42 treatment simulations, 26 (62%) were supine, 5 (12%) prone, and 11 (26%) in the left lateral decubitus position. At a median follow-up of 10.5 months, there were 3 local failures with a 12-month LC rate of 96%., Conclusions: Adrenal SBRT for oligometastatic disease is a feasible, noninvasive option with excellent LC and minimal toxicity. Lesions in close proximity to radiosensitive organs may benefit from dynamic patient positioning and selective simultaneous-integrated boost techniques to allow for dose escalation, while also limiting toxicity risks.

Purpose: Optimal postoperative radiation therapy (PORT) dose is unclear in penile squamous cell carcinoma (PeSCC). Herein, we characterized the radiosensitivity index (RSI) and genomic-adjusted radiation dose (GARD) profiles in a cohort of patients with PeSCC, and assessed the application of GARD to personalize PORT., Methods: A total of 25 PeSCC samples were identified for transcriptomic profiling. The RSI score and GARD were derived for each sample. A cohort of 34 patients was reviewed for clinical correlation., Results: The median RSI for PeSCC was 0.482 (range 0.215-0.682). The majority (n = 21; 84%) of cases were classified as radioresistant. PeSCC GARD ranged from 9.56 to 38.39 (median 18.25), suggesting variable therapeutic effects from PORT. We further determined the optimal GARD-based RT doses to improve locoregional control. We found that therapeutic benefit was only achieved in 52% of PeSCC lesions with PORT of 50 Gy, in contrast to 84% benefit from GARD-modeled PORT of 66 Gy. In the clinical cohort, the majority of patients presented with pathological N2 or N3 disease (n = 31; 91%) and was treated with adjuvant concurrent platinum-based chemoradiotherapy (CRT, n = 30; 88%). Fourteen of the 34 patients (41%) had locoregional recurrence (LRR), of which half had LRR within six months of completion of PORT., Conclusions: The majority of PeSCC are intrinsically radioresistant with a low GARD-based therapeutic effect from PORT dose of 50 Gy, consistent with the observed high rate of LRR in the clinical cohort. A GARD-based strategy will allow personalizing PORT dose prescription to individual tumor biology and improve outcomes., (© 2019 Greater Poland Cancer Centre. Published by Elsevier B.V. All rights reserved.)

Background: Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose., Methods: TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy., Findings: In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1-7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1-29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy., Interpretation: GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC., (Copyright © 2019. Published by Elsevier B.V.)

Background: Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti-PD-1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer-term survivors with MBM treated with this combination., Methods: Patients with MBM treated with radiotherapy and anti-PD-1 who survived >1 year were identified to determine radionecrosis incidence (Cohort A, n = 135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n = 148)., Results: From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery., Conclusions: Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We investigated whether adding radiation (RT) to systemic therapy improved outcomes in early stage diffuse large B-cell lymphoma (DLBCL) patients with or without double- or triple-hit lymphoma (DHL/THL) biology. This analysis included 183 patients profiled with fluorescent in situ hybridization (FISH) for alterations in MYC, BLC2, and/or BCL6. A total of 146 (80%) were non-DHL/THL, 27 (15%) were DHL, and 10 (6%) were THL. Systemic therapy without RT resulted in inferior freedom from relapse (FFR) (HR: 2.28; 95% CI, 1.10-4.77; p = .02). The median FFR for non-DHL/THL was not reached and was 33 and 22.3 months for DHL and THL, respectively; p < .001. Low-risk (R-IPI <2) DHL/THL patients treated with rituximab-based therapy had 3-year FFR rates of 11% and 71% for systemic therapy without and with RT, respectively; p = .04. No differences in overall survival were observed between the treatment groups. Treatment intensification with RT may improve early stage DHL/THL outcomes.

