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Background and objective: Bronchiectasis is a frequent incidental finding on chest computed tomography (CT), but its relevance in lung cancer screening is not fully understood. We investigated the association between bronchiectasis and respiratory symptoms, pulmonary function, and emphysema in lung cancer screening participants with and without chronic obstructive pulmonary disease (COPD). Methods: We included 3260 (ex-)smokers from the Dutch-Belgian lung cancer screening trial (NELSON). Bronchiectasis was scored by chest radiologists. The relationship with pulmonary function (FEV1%predicted, FEV1/FVC), respiratory complaints (cough, dyspnea, wheezing, mucus hypersecretion), and CT-quantified emphysema (15th percentile) was examined with independent t-tests and multivariate regression. Results: Bronchiectasis was present in 5.4% (n = 175/3260). There was no difference in prevalence between subjects with and without COPD (68/1121 [5.9%] vs. 109/2139 [5.1%]; p =.368). COPD subjects with bronchiectasis had a lower FEV1%predicted (76.2% vs. 85.0%; p <.001), lower FEV1/FVC (0.58 vs. 0.62; p <.001), and more emphysema (− 938 HU vs. − 930 HU; p =.001) than COPD subjects without bronchiectasis. In COPD subjects, bronchiectasis was independently associated with a lower FEV1%predicted (B = − 7.7; CI [− 12.3, − 3.3]), lower FEV1/FVC (B = − 2.5; CI [− 4.3, − 0.8]), more cough (OR 2.4; CI [1.3, 4.3]), more mucus hypersecretion (OR 1.8; CI [1.0, 3.1]) and more dyspnea (OR 2.3; CI [1.3, 3.9]). In those without COPD (n = 2139), bronchiectasis was associated with more cough, mucus hypersecretion, and wheezing, but not with deteriorating lung function. Conclusion: Bronchiectasis was present in 5.4% of our lung cancer screening participants and was associated with more respiratory symptoms and, in those with COPD, with lower lung function and more emphysema. Clinical relevance statement: In a lung cancer screening population, bronchiectasis has a prevalence of 5.4% with a mainly mild severity. This finding is of little clinical relevance unless mild COPD is also present. In those subjects, bronchiectasis was associated with a lower lung function, more respiratory symptoms, and more emphysema. Key Points: • Bronchiectasis was found in 5.4% of lung cancer screening participants, consisting of (ex-)smokers with and without mild COPD. • In those with mild COPD, bronchiectasis was associated with a lower lung function, more respiratory symptoms, and more emphysema. • Incidental findings of mild bronchiectasis are not very relevant in a lung cancer screening population, unless COPD is also present. [ABSTRACT FROM AUTHOR]

Background: In the Netherlands, lung cancer is the leading cause of cancer-related death, accounting for more than 10,000 annual deaths. Lung cancer screening (LCS) studies using low-dose computed tomography (LDCT) have demonstrated that early detection reduces lung cancer mortality. However, no LCS program has been implemented yet in the Netherlands. A national LCS program has the potential to enhance the health outcomes for lung cancer patients in the Netherlands. Objective and Methods: This study evaluates the cost-effectiveness of LCS compared to no-screening in the Netherlands, by simulating the screening outcomes based on data from NEderlands–Leuvens Longkanker Screenings ONderzoek (NELSON) and National Lung Screening Trial (NLST). We simulated annual screening up to 74 years of age, using inclusion criteria from the respective studies. A decision tree and Markov model was used to predict the incremental costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICERs) for the screening population. The analysis used a lifetime horizon and a societal perspective. Results: Compared to no-screening, LCS resulted in an ICER of €5,169 per QALY for the NELSON simulation, and an ICER of €17,119 per QALY for the NLST simulation. The screening costs were highly impactful for the cost-effectiveness. The most influential parameter was the CT scan cost. Cost reduction for CT from €201 to €101 per scan would reduce the ICER to €2,335 using NELSON criteria. Additionally, LCS could prevent 15,115 and 12,611 premature lung cancer deaths, accompanied by 1.66 and 1.31 QALYs gained per lung cancer case for the NELSON and NLST simulations, respectively. Conclusion: LCS was estimated to be cost-effective in the Netherlands for both simulations at a willingness-to-pay threshold of €20,000 per QALY. Using the NELSON criteria, less than €5,500 per QALY had to be spent. Lowering the cost per CT exam would lead to a further reduction of this amount. [ABSTRACT FROM AUTHOR]

Pemetrexed is a cytotoxic drug for first‐line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin‐related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P =.196) or volume of distribution (+7% change, P =.002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin. [ABSTRACT FROM AUTHOR]

Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway (MTHFR), cell transport (SLC19A1/ABCC2/ABCC4), intracellular metabolism (FPGS/GGH) and target enzymes (TYMS/DHFR/ATIC) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses. [ABSTRACT FROM AUTHOR]

Abstract Background During the past decades, numerous efforts have been made to decrease the death rate among lung cancer patients. Nonetheless, the improvement in long-term survival has been limited and lung cancer is still a devastating disease. Discussion With this article we would like to point out that survival of lung cancer could be strongly improved by controlling two pivotal prognostic factors: stage and treatment. This is corresponding with recent reports that show a decrease in lung cancer mortality by screening programs. In addition, modulation of the patient’s immune system by immunotherapy either as monotherapy or combined with conventional cancer treatments offers the prospect of tailoring treatments much more precisely and has also been shown to lead to a better response to treatment and overall survival of non-small cell lung cancer patients. Summary Since only small improvements in survival can be expected in advanced disease with the use of conventional therapies, more research should be focused on lung cancer screening programs and patient tailored immunotherapy with or without conventional therapies. If these approaches are clinically combined in a standard multidisciplinary policy we might be able to advance the survival of patients with lung cancer.

