Osimertinib and palbociclib in an EGFR-mutated NSCLC with primary CDK4 amplification after progression under osimertinib.

Precision cancer medicine has changed the treatment paradigm of patients with non-small cell lung cancer (NSCLC) with specific molecular aberrations. A major challenge is management of the resistance that tumor cells eventually develop against targeted therapies, either through primary or acquired resistance mechanisms. We report a 61 year-old male patient with metastatic NSCLC harboring an EGFR exon 19 deletion, a PIK3CA mutation, and CDK4 amplification. After an initial partial response to osimertinib as mono-therapy (third-generation EGFR tyrosine kinase inhibitor), the patient had progression of disease after 4 months of treatment and was referred for combined osimertinib and palbociclib (CDK4/6 inhibitor) treatment. Though complicated by transient pneumonitis, the patient has an ongoing partial response for > 10 months and has experienced clinical improvement on this treatment regimen. As amplification of CDK4 occurs in ~ 10% of treatment-naïve patients with EGFR-mutated NSCLC, the successful treatment of our patient with osimertinib and palbociclib may be highly relevant for future patients with NSCLC.

The determination of pleurodesis using sonography after surgical pleurectomy for pneumothorax: a pilot study.

The aim of this study is to evaluate feasibility of monitoring the process of pleurodesis after surgical pleurectomy with thoracic ultrasound. Repetitive measurements with thoracic ultrasound after surgical pleurectomy could provide information on the extent and development speed of pleurodesis. We conducted a prospective single-center cohort study. Adult patients who required surgical pleurectomy after pneumothorax were eligible. Participants had daily thoracic ultrasound examination until discharge to determine lung sliding [present (0 point), questionable (1 point), or absent (2 points)], and pleural thickening [normal (0 point), questionable (1 point), or present (2 points)]. Thoracic ultrasound was performed in six regions, the sum of all scores was divided by the number of regions. Fourteen patients were enrolled. Thoracic ultrasound on day 1-4 was 0.25±0.26, 0.39±0.48, 0.84±0.49, 1.12±0.56 for mean lung sliding, and 1.0±0.56, 1.17±0.48, 1.44±0.44, 1.54±0.34 for mean pleural thickening. Lung sliding and pleural thickening increased significantly between day 1 and day 4 (P=0.002 and P=0.023, respectively). One (7%) and 3 (21%) patients reached the maximum achievable grade for lung sliding and pleural thickening, respectively. Thoracic ultrasound grades tended to be lower in three patients with recurrent pneumothorax, although this was not statistically significant. This study shows a significant increase in thoracic ultrasound grading for pleurodesis lung sliding and pleural thickening during the first postoperative days after surgical pleurectomy, probably attributable to progressing pleurodesis. Only a minority of patients reached complete pleurodesis before discharge despite complete surgical pleurodesis (SP). The results of this study may guide future research regarding optimal timing of chest tube removal.

Robot-assisted thoracic surgery for stages IIB-IVA non-small cell lung cancer: retrospective study of feasibility and outcome.

Robot-assisted thoracic surgery (RATS) for higher stages non-small cell lung carcinoma (NSCLC) remains controversial. This study reports the feasibility of RATS in patients with stages IIB-IVA NSCLC. A single-institute, retrospective study was conducted with patients undergoing RATS for stages IIB-IVA NSCLC, from January 2015 until January 2020. Unforeseen N2 disease was excluded. Data were collected from the Dutch Lung Cancer Audit database. Conversion rate, radical (R0) resection rate, local recurrence rate and complications were analyzed, as were risk factors for conversion. RATS was performed in 95 patients with NSCLC clinical or pathological stages IIB (N = 51), IIIA (N = 39), IIIB (N = 2) and IVA (N = 3). 10.5% had received neoadjuvant chemoradiotherapy. Pathological staging was T3 in 33.7% and T4 in 34.7%. RATS was completed in 77.9% with a radical resection rate of 94.8%. Lobectomy was performed in 67.4% of the total resections. Conversion was for strategic (18.9%) and emergency (3.2%) reasons. Pneumonectomy (p = 0.001), squamous cell carcinoma (p < 0.001), additional resection of adjacent structures (p = 0.025) and neoadjuvant chemoradiation (p = 0.017) were independent risk factors for conversion. Major post-operative complications occurred in ten patients (10.5%) including an in-hospital mortality of 2.1% (n = 2). Median recurrence-free survival was estimated at 39.4 months (CI 16.4-62.5). Two- and 5-year recurrence-free survival rates were 53.8% and 36.7%, respectively. This study concludes that RATS is safe and feasible in higher staged NSCLC tumors after exclusion of unforeseen N2 disease. It brings new perspective on the potential of RATS in higher stages, dealing with larger and more invasive tumors.

