Health Care Cost Reductions with Machine Learning-Directed Evaluations during Radiation Therapy - An Economic Analysis of a Randomized Controlled Study.

BACKGROUND: Machine learning (ML) may cost-effectively direct health care by identifying patients most likely to benefit from preventative interventions to avoid negative and expensive outcomes. System for High-Intensity Evaluation During Radiation Therapy (SHIELD-RT; NCT04277650) was a single-institution, randomized controlled study in which electronic health record-based ML accurately identified patients at high risk for acute care (emergency visit or hospitalization) during radiotherapy (RT) and targeted them for supplemental clinical evaluations. This ML-directed intervention resulted in decreased acute care utilization. Given the limited prospective data showing the ability of ML to direct interventions cost-efficiently, an economic analysis was performed. METHODS: A post hoc economic analysis was conducted of SHIELD-RT that included RT courses from January 7, 2019, to June 30, 2019. ML-identified high-risk courses (≥10% risk of acute care during RT) were randomized to receive standard of care weekly clinical evaluations with ad hoc supplemental evaluations per clinician discretion versus mandatory twice-weekly evaluations. The primary outcome was difference in mean total medical costs during and 15 days after RT. Acute care costs were obtained via institutional cost accounting. Physician and intervention costs were estimated via Medicare and Medicaid data. Negative binomial regression was used to estimate cost outcomes after adjustment for patient and disease factors. RESULTS: A total of 311 high-risk RT courses among 305 patients were randomized to the standard (n=157) or the intervention (n=154) group. Unadjusted mean intervention group supplemental visit costs were $155 per course (95% confidence interval, $142 to $168). The intervention group had fewer acute care visits per course (standard, 0.47; intervention, 0.31; P=0.04). Total mean adjusted costs were $3110 per course for the standard group and $1494 for the intervention group (difference in means, $1616 [95% confidence interval, $1450 to $1783]; P=0.03). CONCLUSIONS: In this economic analysis of a randomized controlled, health care ML study, mandatory supplemental evaluations for ML-identified high-risk patients were associated with both reduced total medical costs and improved clinical outcomes. Further study is needed to determine whether economic results are generalizable. (Funded in part by The Duke Endowment, The Conquer Cancer Foundation, the Duke Department of Radiation Oncology, and the National Cancer Institute of the National Institutes of Health [R01CA277782]; ClinicalTrials.gov number, NCT04277650.).

Patient-specific meta-analysis of 12-gene colon cancer recurrence score validation studies for recurrence risk assessment after surgery with or without 5FU and oxaliplatin.

Background: Individualized estimates of the risk of recurrence in colon cancer patients are needed that reflect current medical practice and available treatment options. Methods: Three validation studies of the 12-gene colon recurrence score assay were used with pre-specified patient-specific meta-analysis (PSMA) methods to integrate the 12-gene Oncotype DX Colon Recurrence Score result (RS) with the clinical and pathology risk factors stage, T-stage, mis-match repair (MMR) status, and number of nodes examined to calculate individualized recurrence risk estimates. Baseline risk estimation used the most recent studies, so the risk estimates reflect current medical practice. The effect of fluorouracil (5FU) was estimated with a meta-analysis of two studies. The effect of oxaliplatin was estimated using one of the RS assay validation studies, in which patients were randomized to 5FU with or without oxaliplatin. Results: The RS result and each of the clinical-pathologic factors provided independent prognostic information for recurrence. Among stage II, T3, MMR-proficient patients with ≥12 nodes examined (the most common scenario), patients with RS ≤30 (approximately 48%) have estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-deficient patients with ≥12 nodes examined, patients with RS ≤19 (approximately 14%) have an estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-proficient patients with ≥12 nodes examined, those with RS ≤14 (approximately 6%) have estimated 5-year recurrence risk ≤10% with 5FU alone. Discussion: The PSMA integrates the 12-gene colon RS result with clinical and pathology factors to provide individualized recurrence risk estimates that reflect current medical practice. The risk estimates are in a range that may help inform treatment decisions for a substantial number of stage II and stage III patients.

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC. Objectives: To assess whether the addition of atezolizumab to capecitabine and bevacizumab therapy improves progression-free survival (PFS) among patients with refractory mCRC and to perform exploratory analyses among patients with microsatellite-stable (MSS) disease and liver metastasis. Design, Setting, and Participants: This double-blind phase 2 randomized clinical trial enrolled 133 patients between September 25, 2017, and June 28, 2018 (median duration of follow-up for PFS, 20.9 months), with data cutoff on May 4, 2020. The study was conducted at multiple centers through the Academic and Community Cancer Research United network. Adult patients with mCRC who experienced disease progression while receiving fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-epidermal growth factor receptor antibody therapy (if the patient had a RAS wild-type tumor) were included. Interventions: Patients were randomized (2:1) to receive capecitabine (850 or 1000 mg/m2) twice daily on days 1 to 14 and bevacizumab (7.5 mg/kg) on day 1 plus either atezolizumab (1200 mg; investigational group) or placebo (placebo group) on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary end point was PFS; 110 events were required to detect a hazard ratio (HR) of 0.65 with 80% power (1-sided α = .10). Secondary end points were objective response rate, overall survival (OS), and toxic effects. Results: Of 133 randomized patients, 128 individuals (median age, 58.0 years [IQR, 51.0-65.0 years]; 77 men [60.2%]) were assessed for efficacy (82 in the investigational group and 46 in the placebo group). Overall, 15 patients (11.7%) self-identified as African American or Black, 8 (6.3%) as Asian, 1 (0.8%) as Pacific Islander, 101 (78.9%) as White, 1 (0.8%) as multiple races (Asian, Native Hawaiian/Pacific Islander, and White), and 2 (1.6%) as unknown race or unsure of race. Microsatellite-stable disease was present in 110 patients (69 in the investigational group and 41 in the placebo group). Median PFS was 4.4 months (95% CI, 4.1-6.4 months) in the investigational group and 3.6 months (95% CI, 2.2-6.2 months) in the placebo group (1-sided log-rank P = .07, a statistically significant result; HR, 0.75; 95% CI, 0.52-1.09). Among patients with MSS and proficient mismatch repair, the HR for PFS was 0.66 (95% CI, 0.44-0.99). The most common grade 3 or higher treatment-related adverse events in the investigational vs placebo groups were hypertension (6 patients [7.0%] vs 2 patients [4.3%]), diarrhea (6 patients [7.0%] vs 2 patients [4.3%]), and hand-foot syndrome (6 patients [7.0%] vs 2 patients [4.3%]). One treatment-related death occurred in the investigational group. In the investigational group, the response rate was higher among patients without liver metastasis (3 of 13 individuals [23.1%]) vs with liver metastasis (4 of 69 individuals [5.8%]). The benefit of atezolizumab for PFS and OS was greater among patients without vs with liver metastasis (primary analysis of PFS: HR, 0.63 [95% CI, 0.27-1.47] vs 0.77 [95% CI, 0.51-1.17]; OS: HR, 0.33 [95% CI, 0.11-1.02] vs 1.14 [95% CI, 0.72-1.81]). Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to capecitabine and bevacizumab therapy provided limited (ie, not clinically meaningful) clinical benefit. Patients with MSS and proficient mismatch repair tumors and those without liver metastasis benefited more from dual inhibition of the vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 pathways. Trial Registration: ClinicalTrials.gov Identifier: NCT02873195.

Variability in endoscopic assessment of Nissen fundoplication wrap integrity and hiatus herniation.

BACKGROUND: Upper endoscopy (EGD) is frequently performed in patients with esophageal complaints following anti-reflux surgery such as fundoplication. Endoscopic evaluation of fundoplication wrap integrity can be challenging. Our primary aim in this pilot study was to evaluate the accuracy and confidence of assessing Nissen fundoplication integrity and hiatus herniation among gastroenterology (GI) fellows, subspecialists, and foregut surgeons. METHODS: Five variations of post-Nissen fundoplication anatomy were included in a survey of 20 sets of EGD images that was completed by GI fellows, general GI attendings, esophagologists, and foregut surgeons. Accuracy, diagnostic confidence, and inter-rater agreement across providers were evaluated. RESULTS: There were 31 respondents in the final cohort. Confidence in pre-survey diagnostics significantly differed by provider type (mean confidence out of 5 was 1.8 for GI fellows, 2.7 for general GI attendings, 3.6 for esophagologists, and 3.6 for foregut surgeons, P = 0.01). The mean overall accuracy was 45.9%, which significantly differed by provider type with the lowest rate among GI fellows (37%) and highest among esophagologists (53%; P = 0.01). The accuracy was highest among esophagologists across all wrap integrity variations. Inter-rater agreement was low across wrap integrity variations (Krippendorf's alpha <0.30), indicating low to no agreement between providers. CONCLUSION: In this multi-center survey study, GI fellows had the lowest accuracy and confidence in assessing EGD images after Nissen fundoplication, whereas esophagologists had the highest. Diagnostic confidence varied considerably and inter-rater agreement was poor. These findings suggest experience may improve confidence, but highlight the need to improve the evaluation of fundoplication wraps.

