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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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest This research was funded by a grant from Bristol Meyers Squibb, Belgium. Lore Decoster received research grant from BMS, Bhoeringer Ingelheim; Travel grants from BMS, Roche en MSD; Advisory boards from MSD, Roche, Astra Zeneca. Thierry Pieters received speaker's fees from BMS during the study period., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: To evaluate the outcome of patients treated with stereotactic ablative body radiotherapy (SABR) with curative intent for stage I non-small cell lung cancer (NSCLC) with regard to local, regional and distant tumor control, disease-free survival (DFS), overall survival (OS) and toxicity., Methods: Data of 300 patients treated with SABR for NSCLC cancer for the period of November 2007 to June 2016 were retrospectively analyzed. Of which, 189 patients had single primary lung lesion and were included in the study. The prescribed dose for the tumor was 48 Gy, given in 12 Gy × 4 fractions for all patients. In 2010, an improved protocol was established in advanced technology for the planning CT, dose calculation and imaging. Cumulative incidence function (CIF) of local, regional, distant or any recurrences were computed using competing risk analysis with death as a competing event. Survivals (DFS and OS) were estimated using the Kaplan-Meier method and Cox proportional regression was used for comparisons. Toxicities were graded according to the common terminology criteria for adverse events version 4.0 (CTCAE v.4)., Results: Diagnosis was histologically confirmed in 42% of the patients (N = 80). At 1, 2 and 4 years, the cumulative incidence function (CIF) of local relapses were 8% [4-13%], 15% [10-21%] and 18% [12-25%], the CIF of regional relapses were 4% [2-8%], 10% [6-16%] and 12% [8-19%], the CIF of distant relapses were 9% [5-14%], 15% [11-22%] and 20% [15-28%] and the CIF of any relapses were 14% [10-20%], 28% [22-36%], 34% [27-43%], respectively. After 1, 2 and 4 years, the OS rates were 83% [95% CI: 78-89%] (N = 128), 65% [95% CI: 57-73%] (N = 78) and 37% [95% CI: 29-47%] (N = 53), respectively. The median survival time was 37 months. The DFS after 1, 2 and 4 years reached 75% [95% CI: 68-81%] (N = 114), 49% [95% CI: 42-58%] (N = 60) and 31% [95% CI: 24-41%] (N = 41), respectively. No grade 4 or 5 toxicity was observed., Conclusions: We observed a long-term local control and survival after SABR for peripheral stage I NSCLC in this large series of patients with the expected low toxicity.

A multicenter study was performed to determine an optimal workflow for liquid biopsy in a clinical setting. In total, 549 plasma samples from 234 non-small cell lung cancer (NSCLC) patients were collected. Epidermal Growth Factor Receptor ( EGFR) circulating cell-free tumor DNA (ctDNA) mutational analysis was performed using digital droplet PCR (ddPCR). The influence of (pre-) analytical variables on ctDNA analysis was investigated. Sensitivity of ctDNA analysis was influenced by an interplay between increased plasma volume ( p < 0.001) and short transit time ( p = 0.018). Multistep, high-speed centrifugation both increased plasma generation ( p < 0.001) and reduced genomic DNA (gDNA) contamination. Longer transit time increased the risk of hemolysis ( p < 0.001) and low temperatures were shown to have a negative effect. Metastatic sites were found to be strongly associated with ctDNA detection ( p < 0.001), as well as allele frequency ( p = 0.034). Activating mutations were detected in a higher concentration and allele frequency compared to the T790M mutation ( p = 0.003, and p = 0.002, respectively). Optimization of (pre-) analytical variables is key to successful ctDNA analysis. Sufficient plasma volumes without hemolysis or gDNA contamination can be achieved by using multistep, high-speed centrifugation, coupled with short transit time and temperature regulation. Metastatic site location influenced ctDNA detection. Finally, ctDNA levels might have further value in detecting resistance mechanisms.

Endobronchial ultrasound (EBUS) is a minimally invasive investigation method that permits transbronchial needle aspiration (TBNA) of mediastinal and hilar lymphadenopathies in order to determine their etiology. Its indications are notably lung cancer staging and lymphadenopathy exploration in case of sarcoidosis and malignant lymphomas. The employment of EBUS-TBNA has grown over the past few years and has become an alternative to mediastinoscopy due to a lower complication rate. However, in rare cases, complications can occur as hemorrhage, infections (mediastinitis, pneumonia, pericarditis, cyst infection, sepsis) or other (pneumothorax, pneumomediastinitis). We report herein a case of a mediastinitis after endobronchial ultrasound-guided transbronchial needle aspiration which occurred in a 63-year-old patient treated by methotrexate and methylprednisolone for a rheumatoid arthritis. The symptoms appeared as fever and progressive dyspnea some days after the endoscopic procedure.

Background: EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel., Methods: HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated., Results: Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04)., Conclusions: The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization., Trial Registration: ClinicalTrials.gov NCT01537536.

Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in non-small cell lung cancer (NSCLC). Ramucirumab is a human immunoglobulin G1 monoclonal antibody that inhibits VEGF receptor 2. This phase 2 study investigated ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in advanced/metastatic NSCLC., Methods: Eligible stage IV nonsquamous NSCLC patients with no prior chemotherapy for metastatic disease were randomized 1:1 to pemetrexed and carboplatin (or cisplatin) or ramucirumab (10 mg/kg) plus pemetrexed and carboplatin (or cisplatin) once every 3 weeks. Treatment was given for 4 to 6 cycles, and this was followed by a maintenance phase with pemetrexed or ramucirumab and pemetrexed. The primary endpoint was progression-free survival (PFS) with a sample size of sufficient power to detect an increase from 7 to 10.4 months., Results: From October 2010 to October 2011, 140 patients were randomized (pemetrexed-platinum arm, 71; ramucirumab-pemetrexed-platinum arm, 69), and most baseline characteristics were similar for the 2 treatment arms. The median PFS was 5.6 months for the pemetrexed-platinum arm and 7.2 months for the ramucirumab-pemetrexed-platinum arm (hazard ratio, 0.75; P = .132). The objective response rates were 38.0% and 49.3% for the pemetrexed-platinum and ramucirumab-pemetrexed-platinum arms, respectively (P = .180). The disease control rate was 70.4% for the pemetrexed-platinum arm and 85.5% for the ramucirumab-pemetrexed-platinum arm (P = .032). The grade 3 or higher adverse events occurring in 10% or more of patients were thrombocytopenia, neutropenia, fatigue, anemia, nausea, back pain, and hypertension., Conclusions: The primary endpoint of significant prolongation of PFS was not met; however, ramucirumab showed evidence of clinical activity in combination with pemetrexed and platinum in nonsquamous NSCLC patients. The addition of ramucirumab to pemetrexed and platinum did not result in new or unexpected safety findings., (© 2014 American Cancer Society.)

Introduction: The PARAMOUNT Phase III trial showed that maintenance pemetrexed after pemetrexed plus cisplatin induction was well tolerated and effective for patients with advanced nonsquamous non-small-cell lung cancer. Approximately 17% of patients receiving maintenance therapy in this study were 70 years of age or older. Here we report efficacy and safety results from the PARAMOUNT study for elderly (≥70 years) and non-elderly (<70 years) patients., Methods: Final efficacy and safety data from the PARAMOUNT study were analyzed post hoc using subgroup analyses for elderly and non-elderly patients., Results: The median age was 73 years in the elderly subgroup (n = 92) and 60 years in the non-elderly subgroup (n = 447). Subgroups had similar baseline characteristics, except for a higher percentage of males and patients with a performance status of one in the elderly subgroup. For elderly patients, the median PFS was 6.4 months for pemetrexed and 3.0 months for placebo; the median OS was 13.7 months for pemetrexed and 12.1 months for placebo. For non-elderly patients, the median PFS was 4.0 months for pemetrexed and 2.8 months for placebo; the median OS was 13.9 months for pemetrexed and 10.8 months for placebo. Elderly patients experienced similar levels of low-grade toxicities, but had a higher percentage of grade 3/4 anemia and neutropenia than non-elderly patients, although importantly, this did not translate into increased febrile neutropenia., Conclusions: Continuation maintenance pemetrexed had comparable survival and toxicity profiles in the elderly and non-elderly subgroups. However, grade 3/4 anemia and neutropenia were numerically higher for elderly patients.

Erlotinib has been shown to prolong progression-free (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). We report here on effectiveness data on the subsample of 261 patients from 40 centres in Belgium involved in the TRUST study. Median age was 63 years. Most (69.0%) were male and current/former smokers (84.7%); with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (74.3%), stage IV disease (75.1%) and adenocarcinoma by histology (54.0%). Erlotinib was administered mainly as second- (47.1%) or third-line treatment (48.3%). Response rate was 6.5%; disease control rate 58.3%. Median PFS was 2.2 months. Better PS (P = 0.0384), stage IIIB disease (P = 0.0018) and presence of rash (P < 0.0001) were associated with longer PFS. OS rates at 1, 2 and 3 years were 26.4%, 10.9% and 6.4% respectively. Median OS was 5.9 months. Female gender (P = 0.007), better PS (P < 0.0001), stage IIIB disease (P = 0.0355) and presence of rash (P < 0.0001) were associated with longer OS. The findings confirm the therapeutic benefit of erlotinib in a broad range of patients in a sample from a country with a historically high lung cancer morbidity and mortality burden. Several determinants of PFS and OS are identified., (© 2013 John Wiley & Sons Ltd.)