Background: The appropriate follow-up frequency after definitive chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer patients is unknown. Although surveillance guidelines have been proposed, very few data support current recommendations. Here we analyze relapse events after CRT and investigate whether symptomatic relapses versus those detected by surveillance imaging influences outcomes., Patients and Methods: Stage III non-small-cell lung cancer patients treated with CRT at our institution between 2005 and 2014 were retrospectively analyzed. Relapse events were grouped into posttreatment intervals and analyzed with cumulative tables. Time to relapse and overall survival (OS) were compared between patients with relapse detection via symptomatic presentation versus surveillance imaging., Results: A total of 211 patients were identified for analysis. The median follow-up was 43 months for patients alive at the time of analysis. The median age was 63 years, and equal proportions had IIIA or IIIB disease. A total of 135 patients (64%) experienced disease relapse, and of these, 74% did so within 12 months. In those who did not experience relapse at ≤ 12 months, 16%, 6%, and < 5% experienced relapse during 12 to 24, 24 to 36, and > 36 months of follow-up, respectively. In patients with relapse, 56% presented symptomatically, which led to inferior median OS compared to those identified by surveillance imaging (23 vs. 36 months; P = .013)., Conclusion: This study identified that most relapses occur within 1 year of completing CRT, and approximately half of these occur within 6 months. A symptomatic relapse led to inferior OS. More aggressive surveillance imaging may therefore identify asymptomatic relapses that are amenable to earlier salvage therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: We assessed the radiosensitivity of lung metastases on the basis of primary histologic type by using a validated gene signature and model lung metastases for the gnomically adjusted radiation dose (GARD)., Methods: Tissue samples were identified from our prospective observational protocol. The radiosensitivity index (RSI) 10-gene assay was run on samples and calculated alongside the GARD by using the previously published algorithms. A cohort of 105 patients with 137 lung metastases treated with stereotactic body radiation therapy (SBRT) at our institution was used for clinical correlation., Results: A total of 138 unique metastatic lung lesions from our institution's tissue biorepository were identified for inclusion. There were significant differences in the RSI of lung metastases on the basis of histology. In order of decreasing radioresistance, the median RSIs for the various histologic types of cancer were endometrial adenocarcinoma (0.49), soft-tissue sarcoma (0.47), melanoma (0.44), rectal adenocarcinoma (0.43), renal cell carcinoma (0.33), head and neck squamous cell cancer (0.33), colon adenocarcinoma (0.32), and breast adenocarcinoma (0.29) (p = 0.002). We modeled the GARD for these samples and identified the biologically effective dose necessary to optimize local control. The 12- and 24-month Kaplan-Meier rates of local control for radioresistant versus radiosensitive histologic types from our clinical correlation cohort after lung SBRT were 92%/87% and 100%, respectively (p = 0.02)., Conclusions: In this analysis, we have noted significant differences in radiosensitivity on the basis of primary histologic type of lung metastases and have modeled the biologically effective dose necessary to optimize local control. This study suggests that primary histologic type may be an additional factor to consider in selection of SBRT dose to the lung and that dose personalization may be feasible., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Patients with extensive-stage small cell lung cancer (ES-SCLC) often develop brain metastases. There is significant controversy regarding the benefit of prophylactic cranial irradiation (PCI) for patients with ES-SCLC. Our objective is to identify ES-SCLC patients who might be most likely to benefit from PCI., Methods: We retrospectively reviewed 173 patients with ES-SCLC treated between 2010-2015. Of these, 117 patients were initially diagnosed without brain metastases and received systemic chemotherapy. Following exclusion of patients who received PCI and less than 2 cycles of platinum doublet therapy, 93 patients remained. Patient records were reviewed for clinical and radiographic features previously identified as relevant risk factors. Primary outcome was brain metastasis-free survival (BMFS). Kaplan-Meier analysis, log-rank tests and Cox multivariate models were used to compare outcomes., Results: Median follow-up was 10.7 months (range, 3-58 months). Thirty-eight (40.9%) patients developed brain metastases. Three or more metastatic sites was associated with inferior BMFS on univariable (1-year estimate 43.8% vs. 61.3%; P=0.020) and multivariable (MVA) analysis [hazard ratio (HR) 2.33, 95% CI: 1.08-5.01; P=0.03)., Conclusions: Our results suggest that extracranial metastatic burden is associated with an increased risk for brain metastases in patients with ES-SCLC. As there is no clear standard regarding delivery of PCI in this patient population, utilizing the number of metastatic disease sites as a clinical indicator may help to improve selection of patients who benefit from PCI., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Long-term data establishes the efficacy of radiotherapy in the adjuvant management of breast cancer. New dose and fractionation schemas have evolved and are available, each with unique risks and rewards. Current efforts are ongoing to tailor radiotherapy to the unique biology of breast cancer. In this review, we discuss our efforts to personalize radiotherapy dosing using genomic data and the implications for future clinical trials. We also explore immune mechanisms that may contribute to a tumor's unique radiation sensitivity or resistance.