Racial and Socioeconomic Disparities in Utilization of Telehealth in Patients with Liver Disease During COVID-19.

BACKGROUND AND AIMS: The coronavirus disease 2019 (COVID-19) pandemic resulted in a rapid expansion of telehealth services in hepatology. However, known racial and socioeconomic disparities in internet access potentially translate into barriers for the use of telehealth, particularly video technology. The specific aim of this study was to determine if disparities in race or socioeconomic status exist among patients utilizing telehealth visits during COVID-19. METHODS: We performed a retrospective cohort study of all adult patients evaluated in hepatology clinics at Duke University Health System. Visit attempts from a pre-COVID baseline period (January 1, 2020 through February 29, 2020; n = 3328) were compared to COVID period (April 1, 2020 through May 30, 2020; n = 3771). RESULTS: On multinomial regression modeling, increasing age was associated with higher odds of a phone or incomplete visit (canceled, no-show, or rescheduled after May 30,2020), and non-Hispanic Black race was associated with nearly twice the odds of completing a phone visit instead of video visit, compared to non-Hispanic White patients. Compared to private insurance, Medicaid and Medicare were associated with increased odds of completing a telephone visit, and Medicaid was associated with increased odds of incomplete visits. Being single or previously married (separated, divorced, widowed) was associated with increased odds of completing a phone compared to video visit compared to being married. CONCLUSIONS: Though liver telehealth has expanded during the COVID-19 pandemic, disparities in overall use and suboptimal use (phone versus video) remain for vulnerable populations including those that are older, non-Hispanic Black, or have Medicare/Medicaid health insurance.

Image quality of EOS low-dose radiography in comparison with conventional radiography for assessment of ventriculoperitoneal shunt integrity.

OBJECTIVE: Patients with shunted hydrocephalus often accumulate high levels of radiation over their lifetimes during evaluation of hardware integrity. Current practice involves the use of a series of conventional radiographs for this purpose. Newer low-dose EOS radiography is currently used to evaluate scoliosis but has not been explored to evaluate shunt integrity on a large scale. The goal of this study was to compare the quality of imaging using EOS low-dose radiography to conventional radiography to evaluate shunt tubing. METHODS: A retrospective chart review was performed on 57 patients who previously had both conventional radiographs and low-dose EOS images of their cerebral shunt tubing from 2000 to 2018. Patient demographics (age, sex, type of shunt tubing, primary diagnosis) were collected. Conventional radiographic images and low-dose EOS images were independently analyzed by a neurosurgeon and neuroradiologist in three categories: image quality, delineation of shunt, and distinction of shunt compared to adjacent anatomy. RESULTS: All patients had shunted hydrocephalus due to spina bifida and Chiari type II malformation. Ratings of EOS and conventional radiographic images by both raters did not differ significantly in terms of image quality (rater 1, p = 0.499; rater 2, p = 0.578) or delineation of shunt (p = 0.107 and p = 0.256). Conventional radiographic images received significantly higher ratings than EOS on the ability to distinguish the shunt versus adjacent anatomy by rater 1 (p = 0.039), but not by rater 2 (p = 0.149). The overall score of the three categories combined was not significantly different between EOS and conventional radiography (rater 1, p = 0.818; rater 2, p = 0.186). In terms of cost, an EOS image was less costly than a conventional radiography shunt series ($236-$366 and $1300-$1547, respectively). The radiation dose was also lower for EOS images, with an effective dose of 0.086-0.140 mSv compared to approximately 1.6 mSv for a similar field of view with conventional radiography. CONCLUSIONS: The image quality of low-dose EOS radiography does not significantly differ from conventional radiography for the evaluation of cerebral shunts. In addition, EOS affords a much lower radiation dose and a lower cost.

