Association between posttreatment α-fetoprotein reduction and outcomes in real-world US patients with advanced hepatocellular carcinoma.

BACKGROUND: Clinical trials suggest α-fetoprotein (AFP) reduction may be prognostic among patients with advanced hepatocellular carcinoma. However, the association of AFP reduction with outcomes in real-world settings is unclear. METHODS: Patients with advanced hepatocellular carcinoma between January 1, 2011, and June 30, 2021, first-line tyrosine kinase inhibitor, and baseline and posttreatment AFP values (closest to 8 ± 2 weeks after first-line initiation) were included. AFP reduction was defined as ≥20% decrease from baseline vs <20% or no decrease. Real-world overall survival and progression-free survival (rwPFS) were defined as time from posttreatment AFP measurement to death, and the first progression event or death, respectively. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models adjusted for potential confounders and baseline AFP. Effect modification by baseline AFP and hepatocellular carcinoma risk factors was assessed. RESULTS: Among 533 patients, median baseline AFP was higher in those with AFP reduction than those without (N = 166, 210 µg/L vs N = 367, 150 µg/L). There was a 35% decrease in hazard of death for patients with reduction vs without (aHR = 0.65; 95% CI, 0.52-0.81; median, 10.3 vs 5.9 months). Results were similar for rwPFS (aHR = 0.66; 95% CI, 0.54-0.81; median, 4.6 vs 2.6 months). AFP reduction was associated with better outcomes among patients with baseline AFP ≥400 µg/L or with history of hepatitis B virus, hepatitis C virus, or alcohol use. Only the interaction between baseline AFP and reduction in association with rwPFS was statistically significant. CONCLUSIONS: For certain etiologies, posttreatment AFP change may be more important than baseline AFP for prognosis. Further work should characterize the prognostic implications of longitudinal AFP changes during treatment. PLAIN LANGUAGE SUMMARY: The prognostic value of the change in α-fetoprotein (AFP) concentration after treatment initiation is less established, particularly in real-world settings. Longitudinal data from a large nationwide cohort of patients with advanced hepatocellular carcinoma (HCC) treated with first-line tyrosine kinase inhibitor in routine practice revealed that ≥20% reduction in posttreatment AFP levels was associated with better real-world overall survival and progression-free survival after adjusting for baseline AFP levels and other factors. The results also suggested that the associations may be stronger among patients with a history of HCC risk factors (e.g., hepatitis C virus, alcohol) or with higher baseline AFP levels.

Telemedicine use among patients with metastatic breast cancer during the COVID-19 pandemic: Differences by race, age, and region.

PURPOSE: Our objective was to describe differences in telemedicine use among women with metastatic breast cancer (mBC) by race, age, and geographic region. METHODS: This was a retrospective cohort study of women with recurrent or de novo mBC treated in US community cancer practices that initiated a new line of therapy between March 2020 and February 2021. Multivariable modified Poisson regression models were used to calculate adjusted rate ratios (RR) and robust 95% confidence intervals (CI) associated with telemedicine visits within 90 days of therapy initiation. RESULTS: Overall, among 3412 women with mBC, 751 (22%) patients had telemedicine visits following therapy initiation, with lower risks observed among older women (<50 years: 24%; 50-64 years: 22%; 65-74 years: 21%; ≥75 years: 20%). Greater telemedicine use was observed among Asian women (35%) compared to White (21%), Black (18%), and Hispanic (21%) women. Fewer telemedicine visits occurred in Southern (12%) and Midwestern (17%) states versus Northeastern (37%) or Western (36%) states. In multivariable models, women ages ≥75 years had significantly lower risks of telemedicine visits (RR = 0.76, 95% CI 0.62-0.95) compared to ages <50 years. Compared to patients in Northeastern states, women in Midwestern (RR = 0.46, 95% CI 0.37-0.57) and Southern (RR = 0.31, 95% CI 0.26-0.37) states had significantly lower risks of telemedicine visits; but not women in Western states (RR = 0.96, 95% CI 0.83-1.12). No statistically significant differences in telemedicine use were found between racial groups in overall multivariable models. CONCLUSIONS: In this study of community cancer practices, older mBC patients and those living in Southern and Midwestern states were less likely to have telemedicine visits. Preferences for communication and delivery of care may have implications for measurement of exposures and endpoints in pharmacoepidemiologic studies of cancer patients.