Abstract Cancer research has devoted most of its energy over the past decades on unraveling the control mechanisms within tumor cells that govern its behavior. From this we know that the onset of cancer is the result of cumulative genetic mutations and epigenetic alterations in tumor cells leading to an unregulated cell cycle, unlimited replicative potential and the possibility for tissue invasion and metastasis. Until recently it was often thought that tumors are more or less undetected or tolerated by the patient’s immune system causing the neoplastic cells to divide and spread without resistance. However, it is without any doubt that the tumor environment contains a wide variety of recruited host immune cells. These tumor infiltrating immune cells influence anti-tumor responses in opposing ways and emerges as a critical regulator of tumor growth. Here we provide a summary of the relevant immunological cell types and their complex and dynamic roles within an established tumor microenvironment. For this, we focus on both the systemic compartment as well as the local presence within the tumor microenvironment of late-stage non-small cell lung cancer (NSCLC), admitting that this multifaceted cellular composition will be different from earlier stages of the disease, between NSCLC patients. Understanding the paradoxical role that the immune system plays in cancer and increasing options for their modulation may alter the odds in favor of a more effective anti-tumor immune response. We predict that the future standard of care of lung cancer will involve patient-tailor-made combination therapies that associate (traditional) chemotherapeutic drugs and biologicals with immune modulating agents and in this way complement the therapeutic armamentarium for this disease.

Introduction: Erlotinib's gastrointestinal solubility and absorption are decreased by proton pump inhibitors (PPIs). Since erlotinib is a lipophilic drug, we hypothesized that concomitant intake with the fatty beverage milk may be a feasible way to increase erlotinib uptake. We performed a two-period, randomized, crossover study to investigate the influence of cow's milk with 3.9% fat on the exposure of erlotinib with and without the PPI esomeprazole in patients with non-small cell lung cancer (NSCLC). The effect of esomeprazole was studied in an additional intrapatient comparison. Method: Pharmacokinetic sampling was performed on days 7 and 14 during 24 consecutive hours. During the 7 days prior to pharmacokinetic sampling, erlotinib was taken daily with 250 mL of either water or milk. In the PPI arm, esomeprazole (40 mg once daily 3 h prior to erlotinib) was taken for 3 days. Results: Erlotinib area under the curve from time zero to 24 h (AUC24) did not significantly change when administered with milk, compared with water, in both non-PPI users (n = 14; − 3%; 95% confidence interval [CI] − 12 to 8%; p = 0.57) and patients who used esomeprazole (n = 15; 0%; 95% CI − 15 to 17%; p = 0.95). Esomeprazole decreased erlotinib AUC24 by 47% (n = 9; 95% CI − 57 to − 34%; p < 0.001) and Cmax by 56% (95% CI − 64 to − 46%; p < 0.001). No differences in toxicities were observed between milk and water. Conclusion: Milk with 3.9% fat has no effect on the exposure to erlotinib in NSCLC patients, independent of PPI use. The combination with milk is safe and well tolerated. Concomitant esomeprazole treatment strongly decreased both erlotinib AUC24 and Cmax and should be avoided if possible. [ABSTRACT FROM AUTHOR]

Background: Endosonography is accepted as the initial procedure for mediastinal staging in patients with suspected non‐small cell lung cancer (NSCLC). However, the diagnostic value of different staging methods in specific subgroups is unclear. The purpose of this study was to assess the performance and outcome of mediastinal staging in lung cancer in a general teaching hospital. Methods: The records of 870 consecutive patients with potentially resectable NSCLC (cT1‐3NxM0) were analyzed in a retrospective cohort study between January 2010 and December 2016. Patients were divided into four different groups according to ESTS guidelines. The primary endpoint was the rate of unforeseen mediastinal metastasis in these groups and the sensitivity of different staging methods. Results: Mediastinal staging was performed in 336 patients of whom 112 (33%) underwent lobectomy. Unforeseen mediastinal metastasis was seen in 10 (9%) patients after negative mediastinal staging. Sensitivity after combined mediastinal staging (endosonography with mediastinoscopy) in the overall group was 94%. In patients without suspected mediastinal lymph nodes but with suspected hilar lymph nodes (N1), or a peripheral tumor >3 cm, sensitivity of endosonography was 33% and mediastinoscopy 75%. Biopsy of at least level 4L, 4R and 7 was taken in 18% of the endosonographies and 58% of the mediastinoscopies. Discussion Combined mediastinal staging (endosonography with mediastinoscopy) is reliable with a sensitivity of 94%. However, the diagnostic value of endosonography in patients with suspected hilar lymph nodes or a peripheral tumor >3 cm is questionable, and in these patients, performing direct mediastinoscopy should be considered. Key points: Significant findings of this study: The diagnostic value of endosonography in patients without suspected mediastinal lymph nodes but with potential risk factors (suspected N1 disease or peripheral tumor >3 cm) is questionable. Therefore, mediastinoscopy as the first choice should be considered in these patients. What this study adds?: Accurate mediastinal nodal staging is essential in patients with suspected NSCLC to avoid unnecessary lobectomy. Detailed knowledge about sensitivity and specificity of mediastinal staging techniques in different patient groups can make a difference. [ABSTRACT FROM AUTHOR]

