Neoantigen-targeted dendritic cell vaccination in lung cancer patients induces long-lived T cells exhibiting the full differentiation spectrum.

Non-small cell lung cancer (NSCLC) is known for high relapse rates despite resection in early stages. Here, we present the results of a phase I clinical trial in which a dendritic cell (DC) vaccine targeting patient-individual neoantigens is evaluated in patients with resected NSCLC. Vaccine manufacturing is feasible in six of 10 enrolled patients. Toxicity is limited to grade 1-2 adverse events. Systemic T cell responses are observed in five out of six vaccinated patients, with T cell responses remaining detectable up to 19 months post vaccination. Single-cell analysis indicates that the responsive T cell population is polyclonal and exhibits the near-entire spectrum of T cell differentiation states, including a naive-like state, but excluding exhausted cell states. Three of six vaccinated patients experience disease recurrence during the follow-up period of 2 years. Collectively, these data support the feasibility, safety, and immunogenicity of this treatment in resected NSCLC.

Determining the clinical utility of a breath test for screening an asbestos-exposed population for pleural mesothelioma: baseline results.

Pleural mesothelioma (PM) is an aggressive cancer of the serosal lining of the thoracic cavity, predominantly caused by asbestos exposure. Due to nonspecific symptoms, PM is characterized by an advanced-stage diagnosis, resulting in a dismal prognosis. However, early diagnosis improves patient outcome. Currently, no diagnostic biomarkers or screening tools are available. Therefore, exhaled breath was explored as this can easily be obtained and contains volatile organic compounds, which are considered biomarkers for multiple (patho)physiological processes. A breath test, which differentiates asbestos-exposed (AEx) individuals from PM patients with 87% accuracy, was developed. However, before being implemented as a screening tool, the clinical utility of the test must be determined. Occupational AEx individuals underwent annual breath tests using multicapillary column/ion mobility spectrometry. A baseline breath test was taken and their individual risk of PM was estimated. PM patients were included as controls. In total, 112 AEx individuals and six PM patients were included in the first of four screening rounds. All six PM patients were correctly classified as having mesothelioma (100% sensitivity) and out of 112 AEx individuals 78 were classified by the breath-based model as PM patients (30% specificity). Given the large false positive outcome, the breath test will be repeated annually for three more consecutive years to adhere to the 'test, re-test' principle and improve the false positivity rate. A low-dose computed tomography scan in those with two consecutive positive tests will correlate test positives with radiological findings and the possible growth of a pleural tumor. Finally, the evaluation of the clinical value of a breath-based prediction model may lead to the initiation of a screening program for early detection of PM in Aex individuals, which is currently lacking. This clinical study received approval from the Antwerp University Hospital Ethics Committee (B300201837007).

Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors: The CHEERS Phase 2 Randomized Clinical Trial.

Importance: Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. Objective: To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. Design, Setting, and Participants: This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Interventions: Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Results: Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. Conclusions and Relevance: This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03511391.

The correlation between pre-treatment symptoms, acute and late toxicity and patient-reported health-related quality of life in non-small cell lung cancer patients: Results of the REQUITE study.

BACKGROUND AND PURPOSE: To investigate the association between clinician-scored toxicities and patient-reported health-related quality of life (HRQoL), in early-stage (ES-) and locally-advanced (LA-) non-small cell lung cancer (NSCLC) patients receiving loco-regional radiotherapy, included in the international real-world REQUITE study. MATERIALS AND METHODS: Clinicians scored eleven radiotherapy-related toxicities (and baseline symptoms) with the Common Terminology Criteria for Adverse Events version 4. HRQoL was assessed with the European Organization for Research and Treatment of Cancer core HRQoL questionnaire (EORTC-QLQ-C30). Statistical analyses used the mixed-model method; statistical significance was set at p = 0.01. Analyses were performed for baseline and subsequent time points up to 2 years after radiotherapy and per treatment modality, radiotherapy technique and disease stage. RESULTS: Data of 435 patients were analysed. Pre-treatment, overall symptoms, dyspnea, chest wall pain, dysphagia and cough impacted overall HRQoL and specific domains. At subsequent time points, cough and dysphagia were overtaken by pericarditis in affecting HRQoL. Toxicities during concurrent chemo-radiotherapy and 3-dimensional radiotherapy had the most impact on HRQoL. Conversely, toxicities in sequential chemo-radiotherapy and SBRT had limited impact on patients' HRQoL. Stage impacts the correlations: LA-NSCLC patients are more adversely affected by toxicity than ES-NSCLC patients, mimicking the results of radiotherapy technique and treatment modality. CONCLUSION: Pre-treatment symptoms and acute/late toxicities variously impact HRQoL of ES- and LA-NSCLC patients undergoing different treatment approaches and radiotherapy techniques. Throughout the disease, dyspnea seems crucial in this association, highlighting the additional effect of co-existing comorbidities. Our data call for optimized radiotherapy limiting toxicities that may affect patients' HRQoL.

