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.
Androgen deprivation therapy is the gold standard for metastatic prostate cancer, which can be achieved either by surgical or medical castration. In this study of 33,585 patients in the National Cancer Database, there was significant decline in the trend of utilization of surgical castration from 8.6% in 2004 to 3.1% in 2014. However, there was no survival difference with surgical castration when compared with medical castration. Increasing the utilization of surgical castration could help reduce health care expenditures. Patients and physicians need to be aware of treatment options and their financial implications. Background: Androgen deprivation therapy (ADT) is the gold standard for metastatic prostate cancer, which can be achieved either by surgical or medical castration. In this study, we evaluated the trends of utilization of surgical castration and also assess the survival differences of patients who underwent surgical castration when compared with those who underwent medical castration. Materials and Methods: The National Cancer Database was used to identify patients with metastatic prostate cancer from 2004 to 2014. Cochran-Armitage tests were used to assess temporal trends in the proportion of patients receiving surgical castration relative to medical castration. Logistic and Cox regression models were utilized to estimate the odds of utilization of surgical castration and the effect of castration on overall survival (OS). Results: A total of 33,585 patients with metastatic prostate cancer were identified; 31,600 (94.1%) had medical castration, and 1985 (5.9%) underwent surgical castration. There was significant decline in the trend of utilization of surgical castration from 8.6% in 2004 to 3.1% in 2014. On multivariable analysis, being of a non-Caucasian race, having lower median income levels, having non-private insurance, and earlier years of diagnosis were found to be associated with increased odds of choosing surgical castration over medical castration. Notably, the odds of surgical castration were lower at academic centers. On univariable analysis, a survival difference between castration modality was evidenced (P < .01); 5-year OS for medical castration and surgical castration were 24.3% and 18.2%, respectively. However, on multivariable analysis, there was no OS difference between surgical castration and medical castration (P ¼ .13). Conclusions: In this large contemporary analysis, the utilization of surgical castration has declined over time, with no OS difference when compared with medical castration. Increasing the utilization of surgical castration could help reduce health care expenditures. With rising health care costs, patients and physicians need to be aware of treatment options and their financial implications.
In 2011, ipilimumab was approved by the US Food and Drug Administration (FDA) for metastatic melanoma. Since its approval, numerous targeted therapies have been approved by the FDA. Population-based studies assessing the survival benefit from these agents are lacking. We therefore carried out this study to compare the 1-year, 2-year, and median overall survival (OS) among metastatic melanoma patients in pretargeted and post-targeted eras. This is a retrospective study that utilized the Surveillance, Epidemiology, and End Results (SEER-18) database, version 8.3.4 (22 March 2017). The patient groups were defined as the pretargeted era (2004-2010) and the post-targeted era (2011-2014) as ipilimumab was approved by the FDA in 2011. The database comprised of 5471 patients (3314 in the pretargeted era and 2157 in the post-targeted era). OS in the post-targeted era was found to be significantly better compared with the pretargeted era by Kaplan-Meier curve (1-year OS: 38.9 vs. 36.8%, 2-year OS: 28.3 vs. 23.5%, and median survival: 8 vs. 7 months, P=0.001 by the log-rank test). The survival was significantly better in the post-targeted era compared with the pretargeted era on multivariate analysis using a Cox proportional hazard model after adjusting for age, sex, race, and metasectomy status (adjusted hazard ratio of 0.889, 95% CI: of 0.832-0.951, P=0.001). There is significant survival benefit in metastatic melanoma patients since the introduction of immune checkpoint-blocking agents.
Recently antibiotic exposure has been associated with worse outcomes in patients undergoing treatment with antibodies directed against programmed cell death protein-1 (PD-1). We reviewed data of 1264 patients enrolled at Melanoma Skin and Ocular Tissue Repositories at University of Iowa Hospitals and Clinic. Reviewed data included patient demographics, prior medical history, baseline hematologic and disease parameters and outcomes including progression-free survival (PFS) and overall survival (OS). Cox regression models were used to determine predictive markers. Overall, 169 patients with advanced cutaneous melanoma received anti-PD-1 based therapies. Median follow up was 18.46 (range 0.89 to 62.52) months. On multivariable analysis brain metastasis, higher absolute neutrophil count (ANC) and lower absolute lymphocyte count were associated with poorer PFS while brain and liver metastasis and lower albumin were associated with poorer OS. Prior antibiotics, radiation as well as age, gender, basal metabolic index (BMI), smoking status, BRAF mutation, line of therapy (first or latter), prior treatments (ipilimumab or BRAF inhibitors), hemoglobin, neutrophil-to-lymphocyte ratio, white blood cell, platelet and eosinophil counts were not associated with PFS or OS in multivariable analysis. Contrary to some prior studies BMI, radiation, and antibiotics were not associated with PFS or OS.
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