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Objectives: Patients with advanced stage non-small cell lung cancer (NSCLC) are generally considered incurable. The mainstay of treatment for these patients is systemic therapy. The addition of local treatment, including surgery, remains controversial. Oligoprogression is defined as advanced stage NSCLC with limited progression of disease after a period of prolonged disease stabilisation or after a partial or complete response on systemic therapy. In this retrospective study we evaluated outcome and survival of patients who underwent a resection for oligoprogression after systemic therapy for advanced stage NSCLC., Materials and Methods: Patients with oligoprogression after systemic treatment for advanced NSCLC who were operated in the Antoni van Leeuwenhoek Hospital were included. Patient and treatment characteristics were collected in relation to progression free survival (PFS) and overall survival (OS)., Results: Between January 2015 and December 2019, 28 patients underwent surgery for an oligoprogressive lesion (primary tumor lung (n = 12), other metastatic site (n = 16)). Median age at time of resection was 60 years (39-86) and 57% were female. Postoperative complications were observed in 2 patients (7%). Progression of disease after resection of the oligoprogressive site was observed in 17 patients (61%). Median PFS was 7 months since date of resection (95% CI 6.0-25.0) and median OS was not reached. Seven patients (25%) died during follow-up. Age was predictive for OS and clinical T4 stage was predictive for PFS. M1 disease at initial presentation was predictive for better PFS compared to patients who were diagnosed with M0 disease initially. Patients who underwent resection because of oligoprogression of the primary lung tumour had a better PFS, when compared to oligoprogression of another metastastic site., Conclusion: Surgical resection of an oligoprogressive lesion in patients with advanced NSCLC treated with systemic treatment is feasible and might be considered in order to achieve long term survival., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4-10 % of EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to first and second generation EGFR tyrosine kinase inhibitors (TKIs). In vitro and preclinical animal studies have shown that osimertinib exerts antitumor activity against EGFR exon 20 mutation positive NSCLC. We report on a cohort of advanced stage NSCLC patients who harbor an EGFR exon 20 mutation and received osimertinib treatment., Material and Methods: Twenty-one patients were treated with osimertinib 80 or 160 mg once daily from April 2016 to June 2018, in four institutions in the Netherlands. Data were obtained retrospectively. Progression free survival (PFS), disease control rate (DCR), overall survival (OS) and objective response rate (ORR) were assessed using RECIST v1.1., Results: Thirteen patients received prior platinum-based chemotherapy, and three patients a first - or second generation EGFR TKI. We observed 1 partial response, 17 patients with stable disease and 3 with progressive disease as best response to osimertinib (ORR 5 %). Median PFS was 3.6 (95 % CI, 2.6-4.5) months. PFS did not differ for patients with co-occurring TP53 mutations (p = 0.937). The DCR at three months was 71 %. Median OS was 8.7 (95 % CI, 1.1-16.4) months., Conclusion: Osimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5 %., Competing Interests: Declaration of Competing Interest Dr. de Langen reports grants from Boehringer, grants from AstraZeneca, non-financial support from Roche, grants and personal fees from Merck / MSD, grants and personal fees from BMS, outside the submitted work. Dr. Heideman is minority shareholder of Self-screen B.V., a spin-off company of VU University Medical Center (currently known as Amsterdam UMC, Vrije Universiteit Amsterdam). She has been on the speakers bureau of QIAGEN and serves occasionally on the scientific advisory boards of Pfizer and Bristol-Myers Squibb. Dr. Monkhorst reports grants from Roche, grants from MSD, grants from AstraZeneca, non-financial support from Roche, Takeda, Pfizer, and personal fees from MSD, personal fees from BMS, personal fees from Roche, personal fees from Abbvie, personal fees from AstraZeneca, personal fees from Diaceutics. Dr. van der Wekken reports grants from AstraZeneca, Boehringer-Ingelheim and Pfizer, Honorario for Advisory boards from AstraZeneca, Roche (Diagnostics), Bayer, Pfizer and Boehringer-Ingelheim, speakers’s fee from