Impact of Malnutrition on Outcomes in Patients Undergoing Transjugular Intrahepatic Portosystemic Shunt Insertion.

BACKGROUND: Malnutrition is common in patients with cirrhosis and is associated with poor outcomes after hepatic resection and liver transplantation. Transjugular intrahepatic portosystemic shunt (TIPS) is performed for complications of cirrhosis. AIM: To assess the impact of malnutrition on TIPS outcomes. METHODS: A retrospective analysis was performed using the Healthcare Cost and Utilization Project: National Inpatient Sample database for TIPS procedures from 2005 to 2014. The primary end point was in-hospital mortality. The association of specific malnutrition diagnostic codes and race-ethnicity on mortality was evaluated with survey-weighted logistic regression adjusted for age, gender, admission type, insurance payer, hospital region, comorbidities, and length of stay (LOS). RESULTS: From 2005 to 2014, an estimated 53,207 (95% CI 49,330-57,085) admissions with TIPS occurred. A diagnosis of malnutrition was present in 11%. In-hospital death post-TIPS occurred in 15.0% versus 10.7% (p value < 0.001) of patients with and without malnutrition, respectively. Patients with malnutrition had longer post-procedural LOS (median 6.7 vs. 2.9 days, p value < 0.001) and greater total hospital charges (median $144,752 vs. $79,781, p value < 0.001) and were more likely to be discharged to a skilled nursing facility (21.6% vs. 9.7%) than patients without malnutrition. Patients with malnutrition had increased odds of mortality (OR 1.31, 95% CI 1.07, 1.59) compared to patients with no malnutrition. CONCLUSION: Malnutrition was associated with worse outcomes after TIPS. Further research is needed to understand the mechanism of malnutrition in post-procedure outcomes and the ability of interventions for nutritional optimization to improve outcomes.

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial.

IMPORTANCE: Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC). OBJECTIVE: To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease. DESIGN, SETTING, AND PARTICIPANTS: This unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS. INTERVENTIONS OR EXPOSURES: Patients received either 60 mg/m2 of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL. MAIN OUTCOMES AND MEASURES: The primary end point was OS, and progression-free survival (PFS) was a secondary end point. RESULTS: Of 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib. CONCLUSIONS AND RELEVANCE: This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01015833.

The Hepatitis C-Alcohol Reduction Treatment (Hep ART) intervention: Study protocol of a multi-center randomized controlled trial.

INTRODUCTION: Among patients with hepatitis C virus (HCV) infection, alcohol synergistically increases the risk of cirrhosis, hepatocellular carcinoma, and death. Randomized controlled trials of integrated models of HCV-alcohol treatment have been recommended but only performed in patients with severe alcohol use disorders. OBJECTIVES: This pragmatic randomized controlled trial seeks to compare clinical effectiveness and cost-effectiveness of integrated alcohol treatment compared to enhanced treatment as usual (TAU) on alcohol consumption and economic outcomes among patients ever infected with HCV. METHODS: Patients recruited from three liver centers who had current or prior chronic HCV and qualifying alcohol screener scores were randomly assigned to enhanced TAU or the Hepatitis C-Alcohol Reduction Treatment (Hep ART) intervention. All patients received enhanced TAU, consisting of a patient-administered alcohol screener and care from medical providers who were trained in Screening, Brief Intervention and Referral to Treatment (SBIRT), including brief motivational interviewing counseling. The Hep ART intervention combined enhanced TAU with up to six months of integrated co-located individual and/or group therapy that provided motivational, cognitive, and behavioral strategies to reduce alcohol consumption. The Timeline Followback (TLFB) Method was used to evaluate alcohol use at baseline, 3, 6, and 12 months. Primary outcomes are alcohol abstinence and fewer heavy drinking days, and for the cost-effectiveness analysis, measures included grams of alcohol consumed. DISCUSSION: This study will determine whether Hep ART, a six-month integrated alcohol treatment, compared to enhanced TAU, is both clinically effective and cost-effective in patients with a history of comorbid HCV and alcohol use.