Cost-benefit of influenza vaccination in preventing sudden cardiac arrest amongst Australian adults.

OBJECTIVE: The objective of the study was to estimate the economic cost benefit of funding influenza vaccination to all Australian adults 50-64 years and predict its effect on sudden cardiac arrest (SCA) deaths and hospitalisation. METHODS: We combined SCA hospitalisation data from the Australian Institute of Health and Welfare (AIHW) with survival, vaccination, and cost parameters from published literature to create a model estimating the cost benefit of universally funded influenza vaccinations to prevent SCA deaths and hospitalisation. Costs were considered from a government perspective and included cost of vaccines and GP consultations, whilst averted deaths were estimated through the age-adjusted value of a statistical life. RESULTS: The target policy was estimated to prevent 278 SCA hospitalisations and 1269 SCA deaths. This would result in cost-savings of almost $4 billion annually, with an incremental benefit-cost ratio (BCR) of 59.94. The majority of savings were associate with averted deaths. When a sensitivity analysis was performed by altering statistical life year values and reducing life years left, the cost-saving remained significant with a minimum BCR of 29.97 derived. CONCLUSIONS: Reducing SCA through extended vaccination including adults 50-64 years is likely to be a cost beneficial policy from a governmental perspective. SCA deaths account for a significant economic loss due to the high mortality rate, which was far greater than the costs saved through averted hospitalisations. More accurate parameters are needed to improve the reliability of these estimate; however, this model can be used as a basis for further research into the economic impact of SCA.

Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial.

OBJECTIVE: To assess the relationship among measurements of strength, function, and quality of life in an amyotrophic lateral sclerosis (ALS) clinical trial. METHODS: In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either reldesemtiv or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments. Assessments included slow vital capacity (SVC), the ALS Functional Rating Scale-Revised (ALSFRS-R), and the 5-item ALS Assessment Questionnaire (ALSAQ-5). Muscle strength was measured quantitatively with hand-held dynamometry, and grip strength with a dedicated dynamometer. The relationship between strength and ALSFRS-R fine and gross motor domain scores, or responses to ALSAQ-5 questions on hand function and walking, was assessed with Spearman's rank correlation. The relationship between mean upper- or lower-extremity muscle strength and specific ALSFRS-R domains was modeled using principal-components analysis. RESULTS: Upper-extremity muscle strength and hand grip were highly correlated with ALSFRS-R fine motor scores and the ALSAQ-5 hand function question. Similarly, lower-extremity strength correlated well with ALSFRS-R gross motor domain and the ALSAQ-5 walking question. For SVC, correlation was poor with the ALSFRS-R respiratory domain, but stronger with the total score, potentially reflecting the insensitivity of the respiratory questions in the scale. Upper- and lower-extremity strength were both strong predictors of ALSFRS-R domain scores. CONCLUSIONS: In this analysis of data from an ALS clinical trial, muscle strength quantified by dynamometry was strongly correlated with functional capacity. These results suggest that muscle strength directly relates to specific functions of importance to people with ALS.

What Matters Most: The Documented Goals, Values and Motivators of Advanced Cancer Patients.

BACKGROUND: Goals of care conversations are essential to delivery of goal concordant care. Infrequent and inconsistent goals of care documentation potentially limit delivery of goal concordant care. METHODS: At Kaiser Permanente San Francisco Cancer Center, a standardized documentation template was designed and implemented to increase goals of care documentation by oncologists. The centralized, prompt-based template included value clarification of the goals and values of advanced cancer patients beyond treatment preferences. Documented conversations using the template during the initial pilot period were reviewed to characterization the clinical context in which conversations were recorded. Common goals and motivators were also identified. RESULTS: A total of 178 advanced cancer patients had at least 1 documented conversation by a medical oncologist using the goals of care template. Oncologists consistently documented within the template goals of therapy and motivating factors in decision making. The most frequently documented goals of care were "Avoiding Pain and Suffering," "Physical Independence," and "Living as Long as Possible." The least recorded goal was "Comfort Focused Treatment Only." CONCLUSIONS: Review of oncologist documented goals of care conversations using a prompt-based template allowed for characterization of the clinical context, therapy goals and motivators of advanced cancer patients. Communication of goals of care conversations by oncologists using a standardized prompt-based template within a centralized location has the potential to improve delivery of goal concordant care.

COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success.

Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS).Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial.Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort.Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS).

Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving reldesemtiv or placebo in FORTITUDE-ALS.

AIMS: To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving reldesemtiv versus placebo in FORTITUDE-ALS. MATERIALS AND METHODS: We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated reldesemtiv in patients with ALS. Health utilities from the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) were estimated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores collected during the trial. QALYs were estimated using the area under the curve method. RESULTS: The full analysis set consisted of 456 patients (reldesemtiv n = 342, placebo n = 114), who received at least one dose of the double-blind study drug, and had ALSFRS-R assessed at baseline and at least one post-baseline assessment. The difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% confidence interval [CI]: 0.01, 0.05; p = .0008). The incremental QALY of reldesemtiv versus placebo adjusted for baseline utility values showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058). CONCLUSIONS: This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings. CLINICALTRIALS.GOV IDENTIFIER: NCT03160898.

A Comparative Trial of Improving Care for Underserved Asian Americans Infected with Hepatitis B Virus.

BACKGROUND: Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC). Asian Americans have the highest incidence and mortality rates of HCC among all US racial/ethnic groups. Inadequate monitoring and treatment of chronic hepatitis B contribute to poor health outcomes and increased healthcare costs among Asian Americans. AIMS: The goal of this study is to assess the effect of a patient-led strategy on chronic hepatitis B monitoring and treatment adherence specifically among Asian Americans with culturally tailored Patient Navigator-led Intervention. METHODS: From 2015 to 2018, 532 eligible participants living with chronic hepatitis B in the greater Philadelphia and New York city metropolitan areas were randomly assigned to either the intervention group or the control group. Generalized linear mixed-effects models were used to estimate the odds ratio (OR) for rates of doctor visits for chronic hepatitis B and rates of alanine aminotransferase testing for evidence of liver damage. RESULTS: Intervention group had higher rates of doctor visits than the control group at both 6-month (77.22% vs. 45.75%) and 12-month assessments (90.73% vs. 60.61%). Significantly more intervention group participants received ALT testing than control group participants at 6-month (52.90% vs. 25.10%) and 12-month (75.40% vs. 46.75%) follow-up. CONCLUSIONS: Culturally and linguistically appropriate intervention has strong effects on adherence to follow-up care among Asian American hepatitis B patients experiencing challenges to medication adherence and follow up care. These findings further identify opportunities for practical implementation of evidence-based intervention that could lead to reductions in disparities in chronic liver disease and liver cancer among high-risk, underserved populations.

Kidney transplant access for children and young adults with congenital anomalies of the kidney and urinary tract.

PURPOSE: Although congenital anomalies of the kidney and urinary tract (CAKUT) are among the leading causes of end-stage kidney disease (ESKD) in children and young adults, kidney transplantation access for this population has not been well studied in the US. We compared transplantation access in the US based on whether the etiology of kidney disease was secondary to CAKUT, and additionally by CAKUT subgroups (anatomic vs. inherited causes of CAKUT). METHODS: Using the United States Renal Data System, we conducted a retrospective cohort study of 80,531 children and young adults who started dialysis between 1995 and 2015. We used adjusted Cox models to examine the association between etiology of kidney disease (CAKUT vs. non-CAKUT, anatomic vs. inherited) and receipt of kidney transplantation, and secondarily, receipt of a living vs. deceased donor kidney transplant. RESULTS: Overall, we found an increased likelihood of kidney transplantation access for participants with CAKUT compared to those without CAKUT (HR 1.23; 95% CI 1.20-1.27). Among the subset of individuals with CAKUT as the attributed cause of ESKD, we found a lower likelihood of kidney transplantation in those with anatomic causes of CAKUT compared to those with inherited causes of CAKUT (adjusted HR 0.85; 0.81-0.90). CONCLUSION: There are notable disparities in kidney transplantation rates among CAKUT subgroups. Those with anatomic causes of CAKUT started on dialysis have significantly reduced access to kidney transplantations compared to individuals with inherited causes of CAKUT who were initiated on dialysis. Further studies are needed to understand barriers to transplantation access in this population.

