Patterns of Disease Recurrence after SABR for Early Stage Non–Small-Cell Lung Cancer: Optimizing Follow-Up Schedules for Salvage Therapy

Introduction:Stereotactic ablative radiotherapy is a guideline-recommended treatment for early stage non–small-cell lung cancer. We report on incidence and salvage of local recurrences (LR) and second primary lung cancers (SPLC) in a large series of patients with long-term follow-up, to generate data for evidence-based follow-up regimens.Methods:We excluded all patients with double tumors, TNM-stages other than T1-T2N0M0, biologically effective dose less than 100 Gy10 and previous treatment for the index tumor from our institutional database. LR was defined as recurrence in/adjacent to the planning target volume. A diagnosis of SPLC was determined using criteria described by Martini et al.Results:The 855 patients included had a median follow-up of 52 months. Forty-six patients developed LR after a median of 22 months (range 7–87 months). Actuarial local control rates at 3 and 5 years were 92.4% and 90.9%, respectively. Fifty-four percent had isolated LR and 13% had LR in combination with regional recurrences. Ten patients underwent radical salvage treatment; surgery (N = 6), high-dose radiotherapy (N = 3), or chemoradiation (N = 1). Median overall survival following LR was 13 months, but it was 36 months in patients who underwent radical salvage. A SPLC was diagnosed in 79 patients, after a median interval of 34 months. Actuarial cumulative incidences of SPLC at 3 and 5 years were 11.7% and 16.7%, respectively. Radical salvage for SPLC was performed in 63 patients (80%).Conclusions:Both the timing of LR and persistent risk of SPLC serve as rationale for long-term follow-up using computed tomography scans in patients fit enough to undergo any radical treatment

Multicenter Comparison of Molecular Tumor Boards in The Netherlands: Definition, Composition, Methods, and Targeted Therapy Recommendations

Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. Materials and Methods: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. Results: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type–specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%). Conclusion: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a “Dutch MTB model” for an optimal, collaborative, and nationally aligned MTB workflow. Implications for Practice: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing

Pneumomediastinum and (bilateral) pneumothorax after high energy trauma: Indications for emergency bronchoscopy

High energy trauma may cause injury to tracheobronchial structures. This is sometimes difficult to diagnose immediately. Pneumomediastinum and (bilateral) pneumothorax seen on a CT-scan of the thorax may suggest possible damage to central airways. Emergency bronchoscopy should be performed to detect and locate a possible tracheobronchial injury

Dynamics of methylated cell-free DNA in the urine of non-small cell lung cancer patients

High levels of methylated DNA in urine represent an emerging biomarker for non-small cell lung cancer (NSCLC) detection and are the subject of ongoing research. This study aimed to investigate the circadian variation of urinary cell-free DNA (cfDNA) abundance and methylation levels of cancer-associated genes in NSCLC patients. In this prospective study of 23 metastatic NSCLC patients with active disease, patients were asked to collect six urine samples during the morning, afternoon, and evening of two subsequent days. Urinary cfDNA concentrations and methylation levels of CDO1, SOX17, and TAC1 were measured at each time point. Circadian variation and between- and within-subject variability were assessed using linear mixed models. Variability was estimated using the Intraclass Correlation Coefficient (ICC), representing reproducibility. No clear circadian patterns could be recognized for cfDNA concentrations or methylation levels across the different sampling time points. Significantly lower cfDNA concentrations were found in males (p=0.034). For cfDNA levels, the between- and within-subject variability were comparable, rendering an ICC of 0.49. For the methylation markers, ICCs varied considerably, ranging from 0.14 to 0.74. Test reproducibility could be improved by collecting multiple samples per patient. In conclusion, there is no preferred collection time for NSCLC detection in urine using methylation markers, but single measurements should be interpreted carefully, and serial sampling may increase test performance. This study contributes to the limited understanding of cfDNA dynamics in urine and the continued interest in urine-based liquid biopsies for cancer diagnostics.</p

High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from the phase 2 multicenter POSITION20 trial

Introduction: Patients with life-threatening advanced non-small cell lung cancer (NSCLC) who harbor an exon 20 deletion and/or insertion mutation (EGFRex20 + ) have limited effective treatment options. The high dose 3rd generation tyrosine kinase inhibitor (TKI) osimertinib shows promising in vitro activity in EGFRex20 + NSCLC tumors. Methods: The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC. We allowed patients to be treatment naïve and to have asymptomatic brain metastases. The primary endpoint was overall response rate (ORR). Secondary outcomes were duration of response (DoR), progression free survival (PFS), overall survival (OS), and treatment related adverse events (trAEs). Results: From June 2018 to October 2021, 25 patients were enrolled across five centers in the Netherlands. The median age was 70 years (range, 47–87), 20 patients (80%) were women, and the median number of previous lines of therapy was 1 (range, 0–3). The exon 20 mutations were clustered between A763 and L777. The most common exon 20 mutations were p.(N771_H773dup) (n = 3) and p.(A767_V769dup) (n = 3). The ORR was 28% (95% CI, 12–49%), including seven partial responses, with a median DoR of 5.3 months (range, 2.7–27.6). The median PFS was 6.8 months (95% CI, 4.6–9.1) and the median OS was 15.2 months (95% CI, 14.3–16.0). The most common trAEs were diarrhea (72%), dry skin (44%), and fatigue (44%). The primary reason for discontinuation was progressive disease in 14 patients (56%). Conclusion: The POSITION20 study showed modest antitumor activity in patients with EGFRex20 + NSCLC treated with 160 mg osimertinib, with a confirmed ORR of 28% and acceptable toxicity

Multicenter Comparison of Molecular Tumor Boards in The Netherlands: Definition, Composition, Methods, and Targeted Therapy Recommendations

Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. Materials and Methods: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. Results: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type–specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%). Conclusion: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a “Dutch MTB model” for an optimal, collaborative, and nationally aligned MTB workflow. Implications for Practice: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing