Incidence and Costs of Clinically Significant Events with Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma: A Retrospective Cohort Study.

INTRODUCTION: Systemic therapies have been associated with clinically significant events (CSEs) in patients with unresectable hepatocellular carcinoma (uHCC). We evaluated the incidence of CSEs (bleeding, clotting, encephalopathy, and portal hypertension), and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line (1L) atezolizumab plus bevacizumab (A + B), lenvatinib (LEN), or sorafenib (SOR) in the USA. METHODS: A retrospective cohort study was performed using medical/pharmacy claims from Optum® Clinformatics® Data Mart. Patients diagnosed with HCC who initiated 1L A + B between June 01, 2020 and December 31, 2020 or LEN/SOR between January 01, 2016 and May 31, 2020 were included. Outcomes included incidence rates of CSEs, HCRU, and costs. Subgroup analysis was performed in patients with no CSEs or ≥ 1 CSE. RESULTS: In total, 1379 patients were selected (A + B, n = 271; LEN, n = 217; SOR, n = 891). Clotting (incidence rate per 100 patient-years [PY] 94.9) and bleeding (88.1 per 100 PY) were the most common CSEs in the A + B cohort. The most common CSEs in the LEN cohort were clotting (78.6 per 100 PY) and encephalopathy (66.3 per 100 PY). Encephalopathy (73.0 per 100 PY) and portal hypertension (72.3 per 100 PY) were the most common CSEs in the SOR cohort. Mean total all-cause healthcare costs per patient per month (PPPM) were $32,742, $35,623, and $29,173 in the A + B, LEN, and SOR cohorts, respectively. Mean total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (A + B $34,304 versus $30,889; LEN $39,591 versus $30,621; SOR $31,022 versus $27,003). CONCLUSION: Despite improved efficacy of 1L systemic therapies, CSEs remain a concern for patients with uHCC, as well as an economic burden to the healthcare system. Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.

Certain treatments for liver cancer can cause serious side effects, including bleeding, blood clots, brain injury (encephalopathy), or increased blood flow to the liver (portal hypertension). We used an insurance database to find out how often these events, known as clinically significant events, occurred in people with liver cancer who were given treatments that target the immune system (immunotherapy) or specific proteins involved in cancer growth and survival (targeted therapy). The study included 1379 patients treated with atezolizumab (immunotherapy) plus bevacizumab (targeted therapy), or lenvatinib or sorafenib alone (both targeted therapies), as their first treatment. Clotting and bleeding were the most common clinically significant events in patients treated with atezolizumab plus bevacizumab, whereas clotting and encephalopathy were the most common clinically significant events with lenvatinib, and encephalopathy and portal hypertension were the most common clinically significant events with sorafenib. On average, for every 100 patients treated for 1 year, there were more than 50 of each of these events. Average healthcare costs per patient per month ranged from around $29,000 to around $36,000 in the three different treatment groups, and were higher in people who had at least one clinically significant event. These results suggest that clinically significant events are common in people with liver cancer who are given various types of treatment. As well as raising concerns for patient safety, these events result in higher costs to healthcare systems. Therefore, newer treatments that are less likely to cause clinically significant events, while improving survival in patients with liver cancer, are needed.

Estimating excess visual loss from neovascular age-related macular degeneration in the UK during the COVID-19 pandemic: a retrospective clinical audit and simulation model.

OBJECTIVES: To report the reduction in new neovascular age-related macular degeneration (nAMD) referrals during the COVID-19 pandemic and estimate the impact of delayed treatment on visual outcomes at 1 year. DESIGN: Retrospective clinical audit and simulation model. SETTING: Multiple UK National Health Service (NHS) ophthalmology centres. PARTICIPANTS: Data on the reduction in new nAMD referrals were obtained from four NHS Trusts comparing April 2020 with April 2019. To estimate the potential impact on 1-year visual outcomes, a stratified bootstrap simulation model was developed drawing on an electronic medical records dataset of 20 825 nAMD eyes from 27 NHS Trusts. MAIN OUTCOME MEASURES: Simulated mean visual acuity and proportions of eyes with vision ≤6/60, ≤6/24 and ≥6/12 at 1 year under four hypothetical scenarios: 0-month, 3-month, 6-month and 9-month treatment delays. Estimated additional number of eyes with vision ≤6/60 at 1 year nationally. RESULTS: The number of nAMD referrals dropped on average by 72% (range 65%-87%). Simulated 1-year visual outcomes for 1000 nAMD eyes with a 3-month treatment delay suggested an increase in the proportion of eyes with vision ≤6/60 from 15.5% (13.2%-17.9%) to 23.3% (20.7%-25.9%), and a decrease in the proportion of eyes with vision ≥6/12 (driving vision) from 35.1% (32.1%-38.1%) to 26.4% (23.8%-29.2%). Outcomes worsened incrementally with longer modelled delays. Assuming nAMD referrals are reduced to this level for 1 month nationally, these simulated results suggest an additional 186-365 eyes with vision ≤6/60 at 1 year. CONCLUSIONS: We report a large decrease in nAMD referrals during the COVID-19 lockdown and provide an important public health message regarding the risk of delayed treatment. As a conservative estimate, a treatment delay of 3 months could lead to a >50% relative increase in the number of eyes with vision ≤6/60 and 25% relative decrease in the number of eyes with driving vision at 1 year.