Pfizer, Roche, Boehringer-Ingelheim and AstraZeneca, all outside the submitted work and all transfered to UMCG. Dr Smit received fees for participation in advisory boards and speaking engagements as well as research support (all institutional) from AstraZeneca. Dr. Schuuring reports grants from Biocartis, BMS, Bio-Rad, Roche, Agena Bioscience, CC Diagnostics, Boehringer Ingelheim, honoria for advisory boards from AstraZeneca, Roche, Pfizer, Novartis, Bayer, BMS, BioCartis, Illumina, Agena Bioscience, CC Diagnostics, Janssen Cilag (Johnson&Johnson), Diaceutics, and speaker's fee from Bio-Rad, Abbott, Novartis, Roche, Biocartis, Illumina, Pfizer, Astrazeneca, all outside the submitted work and all transfered to UMCG account. The other authors have declared no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: The NVALT-11/DLCRG-02 phase III trial (clinicaltrials.gov identifier: NCT01282437) showed that, after standard curative intent treatment, prophylactic cranial irradiation (PCI) decreased the incidence of symptomatic brain metastases (BM) in stage III non-small cell lung cancer (NSCLC) patients compared to observation. In this study we assessed the impact of PCI on health-related quality of life (HRQoL). In addition, an exploratory analysis was performed to assess the impact of neurocognitive symptoms and symptomatic BM on HRQoL., Materials and Methods: Stage III NSCLC patients were randomized between PCI and observation. HRQoL was measured using the EuroQol 5D (EQ-5D-3L), EORTC QLQ-C30 and QLQ-BN20 instruments at completion of standard curative intent treatment and 4 weeks, 3, 6, 12, 24 and 36 months thereafter. Generalized linear mixed effects (GLM) models were used to assess the impact of PCI compared to observation over time on three HRQoL metrics: the EORTC QLQ-C30 global health status and the EQ-5D-3L utility and visual analogue scale (EQ VAS) scores., Results: In total, 86 and 88 patients were included in the PCI and observation arm, with a median follow-up of 48.5 months (95% CI 39-54 months). Baseline mean HRQoL scores were comparable between the PCI and observation arm for the three HRQoL metrics. In the GLM models, none of the HRQoL metrics were clinically relevant or statistically significantly different between the PCI and the observation arm (p-values ranged between 0.641 and 0.914)., Conclusion: No statistically significant nor a clinically relevant impact of PCI on HRQoL was observed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials., Materials and Methods: From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied., Results: A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days. Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged ≥ 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95 % CI 1.7-2.7; 1.3, 95 % CI 1.0-1.6 and 1.2, 95 % CI 1.1-1.4, respectively)., Conclusions: Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2 + ., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases., Materials and Methods: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH., Results: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010., Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics., Materials and Methods: Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if ≥1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data., Results: DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0-160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3+ in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3+ in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3+ . Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers., Conclusion: The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the relationship between early changes in muscle and adipose tissue during chemotherapy and overall survival (OS) in stage IV non-small cell lung cancer (NSCLC)., Materials and Methods: In this post-hoc analysis of the first line NVALT12 trial (NCT01171170) in stage IV NSCLC, skeletal muscle (SM), radiation attenuation (RA), subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were assessed at the third lumbar level on CT-images obtained before initiation of chemotherapy and shortly after administration of the second cycle. The contribution of changes in different body compartments to overall survival was assessed., Results: CT scans of 111 patients were included. Analysis of body composition changes between the baseline and the follow-up scan, revealed that overall SM cross sectional area (CSA), radiation attenuation and SAT CSA decreased respectively by -1.2 ± 2.9 cm 