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer.

Introduction: Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods: Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results: Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion: Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.

Investigation of the added value of CT-based radiomics in predicting the development of brain metastases in patients with radically treated stage III NSCLC.

Introduction: Despite radical intent therapy for patients with stage III non-small-cell lung cancer (NSCLC), cumulative incidence of brain metastases (BM) reaches 30%. Current risk stratification methods fail to accurately identify these patients. As radiomics features have been shown to have predictive value, this study aims to develop a model combining clinical risk factors with radiomics features for BM development in patients with radically treated stage III NSCLC. Methods: Retrospective analysis of two prospective multicentre studies. Inclusion criteria: adequately staged [18F-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT), contrast-enhanced chest CT, contrast-enhanced brain magnetic resonance imaging/CT] and radically treated stage III NSCLC, exclusion criteria: second primary within 2 years of NSCLC diagnosis and prior prophylactic cranial irradiation. Primary endpoint was BM development any time during follow-up (FU). CT-based radiomics features (N = 530) were extracted from the primary lung tumour on 18-FDG-PET-CT images, and a list of clinical features (N = 8) was collected. Univariate feature selection based on the area under the curve (AUC) of the receiver operating characteristic was performed to identify relevant features. Generalized linear models were trained using the selected features, and multivariate predictive performance was assessed through the AUC. Results: In total, 219 patients were eligible for analysis. Median FU was 59.4 months for the training cohort and 67.3 months for the validation cohort; 21 (15%) and 17 (22%) patients developed BM in the training and validation cohort, respectively. Two relevant clinical features (age and adenocarcinoma histology) and four relevant radiomics features were identified as predictive. The clinical model yielded the highest AUC value of 0.71 (95% CI: 0.58-0.84), better than radiomics or a combination of clinical parameters and radiomics (both an AUC of 0.62, 95% CIs of 0.47-076 and 0.48-0.76, respectively). Conclusion: CT-based radiomics features of primary NSCLC in the current setup could not improve on a model based on clinical predictors (age and adenocarcinoma histology) of BM development in radically treated stage III NSCLC patients.

High Yield of Chest X-ray in the Follow-Up of Colorectal Cancer.

PURPOSE: Worldwide, colorectal carcinoma (CRC) has a high incidence and a substantial cancer-related mortality. The recurrence risk is 30-50% and lung metastases are common. Treatment of lung metastases with stereotactic ablative radiotherapy (SABR) or metastasectomy may increase survival. The best modality for thoracic screening in the follow-up, however, remains controversial. In this study, we aimed to unravel the additional value of routine chest X-ray (CXR) for detecting lung metastases during the follow-up of CRC patients treated with curative surgery. METHODS: Between 2013 and 2017, 668 CRC patients were treated with curative intent, of whom 633 patients were included in follow-up, which consisted of CXR, serum Carcino-Embryonic Antigen (CEA) and ultrasound of the liver. Patients who developed lung metastases, diagnosed with CXR and characterised by a normal concomitant serum CEA level, were identified. Number, size and treatment of lung metastases were described. RESULTS: Thirty-four (5.4%) patients developed lung metastases. Seventeen (50%) were detected by CXR without pathological CEA levels. Eleven (65%) of these patients were treated with curative intent, whereas 21% of patients with lung metastases and elevated CEA levels were treated with curative intent (p = 0.049). Higher numbers of lung metastases were associated with a lower chance of curative treatment. CONCLUSIONS: More than 50% of patients with lung metastases on CXR in the follow-up would not have been detected with CEA-triggered imaging only. In addition, patients with colorectal lung metastases without elevated CEA levels were often suitable for curative treatment and, therefore, CXR seems to have additional value within the follow-up of CRC.

