First-line immune checkpoint inhibitor use in cisplatin-eligible patients with advanced urothelial carcinoma: a secular trend analysis.

Aim: Standard first-line treatment of advanced urothelial cell carcinoma involves cisplatin-based chemotherapy, with carboplatin or immune checkpoint inhibitor therapy (ICI) reserved for cisplatin-ineligible individuals. Methods: Using a large de-identified electronic health record-derived database of patients with advanced urothelial cell carcinoma in the USA, we examined trends in utilization of first-line systemic therapies in cisplatin-eligible patients from 1 January 2015 to 31 March 2018. Results: Among 1181 cisplatin-eligible patients, the quarterly proportion who received first-line ICI increased from 1 to 42% (ptrend <0.001), while the proportion who received cisplatin-based chemotherapy decreased from 53 to 33% (ptrend = 0.018). Patients receiving ICI were older than those receiving cisplatin (median age: 75 vs 68). Conclusion: Our analysis suggests rising off-label ICI use in cisplatin-eligible individuals, potentially because of ICI's favorable toxicity profile.

Comparative toxicity outcomes of proton-beam therapy versus intensity-modulated radiotherapy for prostate cancer in the postoperative setting.

BACKGROUND: Despite increasing utilization of proton-beam therapy (PBT) in the postprostatectomy setting, no data exist regarding toxicity outcomes relative to intensity-modulated radiotherapy (IMRT). The authors compared acute and late genitourinary (GU) and gastrointestinal (GI) toxicity outcomes in patients with prostate cancer (PC) who received treatment with postprostatectomy IMRT versus PBT. METHODS: With institutional review board approval, patients with PC who received adjuvant or salvage IMRT or PBT (70.2 gray with an endorectal balloon) after prostatectomy from 2009 through 2017 were reviewed. Factors including combined IMRT and PBT and/or concurrent malignancies prompted exclusion. A case-matched cohort analysis was performed using nearest-neighbor 3-to-1 matching by age and GU/GI disorder history. Logistic and Cox regressions were used to identify univariate and multivariate associations between toxicities and cohort/dosimetric characteristics. Toxicity-free survival (TFS) was assessed using the Kaplan-Meier method. RESULTS: Three hundred seven men (mean ± SD age, 59.7 ± 6.3 years; IMRT, n = 237; PBT, n = 70) were identified, generating 70 matched pairs. The median follow-up was 48.6 and 46.1 months for the IMRT and PBT groups, respectively. Although PBT was superior at reducing low-range (volumes receiving 10% to 40% of the dose, respectively) bladder and rectal doses (all P ≤ .01), treatment modality was not associated with differences in clinician-reported acute or late GU/GI toxicities (all P ≥ .05). Five-year grade ≥2 GU and grade ≥1 GI TFS was 61.1% and 73.7% for IMRT, respectively, and 70.7% and 75.3% for PBT, respectively; and 5-year grade ≥3 GU and GI TFS was >95% for both groups (all P ≥ .05). CONCLUSIONS: Postprostatectomy PBT minimized low-range bladder and rectal doses relative to IMRT; however, treatment modality was not associated with clinician-reported GU/GI toxicities. Future prospective investigation and ongoing follow-up will determine whether dosimetric differences between IMRT and PBT confer clinically meaningful differences in long-term outcomes.

Understanding the predictive value of continuous markers for censored survival data using a likelihood ratio approach.

BACKGROUND: The likelihood ratio function (LR), the ratio of conditional probabilities of obtaining a specific marker value among those with the event of interest over those without, provides an easily interpretable way to quantify the update of the risk prediction due to the knowledge of the marker value. The LR has been explored for both binary and continuous markers for binary events (e.g., diseased or not), however the use of the LR in censored data has not been fully explored. METHODS: We extend the concept of LR to a time-dependent LR (TD-LR) for survival outcomes that are subject to censoring. Estimation for the TD-LR is done using Kaplan-Meier estimation and a univariate Cox proportional hazards (PH) model. A "scale invariant" approach based on marker quantiles is provided to allow comparison of predictive values between markers with different scales. Relationships to time-dependent receiver-operator characteristic (ROC) curves, area under the curve (AUC), and optimal cut-off values are considered. RESULTS: The proposed methods were applied to data from a bladder cancer clinical trial to determine whether the neutrophil-to-lymphocyte ratio (NLR) is a valuable biomarker for predicting overall survival following surgery or combined chemotherapy and surgery. The TD-LR method yielded results consistent with the original findings while providing an easily interpretable three-dimensional surface display of how NLR related to the likelihood of event in the trial data. CONCLUSIONS: The TD-LR provides a more nuanced understanding of the relationship between continuous markers and the likelihood of events in censored survival data. This method also allows more straightforward communication with a clinical audience through graphical presentation.