2 /m 2 (p < 0.001), -0.7 ± 3.3 HU (p = 0.026) and -1.9 ± 8.7 cm 2 /m 2 (p = 0.026), while no significant changes in VAT tissue were observed. Longitudinally, median OS was significantly shorter among patients losing SM compared to patients with preserved SM (9.4 versus 14.2 months; HR 1.9, 95% CI: 1.23, 2.79, p = 0.003). Multivariate analyses showed that proportional loss of muscle mass was associated with poor OS (HR 0.949, 95% CI: 0.915, 0.985, p = 0.006) independent from important clinical prognostic factors including WHO-PS, gender, age and Charlson comorbidity index., Conclusion: Early loss of SM during first line chemotherapy is a poor prognostic factor in stage IV NSCLC patients. Future studies have to reveal whether early supportive intervention guided by initial CT muscle response to chemotherapy can influence the wasting process and related mortality risk., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare tumor with high mutational burden. Two subtypes of LCNEC are recognized, the co-mutated TP53 and RB1 group and the TP53 and STK11/KEAP1 group. We investigated PD-L1 and CD8 expression in a well characterized stage IV LCNEC cohort and compared expression in the two subtypes., Methods: Immunohistochemical (IHC) analysis for PD-L1 and CD8 was performed on pathological reviewed pretreatment tumor samples for 148 stage IV LCNEC. Data about targeted next generation sequencing (TNGS) (TP53, RB1, STK11, KEAP1) and IHC for RB1 were available for most tumors. IHC staining for PD-L1 (DAKO 28-8) was performed and scored positive if tumors showed ≥1% membranous staining. CD8 was scored for intra-tumor T-cells and stromal cells., Results: PD-L1 IHC expression data could be generated in 98/148 confirmed LCNEC samples along with RB1 IHC (n = 97) of which 77 passed quality control for TNGS. PD-L1 expression was positive in 16/98 cases (16%); 5 (5%) with ≥50%. PD-L1 expression was equal in RB1 mutated and RB1 wildtype tumors. None of STK11 mutated tumors (n = 7) expressed PD-L1. PD-L1 expression was correlated with superior overall survival (OS), hazard ratio 0.55 ((95% Confidence Interval 0.31-0.96), p = 0.038). Intra-tumor CD8 was associated with PD-L1 expression (p = 0.021) and stromal and intra-tumor CD8 were correlated with improved OS (p = 0.037 and p = 0.026 respectively)., Conclusions: PD-L1 expression was positive in 16% of stage IV LCNEC tumors. This was independent of molecular subtype but associated with CD8 expression. In LCNEC patients with PD-L1 and/or CD8 expression superior OS was observed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: There is limited data on the pattern of care for locally advanced, clinical (c) IIIB non-small cell lung cancer (NSCLC) in the TNM-7 staging era. The primary aim of this study was to investigate national patterns of care and outcomes in the Netherlands, with a secondary focus on the use of surgery., Material and Methods: Data from patients treated for TNM-7 cIIIB NSCLC between 2010 and 2014, was extracted from the Netherlands Cancer Registry (NCR). Survival data was obtained from the automated Civil Registry., Results: 43.762 patients with NSCLC were recorded in the NCR during this 5-year period, with cIIIB accounting for 10% (n=4.401). Clinical N2 (37%) and N3 (63%) nodal involvement was pathologically confirmed in 50.8%. The use of endobronchial ultrasound (EBUS) increased with time from 9% to 29% (p<0.001), while the rate of pathological confirmation of N2 or N3 nodes increased from 44% to 54% (p<0.001). 48% of patients received chemoradiotherapy (CRT), 19% chemotherapy (CT), RT in 10% and surgery in 2.2%. 22% received best supportive care (BSC). The percentage of patients treated with CRT decreased from 65% for patients aged <60 years to 13% for patients aged 80 years or older. Overall survival for surgery was 28 months, followed by CRT (19mths), CT (9mths), RT (8mths) and BSC (3mths)., Conclusion: In the Netherlands, CRT is the most frequent treatment for cIIIB NSCLC in the TNM-7 era. The use of surgery is limited. Accurate staging requires specific attention and the scarce use of radical treatment in elderly patients merits further evaluation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Non-small cell lung cancer (NSCLC) therapy has entered a rapidly advancing era of precision medicine with an ever increasing number of drugs directed against a variety of specific tumor targets. Amongst these new agents, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) are most frequently used. However, as only a sensitive subgroup