MiToS and King's staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial.

OBJECTIVE: To evaluate the Milano-Torino staging (MiToS) and King's staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS. METHODS: This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King's stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage. RESULTS: The full analysis set consisted of 456 patients randomized 3:1 (reldesemtiv n = 342, placebo n = 114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King's stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King's stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King's. CONCLUSION: This exploratory analysis showed the feasibility of MiToS and King's staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.

Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome.

BackgroundAcute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. The disease pathophysiology remains elusive, and current dogma suggests that Sweet syndrome is a process of reactivity to an unknown antigen. Corticosteroids and steroid-sparing agents remain frontline therapies, but refractory cases pose a clinical challenge.MethodsA 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole-genome sequencing, transcriptomic profiling, and cellular assays of the patient's skin and neutrophils were performed.ResultsWe identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration toward IL-1ß and neutrophil respiratory burst. Targeted treatment of the patient with an IL-1 receptor 1 antagonist resulted in a dramatic therapeutic response and enabled a tapering off of corticosteroids.ConclusionDysregulated PI3K/AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests that this syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogeneous disease that resulted in a rational and successful clinical intervention. Future patients will benefit from efforts to identify potential mutations. The ability to directly interrogate the diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for patients with clinically challenging disease.Funding SourcesBerstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.

Burden of influenza in adults with cardiac arrest admissions in Australia.

BACKGROUND: Cardiac arrest is the least preventable burden of cardiovascular disease, as treatment depends on timely resuscitation. The incidence of sudden cardiac arrest (SCA) is high, contributing 10-20% of cardiovascular mortality globally. The influenza vaccine reduces the risk of acute cardiovascular events. Little is known about the relationship of influenza infection to cardiac arrest. METHODS: This study aimed to determine the estimated rate of SCA hospitalisations attributable to influenza in Australian adults. A generalised-additive statistical model was applied in the study. Weekly counts of laboratory-confirmed influenza notifications were used as independent variables in the model. RESULTS: Our estimates showed that the yearly rate of SCA hospitalisations varied, and a significant association with influenza was observed in some years in older adults aged 65 years and over. On average, the annual estimated SCA hospitalisations rate due to influenza in adults aged 50-64 years and ≥ 65 years were 0.7 (95%CI: 0.4, 1.1) and 5.3 (95%CI: 4.4, 6.2) per 100,000 population, respectively. CONCLUSION: The association between influenza and SCA is evident in adults and the disease burden is significant in older people. Prevention of influenza by vaccination may reduce SCA.

Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of reldesemtiv in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial.

Objective: To evaluate the possible effect of reldesemtiv, a fast skeletal muscle troponin activator, on prescription and acceptance of durable medical equipment (DME) in the FORTITUDE-ALS trial. Methods: Health economic outcome information was collected in FORTITUDE-ALS (NCT03160898); sites recorded if and when DME, specifically manual or power wheelchairs, gastrostomy tubes, noninvasive ventilators, or augmentative language devices, was prescribed by a physician and accepted by the patient (DME-PAP) during the trial. Acceptance was defined as the patient agreeing the item was needed. Cox regression analysis compared time to DME-PAP for each reldesemtiv dose with placebo. Post hoc analyses evaluated all reldesemtiv doses compared with placebo. Results: At least one DME item was prescribed and accepted by 33/114 (28.9%) of placebo patients, 19/112 (17.0%) of patients receiving reldesemtiv 150 mg bid, 24/113 (21.2%) receiving 300 mg bid, and 29/117 (24.8%) receiving 450 mg bid. The proportion of new DME-PAP was significantly lower in patients receiving reldesemtiv 150 mg bid vs placebo (17.0% vs 28.9%, p = 0.032). The hazard ratio versus placebo for accepting at least one DME item for all reldesemtiv doses combined was 0.61 (confidence interval: 0.39, 0.96, p = 0.032). 25% of placebo patients were prescribed and agreed to obtain a DME item by 84 days; this threshold was met for reldesemtiv-treated patients at 120 days. Conclusions: Results suggest ALS patients receiving reldesemtiv may have lower risk of and delayed need for DME related to impaired mobility, breathing, swallowing, or speaking; this delay is consistent with other measures indicating delay in disease progression.

Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study.

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 µg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS.

OBJECTIVE: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

Activation of TRPA1 nociceptor promotes systemic adult mammalian skin regeneration.

Adult mammalian wounds, with rare exception, heal with fibrotic scars that severely disrupt tissue architecture and function. Regenerative medicine seeks methods to avoid scar formation and restore the original tissue structures. We show in three adult mouse models that pharmacologic activation of the nociceptor TRPA1 on cutaneous sensory neurons reduces scar formation and can also promote tissue regeneration. Local activation of TRPA1 induces tissue regeneration on distant untreated areas of injury, demonstrating a systemic effect. Activated TRPA1 stimulates local production of interleukin-23 (IL-23) by dermal dendritic cells, leading to activation of circulating dermal IL-17-producing γδ T cells. Genetic ablation of TRPA1, IL-23, dermal dendritic cells, or γδ T cells prevents TRPA1-mediated tissue regeneration. These results reveal a cutaneous neuroimmune-regeneration cascade triggered by topical TRPA1 activators that promotes adult mammalian tissue regeneration, presenting a new avenue for research and development of therapies for wounds and scars.

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype.

Highly tumorigenic, drug-resistant cancer stem-like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem-like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem-like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem-like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug-resistant phenotype.

Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer.

Importance: Concurrent chemoradiotherapy is the standard-of-care curative treatment for many cancers but is associated with substantial morbidity. Concurrent chemoradiotherapy administered with proton therapy might reduce toxicity and achieve comparable cancer control outcomes compared with conventional photon radiotherapy by reducing the radiation dose to normal tissues. Objective: To assess whether proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations (Common Terminology Criteria for Adverse Events, version 4 [CTCAEv4], grade ≥3) or other adverse events and similar disease-free and overall survival compared with concurrent photon therapy and chemoradiotherapy. Design, Setting, and Participants: This retrospective, nonrandomized comparative effectiveness study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent from January 1, 2011, through December 31, 2016, at a large academic health system. Three hundred ninety-one patients received proton therapy and 1092, photon therapy. Data were analyzed from October 15, 2018, through February 1, 2019. Interventions: Proton vs photon chemoradiotherapy. Main Outcomes and Measures: The primary end point was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3). Secondary end points included Eastern Cooperative Oncology Group (ECOG) performance status decline during treatment, 90-day adverse events of at least CTCAEv4 grade 2 that limit instrumental activities of daily living, and disease-free and overall survival. Data on adverse events and survival were gathered prospectively. Modified Poisson regression models with inverse propensity score weighting were used to model adverse event outcomes, and Cox proportional hazards regression models with weighting were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach. Results: Among the 1483 patients included in the analysis (935 men [63.0%]; median age, 62 [range, 18-93] years), those receiving proton therapy were significantly older (median age, 66 [range, 18-93] vs 61 [range, 19-91] years; P < .01), had less favorable Charlson-Deyo comorbidity scores (median, 3.0 vs 2.0; P < .01), and had lower integral radiation dose to tissues outside the target (mean [SD] volume, 14.1 [6.4] vs 19.1 [10.6] cGy/cc × 107; P < .01). Baseline grade ≥2 toxicity (22% vs 24%; P = .37) and ECOG performance status (mean [SD], 0.62 [0.74] vs 0.68 [0.80]; P = .16) were similar between the 2 cohorts. In propensity score weighted-analyses, proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse events of at least grade 3 (0.31; 95% CI, 0.15-0.66; P = .002), 90-day adverse events of at least grade 2 (0.78; 95% CI, 0.65-0.93; P = .006), and decline in performance status during treatment (0.51; 95% CI, 0.37-0.71; P < .001). There was no difference in disease-free or overall survival. Conclusions and Relevance: In this analysis, proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar disease-free and overall survival. Prospective trials are warranted to validate these results.