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours.

BACKGROUND: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers. METHODS: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response. RESULTS: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells. CONCLUSIONS: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy. CLINICAL TRIAL REGISTRATION: NCT02303990 ( www.clinicaltrials.gov ).

Initial report of the genitourinary and gastrointestinal toxicity of post-prostatectomy proton therapy for prostate cancer patients undergoing adjuvant or salvage radiotherapy.

PURPOSE: To report acute and late genitourinary (GU) and gastrointestinal (GI) toxicities associated with post-prostatectomy proton therapy (PT). METHODS: The first 100 consecutive patients from 2010 to 2016 were retrospectively assessed. Baseline characteristics, prospectively graded CTCAE v4.0 toxicities, and patient-reported outcomes were reported. Late outcomes were reported for 79 patients with 3 months minimum follow up. Toxicity-free survival Kaplan-Meier curves were estimated. Logistic regression assessed associations between toxicities and clinical and treatment characteristics (p < .05 significance). RESULTS: Median age, months after surgery, and months of follow-up were respectively 64 years (range 42-77), 25 (5-216), and 25 (0-47). PT received was 70.2 Gy (RBE) (89%), salvage (93%), prostate bed only (80%), pencil beam scanning (86%), with IMRT (31%), and with androgen deprivation (34%). Acute and late maximum toxicities, respectively were: GU grade 0 (14%; 18%), 1 (71%; 62%), 2 (15%; 20%), ≥3 (0), and GI: grade 0 (66%; 73%), 1 (34%; 27%), ≥2 (0). Toxicity-free survival at 24 months was GU grade 2 (83%) and GI grade 1 (74%). Mean (±std dev) baseline International Prostate Symptom Score (IPSS), International Index of Erectile Function, and Expanded Prostate Cancer Index Composite bowel function and bother were 6.6 ± 6.1, 10.5 ± 7.3, 90.9 ± 10.8, 93.3 ± 11.2, respectively, and largely unchanged at 2 years: 6.3 ± 3.6, 11.1 ± 6.3, 92.8 ± 5.8, and 90.9 ± 10.3. On multivariate analysis, baseline IPSS (p = .009) associated with GU grade 2 acute toxicity. Bladderless-CTV median dose, V30, and V40 associated with GU grade 2 acute toxicity and maximum dose with late (Ps <0.05). For GI, on multivariate analysis, baseline bowel function (p = .033) associated with acute grade 1 toxicity. Rectal minimum and median dose, V10, and V20, and anterior rectal wall median dose and V10 through V65 associated with acute grade 1 GI toxicity (Ps < .05). CONCLUSIONS: Post-prostatectomy PT for prostate cancer is feasible with a favorable GU and GI toxicity profile acutely and through early follow up.

Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710.

BACKGROUND: Risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Multiple studies have reported the neutrophil-to-lymphocyte ratio (NLR) as a promising candidate; however, these analyses have methodological limitations. Therefore, the authors performed a category B biomarker study to test whether NLR is prognostic for overall survival (OS) after curative treatment or is predictive for the survival benefit from neoadjuvant chemotherapy (NAC). METHODS: This study is an unplanned secondary analysis of SWOG 8710, a randomized phase 3 trial that assessed cystectomy with or without NAC in 317 patients with muscle-invasive BC. NLR was calculated from prospectively collected complete blood counts. For the prognostic analysis, 230 patients were identified; for the predictive analysis, 263 were identified. NLR was evaluated with proportional hazards models including prespecified factors (age, sex, T-stage, lymphovascular invasion, and treatment arm). RESULTS: With a median follow-up of 18.6 years, there were 172 and 205 deaths in the prognostic and predictive cohorts, respectively. In a multivariable analysis, NLR was not prognostic for OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.98-1.11; P = .24). Furthermore, NLR did not predict for the OS benefit from NAC (HR, 1.01; 95% CI, 0.90-1.14; P = .86). Factors associated with worse OS were older age (HR, 1.05; 95% CI, 1.04-1.07; P < .001) and surgery without NAC (HR, 1.39; 95% CI, 1.03-1.88; P = .03). CONCLUSIONS: This is the first analysis of NLR in BC to use prospectively collected clinical trial data. In contrast to previous studies, it suggests that NLR is neither a prognostic nor predictive biomarker for OS in muscle-invasive BC. Cancer 2017;123:794-801. © 2016 American Cancer Society.