BMS-986012, an Anti-Fucosyl-GM1 Monoclonal Antibody as Monotherapy or in Combination With Nivolumab in Relapsed/Refractory SCLC: Results From a First-in-Human Phase 1/2 Study.

Introduction: Fucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1. Methods: CA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival. Results: Patients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 [90%]). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval [CI]) was higher with BMS-986012 plus nivolumab (38% [20.7%-57.7%]) than with monotherapy (4% [0.8%-11.0%]). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4-not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%-20.7%) and 39.3% (21.7%-56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0-7.3) and 18.7 (8.2-37.3) months, respectively. Conclusions: BMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880).

External Validation of a Breath-Based Prediction Model for Malignant Pleural Mesothelioma.

During the past decade, volatile organic compounds (VOCs) in exhaled breath have emerged as promising biomarkers for malignant pleural mesothelioma (MPM). However, as these biomarkers lack external validation, no breath test for MPM has been implemented in clinical practice. To address this issue, we performed the first external validation of a VOC-based prediction model for MPM. The external validation cohort was prospectively recruited, consisting of 47 MPM patients and 76 asbestos-exposed (AEx) controls. The predictive performance of the previously developed model was assessed by determining the degree of agreement between the predicted and actual outcome of the participants (patient/control). Additionally, to optimise the performance, the model was updated by refitting it to the validation cohort. External validation revealed a poor performance of the original model as the accuracy was estimated at only 41%, indicating poor generalisability. However, subsequent updating of the model improved the differentiation between MPM patients and AEx controls significantly (73% accuracy, 92% sensitivity, and 92% negative predictive value), substantiating the validity of the original predictors. This updated model will be more generalisable to the target population and exhibits key characteristics of a potential screening test for MPM, which could significantly impact MPM management.

Application of an Ultrasensitive NGS-Based Blood Test for the Diagnosis of Early-Stage Lung Cancer: Sensitivity, a Hurdle Still Difficult to Overcome.

Diagnosis of lung cancer requires histological examination of a tissue sample, which in turn requires an invasive procedure that cannot always be obtained. Circulating tumor DNA can be reliably detected in blood samples of advanced-stage lung cancer patients and might also be a minimally invasive alternative for early-stage lung cancer detection. We wanted to explore the potential of targeted deep sequencing as a test for the diagnosis of early-stage lung cancer in combination with imaging. Mutation detection on cell-free DNA from pretreatment plasma samples of 51 patients with operable non-small cell lung cancer was performed and results were compared with 12 control patients undergoing surgery for a non-malignant lung lesion. By using a variant allele frequency threshold of 1%, somatic variants were detected in 23.5% of patients with a median variant allele fraction of 3.65%. By using this threshold, we could almost perfectly discriminate early-stage lung cancer patients from controls. Our study results are discussed in the light of those from other studies. Notwithstanding the potential of today's techniques for the use of liquid biopsy-based cell-free DNA analysis, sensitivity of this application for early-stage lung cancer detection is currently limited by a biological background of somatic variants with low variant allele fraction.

Overview of health-related quality of life and toxicity of non-small cell lung cancer patients receiving curative-intent radiotherapy in a real-life setting (the REQUITE study).

