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Background/aim Treatment options for advanced non-small cell lung cancer (NSCLC) include immunotherapy. Elevated carcinoembryonic antigen (CEA) and cancer antigen 125 (Ca-125) levels are associated with poorer prognoses of resected NSCLC, but currently no predictive biomarkers exist for immunotherapy response. This study evaluated CEA and Ca-125 as predictive biomarkers for immunotherapy efficiency in patients with metastatic NSCLC. Patients and methods The single-centre observational retrospective study includes NSCLC stage III/IV patients treated with programmed death-ligand 1 (PD-L1) inhibitors nivolumab or pembrolizumab. The primary study endpoint was treatment response assessed by CT-scan following RECIST-criteria 1.1. CEA/Ca-125 serum values were determined at initiation of treatment and repeated every 2 weeks. Values closest to the day of CT-scan were compared to baseline values. Results A total of 136 patients were treated with mono-immunotherapy. Of these, 73 patients were included in the CEA group and 53 patients were included in the Ca-125 group. Baseline CEA and Ca-125 ranged from 8.14 to 5,909 and 1.1 to 4,238 respectively. The sensitivity for Ca-125 as predictor for tumor response was 62.9% (95% CI=61.8%-63.6%), specificity 61.1% (95% CI=60.2%-62.0%), with a positive predictive value (PPV) of 75.9% (95% CI=75.2%-76.7%). For CEA, the sensitivity was 72.0% (95% CI=71.5%-72.5%), specificity 47.1% (95% CI 46.4%-47.8%), with a PPV of 80.0% (95% CI=79.6%-80.4%). Conclusion Increased serum CEA might predict tumor progression in NSCLC patients treated with PD-L1 inhibitors. Unconfirmed progression accompanied by increased CEA would support discontinuation of the immunotherapy, while continuation would be advised when serum CEA is not increased.

The use of preventive medication in palliative oncology patients may be inappropriate due to limited life expectancy. Deprescribing tools are available but time-consuming and not always tailored to this specific population. Our primary goal was to identify potentially inappropriate medications (PIMs) in palliative oncology patients with a life expectancy of up to 2 years using an adapted deprescribing tool. Our secondary aim was to identify patient characteristics associated with the presence of PIMs.Oncology patients with a life expectancy of up to 2 years were included cross-sectionally. An adapted deprescribing tool was developed to identify PIMs. Logistic regression was used to identify factors associated with having PIMs.A total of 218 patients were included in this study of which 56% had at least one PIM with a population mean of 1.1 PIM per patient. Most frequently defined PIMs were antihypertensive drugs and gastric acid inhibitors. Identification of PIMs by review took an estimated 5-10 min per patient. Polypharmacy, age65 years and inpatient/outpatient status were found to be associated with having at least one PIM.Deprescribing is possible in more than half of palliative oncology patients with a life expectancy of up to 2 years. The adapted deprescribing tool used is non-time consuming and suitable for palliative oncology patients, regardless of age.

Lung cancer is the largest cause of cancer-related deaths worldwide. Eighty-five percent of patients is diagnosed with non-small cell lung cancer (NSCLC). Almost a third of patients is aged over 75, but this group is poorly represented in clinical trials. This study compares the effects of therapy in non-operable stage III NSCLC in elderly patients compared to their younger counterparts.This is a retrospective cohort study. Patients are divided into three groups; patients younger than 65, patients aged between 65 and 75 and patients of 75 years or older. Concurrent chemoradiotherapy is compared to sequential chemoradiotherapy using Cox regression analysis. The primary outcome is survival. A sub analysis is performed for the presence of toxicity using logistic regression.Seven hundred and fifty patients were diagnosed with stage III NSCLC and treated with concurrent (442) or sequential (308) chemoradiotherapy. Concurrent chemoradiotherapy provides a decreased HR of death of 0.72 (0.560-0.85) compared to sequential chemoradiotherapy, even when corrected for age. Elderly patients receiving concurrent chemoradiotherapy do not have a significantly larger risk of toxicity.Patients of all ages with stage III NSCLC benefit from concurrent chemoradiotherapy compared to sequential chemoradiotherapy. Age is not a deciding factor in this prospect, nor do the patients experience more severe toxicity than their younger counterparts.