A case-matched study of toxicity outcomes after proton therapy and intensity-modulated radiation therapy for prostate cancer.

BACKGROUND: The authors assessed whether proton beam therapy (PBT) for prostate cancer (PCa) was associated with differing toxicity compared with intensity-modulated radiation therapy (IMRT) using case-matched analysis. METHODS: From 2010 to 2012, 394 patients who had localized PCa received 79.2 Gray (Gy) relative biologic effectiveness (RBE) delivered with either PBT (181 patients) or IMRT (213 patients). Patients were case-matched on risk group, age, and prior gastrointestinal (GI) and genitourinary (GU) disorders, resulting in 94 matched pairs. Both exact matching (risk group) and nearest-neighbor matching (age, prior GI/GU disorders) were used. Residual confounding was adjusted for by using multivariable regression. Maximum acute and late GI/GU Common Terminology Criteria for Adverse Events-graded toxicities were compared using univariate and multivariable logistic and Cox regression models, respectively. RESULTS: Bladder and rectum dosimetry variables were significantly lower for PBT versus IMRT (P ≤ .01). The median follow-up was 47 months (range, 5-65 months) for patients who received IMRT and 29 months (range, 5-50 months) for those who received PBT. On multivariable analysis, which exploited case matching and included direct adjustment for confounders and independent predictors, there were no statistically significant differences between IMRT and PBT in the risk of grade ≥ 2 acute GI toxicity (odds ratio, 0.27; 95% confidence interval [CI], 0.06-1.24; P = .09), grade ≥ 2 acute GU toxicity (odds ratio, 0.69; 95% CI, 0.32-1.51; P = .36), grade ≥ 2 late GU toxicity (hazard ratio, 0.56; 95% CI, 0.22-1.41; P = .22), and grade ≥ 2 late GI toxicity (hazard ratio, 1.24; 95% CI, 0.53-2.94; P = .62). CONCLUSIONS: In this matched comparison of prospectively collected toxicity data on patients with PCa who received treatment with contemporary IMRT and PBT techniques and similar dose-fractionation schedules, the risks of acute and late GI/GU toxicities did not differ significantly after adjustment for confounders and predictive factors.

Optimizing bladder cancer locoregional failure risk stratification after radical cystectomy using SWOG 8710.

BACKGROUND: Clinical trials of radiation after radical cystectomy (RC) and chemotherapy for bladder cancer are in development, but inclusion and stratification factors have not been clearly established. In this study, the authors evaluated and refined a published risk stratification for locoregional failure (LF) by applying it to a multicenter patient cohort. METHODS: The original stratification, which was developed using a single-institution series, produced 3 subgroups with significantly different LF risk based on pathologic tumor (pT) classification and the number of lymph nodes identified. This model was then applied to patients in Southwest Oncology Group (SWOG) 8710, a randomized trial of RC with or without chemotherapy. LF was defined as any pelvic failure before or within 3 months of distant failure. RESULTS: Patients in the development cohort and the SWOG cohort had significantly different baseline characteristics. The original risk model was not fully validated in the SWOG cohort, because lymph node yield was not as strongly associated with LF as in the development cohort. Regression analysis indicated that margin status could improve the model. A revised stratification using pT classification, margin status, and the number of lymph nodes identified produced 3 subgroups with significantly different LF risk in both cohorts: low risk (≤pT2), intermediate risk (≥pT3 with negative margins AND ≥10 lymph nodes identified), and high risk (≥pT3 with positive margins OR <10 lymph nodes identified) with 5-year LF rates of 8%, 20%, and 41%, respectively, in the SWOG cohort and 8%, 19%, and 41%, respectively, in the development cohort. CONCLUSIONS: A model incorporating pT classification, margin status, and the number of lymph nodes identified stratified LF risk in 2 different RC populations and may inform the design of future trials.

