Immune-related adverse events (irAEs) are a range of complications associated with the use of immune-checkpoint inhibitors (ICIs). Two major classes of ICIs widely used are Cytotoxic T-Lymphocyte ...Antigen 4 (CTLA4) and Programmed Cell death-1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors. High-grade irAEs are life-threatening and often cause a severe decline in performance status in such that patients do not qualify for any further anticancer treatments. It is difficult to generalize the evidence in the current literature on risk factors or biomarkers for the entire class of ICIs as the studies so far are either disease-specific (e.g., lung cancer or melanoma) or ICI agent-specific (e.g., pembrolizumab, ipilimumab) or irAE-specific (e.g., pneumonitis or gastritis). In this review, risk factors and biomarkers to consider before initiating or monitoring ICI are listed with a practical purpose in day-to-day practice. Risk factors are grouped into demographics and social history, medical history, and medication history, tumor-specific and agent-specific risk factors. A higher risk of irAE is associated with age <60 years, high body mass index, women on CTLA4 and men on PD-1/PD-L1 agents, and chronic smokers. Patients with significant kidney (Stage IV-V), cardiac (heart failure, coronary artery disease, myocardial infarction, hypertension), and lung (asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease) are at a higher risk of respective organ-specific irAEs. Pre-existing autoimmune disease and chronic use of certain drugs (proton pump inhibitors, diuretics, anti-inflammatory drugs) also increase the irAE-risk. Biomarkers are categorized into circulating blood counts, cytokines, autoantibodies, HLA genotypes, microRNA, gene expression profiling, and serum proteins. The blood counts and certain protein markers (albumin and thyroid-stimulating hormone) are readily accessible in current practice. High neutrophil-lymphocyte ratio, eosinophil/monocyte/lymphocyte counts; TSH and troponins at diagnosis and drop in the white count and lymphocyte count can predict irAE. Other biomarkers with limited evidence are cytokines, autoantibodies, HLA genotypes, microRNA, and gene expression profiling. With fast-expanding approvals for ICIs in various cancer types, knowledge on risk factors and biomarkers can help providers assess the irAE-risk of their patients. Prospective disease and agent-specific studies are needed to provide further insight on this essential aspect of ICI therapy.
Background
Lung cancer screening (LCS) use among adults with disabilities has not been well characterized. We estimated the prevalence of LCS use by disability types and counts and investigated the ...association between disability counts and LCS utilization among LCS‐eligible adults.
Methods
We used cross‐sectional data from the 2019 Behavioral Risk Factor Surveillance System, Lung Cancer Screening Module. Based on the 2013 US Preventive Services Task Force criteria for LCS, the sample included 4407 LCS‐eligible adults, aged 55–79 years, with current or former (quit smoking in the past 15 years) tobacco use history of at least 30 pack‐years. Disability types included limitations in hearing, vision, cognition, mobility, self‐care, and independent living. We also categorized respondents by number of disabilities (no disability, 1 disability, 2 disabilities, 3+ disabilities). We utilized descriptive statistics and multivariable logistic regression analyses to determine the association between disability counts and the receipt of LCS (yes/no) in the past 12 months.
Results
In 2019, 16.4% of LCS‐eligible adults were screened for lung cancer. Overall, 49.6% of participants had no disability, and 14.5% had >3 disabilities. Mobility was the most prevalent disability type (35.4%), followed by cognitive impairment (18.2%) and hearing (16.6%). LCS was more prevalent in adults with disability in self‐care versus no disability in self‐care (24.0% vs. 15.5%, p = 0.01), disability in independent living versus no disability in independent living (22.2% vs. 15.4%, p = 0.02), and cognitive impairment disability versus no cognitive impairment (22.1% vs. 15.3%, p = 0.03). The prevalence rates of LCS among groups of LCS‐eligible adults with different disability counts were not significant (p = 0.17).
Conclusions
Despite the lack of clinical guidelines on LCS among individuals with disabilities, some individuals with disabilities are being screened for lung cancer. Future research should address this knowledge gap to determine clinical benefit versus harm of LCS among those with disabilities.