Quality assessment of robot assisted thoracic surgical resection of non-small cell lung cancer: nodal upstaging and mediastinal recurrence.

BACKGROUND: Robot assisted thoracic surgery (RATS) is the minimally invasive surgical technique of choice for treatment of patients with non-small cell lung cancer (NSCLC), at the Isala Hospital. The aim of this study is to compare clinical and pathological staging results and mediastinal recurrence after RATS for anatomical resections of lung cancer as surrogate markers for quality of mediastinal lymph node dissection (MLND). METHODS: This single institute retrospective study was conducted in patients who underwent RATS for NSCLC. Excluded were patients with a history of concurrent malignant disease, with other previous neoplasms, with small cell lung cancer (SCLC) and patients in whom the robotic technique was converted to thoracotomy, prior to lymph node dissection. Data were obtained from the hospital database. The difference between clinical and pathological staging was expressed as upstaging and downstaging. Computed Tomography scanning was used for follow-up, and diagnosis of mediastinal recurrence. RESULTS: From November 2011 to May 2016, 227 patients underwent RATS at Isala Hospital Zwolle, the Netherlands. Of those, 130 (mean age, 69.5±9.3 years) met the eligibility criteria. Preoperative mediastinal lymph node staging was done by endoscopic ultrasound/endobronchial ultrasound, by positron emission tomography (PET) or mediastinoscopy. In 14 patients (10.8%) unforeseen N2 disease was found, 6 patients (4.6%) were upstaged from cN0 to pN2 and 8 patients (6.2%) were upstaged from cN1 to pN2. Mediastinal recurrence was detected in 7 patients (5.4%) during a median follow-up of 54 months (range, 1.5-102 months). CONCLUSIONS: In patients with NSCLC, who underwent anatomical resection by means of RATS, an unforeseen N2 disease rate of 10.8% was demonstrated and a mediastinal recurrence rate of 5.4%. It is concluded that robotic surgery provides an accurate lymph node dissection.

Clinical Value of EGFR Copy Number Gain Determined by Amplicon-Based Targeted Next Generation Sequencing in Patients with EGFR-Mutated NSCLC.

BACKGROUND: The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated. OBJECTIVE: We aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value. PATIENTS AND METHODS: Next generation sequencing data were obtained for 1566 patients with non-small cell lung cancer. EGFR copy number gain was defined based on an increase in EGFR read counts relative to internal reference amplicons and normal controls in combination with a modified z-score ≥ 3.5. Clinical follow-up data were available for 60 patients treated with first-line EGFR-tyrosine kinase inhibitors. RESULTS: Specificity and sensitivity of next generation sequencing-based EGFR copy number estimations were above 90%. EGFR copy number gain was observed in 27.9% of EGFR mutant cases and in 7.4% of EGFR wild-type cases. EGFR gain was not associated with progression-free survival but showed a significant effect on overall survival with an adjusted hazard ratio of 3.14 (95% confidence interval 1.46-6.78, p = 0.003). Besides EGFR copy number gain, osimertinib in second or subsequent lines of treatment and the presence of T790M at relapse revealed significant effects in a multivariate analysis with adjusted hazard ratio of 0.43 (95% confidence interval 0.20-0.91, p = 0.028) and 0.24 (95% confidence interval 0.1-0.59, p = 0.001), respectively. CONCLUSIONS: Pre-treatment EGFR copy number gain determined by amplicon-based next generation sequencing data predicts worse overall survival in EGFR-mutated patients treated with first-line EGFR-tyrosine kinase inhibitors. T790M at relapse and subsequent treatment with osimertinib predict longer overall survival.

Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response.

BACKGROUND: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. METHODS: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. FINDINGS: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. INTERPRETATION: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial.

BACKGROUND: Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy. METHODS: We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847. FINDINGS: Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6-8·7]) than in the supportive care group (3·2 months [2·8-4·1]; hazard ratio [HR] 0·48 [95% CI 0·33-0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33-0·72]; p=0·0002). Grade 3-4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection. INTERPRETATION: Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma. FUNDING: Dutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.

Ambulant treatment with a digital chest tube for prolonged air leak is safe and effective.