Prostate Cancer Recurrence: Examining the Role of Salvage Radiotherapy Field and Risk Factors for Regional Disease Recurrence Captured on 18F-DCFPyL PET/CT.

PURPOSE: The role of elective pelvic nodal irradiation in salvage radiotherapy (sRT) remains controversial. Utilizing 18F-DCFPyL PET/CT, this study aimed to investigate differences in disease distribution after whole pelvic (WPRT) or prostate bed (PBRT) radiotherapy and to identify risk factors for pelvic lymph node (LN) relapse. METHODS: This retrospective study included patients with PSA > 0.1 ng/mL post-radical prostatectomy (RP) or post-RP and sRT who underwent 18F-DCFPyL PET/CT. Disease distribution on 18F-DCFPyL PET/CT after sRT was compared using Chi-square tests. Risk factors were tested for association with pelvic LN relapse after RP and salvage PBRT using logistic regression. RESULTS: 979 18F-DCFPyL PET/CTs performed at our institution between 1/1/2022 - 3/24/2023 were analyzed. There were 246 patients meeting criteria, of which 84 received salvage RT after RP (post-salvage RT group) and 162 received only RP (post-RP group). Salvage PBRT patients (n = 58) had frequent pelvic nodal (53.6%) and nodal-only (42.6%) relapse. Salvage WPRT patients (n = 26) had comparatively lower rates of pelvic nodal (16.7%, p = 0.002) and nodal-only (19.2%, p = 0.04) relapse. The proportion of distant metastases did not differ between the two groups. Multiple patient characteristics, including ISUP grade and seminal vesicle invasion, were associated with pelvic LN disease in the post-RP group. CONCLUSION: At PSA persistence or progression, salvage WPRT resulted in lower rates of nodal involvement than salvage PBRT, but did not reduce distant metastases. Certain risk factors increase the likelihood of pelvic LN relapse after RP and can help inform salvage RT field selection.

Associations Between Radiation Oncologist Demographic Factors and Segmentation Similarity Benchmarks: Insights From a Crowd-Sourced Challenge Using Bayesian Estimation.

PURPOSE: The quality of radiotherapy auto-segmentation training data, primarily derived from clinician observers, is of utmost importance. However, the factors influencing the quality of clinician-derived segmentations are poorly understood; our study aims to quantify these factors. METHODS: Organ at risk (OAR) and tumor-related segmentations provided by radiation oncologists from the Contouring Collaborative for Consensus in Radiation Oncology data set were used. Segmentations were derived from five disease sites: breast, sarcoma, head and neck (H&N), gynecologic (GYN), and GI. Segmentation quality was determined on a structure-by-structure basis by comparing the observer segmentations with an expert-derived consensus, which served as a reference standard benchmark. The Dice similarity coefficient (DSC) was primarily used as a metric for the comparisons. DSC was stratified into binary groups on the basis of structure-specific expert-derived interobserver variability (IOV) cutoffs. Generalized linear mixed-effects models using Bayesian estimation were used to investigate the association between demographic variables and the binarized DSC for each disease site. Variables with a highest density interval excluding zero were considered to substantially affect the outcome measure. RESULTS: Five hundred seventy-four, 110, 452, 112, and 48 segmentations were used for the breast, sarcoma, H&N, GYN, and GI cases, respectively. The median percentage of segmentations that crossed the expert DSC IOV cutoff when stratified by structure type was 55% and 31% for OARs and tumors, respectively. Regression analysis revealed that the structure being tumor-related had a substantial negative impact on binarized DSC for the breast, sarcoma, H&N, and GI cases. There were no recurring relationships between segmentation quality and demographic variables across the cases, with most variables demonstrating large standard deviations. CONCLUSION: Our study highlights substantial uncertainty surrounding conventionally presumed factors influencing segmentation quality relative to benchmarks.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC): a review of the literature and a practical approach to therapy.