OBJECTIVES: Radiotherapy-induced toxicity may negatively impact health-related quality of life (HRQoL). This report investigates the impact of curative-intent radiotherapy on HRQoL and toxicity in early stage and locally-advanced non-small cell lung cancer patients treated with radiotherapy or chemo-radiotherapy enrolled in the observational prospective REQUITE study. MATERIALS AND METHODS: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire up to 2 years post radiotherapy. Eleven toxicities were scored by clinicians using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Toxicity scores were calculated by subtracting baseline values. Mixed model analyses were applied to determine statistical significance (p ≤ 0.01). Meaningful clinical important differences (MCID) were determined for changes in HRQoL. Analysis was performed on the overall data, different radiotherapy techniques, multimodality treatments and disease stages. RESULTS: Data of 510 patients were analysed. There was no significant change in HRQoL or its domains, except for deterioration in cognitive functioning (p = 0.01). Radiotherapy technique had no significant impact on HRQoL. The addition of chemotherapy was significantly associated with HRQoL over time (p <.001). Overall toxicity did not significantly change over time. Acute toxicities of radiation-dermatitis (p =.003), dysphagia (p =.002) and esophagitis (p <.001) peaked at 3 months and decreased thereafter. Pneumonitis initially deteriorated but improved significantly after 12 months (p =.011). A proportion of patients experienced meaningful clinically important improvements and deteriorations in overall HRQoL and its domains. In some patients, pre-treatment symptoms improved gradually. CONCLUSIONS: While overall HRQoL and toxicity did not change over time, some patients improved, whereas others experienced acute radiotherapy-induced toxicities and deteriorated HRQoL, especially physical and cognitive functioning. Patient characteristics, more so than radiotherapy technique and treatment modality, impact post-radiotherapy toxicity and HRQoL outcomes. This stresses the importance of considering the potential impact of radiotherapy on individuals' HRQoL, symptoms and toxicity in treatment decision-making.

Neurocognitive functioning following lung cancer treatment: The PRO-Long Study.

This observational cohort study investigates neurocognitive functioning (NCF) and its associations with overall survival (OS), disease-free survival (DFS) and patient-reported psychological toxicities in locally-advanced and metastatic non-small cell lung (NSCLC) cancer patients receiving loco-regional radiotherapy and/or systemic therapy. Objective NCF data was collected with six psychometrically validated neurocognitive tests. Subjective NCF was assessed with the cognitive domain of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items. Psychological toxicity data was collected with the patient-reported outcomes version of the common terminology criteria for adverse events. Meaningful clinical important differences were determined for changes in NCF. Univariate Cox proportional hazards models and generalized linear models were used to determine statistical significance (p < 0.01). In total, 50 patients were recruited. At baseline, 13 (26%) patients had an impaired objective NCF. Over time, deterioration was seen in 11% (n = 3), 5% (n = 1) and 6% (n = 1) of patients at 2-3, 6 and 12 months post-treatment. The OS of patients with a normal NCF at baseline was longer than those with an impaired baseline NCF (29.5 vs 17.1 months). No statistical significance has been reached between NCF and OS (p = .353) nor NCF and DFS (p = .251). Objective NCF was not correlated with subjective NCF (p = .193), nor anxiety (p = .504), depression (p = .513), memory problems (p = .813) and concentration problems (p = .813). Systemic treatment and loco-regional radiotherapy may have a temporarily negative impact on NCF in a small proportion of locally-advanced and metastatic NSCLC. Baseline NCF could be a predictor for OS.

Afatinib for the treatment of advanced non-small-cell lung cancer harboring an epidermal growth factor receptor exon 18 E709_T710delinsD mutation: a case report.

BACKGROUND: The discovery of epidermal growth factor receptor oncogenic driver mutations has changed the therapeutic landscape of advanced non-small cell lung cancer in the past decade. Since the introduction of next-generation sequencing, uncommon epidermal growth factor receptor mutations are more frequently discovered. Because seldom evaluated in clinical trials, their clinical significance and response on tyrosine kinase inhibitors are less well known. CASE PRESENTATION: A 58-year-old Caucasian woman with no smoking history presented with advanced non-small cell lung cancer. Liver biopsy revealed an adenocarcinoma with a programmed death ligand-1 tumor proportion score of 30% and no common oncogenic driver mutations. A combination of chemotherapy and immunotherapy was started as first-line treatment. However, treatment was ceased after 18 weeks because of immune-related renal failure and disease progression. In the meantime, the next-generation sequencing results of the liver biopsy had revealed an exon 18 E709_T710delinsD mutation. Therefore, afatinib was administered, which was moderately tolerated with grade 2 paronychia and acneiform skin eruption. After 6 months, a partial response with ongoing decrease of the liver metastasis was retained. CONCLUSION: Because of the lack of clinical trials, tumor heterogeneity, and a tyrosine kinase inhibitor affinity related to the different mutation types, it is difficult to predict the clinical outcome of tyrosine kinase inhibitor in uncommon mutations. Therefore, a therapeutic trial with tyrosine kinase inhibitor has to be considered, but the expected clinical response is lower than for common mutations.