Priming of Sorafenib Prior to Radiofrequency Ablation Does Not Increase Treatment Effect in Hepatocellular Carcinoma.

BACKGROUND: Preclinical studies have shown that modulation of the tumor microvasculature with anti-angiogenic agents decreases tumor perfusion and may increase the efficacy of radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC). Retrospective studies suggest that sorafenib given prior to RFA promotes an increase in the ablation zone, but prospective randomized data are lacking. AIMS: We conducted a randomized, double-blind, placebo-controlled phase II trial to evaluate the efficacy of a short-course of sorafenib prior to RFA for HCC tumors sized 3.5-7 cm (NCT00813293). METHODS: Treatment consisted of sorafenib 400 mg twice daily for 10 days or matching placebo, followed by RFA on day 10. The primary objectives were to assess if priming with sorafenib increased the volume and diameter of the RFA coagulation zone and to evaluate its impact on RFA thermal parameters. Secondary objectives included feasibility, safety and to explore the relationship between tumor blood flow on MRI and RFA effectiveness. RESULTS: Twenty patients were randomized 1:1. Priming with sorafenib did not increase the size of ablation zone achieved with RFA and did not promote significant changes in thermal parameters, although it significantly decreased blood perfusion to the tumor by 27.9% (p = 0.01) as analyzed by DCE-MRI. No subject discontinued treatment owing to adverse events and no grade 4 toxicity was observed. CONCLUSION: Priming of sorafenib did not enhance the effect of RFA in intermediate sized HCC. Future studies should investigate whether longer duration of treatment or a different antiangiogenic strategy in the post-procedure setting would be more effective in impairing tumor perfusion and increasing RFA efficacy.

Real-world association of HER2/ERBB2 concordance with trastuzumab clinical benefit in advanced esophagogastric cancer.

Aim: To assess concordance between HER2 status measured by traditional methods and ERBB2 amplification measured by next-generation sequencing and its association with first-line trastuzumab clinical benefit in patients with advanced esophagogastric cancer. Methods: Retrospective analysis of HER2/ERBB2 concordance using a deidentified USA-based clinicogenomic database. Clinical outcomes were assessed for patients with HER2+ advanced esophagogastric cancer who received first-line trastuzumab. Results: Overall HER2/ERBB2 concordance was 87.5%. Among patients who received first-line trastuzumab, concordant HER2/ERBB2 was associated with longer time to treatment discontinuation (adjusted hazard ratio [aHR]: 0.63; 95% CI: 0.43-0.90) and overall survival (aHR: 0.51; 95% CI: 0.33-0.79). ERBB2 copy number ≥25 (median) was associated with longer time to treatment discontinuation (aHR: 0.56; 95% CI: 0.35-0.88) and overall survival (aHR: 0.52; 95% CI: 0.30-0.91). Conclusion: HER2/ERBB2 concordance and higher ERBB2 copy number predicted clinical benefit from trastuzumab.

Lay abstract Trastuzumab is a drug that has been shown to prolong survival in some patients with advanced esophagogastric cancer whose tumor expresses a protein biomarker called HER2. There are different methods for assessing whether a patient's tumor expresses HER2, including but not limited to traditional methods such as immunohistochemistry and in situ hybridization and novel methods such as next-generation sequencing, which detects alterations in the gene (ERBB2) that encodes the HER2 protein. In our study, we assessed concordance between HER2 status (HER2-positive or HER2-negative) measured by traditional methods and ERBB2 amplification measured by next-generation sequencing, to determine whether there was an association between concordance and clinical benefit in patients with advanced esophagogastric cancer treated with trastuzumab. Our results suggest that, when HER2 positivity is detected through traditional methods, both ERBB2 concordance (i.e., agreement that a patient's tumor had the biomarker) and a higher ERBB2 copy number (the amount of the ERBB2 gene expressed by the tumor) were associated with longer time to treatment discontinuation and overall survival in patients with advanced esophagogastric cancer treated with first-line trastuzumab.

Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non-small cell lung cancer.

BACKGROUND: Despite the rapid adoption of immunotherapies in advanced non-small cell lung cancer (advNSCLC), knowledge gaps remain about their real-world (rw) performance. METHODS: This retrospective, observational, multicenter analysis used the Flatiron Health deidentified electronic health record-derived database of rw patients with advNSCLC who received treatment with PD-1 and/or PD-L1 (PD-[L]1) inhibitors before July 1, 2017 (N = 5257) and had ≥6 months of follow-up. The authors investigated PD-(L)1 line of treatment and PD-L1 testing rates and the relationship between overall survival (OS) and rw intermediate endpoints: progression-free survival (rwPFS), rw time to progression (rwTTP), rw time to next treatment (rwTTNT), and rw time to discontinuation (rwTTD). RESULTS: First-line PD-(L)1 inhibitor use increased from 0% (in the third quarter of 2014 [Q3 2014]) to 42% (Q2 2017) over the study period. PD-L1 testing also increased (from 3% in Q3 2015 to 70% in Q2 2017). The estimated median OS was 9.3 months (95% CI, 8.9-9.8 months), and the estimated rwPFS was 3.2 months (95% CI, 3.1-3.3 months). Longer OS and rwPFS were associated with ≥50% PD-L1 percentage staining results. Correlations (⍴) between OS and intermediate endpoints were ⍴ = 0.75 (95% CI, 0.73-0.76) for rwPFS and ⍴ = 0.60 (95% CI, 0.57-0.63) for rwTTP, and, for treatment-based intermediate endpoints, correlations were ⍴ = 0.60 (95% CI, 0.56-0.64) for rwTTNT (N = 856) and ⍴ = 0.81 (95% CI, 0.80-0.82) for rwTTD. CONCLUSIONS: The use of first-line PD-(L)1 inhibitors and PD-L1 testing has substantially increased, with better outcomes for patients who have ≥50% PD-L1 percentage staining. Intermediate rw tumor-dynamics estimates were moderately correlated with OS in patients with advNSCLC who received immunotherapy, highlighting the need for optimizing and standardizing rw endpoints to enhance the understanding of patient outcomes outside clinical trials.

A Phase Ib, Open-Label Study of Dalantercept, an Activin Receptor-Like Kinase 1 Ligand Trap, plus Sorafenib in Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: Patients with hepatocellular carcinoma (HCC) often have limited therapeutic responses to the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor sorafenib, which is standard of care in advanced HCC. Targeting the activin receptor-like kinase 1 (ALK1) and VEGF pathways simultaneously by combining the ALK1 ligand trap dalantercept with sorafenib may result in more effective angiogenic blockade and delay tumor progression in patients with advanced HCC.Although the combination was generally well tolerated, there was no additive antitumor activity with the combination of dalantercept plus sorafenib in patients with advanced HCC. No complete or partial responses were observed, and overall survival ranged from 1.9 to 23.3 months.These results suggest that, in this patient population, further development of the possible limited benefits of combination therapy with dalantercept plus sorafenib is not warranted. BACKGROUND: Targeting the activin receptor-like kinase 1 (ALK1) and vascular endothelial growth factor (VEGF) pathways may result in more effective angiogenic blockade in patients with hepatocellular carcinoma (HCC). METHODS: In this phase Ib study, patients with advanced HCC were enrolled to dose-escalation cohorts, starting at 0.6 mg/kg dalantercept subcutaneously every 3 weeks plus 400 mg sorafenib orally once daily, or to a dose expansion cohort. The primary objective was to determine the safety and tolerability and the dalantercept maximum tolerated dose (MTD) level. Secondary objectives were to assess the preliminary activity and the association of pharmacodynamic biomarkers with tumor response. RESULTS: A total of 21 patients were enrolled in the study. Five patients received 0.6 mg/kg dalantercept in the first dose escalation cohort. Based on the initial safety results, the dose level was de-escalated to 0.4 mg/kg in the second cohort (n = 6). The MTD was identified as 0.4 mg/kg and used for the dose expansion cohort (n = 10). At this dose level, the combination was generally well tolerated. Overall survival ranged from 1.9 to 23.3 months, and the best overall response was stable disease. CONCLUSION: The addition of dalantercept to sorafenib did not improve antitumor activity in patients with HCC. The dalantercept program in this population was discontinued.

Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.

BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded. RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS. CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

Liver function changes after transarterial chemoembolization in US hepatocellular carcinoma patients: the LiverT study.

BACKGROUND: The real-world incidence of chronic liver damage after transarterial chemoembolization (TACE) is unclear. LiverT, a retrospective, observational study, assessed liver function deterioration after a single TACE in real-world hepatocellular carcinoma (HCC) patients in US practice. METHODS: Eligible HCC patients identified from Optum's integrated database using standard codes as having had an index TACE between 2010 and 2016 with no additional oncologic therapy in the subsequent 3 months. At least one laboratory value (bilirubin, albumin, aspartate transaminase [AST], alanine transaminase [ALT], international normalized ratio [INR]) was required at baseline and the acute (≤29 days after TACE) and chronic (30-90 days after TACE) periods. Due to lack of universally accepted liver function deterioration criteria, clinically meaningful changes in laboratory parameters were pre-defined by authors (FP, RM, and SO). RESULTS: Of the 3963 TACE patients, 572 were eligible for analyses. Deterioration of liver function from baseline occurred in the acute period and persisted in the chronic period (bilirubin 30 and 23%, albumin 52 and 31%, AST 44 and 25%, ALT 43 and 25%, INR 25 and 15%, respectively). In a subgroup analysis, a higher proportion of patients with diabetes had deterioration in AST and ALT. CONCLUSIONS: A clinically meaningful proportion of real-world HCC patients had deterioration of liver function-related laboratory values 30-90 days after a single TACE in modern US practice. Future electronic health record research may help determine causality. The present findings highlight the need for the careful selection of patients for TACE, which is important to help optimize the benefit of the overall HCC treatment course.

Hepatocellular Carcinoma with Portal Vein Tumor Involvement: Best Management Strategies.

Portal vein tumor thrombosis (PVTT) commonly occurs in patients with hepatocellular carcinoma (HCC). Patients with PVTT usually have an aggressive disease course, decreased liver function reserve, limited treatment options, higher recurrence rates after treatment, and, therefore, worse overall survival. Among untreated HCC patients with PVTT, the median overall survival has been reported as low as 2 to 4 months. Historically, many aspects of PVTT have impacted the theoretical and practical safety and efficacy of treatment, for example, disordered blood flow and associated impairment of liver function, heat-sink effects of blood flow in the area of the PVTT, and risk of recurrence due to tumor location in the blood vessel. The current Barcelona Clinic Liver Cancer staging system categorizes HCC patients with PVTT as advanced stage, for which the standard of care is targeted therapy with sorafenib. However, sorafenib is associated with only marginal benefits among patients with PVTT. First-line lenvatinib, which was shown to be noninferior to sorafenib, excluded patients with main portal trunk invasion. Regorafenib and nivolumab, an immune-based therapy, were recently approved in the United States for second-line therapy after sorafenib. Preliminary results for cabozantinib suggest a benefit in the second-/third-line after sorafenib failure. In addition, rapid advances in many fields (surgery, interventional radiology, nuclear medicine, and immunotherapy) have increased the potential treatment options for the management of this complex disease entity. A large portion of the emerging evidence focuses on the broader category of advanced HCC of which PVTT is a subgroup. While many of these studies show promising results, the efficacy among PVTT patients requires validation in prospective studies. Real-world data may help fill the evidence gap for patients not eligible for clinical trials due to common hepatic function requirements. The variety of new treatment advances for the heterogeneous and complex disease entity of HCC with PVTT means that personalized, multidisciplinary management may be necessary to achieve optimal outcomes. In this narrative review, we summarize the evolving management strategies for patients with HCC and PVTT.

Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival.

BACKGROUND: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC). METHODS: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy. RESULTS: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all Ptrend<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both Pinteraction<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence. CONCLUSIONS: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.

Cabozantinib in the treatment of hepatocellular carcinoma.

Despite clinical studies with different mechanisms of action, no new systemic therapies were approved for hepatocellular carcinoma (HCC) between sorafenib in 2007 and regorafenib in 2017. This is an area of interest to improve outcomes and quality of life. Cabozantinib is oral, small-molecule tyrosine kinase inhibitor that primarily targets MET, VEGFR2, AXL and RET, with additional effect on KIT and FLT3. Cabozantinib is approved for progressive metastatic medullary thyroid cancer and previously treated renal cell carcinoma, and is in development for multiple solid tumors. Given positive results from a Phase II study, cabozantinib is under evaluation in a Phase III randomized controlled trial for patients with advanced HCC previously treated with sorafenib. It has been granted orphan drug status in the USA for this indication. This review summarizes the development of cabozantinib in HCC.

Identification of prognostic biomarkers in hepatitis B virus-related hepatocellular carcinoma and stratification by integrative multi-omics analysis.

BACKGROUND & AIMS: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy. METHODS: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patients with multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to contrast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174). RESULTS: The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual-specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort. CONCLUSIONS: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

Systemic Anticancer Therapy and Overall Survival in Patients With Very Advanced Solid Tumors.

Importance: Two prominent organizations, the American Society of Clinical Oncology and the National Quality Forum (NQF), have developed a cancer quality metric aimed at reducing systemic anticancer therapy administration at the end of life. This metric, NQF 0210 (patients receiving chemotherapy in the last 14 days of life), has been critiqued for focusing only on care for decedents and not including the broader population of patients who may benefit from treatment. Objective: To evaluate whether the overall population of patients with metastatic cancer receiving care at practices with higher rates of oncologic therapy for very advanced disease experience longer survival. Design, Setting, and Participants: This nationwide population-based cohort study used Flatiron Health, a deidentified electronic health record database of patients diagnosed with metastatic or advanced disease, to identify adult patients (aged ≥18 years) with 1 of 6 common cancers (breast cancer, colorectal cancer, non-small cell lung cancer [NSCLC], pancreatic cancer, renal cell carcinoma, and urothelial cancer) treated at health care practices from 2015 to 2019. Practices were stratified into quintiles based on retrospectively measured rates of NQF 0210, and overall survival was compared by disease type among all patients treated in each practice quintile from time of metastatic diagnosis using multivariable Cox proportional hazard models with a Bonferroni correction for multiple comparisons. Data were analyzed from July 2021 to July 2023. Exposure: Practice-level NQF 0210 quintiles. Main Outcome and Measure: Overall survival. Results: Of 78 446 patients (mean [SD] age, 67.3 [11.1] years; 52.2% female) across 144 practices, the most common cancer types were NSCLC (34 201 patients [43.6%]) and colorectal cancer (15 804 patients [20.1%]). Practice-level NQF 0210 rates varied from 10.9% (quintile 1) to 32.3% (quintile 5) for NSCLC and 6.8% (quintile 1) to 28.4% (quintile 5) for colorectal cancer. No statistically significant differences in survival were observed between patients treated at the highest and the lowest NQF 0210 quintiles. Compared with patients seen at practices in the lowest NQF 0210 quintiles, the hazard ratio for death among patients seen at the highest quintiles varied from 0.74 (95% CI, 0.55-0.99) for those with renal cell carcinoma to 1.41 (95% CI, 0.98-2.02) for those with urothelial cancer. These differences were not statistically significant after applying the Bonferroni-adjusted critical P = .008. Conclusions and Relevance: In this cohort study, patients with metastatic or advanced cancer treated at practices with higher NQF 0210 rates did not have improved survival. Future efforts should focus on helping oncologists identify when additional therapy is futile, developing goals of care communication skills, and aligning payment incentives with improved end-of-life care.

Socioeconomic status and inequities in treatment initiation and survival among patients with cancer, 2011-2022.

BACKGROUND: Lower neighborhood socioeconomic status (SES) is associated with suboptimal cancer care and reduced survival. Most studies examining cancer inequities across area-level socioeconomic status tend to use less granular or unidimensional measures and pre-date the COVID-19 pandemic. Here, we examined the association of area-level socioeconomic status on real-world treatment initiation and overall survival among adults with 20 common cancers. METHODS: This retrospective cohort study used electronic health record-derived deidentified data (Flatiron Health Research Database, 2011-2022) linked to US Census Bureau data from the American Community Survey (2015-2019). Area-level socioeconomic status quintiles (based on a measure incorporating income, home values, rental costs, poverty, blue-collar employment, unemployment, and education information) were computed from the US population and applied to patients based on their mailing address. Associations were examined using Cox proportional hazards models adjusted for diagnosis year, age, sex, performance status, stage, and cancer type. RESULTS: This cohort included 291 419 patients (47.7% female; median age = 68 years). Patients from low-SES areas were younger and more likely to be Black (21.9% vs 3.3%) or Latinx (8.4% vs 3.0%) than those in high-SES areas. Living in low-SES areas (vs high) was associated with lower treatment rates (hazard ratio = 0.94 [95% confidence interval = 0.93 to 0.95]) and reduced survival (median real-world overall survival = 21.4 vs 29.5 months, hazard ratio = 1.20 [95% confidence interval = 1.18 to 1.22]). Treatment and survival inequities were observed in 9 and 19 cancer types, respectively. Area-level socioeconomic inequities in treatment and survival remained statistically significant in the COVID-19 era (after March 2020). CONCLUSION: To reduce inequities in cancer outcomes, efforts that target marginalized, low-socioeconomic status neighborhoods are necessary.

The Association Between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients With Non-Small Cell Lung Cancer Treated With a PD-1/PD-L1 Blocking Antibody Using Real-World and Trial Data.

Clinical trials have demonstrated the benefit of PD-1/PD-L1 blocking antibodies for the treatment of patients with advanced non-small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD-1/PD-L1 blocking antibodies in real-world data (RWD; patient-level data from electronic health records) and pooled clinical trial data submitted to the US Food and Drug Administration (FDA). The Kaplan-Meier estimator was used to estimate OS in different subgroups based on organ function. Unadjusted and adjusted Cox proportional hazards models were used to estimate the association between OS and organ function. In this hypothesis-generating study, baseline renal impairment did not appear to be associated with OS, while patients with baseline liver impairment had shorter OS. RWD provided information on a broader range of renal and hepatic function than was evaluated in clinical trials and hold promise to complement trial data in better understanding populations not represented in clinical trials.

A machine learning framework supporting prospective clinical decisions applied to risk prediction in oncology.

We present a general framework for developing a machine learning (ML) tool that supports clinician assessment of patient risk using electronic health record-derived real-world data and apply the framework to a quality improvement use case in an oncology setting to identify patients at risk for a near-term (60 day) emergency department (ED) visit who could potentially be eligible for a home-based acute care program. Framework steps include defining clinical quality improvement goals, model development and validation, bias assessment, retrospective and prospective validation, and deployment in clinical workflow. In the retrospective analysis for the use case, 8% of patient encounters were associated with a high risk (pre-defined as predicted probability ≥20%) for a near-term ED visit by the patient. Positive predictive value (PPV) and negative predictive value (NPV) for future ED events was 26% and 91%, respectively. Odds ratio (OR) of ED visit (high- vs. low-risk) was 3.5 (95% CI: 3.4-3.5). The model appeared to be calibrated across racial, gender, and ethnic groups. In the prospective analysis, 10% of patients were classified as high risk, 76% of whom were confirmed by clinicians as eligible for home-based acute care. PPV and NPV for future ED events was 22% and 95%, respectively. OR of ED visit (high- vs. low-risk) was 5.4 (95% CI: 2.6-11.0). The proposed framework for an ML-based tool that supports clinician assessment of patient risk is a stepwise development approach; we successfully applied the framework to an ED visit risk prediction use case.