Background: Identification of patient-related factors associated with Health-Related Quality of Life (HRQoL) and Quality of Life (QoL) at the start of treatment may identify patients who are prone to a decrease in HRQoL and/or QoL resulting from chemotherapy. Identification of these factors may offer opportunities to enhance patient care during treatment by adapting communication strategies and directing medical and psychological interventions. The aim was to examine the association of sociodemographic factors, personality traits, and depressive symptoms with HRQoL and QoL in patients with advanced-stage lung cancer at the start of chemotherapy.Methods: Patients (n = 151) completed the State-Trait Anxiety Inventory (trait anxiety subscale), the Neuroticism-Extraversion-Openness-Five Factor Inventory (NEO-FFI), the Center for Epidemiologic Studies Depression (CES-D), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Simple linear regression analyses were performed to select HRQoL and QoL associated factors (a P ≤ 0.10 was used to prevent non-identification of important factors) followed by multiple linear regression analyses (P ≤ 0.05).Results: In the multiple regression analyses, CES-D score (β = - 0.63 to - 0.53; P-values < 0.001) was most often associated with the WHOQOL-BREF domains and general facet, whereas CES-D score (β = - 0.67 to - 0.40; P-values < 0.001) and Eastern Cooperative Oncology Group (ECOG) performance status (β = - 0.30 to - 0.30; P-values < 0.001) were most often associated with the scales of the EORTC QLQ-C30. Personality traits were not related with HRQoL or QoL except for trait anxiety (Role functioning: β = 0.30; P = 0.02, Environment: β = - 0.39; P = 0.007) and conscientiousness (Physical health: β = 0.20; P-value < 0.04).Conclusions: Higher scores on depressive symptoms and ECOG performance status were related to lower HRQoL and QoL in patients with advanced-stage non-small cell lung cancer. Supportive care interventions aimed at improvement of depressive symptoms and performance score may facilitate an increase of HRQoL and/or QoL during treatment. [ABSTRACT FROM AUTHOR]

Purpose: In lung cancer, the preservation of well-being is warranted given the limited prognosis. Chemotherapy may negatively influence health-related quality of life (HRQoL) due to adverse events. However, patients' judgement about this negative impact is not well understood. We examined the relationship between expectations, feelings about side effects, and satisfaction with therapy and (HR)QoL in advanced-stage thoracic cancer and investigated which of these factors has the highest impact on (HR)QoL.Methods: Sixty-nine patients completed the Cancer Therapy Satisfaction Questionnaire (CTSQ), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Multiple regression analyses were performed to investigate the relation of the CTSQ domains (i.e., expectations of therapy, feelings about side effects, satisfaction with therapy) with (HR)QoL and simple regression analyses to identify the factors of the CTSQ domain that was most often associated with (HR)QoL.Results: Feelings about side effects were associated with the (HR)QoL domain/scale scores (i.e., WHOQOL-BREF domains: β = 0.36 to 0.58; EORTC QLQ-C30 scales: β = 0.33 to 0.61) except social relationships of the WHOQOL-BREF. Low-grade adverse events were related to feelings about side effects (β = - 0.326; P = 0.007).Conclusions: Patients experiencing negative feelings about side effects have worse (HR)QoL. Additional care should be provided to prevent low-grade adverse events. [ABSTRACT FROM AUTHOR]

The article presents case study of a patient with a targetable somatic epidermal growth factor receptor (EGFR) mutation and a novel EGFR germline variant, which also occurred in other family members with lung cancer. It mentions that patient was treated with the EGFR tyrosine kinase inhibitor (TKI) erlotinib. It presents information on lung cancer surveillance programs have been mainly recommended for active smokers or patients with a smoking history.

Brain metastases are the most common tumors of the central nervous system (CNS). Incidence rates vary according to primary tumor origin, whereas the majority of the cerebral metastases arise from primary tumors in the lung (40-50%). Brain metastases from lung cancer can occur concurrently or within months after lung cancer diagnosis. Survival rates after lung cancer brain metastasis diagnosis remain poor, to an utmost of 10 months. Therefore, prevention of brain metastasis is a critical concern in order to improve survival among cancer patients. Although several studies have been made in order to disclose the genetic and molecular mechanisms associated with CNS metastasis, the precise mechanisms that govern the CNS metastasis from lung cancer are yet to be clarified. The ability to forecast, which patients have a higher risk of brain metastasis occurrence, would aid cancer management approaches to diminish or prevent the development of brain metastasis and improve the clinical outcome for such patients. In this work, we revise genetic and molecular targets suitable for prediction of lung cancer CNS disease. [ABSTRACT FROM AUTHOR]

In the last decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors (CPIs), antibodies that unleash the antitumor immune response. After the success in melanoma, numerous clinical trials are being conducted investigating CPIs in lung cancer and mesothelioma. The programmed death protein (PD) 1-PD ligand 1/2 pathway and cytotoxic T lymphocyte-associated protein 4 are currently the most studied immunotherapeutic targets in these malignancies. In non-small cell lung cancer, anti-PD-1 antibodies have become part of the approved treatment arsenal. In small cell lung cancer and mesothelioma, the efficacy of checkpoint inhibition has not yet been proven. In this Concise Clinical Review, an overview of the landmark clinical trials investigating checkpoint blockade in lung cancer and mesothelioma is provided. Because response rates are around 20% in the majority of clinical trials, there is much room for improvement. Predictive biomarkers are therefore essential to fully develop the potential of CPIs. To increase efficacy, multiple clinical trials investigating the combination of cytotoxic T lymphocyte-associated protein 4 inhibitors and PD-1/PD ligand 1 blockade in lung cancer and mesothelioma are being conducted. Given the potential benefit of immunotherapy, implementation of current and new knowledge in trial designs and interpretation of results is essential for moving forward. [ABSTRACT FROM AUTHOR]

Background Mediastinoscopy is considered to be the gold standard for mediastinal staging for patients with non-small cell lung cancer (NSCLC). The diagnostic value depends on how this procedure is performed, which has resulted in drafting a guideline by the European Society of Thoracic Surgery (ESTS). Biopsy of at least stations 4R, 4L, 7, and if present stations 2R and 2L, is recommended. The objective of this study is to assess the quality of the mediastinoscopies performed in our hospital for NSCLC. Methods Medical records of 102 consecutive patients with suspected or proven NSCLC and a performed cervical mediastinoscopy between January 2009 and November 2014 were analyzed in a retrospective cohort study. The number of biopsied stations and complications has been prospectively documented, together with their clinical data. Results Cervical mediastinoscopy was performed in 102 patients and in 51 (50%) patients biopsy was taken of stations 4R, 4L, and 7. N2/N3 disease emerged more significantly (p < 0.05) if biopsies were taken of at least the paratracheal stations 4R/4L and the subcarinal region. The incidence of major complications was 3.9%. Conclusion In our clinic, 50% of the mediastinoscopies performed are executed following the ESTS guidelines. Our results subscribe the need to biopsy at least the paratracheal stations 4L/4R and the subcarinal region to obtain a reliable assessment of the mediastinum. [ABSTRACT FROM AUTHOR]

Purpose: To determine the long-term impact of stereotactic radiotherapy (SRT) on the quality of life (QoL) of inoperable patients with early-stage non-small cell lung cancer (NSCLC). Methods and materials: From January 2006 to February 2008, 39 patients with pathologically confirmed T1-2N0M0 NSCLC were treated with SRT. QoL, overall survival and local tumor control were assessed. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the lung cancer-specific questionnaire QLQ-LC13 were used to investigate changes in QoL. Assessments were done before treatment, at 3 weeks, every 2-3 months during the first two years, and then every 6 months until 5 years after the treatment or death or progressive disease. The median follow up was 38 months. Results: During the 5 years after treatment with SRT for stage I NSCLC, the level of QoL was maintained: There was a slow decline (slope: -0.015) of the global health status over the 5 years (p < 0.0001). The physical functioning and the role functioning improved slowly (slope: 0.006 and 0.004, resp.) over the years and this was also significant (p < 0.0001). The emotional functioning (EF) improved significantly at 1 year compared to the baseline. Two years after the treatment dyspnea slowly increased (slope: 0.005, p = 0.006). The actuarial overall survival was 62% at 2 years and 31% at 5-years. Conclusion: QoL was maintained 5 years after SRT for stage I NSCLC and EF improved significantly. Dyspnea slowly increased 2 years after the treatment. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: It is well known that pulmonary tuberculosis is associated with an increased risk of lung cancer. We investigated whether a history of pulmonary tuberculosis is an independent risk factor for lung cancer survival in Caucasian patients. Methods: The data of the prospective population-based cohort of The Rotterdam Study were used. During a mean follow-up time of 18 years, there were 214 incident cases of pathology-proven lung cancer in a source population of 7983 study participants. History of tuberculosis was assessed at baseline by interviewers using standardized questionnaires. Associations of lung cancer survival with the occurrence of pulmonary tuberculosis were assessed using Cox''s proportional hazard regression analysis adjusted for age, gender, pack-years, educational level and tumor stage. Results: A history of tuberculosis was reported in 13 of the 214 subjects with lung cancer. The survival of patients with lung cancer was significantly shorter in subjects with a history of pulmonary tuberculosis (HR=2.36, CI95%: 1.1–4.9), than in subjects without a history of pulmonary tuberculosis with a mean difference of 311 days. Conclusion: The presence of a history of pulmonary tuberculosis may be an important prognostic factor in the survival of lung cancer. [Copyright &y& Elsevier]

Background: Current clinical therapy of non-small cell lung cancer depends on histo-pathological classification. This approach poorly predicts clinical outcome for individual patients. Gene expression profiling holds promise to improve clinical stratification, thus paving the way for individualized therapy. Methodology and Principal Findings: A genome-wide gene expression analysis was performed on a cohort of 91 patients. We used 91 tumor- and 65 adjacent normal lung tissue samples. We defined sets of predictor genes (probe sets) with the expression profiles. The power of predictor genes was evaluated using an independent cohort of 96 non-small cell lung cancer- and 6 normal lung samples. We identified a tumor signature of 5 genes that aggregates the 156 tumor and normal samples into the expected groups. We also identified a histology signature of 75 genes, which classifies the samples in the major histological subtypes of non-small cell lung cancer. Correlation analysis identified 17 genes which showed the best association with post-surgery survival time. This signature was used for stratification of all patients in two risk groups. Kaplan-Meier survival curves show that the two groups display a significant difference in post-surgery survival time (p = 5.6E-6). The performance of the signatures was validated using a patient cohort of similar size (Duke University, n = 96). Compared to previously published prognostic signatures for NSCLC, the 17 gene signature performed well on these two cohorts. Conclusions: The gene signatures identified are promising tools for histo-pathological classification of non-small cell lung cancer, and may improve the prediction of clinical outcome. [ABSTRACT FROM AUTHOR]

The article presents a study whose aim was to analyze the accuracy of different optical spectroscopic techniques for the classification of cancerous lesions of the bronchial tree. In the study, patients with suspected or known malignancies of the lung and with a medical indication for a bronchoscopy were invited to participate. All patients were above 18 years of age and they signed informed consent. The Medical Ethics Review Board of Erasmus Medical Centre Rotterdam approved the study. Spectroscopic measurements were performed on 191 different endobronchial lesions in 1.07 patients studied over an 18- month period.