of patients benefits from targeting drugs, predictive biomarkers are needed. Positron emission tomography (PET) may offer such a biomarker for predicting therapy efficacy. Some of the TKIs and mAbs that are in clinical use can be radioactively labeled and used as tracers. PET can visualize and quantify tumor specific uptake of radiolabeled targeting drugs, allowing for characterization of their pharmacokinetic behavior. In this review, the clinical potential of PET using radiolabeled TKIs (TKI-PET) and mAbs (immuno-PET) in NSCLC is discussed, and an overview is provided of the most relevant preclinical and clinical studies., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Curative intent treatment options for locoregional recurrence or persistent tumor after radical chemoradiotherapy for locally-advanced non-small cell lung cancer (NSCLC) are limited. In selected patients, surgery can be technically feasible, although it is widely believed to be hazardous. As data regarding the outcome of this approach is sparse, we evaluated our institutional experience with salvage surgery., Materials and Methods: Patients with a pulmonary resection for in-field locoregional recurrence or persistent tumor after high dose chemoradiotherapy (≥60 Gy) for the treatment of non-small cell lung cancer, were identified and retrospectively analyzed., Results: A total of 15 patients treated between January 2007 and August 2015 were eligible for evaluation. In 13 patients (87%), the indication for surgery was a locoregional recurrence, while 2 patients had persistent tumor. The prior median radiotherapy dose was 66 Gy (range 60-70). All patients underwent an anatomical resection, with 8 patients having a pneumonectomy, and all pathological specimens revealed the presence of viable tumor. The in-hospital morbidity rate was 40% (6 patients), and the 90-day mortality rate was 6.7% (1 patient). Median follow-up was 12.1 months. The estimated median overall and event-free survivals were 46 months and 43.6 months, respectively., Conclusion: Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy, resulted in acceptable morbidity, mortality and promising outcome. It should be considered as a treatment option for selected patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Real-world resource use and cost data on non-small cell lung cancer (NSCLC) are scarce. This data is needed to inform health-economic modelling to assess the impact of new diagnostic and/or treatment technologies. This study provides detailed insight into real-world medical resource use and costs of stage I-IV NSCLC in the Netherlands., Materials and Methods: A random sample of patients newly diagnosed with NSCLC (2009-2011) was selected from four Dutch hospitals. Data was retrospectively collected from patient charts. This data included patient characteristics, tumour characteristics, treatment details, adverse events, survival and resource use. Resource use was multiplied by Dutch unit costs expressed in EUR 2012. Total mean costs were corrected for censoring using the Bang and Tsiatis weighted complete-case estimator. Furthermore, costs of adverse events, costs per phase of NSCLC management and costs of second opinions are presented., Results: Data was collected on 1067 patients. Total mean costs for NSCLC diagnosis, treatment and follow-up are €28,468 during the study period and €33,143 when corrected for censoring. Adverse events were recorded in the patient charts for 369 patients (41%) and 82 patients (9%) experienced an adverse event of grade III or higher. For these patients, adverse event-related hospital admissions cost on average €2,091. Mean total costs are €1,725 for the diagnostic period, €17,296 for first treatment line, and €13,236 for each later treatment line. Costs of providing a second opinion are €2,580 per patient., Conclusions: Total mean hospital costs per NSCLC patient are €33,143 for the total duration of the disease. Ignoring censoring in our data underestimates these costs by 14%. Main limitations of the study relate to the short follow-up time, staging difficulties and missing data. Its main strength is that it provides highly detailed, real-world data on the costs of NSCLC., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Pathological complete response and tumor regression to less than 10% vital tumor cells after induction chemoradiotherapy have been shown to be prognostically important in non-small cell lung cancer (NSCLC). Predictive imaging biomarkers could help treatment decision-making. The purpose