Analysis of a Real-World Progression Variable and Related Endpoints for Patients with Five Different Cancer Types.

INTRODUCTION: We previously demonstrated that real-world progression (rwP) can be ascertained from unstructured electronic health record (EHR)-derived documents using a novel abstraction approach for patients with advanced non-small cell lung cancer (base case). The objective of this methodological study was to assess the reliability, clinical relevance, and the need for disease-specific adjustments of this abstraction approach in five additional solid tumor types. METHODS: Patients with metastatic breast cancer (mBC), advanced melanoma (aMel), small cell lung cancer (SCLC), metastatic renal cell carcinoma (mRCC), and advanced gastric/esophageal cancer (aGEC) were selected from a real-world database. Disease-specific additions to the base case were implemented as needed. The resulting abstraction approach was applied to each disease cohort to capture rwP events and dates. To provide comprehensive clinical context, real-world progression-free survival (rwPFS) and time to progression (rwTTP) were compared to real-world overall survival (rwOS), time to next treatment (rwTTNT), and time to treatment discontinuation (rwTTD). Endpoint estimates were assessed using the Kaplan-Meier method. Correlations between real-world endpoints and rwOS were calculated using Spearman's ρ. RESULTS: Additions to the base-case rwP abstraction approach were required for mBC, aMel, and SCLC. Inter-abstractor agreement for rwP occurrence, irrespective of date, ranged from 88% to 97%. Occurrence of clinically relevant downstream events (new antineoplastic systemic therapy start, antineoplastic systemic therapy end, or death relative to the rwP event) ranged from 59% (aMel) to 72% (mBC). Median rwPFS ranged from 3.7 (aMel) to 7.7 (mBC) months, and median rwTTP ranged from 4.6 (aMel) to 8.3 (mRCC) months. Correlations between rwOS and rwPFS ranged from 0.52 (aMel) to 0.82 (SCLC). The correlation between rwOS and rwTTD was often lower relative to other comparisons (range 0.40-0.62). CONCLUSION: Derivation of a rwP variable from EHR documentation is feasible and reliable across the five solid tumors. Endpoint analyses show that rwP produces clinically meaningful information.

Emulating Control Arms for Cancer Clinical Trials Using External Cohorts Created From Electronic Health Record-Derived Real-World Data.

Electronic health record (EHR)-derived real-world data (RWD) can be sourced to create external comparator cohorts to oncology clinical trials. This exploratory study assessed whether EHR-derived patient cohorts could emulate select clinical trial control arms across multiple tumor types. The impact of analytic decisions on emulation results was also evaluated. By digitizing Kaplan-Meier curves, we reconstructed published control arm results from 15 trials that supported drug approvals from January 1, 2016, to April 30, 2018. RWD cohorts were constructed using a nationwide EHR-derived de-identified database by aligning eligibility criteria and weighting to trial baseline characteristics. Trial data and RWD cohorts were compared using Kaplan-Meier and Cox proportional hazards regression models for progression-free survival (PFS) and overall survival (OS; individual cohorts) and multitumor random effects models of hazard ratios (HRs) for median endpoint correlations (across cohorts). Post hoc, the impact of specific analytic decisions on endpoints was assessed using a case study. Comparing trial data and weighted RWD cohorts, PFS results were more similar (HR range = 0.63-1.18, pooled HR = 0.84, correlation of median = 0.91) compared to OS (HR range = 0.36-1.09, pooled HR = 0.76, correlation of median = 0.85). OS HRs were more variable and trended toward worse for RWD cohorts. The post hoc case study had OS HR ranging from 0.67 (95% confidence interval (CI): 0.56-0.79) to 0.92 (95% CI: 0.78-1.09) depending on specific analytic decisions. EHR-derived RWD can emulate oncology clinical trial control arm results, although with variability. Visibility into clinical trial cohort characteristics may shape and refine analytic approaches.