This meta-analysis aimed to evaluate the effectiveness of intensive follow-up after curative intent treatment for five common solid tumours, in terms of survival and treatment of recurrences. A systematic literature search was conducted, identifying comparative studies on follow-up for colorectal, lung, breast, upper gastro-intestinal and prostate cancer. Outcomes of interest were overall survival (OS), cancer specific survival (CSS), and treatment of recurrences. Random effects meta-analyses were conducted, with particular focus on studies at low risk of bias. Fourteen out of 63 studies were considered to be at low risk of bias (8 colorectal, 4 breast, 0 lung, 1 upper gastro-intestinal, 1 prostate). These studies showed no significant impact of intensive follow-up on OS (hazard ratio, 95% confidence interval) for colorectal (0.99; 0.92–1.06), breast 1.06 (0.92–1.23), upper gastro-intestinal (0.78; 0.51–1.19) and prostate cancer (1.00; 0.86–1.16). No impact on CSS (hazard ratio, 95% confidence interval) was found for colorectal cancer (0.94; 0.77–1.16). CSS was not reported for other cancer types. Intensive follow-up increased the rate of curative treatment (relative risk; 95% confidence interval) for colorectal cancer recurrences (1.30; 1.05–1.61), but not for upper gastro-intestinal cancer recurrences (0.92; 0.47–1.81). For the other cancer types, no data on treatment of recurrences was available in low risk studies. For colorectal and breast cancer, high quality studies do not suggest an impact of intensive follow-up strategies on survival. Colorectal cancer recurrences are more often treated locally after intensive follow-up. For other cancer types evaluated, limited high quality research on follow-up is available. • Intensive follow-up after surgery for colorectal and breast cancer has little impact on survival. • Colorectal cancer recurrences are more often treated locally after intensive follow-up. • High quality research on follow-up for other cancers is scarce. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with non-small cell lung cancer with an activating EGFR mutation in the tumor, are treated with targeted therapy against this mutation. In the end, all patients develop resistance against this therapy, but some patients have a very short or no benefit. In this study, the authors used blood samples from 41 patients to investigate predictive factors for lack of or short efficacy of targeted therapy. They found that lack of disappearance of the treated mutation in blood after 6 or 12 weeks, the presence of co-occurring TP53 mutations, and decrease of erlotinib therapy concentrations in time are correlated to a shorter time of benefit. Confirmation of these findings in a larger cohort is desirable, this may lead to implementation of blood sampling for DNA analysis and therapy concentration measurement in daily practice in the future, to identify patients in need of closer follow-up or more extensive treatment. Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC), not all patients benefit. We therefore explored the impact of the presence of mutations found in cell-free DNA (cfDNA) and TKI plasma concentrations during treatment on progression-free survival (PFS). In the prospective START-TKI study blood samples from 41 patients with EGFR-mutated NSCLC treated with EGFR-TKIs were available. Next generation sequencing (NGS) on cfDNA was performed, and plasma TKI concentrations were measured. Patients without complete plasma conversion of EGFR mutation at week 6 had a significantly shorter PFS (5.5 vs. 17.0 months, p = 0.002) and OS (14.0 vs. 25.5 months, p = 0.003) compared to patients with plasma conversion. In thirteen (second line) osimertinib-treated patients with a (plasma or tissue) concomitant TP53 mutation at baseline, PFS was significantly shorter compared to six wild-type cases; 8.8 vs. 18.8 months, p = 0.017. Erlotinib Cmean decrease of ≥10% in the second tertile of treatment was also associated with a significantly shorter PFS; 8.9 vs. 23.6 months, p = 0.037. We obtained evidence that absence of plasma loss of the primary EGFR mutation, isolated plasma p.T790M loss after six weeks, baseline concomitant TP53 mutations, and erlotinib Cmean decrease during treatment are probably related to worse outcome. [ABSTRACT FROM AUTHOR]