of this study was to assess whether postinduction changes in tumor FDG uptake could predict pathological response and to evaluate the correlation between residual vital tumor cells and post-induction FDG uptake., Methods: NSCLC patients with sulcus superior tumor (SST), planned for trimodality therapy, routinely undergo FDG PET/CT scans before and after induction chemoradiotherapy in our institute. Metabolic end-points based on standardized uptake values (SUV) were calculated, including SUV(max) (maximum SUV), SUV(TTL) (tumor-to-liver ratio), SUV(peak) (SUV within 1 cc sphere with highest activity), and SUV(PTL) (peak-to-liver ratio). Pathology specimens were assessed for residual vital tumor cell percentages and scored as no (grade 3), <10% (grade 2b) and >10% vital tumor cells (grade 2a/1)., Results: 19 and 23 patients were evaluated for (1) metabolic change and (2) postinduction PET-pathology correlation, respectively. Changes in all parameters were predictive for grade 2b/3 response. ΔSUV(TTL) and ΔSUV(PTL) were also predictive for grade 3 response. Remaining vital tumor cells correlated with post-induction SUV(peak) (R=0.55; P=0.007) and postinduction SUV(PTL) (R=0.59; P=0.004). Postinduction SUV(PTL) could predict both grades 3 and 2b/3 response., Conclusion: In NSCLC patients treated with chemoradiotherapy, changes in SUV(max), SUV(TTL), SUV(peak), and SUV(PTL) were predictive for pathological response (grade 2b/3 and for SUV(TTL) and SUV(PTL) grade 3 as well). Postinduction SUV(PTL) correlated with residual tumor cells., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Although the standard treatment for patients with stage IIIA non-small cell lung cancer (NSCLC) is chemoradiotherapy, some patients are considered for trimodality therapy [TT]. We analyzed outcomes for stage IIIA NSCLC, treated with TT and compared them with concurrent chemoradiotherapy [con-CRT]., Materials and Methods: Patients treated between January 2007 and December 2011 were retrospectively analyzed. Not included were patients with sulcus superior tumors, unknown T/N-status, or recurrent disease after con-CRT followed by surgery. All patients were discussed at our multidisciplinary thoracic tumor board (MTB)., Results: Mean Charlson Comorbidity Index was 2 for TT and con-CRT patients. TT patients were younger (median TT=56 years vs. con-CRT=62 years; p=0.001) and had less advanced cN-stage (TT cN2=41% vs. 83% for CRT; p<0.001). 44% of TT patients had T4-stage vs. 12% of con-CRT patients. Median RT dose was lower for TT (50 Gy vs. 66 Gy; p=0.001) and median RT planning target volume (PTV) in TT and con-CRT patients was 525 cm(3) and 655 cm(3) (p=0.010), respectively. The majority of TT patients had a lobectomy (23/32). Median follow-up was 30.3 months (95% CI=18.7-41.9) for TT and 51 months (95% CI=24.9-77.4) for con-CRT. Median overall survival was not reached for TT and was 18.6 months (95% CI=12.8-24.4) for con-CRT (p=0.001). For PTV

Aim: Non-small cell lung cancer (NSCLC)-patients with an epidermal growth factor receptor (EGFR)-mutation have median progression-free survival (PFS) of 12 months on tyrosine kinase inhibitors (TKIs). Resistance is mediated by the EGFR T790M-mutation in the majority of patients. Longitudinal follow-up data are lacking. We retrospectively evaluated EGFR-mutated NSCLC-patients who were rebiopsied after TKI-treatment. A subgroup was sequentially rebiopsied along the course of the disease., Patients and Methods: Advanced EGFR-mutated NSCLC-patients who had both a pre-TKI biopsy and post-TKI biopsy available were included. Information on treatments and (re)biopsies was collected chronologically. Primary endpoint was the incidence of the T790M-mutation., Results: Sixty-six patients fulfilled the inclusion criteria. In first post-TKI biopsies, T790M-mutation was detected in 34 patients (52%) of patients. Twenty-seven patients had subsequent post-TKI rebiopsies with mutation analysis available; in 10 patients (37%) the T790M-status in subsequent post-TKI rebiopsies was not consistent with the T790M-status of the first post-TKI biopsy. Progression free survival (PFS) on TKI-treatment was 12.0 months. Objective response rate on TKI-treatment was 81%. Patients developing T790M-mutation at post-TKI biopsy had longer median PFS compared to T790M-negative patients (14.2 versus 11.1 months respectively (P=0.034)) and longer overall survival (45.9 months versus 29.8 months respectively (P=0.213)). Transformation to SCLC was detected in 1 patient (2%)., Conclusion: Incidence of T790M-mutation