OBJECTIVES: Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC.MATERIALS AND METHODS: Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis. Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5 % discounting for health effects, and 4 % discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses.RESULTS: Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74 % of the probabilistic simulations.CONCLUSION: Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations.

Metachronous oligo-metastatic disease is variably defined as one to five metastases detected after a disease-free interval and treatment of the primary tumour with curative intent. Oligo-metastases in non-small cell lung cancer (NSCLC) are often treated with curative intent. However additional metastases are often detected later in time, and 5-year survival is low. Burdensome surgical treatment in patients with undetected metastases may be avoided if patients with high versus low-risk of undetected metastases can be separated.Because there is no clinical data on undetected metastases available, a microsimulation-model of the development and detection of metastases in 100.000 stage I NSCLC patients with a controlled primary tumour was constructed. The model uses data from the literature as well as patient-level data. Calibration was used for unobservable model parameters. Metastases can be detected by a scheduled scan, or an unplanned scan when the patient develops symptoms. The observable information at time of detection is used to identify subgroups of patients with different risk of undetectable metastases. We identified size and number of detected oligo-metastases, as well as presence of symptoms to be the most important risk predictors. Based on these predictors, patients could be divided into a low-risk and a high-risk group having a model-based predicted probability of 8.1% and 89.3% to have undetected metastases, respectively.Currently, the model is based on a synthesis of literature data and individual patient-level data that was not collected for the purpose of this study. Optimisation and validation of the model is necessary to allow clinical usability. We describe the type of data that needs to be collected to update our model, as well as the design of such validation study.

BACKGROUND/AIM Epidermal growth factor receptor (EGFR) mutation testing is standard-of-care for advanced non-small cell lung cancer (NSCLC). Outcomes of second-/third-line compared to first-line tyrosine kinase inhibitors (TKIs) have shown conflicting results. We investigated utilization of molecular diagnostics and the outcomes of treatment with first-/second-line TKIs in patients with advanced NSCLC. MATERIALS AND METHODS Retrospective analysis was carried out of 2,206 patients with stage IIIb/IV NSCLC treated between 2008 and 2014 in four hospitals in the Netherlands. RESULTS The rate of performing molecular diagnostics increased from 20.8% to 74.4% in the study period. The median overall survival of EGFR mutation-positive patients treated with TKIs was superior compared to EGFR mutation-negative patients treated with chemotherapy (720 vs. 274 days, p

Background/aim Patients treated for early-stage non-small cell lung cancer (NSCLC) need post-treatment surveillance for detecting recurrence of disease. The aim of this study was to provide evidence for the appropriate follow-up. Patients and methods The overall survival (OS), 1- and 3-year survival and progression-free survival (PFS) were retrospectively compared between two imaging modality groups. One group received only chest radiographs (CR group) and one group received chest radiographs and at least one computed tomography scan (CT group). Results Patients in the CR group (n=50) had no inferior OS (hazard ratio (HR)=1.427, 95% confidence interval (CI)=0.755-2.695, p=0.273) and PFS (HR=1.156, 95% CI=0.645-2.069, p=0.627) compared to patients in the CT group (n=23). Both 1- and 3-year survival were equal in the two groups (HR=5.544, 95% CI=0.530-58.031, p=0.153 and HR=1.540, 95% CI=0.752-3.154, p=0.238, respectively). Conclusion Follow-up with a chest radiography did not result in inferior clinical outcomes compared to follow-up with a CT scan.