Objective: Previous studies in patients with lung cancer examined the association between psychological factors with quality of life (QoL), as well as the association between psychological factors with sociodemographic and medical characteristics. However, knowledge about the impact of combinations of psychological characteristics on QoL is still lacking. Therefore, the current study aimed to identify psychological profiles, covering multiple psychological factors. Additionally, the association between these profiles with QoL and with sociodemographic and medical characteristics was explored.Methods: Patients with lung cancer (n = 130, mean age = 68.3 ± 8.6 years; 49% men) completed questionnaires focusing on sociodemographic information, anxiety and depressive symptoms (HADS), coping (COPE-easy), perceived social support (PSSS), and QoL (WHOQOL-BREF). Medical information was extracted from patients' medical records. A step-3 latent profile analysis was performed to identify the psychological profiles. Multinomial logit models were used to explore the medical and sociodemographic correlates of the profiles and the relation with QoL.Results: Four psychological profiles were identified as follows: (1) anxious, extensive coping repertoire (33%); (2) depressive, avoidant coping (23%); (3) low emotional symptoms, active/social coping (16%); and (4) low emotional symptoms, limited coping repertoire (29%). QoL in profile 1 (QoL = 6.59) was significantly different from QoL in profile 3 (QoL = 8.11, p = .001) and profile 4 (QoL = 7.40, p = .01). QoL in profile 2 (QoL = 6.43) was significantly different from QoL in profile 3 (QoL = 8.11, p = .003) and profile 4 (QoL = 7.40, p = .02). Regarding QoL, no other significant differences were found. Sociodemographic and medical characteristics were not distinctive for the profiles (all p values > .05).Conclusion: Determining psychological profiles of patients with lung cancer in an early stage provides information that may be helpful in aligning care with patients' unique needs, as it will help in more adequately selecting those patients who are in need of psychological screening and/or psychological treatment as compared with determining scores on single psychological factors. [ABSTRACT FROM AUTHOR]

Immunotherapy-induced pneumonitis (IIP) is a serious side-effect which requires accurate diagnosis and management with high-dose corticosteroids. The differential diagnosis between IIP and other types of pneumonitis (OTP) remains challenging due to similar radiological patterns. This study was aimed to develop a prediction model to differentiate IIP from OTP in patients with stage IV non-small cell lung cancer (NSCLC) who developed pneumonitis during immunotherapy. Consecutive patients with metastatic NSCLC treated with immunotherapy in six centres in the Netherlands and Belgium from 2017 to 2020 were reviewed and cause-specific pneumonitis events were identified. Seven regions of interest (segmented lungs and spheroidal/cubical regions surrounding the inflammation) were examined to extract the most predictive radiomic features from the chest computed tomography images obtained at pneumonitis manifestation. Models were internally tested regarding discrimination, calibration and decisional benefit. To evaluate the clinical application of the models, predicted labels were compared with the separate clinical and radiological judgements. A total of 556 patients were reviewed; 31 patients (5.6%) developed IIP and 41 patients developed OTP (7.4%). The line of immunotherapy was the only predictive factor in the clinical model (2nd versus 1st odds ratio = 0.08, 95% confidence interval:0.01–0.77). The best radiomic model was achieved using a 75-mm spheroidal region of interest which showed an optimism-corrected area under the receiver operating characteristic curve of 0.83 (95% confidence interval:0.77–0.95) with negative and positive predictive values of 80% and 79%, respectively. Good calibration and net benefits were achieved for the radiomic model across the entire range of probabilities. A correct diagnosis was provided by the radiomic model in 10 out of 12 cases with non-conclusive radiological judgements. Radiomic biomarkers applied to computed tomography imaging may support clinicians making the differential diagnosis of pneumonitis in patients with NSCLC receiving immunotherapy, especially when the radiologic assessment is non-conclusive. • There is no gold-standard to make the differential diagnosis of pneumonitis. • The best radiomic model was developed using the 75-mm spheroidal region of interest. • The proposed radiomic model had area under the receiver operating characteristic curve = 0.83 with good calibration and net benefits. • The radiomic model diagnosed 83% of cases with non-conclusive radiological judgement. [ABSTRACT FROM AUTHOR]

With increasing use of immune checkpoint inhibitors (ICIs) more patients will develop severe and potentially life-threatening immune-related adverse events (irAEs). So far, predictive models for the occurrence of grade ≥3 irAEs are lacking. Therefore, we analysed associations between patient and disease characteristics, and the occurrence of grade ≥3 irAEs. Patients with cancer who were treated with anti-PD-1 (+/−anti-CTLA-4) between July 2015 and February 2020, and who were prospectively included in the MULTOMAB-trial, were eligible for this cohort study. Time to and occurrence of grade ≥3 irAEs according to CTCAE v5.0 were retrospectively registered. The associations between patient and disease characteristics and irAE occurrence were analysed using the competing risk cox-regression model of Fine and Gray. Analyses were performed separately in patients treated with monotherapy (anti-PD-1) and combination therapy (anti-PD-1 + anti-CTLA-4). Subgroup analyses were performed in tumour types with the highest number of patients; melanoma and NSCLC. Out of 641 patients, 106 patients (17%) experienced grade ≥3 irAEs. None of the analysed factors were associated with grade ≥3 irAE occurrence in the monotherapy (n = 550) or the combination therapy (n = 91) groups, nor in the subgroup analyses. Of interest, none of the patients with NSCLC with a WHO performance status of 0 (n = 34) experienced grade ≥3 irAEs. Most common NSCLC histology types were adenocarcinoma (n = 99/55%) and squamous cell carcinoma (n = 39/22%). This study shows that patient and disease characteristics are not able to predict the occurrence of serious AEs in patients treated with ICIs. • 12% of patients receiving anti-PD-1 monotherapy experienced grade ≥3 toxicities. • 44% of patients receiving anti-PD-1 + CTLA-4 therapy experienced grade ≥3 toxicities. • No clinical factor was associated with toxicities during anti-PD-1 (+CTLA4) therapy. • This was found across tumour types, as well as in melanoma and NSCLC patients. [ABSTRACT FROM AUTHOR]