at first post-TKI biopsy in this cohort of EGFR-mutated NSCLC-patients was 52%. Detection of T790M-mutation was not consistent over time; some patients who were T790M-positive at first post-TKI biopsy became T790M-negative in later post-TKI rebiopsies and vice versa. T790M-positive patients showed longer PFS than T790M-negative patients. Whether the low incidence of transformation to SCLC is justifying post-TKI rebiopsy in EGFR-mutated NSCLC-patients with acquired TKI-resistance in regular clinical practice is debatable., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Both bone and brain are frequent sites of metastasis in non-small cell lung cancer (NSCLC). Conflicting data exist whether EGFR mutant (+) patients are more prone to develop brain metastases or have a better outcome with brain metastases compared to EGFR/KRAS wildtype (WT) or KRAS+ patients. For bone metastases this has not been studied., Methods: In this retrospective case-control study all EGFR+ (exons 19 and 21) patients diagnosed at two pathology departments were selected (2004/2008 to 2012). For every EGFR+ patient a consecutive KRAS+ and WT patient with metastatic NSCLC (mNSCLC) was identified. Patients with another malignancy within 2 years of mNSCLC diagnosis were excluded. Data regarding age, gender, performance score, histology, treatment, bone/brain metastases diagnosis, skeletal related events (SRE) and subsequent survival were collected., Results: 189 patients were included: 62 EGFR+, 65 KRAS+, 62 WT. 32%, 35% and 40%, respectively, had brain metastases (p=0.645). Mean time to brain metastases was 20.8 [± 12.0], 10.8 [± 9.8], 16.4 [± 10.2] months (EGFR+-KRAS+, p = 0.020, EGFR+-WT, p = 0.321). Median post brain metastases survival was 12.1 [5.0-19.1], 7.6 [1.2-14.0], 10.7 [1.5-19.8] months (p = 0.674). 60%, 52% and 50% had metastatic bone disease (p=0.528). Mean time to development of metastatic bone disease was 13.4 [± 10.6], 23.3 [± 19.4], 16.4 [± 9.6] months (p = 0.201). Median post metastatic bone disease survival was 15.0 [10.6-20.3], 9.0 [5.2-12.9], 3.2 [0.0-6.9] months (p = 0.010). Time to 1st SRE was not significantly different., Conclusions: Incidence of brain and bone metastases was not different between EGFR+, KRAS+ and WT patients. Post brain metastases survival, time from mNSCLC diagnosis to metastatic bone disease and 1st SRE did not differ either. Post metastatic bone disease survival was significantly longer in EGFR+ patients. Although prevention of SRE's is important for all patients, the latter finding calls for a separate study for SRE preventing agents in EGFR+ patients., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A considerable number of patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) develop leptomeningeal metastases. Leptomeningeal metastases are associated with deterioration of clinical symptoms and poor survival. Traditionally, treatment of metastases in the central nervous system consists of radiotherapy and less frequently, surgery. The role of systemic therapy is limited due to the blood-brain barrier inhibiting pharmacological doses to be reached in the central nervous system. Several case reports have described high-dose, pulsatile tyrosine kinase inhibitors as an effective treatment of leptomeningeal metastases, based on the hypothesis that higher concentrations in the cerebrospinal fluid can be reached by higher systemic concentrations. Here, we describe two patients with EGFR-mutated non-small cell lung cancer, with both clinical and radiological response to this high-dose, pulsatile regimen. Interestingly, one patient showed a remarkable response of intrathoracic response as well., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

In patients with non-small cell lung carcinoma (NSCLC) fluorine-18 fluorodeoxyglucose positron emission tomography (18FDG-PET)-scanning is shown to be of prognostic value. Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis. Limited results on the prognostic and predictive value of the maximum standard uptake values (SUVmax) obtained during 18FDG-PET scanning in SCLC are available. An observational study in 75 chemonaive patients diagnosed with SCLC who underwent a 18FDG-PET scan was performed. SUVmax values of the primary tumor were related to the overall survival (OS) and the progression free survival (PFS). Significant lower SUVmax values of the primary tumor were observed in patients with stage I-III disease compared to stage IV disease. SUVmax did not discriminate for either OS or PFS in the whole group of patients. In patients with stage IV disease and treatment with chemotherapy, OS and PFS were significantly higher in patients with a high SUVmax. (p-value 0.005 and 0.002 respectively) compared to patients with a low SUVmax value. In patients with SCLC metabolic activity determined using 18FDG-PET (SUVmax) differed between stage I-III and stage IV diseases. Compared to NSCLC, the relationship between SUVmax) and prognosis seems more complex., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival., Patients and Methods: Treatment naïve patients received 1 cycle of cisplatin 80 mg/m(2) in study I (stage III NSCLC), 75 mg/m(2) in study II (LD-SCLC) and pemetrexed 500 mg/m(2) before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60-80 mg/m(2)), pemetrexed doses (400-500 mg/m(2)) and concurrent escalating radiotherapy doses (66 Gy in 33-27 fractions). In study II, patients were treated with cisplatin 75 mg/m(2) and escalating pemetrexed doses (400-500 mg/m(2)) with concurrent escalating radiotherapy doses (50-62 Gy)., Results: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed., Conclusions: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66 Gy (33 x 2 Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region can cause loss of p16 expression. Recent studies suggest overexpression of the polycomb-group gene BMI-1 might also down-regulate p16 expression. In this study, we analyzed the p16 expression in relation to the methylation status of the p16 promoter region of the p16(INK4a) gene and the expression of BMI-1 in bronchial squamous cell carcinomas (SCC) and its premalignant lesions. Nine (69%) SCC showed loss of p16 expression and 10 (77%) showed expression of BMI-1. Of four p16 positive samples two (50%) were BMI-1 positive, whereas among nine p16 negative samples, eight (89%) revealed BMI-1 staining. Four (44%) p16 negative samples were hypermethylated at the p16(INK4a) promoter region; the other p16 negative tumors that showed no hypermethylation revealed BMI-1 staining. Only two premalignant lesions showed absence of p16 expression, of which one (carcinoma in situ) was hypermethylated at the p16(INK4a) promoter region and the other (severe dysplasia) showed BMI-1 expression. In total, 11 precursor lesions (48%) revealed BMI-1 expression. In conclusion, the results of this study suggest that loss of p16 expression by promoter hypermethylation is inconsistently and occurs late in the carcinogenic process at the level of severe dysplasia. To what extent overexpression of the polycomb-group protein BMI-1 attributes to down regulating of p16 expression remains unclear.

Study Objective: To asses the value of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) in the nodal staging of patients with (suspected) non-small cell lung cancer (NSCLC) and a (18)FDG positron emission tomography (PET) scan suspect for N2/N3 mediastinal lymph node (MLN) metastases., Background: Due to the imperfect specificity of positron emission tomography, PET positive MLN should be biopsied in order to confirm or rule out metastasis. Currently, invasive surgical diagnostic techniques such as mediastinoscopy/-tomy are standard procedures to obtain MLN tissue. The minimally invasive technique of EUS-FNA has a high diagnostic accuracy (90-94%) for the analysis of MLN in patients with enlarged MLN on computed tomography of the chest (CT)., Design and Patients: Thirty-six patients with proven n=26 or suspected n=10 non-small cell lung cancer and a PET scan suspect for N2/N3 lymph node metastases underwent EUS-FNA. When EUS-FNA did not confirm metastasis and the PET lesion was within reach of mediastinoscopy, a mediastinoscopy was performed. EUS-FNA negative patients with PET lesions beyond the reach of mediastinoscopy or those with a negative mediastinoscopy were referred for surgical resection of the tumour and MLN sampling or dissection., Results: EUS-FNA confirmed N2/N3 disease in 25 of the 36 patients (69%) and was highly suspicious in one. In the remaining 10 patients, one PET positive and one PET negative N2 metastasis was detected at thoracotomy. The PPV, NPV, sensitivity, specificity and accuracy of EUS-FNA in analysing PET positive MLN were 100%, 80%, 93%, 100% and 94%, respectively. No complications of EUS-FNA were recorded., Conclusions and Significance: EUS-FNA yields minimally invasive confirmation of MLN metastases in 69% of the patients with potential mediastinal involvement at FDG PET. The combination of PET and EUS-FNA might qualify as a minimally invasive staging strategy for NSCLC.