Survival rates after lung transplantation are the lowest among solid organ transplantations. Long-term survival is limited by the development of chronic rejection, known as bronchiolitis obliterans syndrome (BOS). Risk factors, such as acute rejection and cytomegalovirus infection, contribute to the development of BOS. However, these risk factors alone do not explain the interindividual variability seen in the development of BOS. There is growing evidence that genetic variations might contribute to an individual's susceptibility to rejection. In this systematic review, based on a literature search through Medline and Embase, an overview is given of the genetic polymorphisms that have been investigated in lung transplant recipients in relation to the devlopment of BOS. Functional genetic polymorphisms in the genes of IFNG (+874 A/T), TGFB1 (+915 G/C), and IL6 (-174 G/C) have been found to be associated with the development of BOS and allograft fibrosis after lung transplantation. However, confirmation was not consistent across all studied cohorts. Genetic polymorphisms in the genes of several Toll-like receptors, mannose-binding lectin, CD14, killer immunoglobulin-like receptors, and matrix metalloproteinase-7 were also found to be associated with the development of BOS, but these studies need to be replicated in independent cohorts. This review shows that there may be involvement of genetic polymorphisms in the development of BOS. Genetic risk profiling of lung transplant recipients could be a promising approach for the future, enabling individualized risk stratification and personalized immunosuppressive treatment after transplantation. Further studies are needed to define risk alleles.

Background Activation of the immune system is suggested to prevent transplant tolerance and to promote the development of bronchiolitis obliterans syndrome (BOS). The innate immune system is activated by the interaction of pathogen-associated molecular patterns of microorganisms with Toll-like receptors (TLRs). Activation of innate immunity via TLRs was shown to be a barrier to the induction of transplantation tolerance after lung transplantation. We hypothesized that polymorphisms in 10 genes coding for TLR1 to TLR10 might contribute to an altered immune response and the subsequent development of BOS. Methods DNA was collected from 110 lung transplant recipients. Twenty patients developed BOS. The control group comprised 422 individuals. Sixty-four single-nucleotide polymorphisms (SNPs) in 10 genes coding for TLR1 to TLR10 were genotyped. Results The genotype distribution of TLR2 (rs1898830 and rs7656411), TLR4 (rs1927911) and TLR9 (rs352162 and rs187084) was significantly different between BOS pos patients and BOS neg patients and controls. The BOS pos group had significantly more patients with 3 or 4 of these risk alleles compared with the BOS neg and control groups. Conclusions Polymorphisms in TLR2, TLR4 and TLR9 that recognize bacterial and viral pathogens are associated with BOS after lung transplantation.

Background Pulmonary epithelium is the primary target of injury in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. Matrix metalloproteinases (MMP)-8 and -9 already have been implicated in the pathogenesis of BOS. MMP-7, which is involved in the repair of the lung epithelium, has not been studied in this respect. We hypothesized that genetic polymorphisms in MMP7 influence its expression and correlate with serum MMP-7 levels and the development of BOS. Methods DNA was collected from 110 lung transplant recipients, including 21 patients with BOS. We genotyped 7 single nucleotide polymorphisms in MMP7 and measured serum MMP-7 levels. The control group comprised 422 healthy individuals. Results BOS pos patients had lower levels of MMP-7 than BOS neg patients (7.87 vs 10.18 ng/ml). Significant differences in genotype and haplotype distribution between the BOS pos and BOS neg patients and controls were found. An increased risk for BOS development was found in patients homozygous for the major alleles of rs17098318 , rs11568818 , and rs12285347 , and for the minor allele rs10502001 (odds ratio, 3.88–5.30). Haplotypes constructed with 3 or 4 risk alleles correlated with lower MMP-7 levels. Conclusions Genetic polymorphisms of MMP7 predispose to the development of BOS. Patients carrying these risk alleles express lower levels of MMP-7, which may contribute to aberrant tissue repair and culminate in the development of BOS.

To evaluate changes in pulmonary function tests (PFTs) at different follow-up durations after stereotactic body radiotherapy (SBRT) and surgery in stage I and II non-small-cell lung cancer (NSCLC).Differences between pre-treatment- and follow-up PFTs were analyzed in 93 patients treated with surgery and 30 patients treated with SBRT for NSCLC. Follow-up durations were categorized into: early (0-9 months), middle (10-21 months) and late (≥22 months). Wilcoxon signed-rank test was used to analyze differences between pre-treatment and follow-up PFTs.Forced expiratory volume in one second, forced vital capacity and diffusion capacity for carbon monoxide corrected for the actual hemoglobin level significantly diminished after surgery for all follow-up durations: 11-17% of predicted values. After SBRT, PFTs remained stable, but a declining trend of 6% (p=0.1) was observed after 22 months.SBRT might lead to less treatment-related toxicity measured by PFTs than surgery in both the short and long term.

Surgical resection is the treatment of first choice for patients with stage I-II non-small cell lung cancer (NSCLC). However, stereotactic body radiotherapy (SBRT) has been shown to be a good alternative treatment.Overall survival (OS), progression-free survival (PFS) and recurrence rates were compared between patients with stage I-II NSCLC treated with SBRT (n=53) and those treated with surgical resection (n=175). The propensity score method was used to correct for confounding by indication.Before correction, the OS and PFS rates at 1 and 3 years were significantly different between SBRT and surgery, in favor of surgery. After correction, the OS and PFS after SBRT were not significantly different compared to surgery. The recurrence rates for the two treatments were also similar both before and after correction.This retrospective study showed that clinical outcomes after SBRT are equal to those after surgery in patients with stage I-II NSCLC.

Background. Caveolin-1 (CAV-1), a structural protein of the cell membrane, is involved in tissue homeostasis, inflammation, oxidative stress, microbial clearance, and fibrosis. Methods. We investigated a genetic predisposition of the CAV-1 gene on survival, acute and chronic rejection, lymphocytic bronchiolitis (LB), and respiratory infection after lung transplantation (LTx). Results. In 503 of 568 patients, the CAV-1 (rs3807989) polymorphism was successfully determined; 92 had the AA, 234 the AG, and 177 the GG genotype. Patients with the GG genotype had a decreased mortality with a adjusted hazard ratio of 0.72 (CI=0.53-0.98; P=0.034), but no association was found with chronic rejection, LB, acute rejection, or respiratory infections, although significantly less patients with the GG genotype died of infections (P=0.029). Airway neutrophilia (P=0.047) and systemic C-reactive protein (CRP, P=0.034) were decreased over time in the GG carriers compared to carriers of the A allele. Conclusion. We conclude that the GG genotype of CAV-1 is protective, associated with a decreased overall mortality but not with acute or chronic rejection, LB, and respiratory infections after LTx. The decreased mortality was linked with less infections of any kind and also lower systemic CRP, and airway neutrophils were observed, suggesting an overall decreased susceptibility for infectious complications in carriers of the GG genotype.

Background The mechanisms that lead to the fibrotic obliteration in bronchiolitis obliterans syndrome (BOS) may involve the interactions between T-helper (Th)1 and Th2 cytokines. The aim of this study is to determine the Th1 and Th2 cytokine and chemokine profiles in serum and exhaled breath condensate (EBC) in lung transplant recipients and to assess their usefulness as biomarkers to predict the development of BOS. Methods Serum and EBC from 10 patients with BOS (BOS pos ) and 10 patients without BOS (BOS neg ), matched for clinical and demographic variables, were analyzed with a multiplex immunoassay to measure a panel of 27 cytokines and chemokines. Results The pro-inflammatory cytokines in serum were elevated in lung transplant recipients compared with controls. BOS pos patients had significantly lower concentrations of interleukin (IL)-4, IL-13, and vascular endothelial growth factor (VEGF) compared with BOS neg patients. The concentration of IL-5, however, was significantly higher in BOS pos patients. Levels of IL-4 and IL-5 were hardly detectable in EBC. IL-13 and VEGF, both decreased in serum in BOS pos patients, were also decreased in EBC in BOS pos patients compared with BOS neg patients. Longitudinal analysis of cytokines and chemokines in serum and EBC from the time of lung transplantation onwards did not reveal significant trends in cytokines and chemokines that preceded the diagnosis of BOS. Conclusions Levels of pro-inflammatory cytokines were increased in lung transplant recipients compared with controls. From the moment of transplantation onwards, there is a different pattern of Th2 cytokines in serum in BOS pos patients than in BOS neg patients.