We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This 'drug score' was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1–2 and poor risk with score 3–4. Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non–small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy). Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts. Our 'drug score' showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients. • Multiple medications may affect immunotherapy efficacy in patients with NSCLC. • Two large cohorts treated with pembrolizumab and chemotherapy were analysed. • We validated the predictive and prognostic abilities of a drug-based score. • Our drug-score identifies patients unlikely to benefit from first-line pembrolizumab. • A web-app is available at: https://medscore.shinyapps.io/NSCCdrugbased_score/. [ABSTRACT FROM AUTHOR]

Treatment sequencing with first-line immunotherapy, followed by second-line chemotherapy, is still a viable option for NSCLC patients with PD-L1 expression ≥50%. We evaluated post-progression treatment pathways in a large real-world cohort of metastatic NSCLC patients with PD-L1 expression ≥ 50% treated with first-line pembrolizumab monotherapy. Overall, 974 patients were included. With a median follow-up of 22.7 months (95%CI: 21.6–38.2), the median overall survival (OS) of the entire population was 15.8 months (95%CI: 13.5–17.5; 548 events). At the data cutoff, among the 678 patients who experienced disease progression, 379 (55.9%) had not received any further treatment, and 359 patients (52.9%) had died. Patients who did not receive post-progression therapies were older (p = 0.0011), with a worse ECOG-PS (p < 0.0001) and were on corticosteroids prior to pembrolizumab (p = 0.0024). At disease progression, 198 patients (29.2%) received a switched approach and 101 (14.9%) received pembrolizumab ByPD either alone (64 [9.4%]) or in combination with local ablative treatments (37 [5.5%]) (LATs). After a random-case control matching according to ECOG-PS, CNS metastases, bone metastases, and (previous) best response to pembrolizumab, patients receiving pembrolizumab ByPD plus LATs were confirmed to have a significantly longer post-progression OS compared to patients receiving pembrolizumab ByPD alone 13.9 months versus 7.8 months (p = 0.0179) 241 patients (35.5%) among the 678 who had experienced PD, received a second-line systemic treatment (regardless of previous treatment beyond PD). As compared to first-line treatment commencement, patients' features at the moment of second-line initiation showed a significantly higher proportion of patients aged under 70 years (p = 0.0244), with a poorer ECOG-PS (p < 0.0001) and having CNS (p = 0.0001), bone (p = 0.0266) and liver metastases (p = 0.0148). In the real-world scenario NSCLC patients with PD-L1 expression ≥50% treated with first-line single-agent pembrolizumab achieve worse outcomes as compared to the Keynote-024 trial. Poor post-progression outcomes are major determinants of the global results that should be considered when counselling patients for first-line treatment choices. • Treatment sequencing is a viable option for NSCLC with a PD-L1 expression ≥ 50%. • Post-progression pathways of a cohort of NSCLC receiving pembrolizumab were reported. • Post-progression outcomes are major determinants for worse clinical outcomes. • Our results should be considered when counselling patients for first-line choices. [ABSTRACT FROM AUTHOR]

In preclinical models, statins showed vaccine adjuvant activities and synergized with PD-1 inhibitors. We analyzed the impact of statin treatment on clinical outcome in thoracic cancer patients treated with PD-1 inhibitors. A total of 82 malignant pleural mesothelioma (MPM) and 179 advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 inhibitors as second or further line treatment were examined. Seventy-seven MPM patients treated with standard chemotherapy were analyzed as control cohort. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were calculated. Among 253 patients with available data, statin use was associated with increased ORR (32% versus 18%, P =.02), PFS (median 6.7 versus 2.9 months, hazard ratio [HR] 0.57, 95% CI 0.39–0.83, P <.01), and OS (median 13.1 versus 8.7 months, HR 0.67, 95% CI 0.45–1.00, P =.05). In the control MPM cohort treated with chemotherapy (n = 77), no association was found. MPM patients who used statins showed improved ORR (22% versus 6%, P =.05), PFS (median 6.7 versus 2.4 months, P <.01), and OS (median not reached versus 6.0 months, P =.01). In aNSCLC patients, statin use was associated with improved ORR (40% versus 22%, P =.04) and PFS (median 7.8 versus 3.6 months, P =.03), but no significant difference in OS was found (median 13.1 versus 10.1 months, P =.30). Multivariable analysis confirmed the correlation between statin use and better PFS and OS in MPM and better PFS in aNSCLC. In the whole cohort, high but not low/moderate-intensity statins were associated with better OS compared to no user (P =.02 and P =.59, respectively). Our study showed that statins are associated with better clinical outcome in MPM and aNSCLC patients treated with PD-1 inhibitors in an intensity-dependent manner. • In pre-clinical models, statins synergized with PD-1 inhibitors. • Statins associated with outcome in MPM and NSCLC patients treated with PD-1 inhibitors. • This association was stronger in patients who used high-intensity statins. • No association found between statins & outcome in the control MPM chemotherapy cohort. [ABSTRACT FROM AUTHOR]