Combined, patient-level, analysis of two randomised trials evaluating the addition of denosumab to standard first-line chemotherapy in advanced NSCLC - The ETOP/EORTC SPLENDOUR and AMGEN-249 trials.

INTRODUCTION: The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC. METHODS: Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed. RESULTS: The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm. In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0-10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2-11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82-1.18]; P = 0.85). Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a statistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49-0.98]; P = 0.038), from 7.6 to 9.0 months median OS. With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4-5.3]) and 4.9 months (95%CI:[4.3-5.4]). HR for PFS was 0.97(95%CI:[0.83-1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS. CONCLUSION: In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

Real Life Data on Patient-Reported Outcomes and Neuro-Cognitive Functioning of Lung Cancer Patients: The PRO-Long Study.

INTRODUCTION: This report investigates the impact of systemic treatments (chemotherapy or immunotherapy) with(out) loco-regional radiotherapy, on HRQoL, toxicity and neurocognitive functioning (NCF) in locally advanced and metastatic non-small cell lung cancer patients enrolled in the PRO-Long study. MATERIALS AND METHODS: Data on patient-reported HRQoL and fourteen toxicities was collected, while NCF was tested, up to one-year post-treatment. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30. Lung cancer, treatment and neuro-psychological related toxicities were scored with the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events. NCF was evaluated with six neurocognitive tests. Mixed model analyses were conducted to determine statistical significance (p = .01). Meaningful clinical important differences (MCIDs) were applied for changes in HRQoL and NCF data, while toxicities were compared to baseline values. RESULTS: In total, 50 patients were enrolled. Overall HRQoL (p = .357) nor its domains (physical, p = .643; role, p = .069; emotional, p = .254; cognitive, p = 494; social, p = .735) changed significantly over time. Meaningful improvements in overall HRQoL were seen in 22, 38 and 39% and deteriorations in 22, 5 and 28% of patients at 2-3, 6 and 12 months respectively post-treatment. Overall toxicity (p = .007), lack of appetite (p = .001), nausea (p = .004) and dysphagia (p = .000) significantly decreased over time. Treatment caused acute toxicity, such as dyspnoea (45%) and memory problems (42%), but also alleviated pre-existing symptoms, including lack of appetite (32%), anxiety (29%) and depression (28%) at 2/3 months. The NCF domains of visual memory (p = .000) and cognitive processing speed (p = .000) showed significant improvements over time. In terms of MCIDs, at 2-3 months (18%) and 6 months (15%), verbal memory was particularly impacted; at 12 months, visual memory (18%) and executive function (18%) deteriorated primarily. CONCLUSION: The results suggest that therapy has no significant negative impact on overall HRQoL, its domains, and NCF. About one-third of patients reported a meaningful improved HRQoL at 1 year post-treatment. Treatment caused toxicity, but also alleviated pre-existing symptoms.

Checkpoint inhibition in combination with an immunoboost of external beam radiotherapy in solid tumors (CHEERS): study protocol for a phase 2, open-label, randomized controlled trial.

BACKGROUND: While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors. METHODS/DESIGN: Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study's primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples. DISCUSSION: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03511391 . Registered 17 April 2018.

Coping Strategy Influences Quality of Life in Patients With Advanced Lung Cancer by Mediating Mood.