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Bladder preservation therapies for muscle-invasive bladder cancer (MIBC) have been developed to address the needs of two cohorts: patients with severe medical co-morbidities for whom radical cystectomy is too high risk and patients with limited disease who wish to avoid aggressive surgery. There are multiple bladder preservation options, although the trimodal approach of maximal transurethral resection with chemoradiotherapy is the most strongly supported. While outcomes are worse for patients unfit for surgery than those otherwise fit for surgery, bladder preservation approaches still offer curative potential. We present a comprehensive review of the literature and outline a practical approach to bladder preservation therapy for MIBC. This review aims to help urologists easily navigate through the decision tree of therapeutic options. Radical cystectomy (RC) is associated with considerable morbidity. Aside from the perioperative period, RC with urinary diversion poses great potential for long-term complications and morbidity. Bladder preservation therapies for muscle-invasive bladder cancer (MIBC) have been developed to address the needs of two cohorts: patients with severe medical co-morbidities for whom a radical surgery is too high risk and patients with limited disease who wish to avoid radical surgery. The goal of achieving complete response to treatment while maintaining bladder form and function has led to the development of multimodal approaches to this disease. There are multiple bladder preservation options, although the trimodal approach of maximal transurethral resection with chemoradiotherapy is the most strongly supported. In medically operable patients ('fit' for surgery), there is abundant evidence to support trimodal therapy as an acceptable treatment option for highly selected patients with MIBC with favourable pathological parameters. While outcomes are worse for medically inoperable patients ('unfit' for surgery), bladder preservation approaches still offer curative potential. However, prospective trials comparing the above regimens to RC are still needed to better define their role in the treatment of MIBC. We present a comprehensive review of the literature and outline a practical approach to bladder preservation therapy for MIBC.

Cancer Control, Toxicity, and Secondary Malignancy Risks of Proton Radiation Therapy for Stage I-IIB Testicular Seminoma.

Purpose: This study's objective was to report cancer control and toxicity outcomes after proton radiation therapy (RT) in testicular seminoma and to compare secondary malignancy (SMN) risks with photon-based treatment alternatives. Methods and Materials: Consecutive patients with stage I-IIB testicular seminoma treated with proton RT at a single institution were retrospectively analyzed. Kaplan-Meier estimates for disease-free and overall survival were computed. Toxicities were scored using Common Terminology Criteria for Adverse Events version 5.0. Photon comparison plans, including 3-dimensional conformal RT (3D-CRT) and intensity modulated RT (IMRT)/volumetric arc therapy (VMAT), were created for each patient. Dosimetric parameters and SMN risk predictions for different in-field organs-at-risk were compared between the techniques. Excess absolute SMN risks were estimated with organ equivalent dose modeling. Results: Twenty-four patients were included (median age, 38.5 years). The majority of patients had stage II disease (IIA, 12 [50.0%]; IIB, 11 [45.8%]; IA, 1 [4.2%]). Seven (29.2%) and 17 (70.8%) patients had de novo and recurrent disease, respectively (de novo/recurrent: IA, 1/0; IIA, 4/8; IIB, 2/9). Most acute toxicities were mild (grade 1 [G1], 79.2%; G2, 12.5%) with G1 nausea being most common (70.8%). No serious events (G3-5) occurred. With a median follow-up time of 3 years (interquartile range, 2.1-3.6 years), 3-year disease-free and overall survival rates were 90.9% (95% confidence interval, 68.1%-97.6%) and 100% (95% confidence interval, 100%-100%), respectively. There were no documented late toxicities in the follow-up period, including worsening serial creatinine levels suggestive of early nephrotoxicity. Proton RT had significant reductions in mean organ-at-risk doses to the kidneys, stomach, colon, liver, bladder, and body compared with both 3D-CRT and IMRT/VMAT. Proton RT had significantly lower SMN risk predictions compared with 3D-CRT and IMRT/VMAT. Conclusions: Cancer control and toxicity outcomes using proton RT in stage I-IIB testicular seminoma are consistent with existing photon-based RT literature. However, proton RT may be associated with significantly lower SMN risks.

Case-Matched Outcomes of Proton Beam and Intensity-Modulated Radiation Therapy for Localized Prostate Cancer.

Purpose: Although both intensity-modulated radiation therapy (IMRT) and proton beam therapy (PBT) offer effective long-term disease control for localized prostate cancer (PCa), there are limited data directly comparing the 2 modalities. Methods: The data from 334 patients treated with conventionally fractionated (79.2 GyRBE in 44 fractions) PBT or IMRT were retrospectively analyzed. Propensity score matching was used to balance factors associated with biochemical failure-free survival (BFFS). Age, race, and comorbidities (not BFFS associates) remained imbalanced after matching. Univariable and covariate-adjusted multivariable (MVA) Cox regression models were used to determine if modality affected BFFS. Results: Of 334 patients, 176 (52.7%) were included in the matched cohort with exact matching to National Comprehensive Cancer Network (NCCN) risk group. With a median follow-up time of 9.0 years (interquartile range [IQR]: 7.8-10.2 years), long-term BFFS was similar between the IMRT and PBT matched arms with 8-year estimates of 85% (95% CI: 76%-91%) and 91% (95% CI: 82%-96%, P = .39), respectively. On MVA, modality was not significantly associated with BFFS in both the unmatched (hazard ratio [HR] = 0.75, 95% CI: 0.35-1.63, P = .47) and matched (HR = 0.87, 95% CI: 0.33-2.33, P = .78) cohorts. Prostate cancer-specific survival (PCSS) and overall survival (OS) were also similar (P > .05). However, in an unmatched analysis, the PBT arm had significantly fewer incidences of secondary cancers within the irradiated field (0.6%, 95% CI: 0.0%-3.1% versus 4.5%, 95% CI: 1.8%-9.0%, P = .028). Conclusions: Both PBT and IMRT offer excellent long-term disease control for PCa, with no significant differences between the 2 modalities in BFFS, PCSS, and OS in matched patients. In the unmatched cohort, fewer incidences of secondary malignancy were noted in the PBT group; however, owing to overall low incidence of secondary cancer and imbalanced patient characteristics between the 2 groups, these data are strictly hypothesis generating and require further investigation.

E pluribus unum: prospective acceptability benchmarking from the Contouring Collaborative for Consensus in Radiation Oncology crowdsourced initiative for multiobserver segmentation.

Purpose: Contouring Collaborative for Consensus in Radiation Oncology (C3RO) is a crowdsourced challenge engaging radiation oncologists across various expertise levels in segmentation. An obstacle to artificial intelligence (AI) development is the paucity of multiexpert datasets; consequently, we sought to characterize whether aggregate segmentations generated from multiple nonexperts could meet or exceed recognized expert agreement. Approach: Participants who contoured ≥ 1 region of interest (ROI) for the breast, sarcoma, head and neck (H&N), gynecologic (GYN), or gastrointestinal (GI) cases were identified as a nonexpert or recognized expert. Cohort-specific ROIs were combined into single simultaneous truth and performance level estimation (STAPLE) consensus segmentations. STAPLE nonexpert ROIs were evaluated against STAPLE expert contours using Dice similarity coefficient (DSC). The expert interobserver DSC ( IODSC expert ) was calculated as an acceptability threshold between STAPLE nonexpert and STAPLE expert . To determine the number of nonexperts required to match the IODSC expert for each ROI, a single consensus contour was generated using variable numbers of nonexperts and then compared to the IODSC expert . Results: For all cases, the DSC values for STAPLE nonexpert versus STAPLE expert were higher than comparator expert IODSC expert for most ROIs. The minimum number of nonexpert segmentations needed for a consensus ROI to achieve IODSC expert acceptability criteria ranged between 2 and 4 for breast, 3 and 5 for sarcoma, 3 and 5 for H&N, 3 and 5 for GYN, and 3 for GI. Conclusions: Multiple nonexpert-generated consensus ROIs met or exceeded expert-derived acceptability thresholds. Five nonexperts could potentially generate consensus segmentations for most ROIs with performance approximating experts, suggesting nonexpert segmentations as feasible cost-effective AI inputs.