BACKGROUND: Outpatient or ambulatory treatment for prolonged air leak (PAL) has been reported previously in various studies. Evidence regarding efficiency and safety is nevertheless poor. This report describes the experience of 10 years ambulatory care with a digital chest drain system monitored by specialized nurses in our centre. The aim of the study is to give further insights in the effectiveness and safety of this treatment. METHODS: Retrospective data of 10 years ambulatory care for PAL were examined. One hundred and forty patients with PAL after pneumothorax or pulmonary surgery were included. RESULTS: A total of 140 patients with PAL were included. Treatment was successful in 112 patients (80.0%). Hospital readmission was necessary in 33 patients (23.6%) and 28 (20.0%) of them received additional treatment. Additional treatment consisted of video-assisted thoracoscopic surgery (VATS) in 19 patients (13.6%), new chest tube placement in 8 patients (5.7%) and pleurodesis (with talc slurry) in 1 patient (0.7%). Minor complications occurred in 10 patients (7.1%), major complications requiring readmission occurred in 14 patients (10.0%). CONCLUSIONS: Ambulatory treatment of PAL with a digital monitoring device resulted in a high success rate with a limited complication rate.

Relevance and Effectiveness of Molecular Tumor Board Recommendations for Patients With Non-Small-Cell Lung Cancer With Rare or Complex Mutational Profiles.

PURPOSE: Molecular tumor boards (MTBs) provide physicians with a treatment recommendation for complex tumor-specific genomic alterations. National and international consensus to reach a recommendation is lacking. In this article, we analyze the effectiveness of an MTB decision-making methodology for patients with non-small-cell lung cancer (NSCLC) with rare or complex mutational profiles as implemented in the University Medical Center Groningen (UMCG). METHODS: The UMCG-MTB comprises (pulmonary) oncologists, pathologists, clinical scientists in molecular pathology, and structural biologists. Recommendations are based on reported actionability of variants and molecular interpretation of pathways affected by the variant and supported by molecular modeling. A retrospective analysis of 110 NSCLC cases (representing 106 patients) with suggested treatment of complex genomic alterations and corresponding treatment outcomes for targeted therapy was performed. RESULTS: The MTB recommended targeted therapy for 59 of 110 NSCLC cases with complex molecular profiles: 24 within a clinical trial, 15 in accordance with guidelines (on label) and 20 off label. All but 16 recommendations involved patients with an EGFR or ALK mutation. Treatment outcome was analyzed for patients with available follow-up (10 on label and 16 off label). Adherence to the MTB recommendation (21 of 26; 81%) resulted in an objective response rate of 67% (14 of 21), with a median progression-free survival of 6.3 months (interquartile range, 3.2-10.6 months) and an overall survival of 10.4 months (interquartile range, 6.3-14.6 months). CONCLUSION: Targeted therapy recommendations resulting from the UMCG-MTB workflow for complex molecular profiles were highly adhered to and resulted in a positive clinical response in the majority of patients with metastatic NSCLC.

[Pseudoprogression in immune therapy]. / Pseudoprogressie bij immuuntherapie.

Immune therapy is increasingly used as an effective treatment for various types of cancer. The response of tumours to immune therapy is different from conventional chemotherapy. In about 10% of patients, pseudoprogression may occur. This is a phenomenon where disease progression initially appears on imaging due to inflammation, but response is seen with repeated imaging. Pseudoprogression is often accompanied by a good clinical status. We describe a 63-year-old woman with metastasized melanoma, a 53-year-old woman with metastasized lung cancer and a 77-year-old woman with metastasized renal cancer who all developed pseudoprogression upon treatment with immune therapy. Premature discontinuation of treatment should be prevented when suspecting pseudoprogression and care should be taken to avoid burdening patients with bad news. Imaging should be repeated after a minimum interval of four weeks if pseudoprogression is suspected. When in doubt, a biopsy may be performed.

[Immunotherapy for cancer: from medical breakthrough to application in daily practice]. / Immuuntherapie voor kanker.