INTRODUCTION: Patients with advanced lung cancer experience high physical symptom burden with substantial psychological distress. Depressive and anxiety symptoms are common and associated with worse quality of life (QoL). Early palliative care (EPC) addresses the complex supportive care needs improving QoL and mood. The mechanisms of EPC are uncertain. We examined whether and how coping strategy, a primary component of EPC, influenced QoL in these patients. MATERIALS AND METHODS: We conducted a multicenter cross-sectional study of patients with advanced lung cancer. A total of 125 patients completed assessments of QoL (QLQ-C15-PAL), depressive and anxiety symptoms (HADS), and coping (brief COPE questionnaire). The data were analyzed by descriptive statistics. To determine whether and how coping strategy influences QoL, correlations and logistic regressions were performed. RESULTS: Positive reframing correlates significantly with global QoL (r = 0.25, P < .01), emotional well-being (r = 0.33, P < .01), pain (r = -0.30, P < .01), fatigue (r = -0.22, P < .01), loss of appetite (r = -0.22, P < .01) and nausea (r = -0.24, P < .01). Self-blame correlates significantly with worse emotional well-being (r = -0.19, P < .05) and insomnia (r = 0.19, P < .05). Using a 4-step logistic regression model, it was found that anxiety and depressive symptoms fully mediated the relationship between positive reframing and QoL. CONCLUSIONS: Patients with advanced lung cancer using positive reframing as coping strategy, experience higher QoL. The mechanism behind it seems that positive reframing goes along with less anxiety and depressive symptoms leading to a better QoL. Self-blame leads to more insomnia and worse emotional well-being. Providing skills to cope effectively could impact QoL in these patients.

Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma.

BACKGROUND: Accurate lung cancer classification is crucial to guide therapeutic decisions. However, histological subtyping by pathologists requires tumor tissue-a necessity that is often intrinsically associated with procedural difficulties. The analysis of circulating tumor DNA present in minimal-invasive blood samples, referred to as liquid biopsies, could therefore emerge as an attractive alternative. METHODS: Concerning adenocarcinoma, squamous cell carcinoma, and small cell carcinoma, our proof of concept study investigates the potential of liquid biopsy-derived copy number alterations, derived from single-end shallow whole-genome sequencing (coverage 0.1-0.5×), across 51 advanced stage lung cancer patients. RESULTS: Genomic abnormality testing reveals anomalies in 86.3% of the liquid biopsies (16/20 for adenocarcinoma, 13/16 for squamous cell, and 15/15 for small cell carcinoma). We demonstrate that copy number profiles from formalin-fixed paraffin-embedded tumor biopsies are well represented by their liquid equivalent. This is especially valid within the small cell carcinoma group, where paired profiles have an average Pearson correlation of 0.86 (95% CI 0.79-0.93). A predictive model trained with public data, derived from 843 tissue biopsies, shows that liquid biopsies exhibit multiple deviations that reflect histological classification. Most notably, distinguishing small from non-small cell lung cancer is characterized by an area under the curve of 0.98 during receiver operating characteristic analysis. Additionally, we investigated how deeper paired-end sequencing, which will eventually become feasible for routine diagnosis, empowers tumor read enrichment by insert size filtering: for all of the 29 resequenced liquid biopsies, the tumor fraction could be increased in silico, thereby "rescuing" three out of five cases with previously undetectable alterations. CONCLUSIONS: Copy number profiling of cell-free DNA enables histological classification. Since shallow whole-genome sequencing is inexpensive and often fully operational at routine molecular laboratories, this finding has current diagnostic potential, especially for patients with lesions that are difficult to reach.

The effect of early and systematic integration of palliative care in oncology on quality of life and health care use near the end of life: A randomised controlled trial.

PURPOSE: This study evaluated the effect of early integrated palliative care (PC) in oncology on quality of life (QOL) near the end of life and use of health care resources near the end of life. METHOD: Patients with advanced cancer and a life expectancy of approximately 1 year were randomly assigned to either early and systematic integration of PC into oncological care (intervention) or standard oncological care alone (control). QOL was assessed with the EORTC QLQ-C30 global health status/QOL scale and McGill Quality of Life (MQOL) Single Item Scale and Summary Scale at baseline, 12 weeks and 6 weekly thereafter until death. Use of health care resources was collected from chart review in patient's electronic medical file for patients who died while participating in the study. RESULTS: Of the 186 randomised patients, 185 participants had a baseline measurement and were analysed. By November 2017, 128 patients had died while participating in the study. When applying the terminal decline model, patients in the intervention group scored significantly higher on global health status/QOL of the EORTC QLQ C30, at 6 months (difference: 5.9 [0.06; 11.1], p = 0.03), 3 (difference: 6.8 [1.0; 12.6], p = 0.02), and 1 month (difference: 7.6 [0.7; 14.5], p = 0.03) prior to the patient's death compared to the control group. Similar results were found for the Single Item Scale and Summary Score of the MQOL. We did not observe differences in use of health care resources between groups. DISCUSSION: Early integrated palliative care in oncology is a valuable approach since it also increases QOL near the end of life and not only soon after initiation of PC.