Quality assurance assessment of intra-acquisition diffusion-weighted and T2-weighted magnetic resonance imaging registration and contour propagation for head and neck cancer radiotherapy.

BACKGROUND/PURPOSE: Adequate image registration of anatomical and functional magnetic resonance imaging (MRI) scans is necessary for MR-guided head and neck cancer (HNC) adaptive radiotherapy planning. Despite the quantitative capabilities of diffusion-weighted imaging (DWI) MRI for treatment plan adaptation, geometric distortion remains a considerable limitation. Therefore, we systematically investigated various deformable image registration (DIR) methods to co-register DWI and T2-weighted (T2W) images. MATERIALS/METHODS: We compared three commercial (ADMIRE, Velocity, Raystation) and three open-source (Elastix with default settings [Elastix Default], Elastix with parameter set 23 [Elastix 23], Demons) post-acquisition DIR methods applied to T2W and DWI MRI images acquired during the same imaging session in twenty immobilized HNC patients. In addition, we used the non-registered images (None) as a control comparator. Ground-truth segmentations of radiotherapy structures (tumour and organs at risk) were generated by a physician expert on both image sequences. For each registration approach, structures were propagated from T2W to DWI images. These propagated structures were then compared with ground-truth DWI structures using the Dice similarity coefficient and mean surface distance. RESULTS: 19 left submandibular glands, 18 right submandibular glands, 20 left parotid glands, 20 right parotid glands, 20 spinal cords, and 12 tumours were delineated. Most DIR methods took <30 s to execute per case, with the exception of Elastix 23 which took ∼458 s to execute per case. ADMIRE and Elastix 23 demonstrated improved performance over None for all metrics and structures (Bonferroni-corrected p < 0.05), while the other methods did not. Moreover, ADMIRE and Elastix 23 significantly improved performance in individual and pooled analysis compared to all other methods. CONCLUSIONS: The ADMIRE DIR method offers improved geometric performance with reasonable execution time so should be favoured for registering T2W and DWI images acquired during the same scan session in HNC patients. These results are important to ensure the appropriate selection of registration strategies for MR-guided radiotherapy.

Large scale crowdsourced radiotherapy segmentations across a variety of cancer anatomic sites.

Clinician generated segmentation of tumor and healthy tissue regions of interest (ROIs) on medical images is crucial for radiotherapy. However, interobserver segmentation variability has long been considered a significant detriment to the implementation of high-quality and consistent radiotherapy dose delivery. This has prompted the increasing development of automated segmentation approaches. However, extant segmentation datasets typically only provide segmentations generated by a limited number of annotators with varying, and often unspecified, levels of expertise. In this data descriptor, numerous clinician annotators manually generated segmentations for ROIs on computed tomography images across a variety of cancer sites (breast, sarcoma, head and neck, gynecologic, gastrointestinal; one patient per cancer site) for the Contouring Collaborative for Consensus in Radiation Oncology challenge. In total, over 200 annotators (experts and non-experts) contributed using a standardized annotation platform (ProKnow). Subsequently, we converted Digital Imaging and Communications in Medicine data into Neuroimaging Informatics Technology Initiative format with standardized nomenclature for ease of use. In addition, we generated consensus segmentations for experts and non-experts using the Simultaneous Truth and Performance Level Estimation method. These standardized, structured, and easily accessible data are a valuable resource for systematically studying variability in segmentation applications.

Magnetic Resonance-Guided Adaptive Radiation Therapy for Prostate Cancer: The First Results from the MOMENTUM study-An International Registry for the Evidence-Based Introduction of Magnetic Resonance-Guided Adaptive Radiation Therapy.

PURPOSE: Magnetic resonance (MR)-guided radiation therapy (MRgRT) is a new technique for treatment of localized prostate cancer (PCa). We report the 12-month outcomes for the first PCa patients treated within an international consortium (the MOMENTUM study) on a 1.5T MR-Linac system with ultrahypofractionated radiation therapy. METHODS AND MATERIALS: Patients treated with 5 × 7.25 Gy were identified. Prostate specific antigen-level, physician-reported toxicity (Common Terminology Criteria for Adverse Events [CTCAE]), and patient-reported outcomes (Quality of Life Questionnaire PR25 and Quality of Life Questionnaire C30 questionnaires) were recorded at baseline and at 3, 6, and 12 months of follow-up (FU). Pairwise comparative statistics were conducted to compare outcomes between baseline and FU. RESULTS: The study included 425 patients with localized PCa (11.4% low, 82.0% intermediate, and 6.6% high-risk), and 365, 313, and 186 patients reached 3-, 6-, and 12-months FU, respectively. Median prostate specific antigen level declined significantly to 1.2 ng/mL and 0.1 ng/mL at 12 months FU for the nonandrogen deprivation therapy (ADT) and ADT group, respectively. The peak of genitourinary and gastrointestinal CTCAE toxicity was reported at 3 months FU, with 18.7% and 1.7% grade ≥2, respectively. The QLQ-PR25 questionnaire outcomes showed significant deterioration in urinary domain score at all FU moments, from 8.3 (interquartile range [IQR], 4.1-16.6) at baseline to 12.4 (IQR, 8.3-24.8; P = .005) at 3 months, 12.4 (IQR, 8.3-20.8; P = .018;) at 6 months, and 12.4 (IQR, 8.3-20.8; P = .001) at 12 months. For the non-ADT group, physician- and patient-reported erectile function worsened significantly between baseline and 12 months FU. CONCLUSIONS: Ultrahypofractionated MR-guided radiation therapy for localized PCa using a 1.5T MR-Linac is effective and safe. The peak of CTCAE genitourinary and gastrointestinal toxicity was reported at 3 months FU. Furthermore, for patients without ADT, a significant increase in CTCAE erectile dysfunction was reported at 12 months FU. These data are useful for educating patients on expected outcomes and informing study design of future comparative-effectiveness studies.

Determining The Role Of Radiation Oncologist Demographic Factors On Segmentation Quality: Insights From A Crowd-Sourced Challenge Using Bayesian Estimation.

BACKGROUND: Medical image auto-segmentation is poised to revolutionize radiotherapy workflows. The quality of auto-segmentation training data, primarily derived from clinician observers, is of utmost importance. However, the factors influencing the quality of these clinician-derived segmentations have yet to be fully understood or quantified. Therefore, the purpose of this study was to determine the role of common observer demographic variables on quantitative segmentation performance. METHODS: Organ at risk (OAR) and tumor volume segmentations provided by radiation oncologist observers from the Contouring Collaborative for Consensus in Radiation Oncology public dataset were utilized for this study. Segmentations were derived from five separate disease sites comprised of one patient case each: breast, sarcoma, head and neck (H&N), gynecologic (GYN), and gastrointestinal (GI). Segmentation quality was determined on a structure-by-structure basis by comparing the observer segmentations with an expert-derived consensus gold standard primarily using the Dice Similarity Coefficient (DSC); surface DSC was investigated as a secondary metric. Metrics were stratified into binary groups based on previously established structure-specific expert-derived interobserver variability (IOV) cutoffs. Generalized linear mixed-effects models using Markov chain Monte Carlo Bayesian estimation were used to investigate the association between demographic variables and the binarized segmentation quality for each disease site separately. Variables with a highest density interval excluding zero - loosely analogous to frequentist significance - were considered to substantially impact the outcome measure. RESULTS: After filtering by practicing radiation oncologists, 574, 110, 452, 112, and 48 structure observations remained for the breast, sarcoma, H&N, GYN, and GI cases, respectively. The median percentage of observations that crossed the expert DSC IOV cutoff when stratified by structure type was 55% and 31% for OARs and tumor volumes, respectively. Bayesian regression analysis revealed tumor category had a substantial negative impact on binarized DSC for the breast (coefficient mean ± standard deviation: -0.97 ± 0.20), sarcoma (-1.04 ± 0.54), H&N (-1.00 ± 0.24), and GI (-2.95 ± 0.98) cases. There were no clear recurring relationships between segmentation quality and demographic variables across the cases, with most variables demonstrating large standard deviations and wide highest density intervals. CONCLUSION: Our study highlights substantial uncertainty surrounding conventionally presumed factors influencing segmentation quality. Future studies should investigate additional demographic variables, more patients and imaging modalities, and alternative metrics of segmentation acceptability.