Contextualizing single-arm trials with real-world data: An emulated target trial comparing therapies for neovascular age-related macular degeneration.

One-in-four ophthalmology trials are single-armed, which poses challenges to their interpretation. We demonstrate how real-world cohorts used as external/synthetic control arms can contextualize such trials. We herein emulated a target trial on the intention-to-treat efficacy of off-label bevacizumab (q6w) pro re nata relative to fixed-interval aflibercept (q8w) for improving week 54 visual acuity of eyes affected by neovascular age-related macular degeneration. The bevacizumab arm (n = 65) was taken from the ABC randomized controlled trial. A total of 4,471 aflibercept-treated eyes aligning with the ABC trial eligibility were identified from electronic health records and synthetic control arms were created by emulating randomization conditional on age, sex, and baseline visual read via exact matching and propensity score methods. We undertook an inferiority analysis on mean difference at 54 weeks; outcomes regression on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to -15 Early Treatment Diabetic Retinopathy (ETDRS) letters at week 54; and a time-to-event analysis on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to -15 ETDRS letters by week 54. The findings suggest off-label bevacizumab to be neither inferior nor superior to licensed aflibercept. Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed trials when analyzed in accord to the target trial framework. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? One-in-four randomized controlled trials in ophthalmology are single-armed, which poses challenges for interpreting their efficacy relative to standard of care. Recent conceptual advances in the methods of causal inference and in the emulation of target trials suggests that the standard-of-care arms representing the counterfactual intervention can be approximated with observational data. WHAT QUESTION DID THIS STUDY ADDRESS? How real-world cohorts representing the counterfactual intervention can aid the interpretation of single-armed ophthalmological trials. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed ophthalmological trials when undertaken in accord with the target trial framework. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? External counterfactual arms could reduce the time and cost to reach potential regulatory approval.

Quantification of Key Retinal Features in Early and Late Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: We sought to develop and validate a deep learning model for segmentation of 13 features associated with neovascular and atrophic age-related macular degeneration (AMD). DESIGN: Development and validation of a deep-learning model for feature segmentation. METHODS: Data for model development were obtained from 307 optical coherence tomography volumes. Eight experienced graders manually delineated all abnormalities in 2712 B-scans. A deep neural network was trained with these data to perform voxel-level segmentation of the 13 most common abnormalities (features). For evaluation, 112 B-scans from 112 patients with a diagnosis of neovascular AMD were annotated by 4 independent observers. The main outcome measures were Dice score, intraclass correlation coefficient, and free-response receiver operating characteristic curve. RESULTS: On 11 of 13 features, the model obtained a mean Dice score of 0.63 ± 0.15, compared with 0.61 ± 0.17 for the observers. The mean intraclass correlation coefficient for the model was 0.66 ± 0.22, compared with 0.62 ± 0.21 for the observers. Two features were not evaluated quantitatively because of a lack of data. Free-response receiver operating characteristic analysis demonstrated that the model scored similar or higher sensitivity per false positives compared with the observers. CONCLUSIONS: The quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features. The quantified parameters provided by the model can be used in the current clinical routine and open possibilities for further research into treatment response outside clinical trials.

Colorectal cancer ascertainment through cancer registries, hospital episode statistics, and self-reporting compared to confirmation by clinician: A cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: Electronic health records are frequently used for cancer epidemiology. We report on their quality for ascertaining colorectal cancer (CRC) in UK women. METHODS: Population-based, retrospective cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Postmenopausal women aged 50-74 who were diagnosed with CRC during 2001-11 following randomisation to the UKCTOCS were identified and their diagnosis confirmed with their treating clinician. The sensitivity and positive predictive value (PPV) of cancer and death registries, hospital episode statistics, and self-reporting were calculated by pairwise comparisons to the treating clinician's confirmation, while specificity and negative predictive value were estimated relative to expected cases. RESULTS: Notification of CRC events were received for 1,085 women as of 24 May 2011. Responses were received from 61% (660/1,085) of clinicians contacted. Nineteen women were excluded (18 no diagnosis date, one diagnosed after cut-off). Of the 641 eligible, 514 had CRC, 24 had a benign polyp, and 103 had neither diagnosis. The sensitivity of cancer registrations at one- and six-years post-diagnosis was 92 (95% CI 90-94) and 99% (97-100), respectively, with a PPV of 95% (95% CI 92/93-97). The sensitivity & PPV of cancer registrations (at one-year post-diagnosis) & hospital episode statistics combined were 98 (96-99) and 92% (89-94), respectively. CONCLUSIONS: Cancer and death registrations in the UK are a reliable resource for CRC ascertainment in women. Hospital episode statistics can supplement delays in cancer registration. Self-reporting seems less reliable.