Immunotherapy induces a response against cancer by activating the immune system. Examples are therapies with checkpoint inhibitors, oncolytic viruses and chimeric antigen receptor T-cells (CAR T-cells). These therapies have, due to their rapid development, found their way to daily practice. For some patients with metastatic disease immunotherapy has led to significant long-term survival. Currently, there is a shift in the treatment with checkpoint inhibitors towards the (neo)adjuvant setting. Treatments with CAR T-cells seem particularly effective in haematological malignancies. Oncolytic viruses are used in the treatment for melanoma, but presently only on a limited scale. Only a limited number of patients benefit from immunotherapy. There remain many challenges for the future, most importantly the optimal use of treatment, recognition and treatment of side effects, determining the optimal duration of treatment and the increasing healthcare costs.

Systematic and combined endosonographic staging of lung cancer (SCORE study).

Guidelines recommend endosonography for mediastinal nodal staging in patients with resectable nonsmall cell lung cancer (NSCLC). We hypothesise that a systematic endobronchial ultrasound (EBUS) evaluation combined with an oesophageal investigation using the same EBUS bronchoscope (EUS-B) improves mediastinal nodal staging versus the current practice of targeted positron emission tomography (PET)-computed tomography (CT)-guided EBUS staging alone.A prospective, multicentre, international study (NCT02014324) was conducted in consecutive patients with (suspected) resectable NSCLC. After PET-CT, patients underwent systematic EBUS and EUS-B. Node(s) suspicious on CT, PET, EBUS and/or EUS-B imaging and station 4R, 4L and 7 (short axis ≥8 mm) were sampled. For patients without N2/N3 disease determined on endosonography, surgical-pathological staging was the reference standard.229 patients were included in this study. The prevalence of N2/N3 disease was 103 out of 229 patients (45%). A PET-CT-guided targeted approach by EBUS identified 75 patients with N2/N3 disease (sensitivity 73%, 95% CI 63-81%; negative predictive value (NPV) 81%, 95% CI 74-87%). Four additional patients with N2/N3 disease were found by systematic EBUS (sensitivity 77%, 95% CI 67-84%; NPV 84%, 95% CI 76-89%) and five more by EUS-B (84 patients total; sensitivity 82%, 95% CI 72-88%; NPV 87%, 95% CI 80-91%). Additional clinical relevant staging information was obtained in 23 out of 229 patients (10%).Systematic EBUS followed by EUS-B increased sensitivity for the detection of N2/N3 disease by 9% compared to PET-CT-targeted EBUS alone.

Workplace mentoring of residents in generic competencies by an independent coach.

INTRODUCTION: During postgraduate education in pulmonology, supervisors are responsible for training residents in generic competencies such as communication, professionalism and collaboration, but their focus commonly lies more on medical-technical competencies. As an alternative approach to supporting residents to develop generic skills, we developed a personal mentoring program with a non-medical professional as mentor. In this study, the residents' experiences with the mentoring program were evaluated. METHODS: After an introductory session in which individual learning goals were established, pulmonology residents received at least six, 60-90-minute, individual, mentoring sessions largely consisting of feedback after being observed during daily clinical activities, over a period of 9 months. The residents' experiences with mentoring were explored through in-depth interviews followed by a qualitative content analysis. RESULTS: From March to November 2016, ten residents in pulmonology completed the program. Despite initial scepticism, mentoring encouraged residents to reflect deeply on their professional interactions. This caused an increased awareness of the effects of their communication and behaviour on patients. Experimenting with communication and different behaviours in subsequent interactions felt rewarding and contributed to further development, resulting in increased self-confidence and job satisfaction. DISCUSSION: Mentoring residents by non-medical coaching was associated with improved residents' proficiency in generic competencies.

Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study.

Purpose The purpose of the current study was to investigate whether prophylactic cranial irradiation (PCI) reduces the incidence of symptomatic brain metastases in patients with stage III non-small-cell lung cancer (NSCLC) treated with curative intention. Patients and Methods Patients with stage III NSCLC-staged with a contrast-enhanced brain computed tomography or magnetic resonance imaging-were randomly assigned to either observation or PCI after concurrent/sequential chemoradiotherapy with or without surgery. The primary end point-development of symptomatic brain metastases at 24 months-was defined as one or a combination of key symptoms that suggest brain metastases-signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms-and magnetic resonance imaging or computed tomography demonstrating the existence of brain metastasis. Adverse effects, survival, quality of life, quality-adjusted survival, and health care costs were secondary end points. Results Between 2009 and 2015, 175 patients were randomly assigned: 87 received PCI and 88 underwent observation only. Median follow-up was 48.5 months (95% CI, 39 to 54 months). Six (7.0%) of 86 patients in the PCI group and 24 (27.2%) of 88 patients in the control group had symptomatic brain metastases ( P = .001). PCI significantly increased the time to develop symptomatic brain metastases (hazard ratio, 0.23; [95% CI, 0.09 to 0.56]; P = .0012). Median time to develop brain metastases was not reached in either arm. Overall survival was not significantly different between both arms. Grade 1 and 2 memory impairment (26 of 86 v seven of 88 patients) and cognitive disturbance (16 of 86 v three of 88 patients) were significantly increased in the PCI arm. Quality of life was only decreased 3 months post-PCI and was similar to the observation arm thereafter. Conclusion PCI significantly decreased the proportion of patients who developed symptomatic brain metastases with an increase of low-grade toxicity.

Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial.

INTRODUCTION: In ES-SCLC patients with residual intrathoracic disease after first-line chemotherapy, the addition of thoracic radiotherapy reduces the risk of intrathoracic recurrence, and improves 2-year survival. To identify patient subgroups for future trials investigating higher dose (extra)thoracic radiotherapy, we investigated the prognostic importance of number and sites of metastases in patients included in the CREST trial. MATERIALS/ METHODS: Additional data on sites and numbers of metastases were collected from individual records of 260 patients from the top 9 recruiting centers in the randomized CREST trial (53% of 495 study patients), which compared thoracic radiotherapy (TRT) to no TRT in ES-SCLC patients after any response to chemotherapy. All patients received prophylactic cranial irradiation. RESULTS: The clinical characteristics and outcomes of the 260 patients analyzed here did not differ significantly from that of the other 235 patients included in the CREST trial, except that fewer patients had a WHO=0 performance status (24% vs 45%), and a higher proportion had WHO=2 (15% vs 5%; p<0.0001). No distant metastases were recorded in 5%, 39% had metastases confined to one organ, 34% to two, and 22% to three or more organ sites. Metastases were present in the liver (47%), bone (40%), lung (28%), extrathoracic (non-supraclavicular) lymph nodes (19%), supraclavicular nodes (18%), adrenals (17%) and other sites (12%). The OS (p=0.02) and PFS (p=0.04) were significantly better in patients with 2 or fewer metastases, with OS significantly worse if liver (p=0.03) and/or bone metastases (p=0.04) were present. DISCUSSION: This analysis of patients recruited from the top 9 accruing centers in the CREST trial suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases.

EUS-B-FNA vs conventional EUS-FNA for left adrenal gland analysis in lung cancer patients.

INTRODUCTION: In patients with lung cancer, left adrenal glands (LAG) suspected for distant metastases (M1b) based on imaging require further evaluation for a definitive diagnosis. Tissue acquisition is regularly performed using conventional EUS-FNA. The aim of this study was to investigate the success rate of endoscopic ultrasound guided fine-needle aspiration using the EBUS scope (EUS-B-FNA) for LAG analysis. METHODS: This is a prospective multicenter study in consecutive patients with (suspected) lung cancer and suspected mediastinal and LAG metastases. Following complete mediastinal staging using the EBUS scope (EBUS+EUS-B), the LAG was evaluated and sampled by both EUS-B (experimental procedure) and conventional EUS (current standard of care). RESULTS: The success rate for LAG analysis (visualized, sampled and adequate tissue obtained) was 89% (39/44; 95% CI 76-95%) for EUS-B-FNA, and 93% (41/44; 95%CI 82-98%) for EUS-FNA. In the absence of metastases at EUS-B and/or EUS, surgical verification of the LAG or 6 months clinical and radiological follow-up was obtained, but missing for 5 patients. The prevalence of LAG metastases was 54% (21/39). In patients in whom LAG was seen and sampled, sensitivity for LAG metastases was at least 87% (95%CI 65-97%) for EUS-B, and at least 83% (95%CI 62-95%) for conventional EUS. CONCLUSION: LAG analysis by EUS-B shows a similar high success rate in comparison to conventional EUS. IMPLICATION: Both a mediastinal nodal and LAG evaluation can be adequately performed with just an EBUS scope and single endoscopist. This staging strategy is likely to reduce patient-burden and costs.