• Lung cancer subtypes are differentiated by conserved methylated loci. • Immune modulating genes with ks-score ≥ 70 % are under methylation control. • Lung cancer exhibits selective suppression of antigen presentation and processing. Non-small-cell lung cancer exhibits a range of transcriptional and epigenetic patterns that not only define distinct phenotypes, but may also govern immune related genes, which have a major impact on survival. We used open-source RNA expression and DNA methylation data of the Cancer Genome Atlas with matched non-cancerous tissue to evaluate whether these pretreatment molecular patterns also influenced genes related to the immune system and overall survival. The distinction between lung adenocarcinoma and squamous cell carcinoma are determined by 1083 conserved methylation loci and RNA expression of 203 genes which differ for >80 % of patients between the two subtypes. Using the RNA expression profiles of 6 genes, more than 95 % of patients could be correctly classified as having either adeno or squamous cell lung cancer. Comparing tumor tissue with matched normal tissue, no differences in RNA expression were found for costimulatory and co-inhibitory genes, nor genes involved in cytokine release. However, genes involved in antigen presentation had a lower expression and a wider distribution in tumor tissue. Only a small number of genes, influenced by DNA methylation, determine the lung cancer subtype. The antigen presentation of cancer cells is dysfunctional, while other T cell immune functions appear to remain intact. [ABSTRACT FROM AUTHOR]

Abstract Introduction Nivolumab treatment is subject to large interpatient variability in both efficacy and toxicity, which may partly be explained by differences in nivolumab exposure. Exposure–response relationships in regular healthcare have not been extensively investigated for nivolumab. Therefore, we aimed to identify possible exposure–response relationships in nivolumab-treated patients with non–small-cell lung cancer (NSCLC). Methods Patients with NSCLC who started second-line nivolumab therapy (3 mg/kg Q2W) between May 5th 2016 and August 1st 2017, and from whom serial blood samples, toxicity data and outcome data were prospectively collected, were included. Follow-up was carried out until November 1st 2017. Patients were classified according to the best overall response (BOR) based on the Response Evaluation Criteria in Solid Tumours, v1.1, and toxicities according to the Common Terminology Criteria for Adverse Events. Nivolumab trough concentrations were measured after 2, 4 and 10 weeks of treatment, excluding dose delays, and calculated geometric means were tested versus BOR or toxicity using analysis of variance and an independent samples t -test, respectively. Overall survival (OS) and progression-free survival were compared between high and low trough concentration groups. Results Seventy-six patients were evaluable for analyses. Responders (n = 15) had higher mean trough concentrations than patients with progression (n = 33): 47% higher after 2 weeks (p = 0.001), 53% higher after 4 weeks (p = 0.008) and 73% higher after 10 weeks (p = 0.002). Higher trough concentrations were associated with longer OS (p = 0.001). Conclusions This study shows that patients with NSCLC with a response to nivolumab had a higher nivolumab exposure than patients with progression, indicating a potential exposure–response relationship. Further clinical research should focus on clarifying these exposure–response relationships. Highlights • Responders to nivolumab treatment had higher nivolumab exposure than progressors. • No difference in exposure was seen in patients with and without toxicity. • Factors influencing exposure should be clarified in future research. [ABSTRACT FROM AUTHOR]

A letter to the editor about the findings of the National Lung Screening Trial (NLST) in the U.S. is presented.

The article discusses research which compared effectiveness and safety of nivolumab and docetaxel in treating patients with advanced squamous-cell non-small-cell lung cancer (NSCLC). Topics explored include the research participant recruitment and screening process, the nivolumab and docetaxel dosage administered to patients, and the patient outcomes recorded such as tumor response and adverse effects.

Summary: Detection of malignancies of the bronchial tree in an early stage, such as carcinoma in situ (CIS), augments the cure rate considerably. It has been shown that the sensitivity of autofluorescence bronchoscopy is better than white light bronchoscopy for the detection of CIS and dysplastic lesions. Autofluorescence bronchoscopy is, however, characterized by a low specificity with a high rate of false positive findings. In the present paper we propose to combine autofluorescence bronchoscopy with optical spectroscopy to improve the specificity of autofluorescence imaging, while maintaining the high sensitivity. Standard autofluorescence bronchoscopy was used to find suspect lesions in the upper bronchial tree, and these lesions were subsequently characterized spectroscopically using a custom made fiberoptic probe. Autofluorescence spectra of the lesions as well as reflectance spectra were measured. We will show in this preliminary report that the addition of either of these spectroscopic techniques decreases the rate of false positives findings, with the best results obtained when both spectroscopic modalities are combined. [Copyright &y& Elsevier]

Purpose: To establish the recurrence patterns when elective mediastinal irradiation was omitted, patients with Stage III non-small-cell lung cancer were treated with sequential chemotherapy (CHT) and involved-field radiotherapy (RT).Methods and Materials: Fifty patients were treated with either two or four cycles of induction CHT, followed by once-daily involved-field RT to 70 Gy, delivered using three-dimensional treatment planning. The contoured gross tumor volume consisted of the pre-CHT tumor volume and nodes with a short-axis diameter of ≥1 cm. Patients were reevaluated at 3 and 6 months after RT using bronchoscopy and chest CT. Elective nodal failure was defined as recurrence in the regional nodes outside the clinical target volume, in the absence of in-field failure.Results: Of 43 patients who received doses ≥50 Gy, 35% were disease free at last follow-up; in-field recurrences developed in 27% (of whom 16% had exclusively in-field recurrences); 18% had distant metastases exclusively. No elective nodal failure was observed. The median actuarial overall survival was 18 months (95% confidence interval 14–22) and the median progression-free survival was 12 months (95% confidence interval 6–18).Conclusion: Omitting elective mediastinal irradiation did not result in isolated nodal failure. Future studies of concurrent CHT and RT for Stage III non-small-cell lung cancer should use involved-field RT to limit toxicity. [Copyright &y& Elsevier]