Real life safety and effectiveness of nivolumab in older patients with non-small cell lung cancer: Results from the Belgian compassionate use program.

OBJECTIVES: To compare real life effectiveness and safety of nivolumab in patients with non-small cell lung cancer (NSCLC), according to age and Eastern Cooperative Group performance status (ECOG-PS). METHODS: We performed a retrospective analysis of patients treated with nivolumab for NSCLC within a Belgian compassionate use program from July 2015 until December 2016. Safety and effectiveness were compared between patients aged ≥70 years and < 70 years and between ECOG-PS 0/1 and ≥ 2. RESULTS: A total of 324 patients with NSCLC were included. There was no significant difference between older (≥70) and younger (<70 years) patients with regards to progression free survival (PFS) (4 months (95%CI 2.6;4.8) versus 3.7 months (95%CI 1;7), p = 0.483) and overall survival (OS) (9.3 months (95% CI 5.5;13.1 months) versus 8.4 months (95%CI 6.3; 10.5), p = 0,638). Patients with an ECOG-PS ≥2 had a significant lower median PFS and OS compared to patients with an ECOG-PS 0-1 (2.2 (95%CI 1.4; 2.9) versus 5.6 months (95%CI 4.1; 7.1), p = 0.001 and 3.4 (95%CI 2.3; 4.5) versus 11.1 months (95%CI 8.9; 13.2), p < 0.001 respectively). No significant difference in all grades or grade 3/4 adverse events (AEs) were observed between the different age groups (p = 0.526 and p = 0.603 respectively). Patients with an ECOG-PS 0/1 had significantly more all grades AEs (p = 0.009) but no difference in grade 3/4 AEs was observed (p = 0.406) compared to ECOG-PS ≥2. CONCLUSION: This real life retrospective study confirms that safety and effectiveness of nivolumab is similar between different age groups, but that effectiveness is driven by performance status.

Health-Related Quality of Life in Advanced Non-small Cell Lung Cancer: A Methodological Appraisal Based on a Systematic Literature Review.

Background: The majority of lung cancer patients are diagnosed with advanced non-small cell lung cancer (NSCLC), the bulk of which receive palliative systemic treatment with the goal to provide effective symptom palliation and safeguard health-related quality of life (HRQoL). Advanced NSCLC trials with HRQoL endpoints face methodological constraints limiting interpretability. Objectives: We provide a comprehensive overview of recent clinical trials evaluating the impact of systemic therapies on HRQoL in advanced NSCLC, focusing on the methodological quality, with the ultimate goal to improve interpretation, comparison and reporting of HRQoL data. Methods: A systematic literature review was performed. Prospective studies published over the last decade evaluating the impact of systemic treatments on HRQoL in advanced NSCLC were included. Methodological quality of HRQoL reporting was assessed with the CONSORT-PRO extension. Results: Hundred-twelve manuscripts describing 85 trials met all criteria. No formal conclusion can be drawn regarding the impact on HRQoL of different treatments. We report an important variety in methodological quality in terms of definitions of HRQoL, missing data points, lack of standardization of analyzing and presenting HRQoL and no standard follow-up time. The quality of HRQoL data reporting varies substantially between studies but improves over time. Conclusion: This review shows that in the heterogeneous landscape of trials addressing HRQoL in advanced stage NSCLC. Methodology reporting remains generally poor. Adequate reporting of HRQoL outcome data is equally important to support clinical decision-making as to correctly inform health policy regarding direct approval and reimbursement of the new drugs and combinations that will come online.