Purpose: The EORTC 08062 phase II randomised trial investigated the activity and safety of single agent amrubicin, cisplatin combined with amrubicin, and cisplatin combined with etoposide as first line treatment in extensive disease (ED) small cell lung cancer (SCLC)., Patients and Methods: Eligible patients with previously untreated ED-SCLC, WHO performance status (PS) 0-2 and measurable disease were randomised to 3 weekly cycles of either amrubicin alone 45mg/m(2) i.v. day(d) 1-3 (A), cisplatin 60mg/m(2) i.v. d1 and amrubicin 40mg/m(2) i.v. d1-3 (PA), or cisplatin 75mg/m(2) i.v. d1 and etoposide 100mg/m(2) d1, d2-3 i.v./po (PE). The primary end-point was overall response rate (ORR) as assessed by local investigators (RECIST1.0 criteria). Secondary end-points were treatment toxicity, progression-free survival and overall survival., Results: The number of randomised/eligible patients who started treatment was 33/28 in A, 33/30 in PA and 33/30 in PE, respectively. Grade (G) ⩾3 haematological toxicity in A, PA and PE was neutropenia (73%, 73%, 69%); thrombocytopenia (17%, 15%, 9.4%), anaemia (10%, 15%, 3.1%) and febrile neutropenia (13%, 18%, 6%). Early deaths, including treatment related, occurred in 1, 3 and 3 patients in A, PA and PE arms, respectively. Cardiac toxicity did not differ among the 3 arms. Out of 88 eligible patients who started treatment, ORR was 61%, (90% 1-sided confidence intervals [CI] 47-100%), 77% (CI 64-100%) and 63%, (CI 50-100%) for A, PA and PE respectively., Conclusion: All regimens were active and PA met the criteria for further investigation, despite slightly higher haematological toxicity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles. On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer (NSCLC), we aimed to assess efficacy and safety of this combination in a phase 3 trial., Methods: In our double-blind, placebo-controlled, randomised phase 3 trial (BeTa), we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment. Patients were randomly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group) according to a computer-generated randomisation sequence by use of an interactive voice response system. The primary endpoint was overall survival in all enrolled patients. Patients, study staff, and investigators were masked to treatment assignment. We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses. This trial is registered with ClinicalTrials.gov, number NCT00130728., Findings: Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group (hazard ratio [HR] 0·97, 95% CI 0·80-1·18, p=0·7583). Median overall survival was 9·3 months (IQR 4·1-21·6) for patients in the bevacizumab group compared with 9·2 months (3·8-20·2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3·4 months [1·4-8·4]) than in the control group (1·7 months [1·3-4·1]; HR 0·62, 95% CI 0·52-0·75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate. In the bevacizumab group, 130 (42%) of 313 patients with safety data had a serious adverse event, compared with 114 (36%) controls. There were 20 (6%) grade 5 adverse events, including two arterial thromboembolic events, in the bevacizumab group, and 14 (4%) in the control group., Interpretation: Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC., Funding: Genentech., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Catamenial pneumothorax is an unusual and rarely recognized entity that belongs to the thoracic endometriosis syndrome. The increase a number of published cases over the last years allows a more frequent diagnosis and understanding. We describe the story of a young woman with a recurrent right sided pneumothorax and discuss the different pathogenic mechanisms and current therapies. The rarity of the disease makes a prospective study very difficult. To this day, there is no consensus on a standardized therapeutic attitude.

We observed oat-cell lung carcinoma in a man who presented with diabetes insipidus. The chest radiograph showed a suspect nodule within a context of major nicotine addiction. Histopathological examination of the transbronchial biopsy confirmed the diagnosis of oat-cell carcinoma. Brain CT revealed metastasis to the pituitary gland and the pituitary stalk. Vasopressin was undetectable. This case illustrates an uncommon clinical presentation of small-cell lung carcinoma. Oat-cell carcinoma can modify osmoregulation in two different ways. Only sporadic cases of neurogenic diabetes insipidus due to the primary involvement of small-cell lung carcinoma have been reported. More often, this type of lung tumor is associated with inappropriate antidiuretic hormone secretion.

Bourneville's disease, first described in 1862, is a phacomatosis that is either autosomal dominant or sporadic. Its typical clinical signs include mental retardation, epilepsy and cutaneous adenomas. The pulmonary form is rare, less than 1%, and is secondary to occlusion of the bronchus, vascular and lymphatics by immature smooth muscle cells. Chylothorax may appear in more than 50% of all cases. No guidelines currently exist for treatment of recurrent chylothorax. However, several possibilities are described in the literature.

An episode of fever of prolonged duration and undetermined origin always remains a difficult clinical problem. Several etiologies can indeed be responsible. If one wishes to obtain a diagnosis of the origin of the fever, one should adopt a well-structured strategy in which the various investigations are carried out in a strictly determined hierarchical order. This is badly needed if one wishes to reach a clue to the diagnosis and be able to implement an adequate therapy. In spite of all this, some cases will remain without precise diagnosis. The treatment of those cases will primary be empirical.