Lung cancer is a product of inflammation and a dysfunctional immune system, and depression has similar dysregulation. Depression disproportionately affects lung cancer patients, having the highest ...rates of all cancers. Systemic inflammation and depression are both predictive of non-small cell lung cancer (NSCLC) survival, but the existence and extent of any co-occurrence is unknown. Studied is the association between systemic inflammation ratio (SIR) biomarker levels and patients' depressive symptoms, with the hypothesis that depression severity would be significantly associated with prognostically poor inflammation. Newly diagnosed stage-IV non-small cell lung cancer (NSCLC; N = 186) patients were enrolled (ClinicalTrials.gov Identifier: NCT03199651) and blood draws and depression self-reports (Patient Health Questionnaire-9) were obtained. For SIRs, cell counts of neutrophils (N), lymphocytes (L), and platelets (P) were abstracted for ratio (R) calculations for NLR, PLR, and the Advanced Lung cancer Inflammation Index (ALI). Patients were followed and biomarkers were tested as predictors of 2-year overall survival (OS) to confirm their relevance. Next, multivariate linear regressions tested associations of depression with NLR, PLR, and ALI. Overall 2-year mortality was 61% (113/186). Cox model analyses confirmed higher NLR hazard ratio (HR) = 1.91; p = 0.001 and PLR (HR = 2.08; p<0.001), along with lower ALI (HR = 0.53; p = 0.005), to be predictive of worse OS. Adjusting for covariates, depression was reliably associated with biomarker levels (p ≤ 0.02). Patients with moderate/severe depressive symptoms were 2 to 3 times more likely to have prognostically poor biomarker levels. Novel data show patients' depressive symptoms were reliably associated with lung-relevant systemic inflammation biomarkers, all assessed at diagnosis/pretreatment. The same SIRs were found prognostic for patients' 2-year OS. Intensive study of depression, combined with measures of cell biology and inflammation is needed to extend these findings to discover mechanisms of depression toxicity for NSCLC patients' treatment responses and survival.
Broad-based genomic sequencing is being used more frequently for patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic ...sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting.
To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone.
Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment.
Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment.
Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received.
Among 5688 individuals with advanced NSCLC (median age, 67 years interquartile range, 41-85, 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference -3.6% 95% CI, -18.4% to 11.1%; P = .63). The results were consistent in the propensity score-matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 95% CI, 0.73 to 1.11; P = .40) vs unmatched cohort (hazard ratio, 0.69 95% CI, 0.62 to 0.77; log-rank P < .001).
Among patients with advanced non-small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.
The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to ...identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs.
We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culture-based antibiotic susceptibilities.
Of the medications assessed, only antibiotics and corticosteroids significantly associated with shorter OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, β-lactams showed the strongest association with OS across all tested cancers.
The timing and strength of the correlations with antibiotics and corticosteroids after controlling for confounding factors are consistent with the microbiome involvement with the response to ICIs across several cancers.
Background
The neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a ...single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR.
Methods
A retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in
R
, and SPSS.
Results
509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (
P
< 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with
P
< 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8–33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1–16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9–9.1).
Conclusions
We confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.
Increased treatment options and longer survival for lung cancer have generated increased interest in patient preferences. Previous studies of patient preferences in lung cancer have not fully ...explored preference heterogeneity. We demonstrate a method to explore preference heterogeneity in the willingness of patients with lung cancer and caregivers to trade progression-free survival (PFS) with side effects.
Patients and caregivers attending a national lung cancer meeting completed a discrete-choice experiment (DCE) designed through a collaboration with patients. Participants answered 13 choice tasks described across PFS, short-term side effects, and four long-term side effects. Side effects were coded as a one-level change in severity (none-mild, mild-moderate, or moderate-severe). A mixed logit model in willingness-to-pay space estimated preference heterogeneity in acceptable tradeoffs (time equivalents) between PFS and side effects. The study was reported following quality indicators from the United States Food and Drug Administration's patient preference guidance.
A total of 87 patients and 24 caregivers participated in the DCE. Participants would trade 3.7 month PFS (95% CI (CI): 3.3-4.1) for less severe functional long-term treatment side effects, 2.3 months for less severe physical long-term effects (CI: 1.9-2.8) and cognitive long-term effects (CI: 1.8-2.8), 0.9 months (CI: 0.4-1.4) for less severe emotional long-term effects, and 1.8 months (CI: 1.4-2.3) for less severe short-term side effects. Most participants (90%) would accept treatment with more severe functional long-term effects for 8.4 additional month PFS.
Participants would trade PFS for changes in short-term side effects and long-term side effects, although preference heterogeneity existed. Lung cancer treatments that offer less PFS but also less severe side effects might be acceptable to some patients.
Evidence-based practice in geriatric oncology is growing, and national initiatives have focused on expanding cancer care and research to improve health outcomes for older adults. However, there are ...still gaps between knowledge and practice for older adults with cancer.
Here we provide a detailed methodology of geriatric oncology care delivery within a single institution. The Cancer and Aging Resiliency (CARE) clinic is a multidisciplinary approach for implementing geriatric-driven health care for older adults with cancer. The CARE clinic was developed as a direct response to recommendations targeting key multifactorial geriatric health conditions (e.g. falls, nutritional deficits, sensory loss, cognitive impairment, frailty, multiple chronic conditions, and functional status). The multidisciplinary team assesses and delivers a comprehensive set of recommendations, all in one clinic visit, to minimize burden on the patient and the caregiver. The CARE clinic consultative model is a novel approach integrating cancer subspecialties with geriatric oncology healthcare delivery.
Older adults with cancer have unique needs that are independent of routine oncology care. The CARE clinic model provides specific assessments and interventions to improve health outcomes among older adults with cancer.
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