The main critical factors for lung cancer patient management, apart from TNM staging, include expertise required to offer optimal management and conditions related to the patient, including performance status and weight loss and the presence of lung, cardiac or other comorbidities. Performance status and weight loss must be assessed for all patients. The minimal pulmonary functional evaluation should include spirometry. The minimal cardiac evaluation should consist of a clinical history and evaluation for cardiac risk factors and disease and at least preoperatively, and ECG. Age per se is not a contraindication for curative treatment.

Combined modality treatment (CMT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is at present studied extensively. To select patients with truly stage IIIA-N2 disease, however, proves to be difficult with current diagnostic tests. Distant metastases may become clinically overt during induction chemotherapy (IC) or shortly after, revealing the inaccuracies of current staging algorithms. A prospective study with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in IIIA-N2 NSCLC patients was performed to assess its value in the selection of this patient group. Fifty-seven patients received a whole body FDG PET scan as part of an ongoing response monitoring trial. Results were compared with conventional staging. In 32/57 (56%) PET suggested upstaging, which was confirmed in 17/57 (30%) with a median follow-up of 16 (range 2-49) months. These results show that using the conventional staging algorithm a substantial group of patients was understaged. FDG PET improves the selection of patients suitable for CMT., (Copyright 2002 Elsevier Science Ireland Ltd.)

The conventional method of bronchoscopy has only a 30% sensitivity to detect early stage cancer in the central airways. For patients with positive sputum cytology who clearly harbor early cancers, repeat and lengthy sessions of bronchoscopies are required for accurate localization of these lesions. This leads to a significant delay in obtaining the diagnosis, postponing an appropriate treatment and reduces the chance for cure. There are valid reasons for improving the detection rate of early stage lung cancers. The number of individuals at risk forms a large population, the outcome of patients treated with early stage cancer has been shown to be better and bronchoscopic treatments, e.g. photodynamic therapy and electrocautery, are currently alternatives for surgical resection. Finding more early stage cancers by screening the population at risk and accurate staging to enable treatment at the earliest stage feasible, may improve the dismal prognosis of many patients. This article deals with the clinical background and current problems in early detection of lung cancer and discusses our expectations regarding new developments in bronchoscopy for early detection, accurate staging and treatment of lung cancer.

Background: Many regimens of gemcitabine-cisplatin chemotherapy have proven activity in patients with advanced non-small cell lung cancer (NSCLC). However, the optimal dose and schedule still have to be established., Patients and Methods: We conducted a phase II study with administration of cisplatin 50 mg/m(2) on days 1 and 8 and gemcitabine 800 mg/m(2) on days 2, 9 and 15. This schedule was selected to optimise the synergism between the two drugs and reduce toxicity due to high dose cisplatin., Results: Thirty-six chemo-naive patients with stage IIIA, IIIB or IV NSCLC entered the study (26 men, 10 women; median age 58 years, range 29-74). Twenty patients achieved a partial response: 7 out of 10 stage IIIA patients, 7 out of 13 stage IIIB patients and 6 out of 13 stage IV patients. On intent-to-treat basis, the overall response rate (RR) was 58% (95% confidence interval, 42-74%). Ninety percent of stage IIIA patients and 46% of stage IIIB patients received adjuvant surgery or radiotherapy. Overall median duration of response was 28 weeks (range 6-147 weeks). For stage IIIA, IIIB and IV patients, these numbers were 91, 13 and 23 weeks, respectively. One-year survival was 49% with 90%, 23% and 42% for stage IIIA, IIIB and IV patients, respectively. The main toxicity was myelosuppression. WHO grades 3 and 4 leukopenia occurred in 67% of patients, whereas 61% experienced grade 3 or 4 thrombocytopenia. Although hematological toxicity was clinically tolerable, it frequently led to omission of gemcitabine administration on day 15. The incidence of non-hematological toxicity was very low., Conclusion: This regimen of cisplatin on days 1 and 8 and gemcitabine on days 2, 9 and 15 induced a high RR in patients with advanced NCSLC. Frequent omission of gemcitabine day 15 is a limitation of this schedule. This should be an important factor in a practical approach to decide on the most optimal schedule of the cisplatin plus gemcitabine combination.

Background: Combination chemotherapy improves survival in patients with disseminated non-small cell lung cancer (NSCLC). Gemcitabine is active against NSCLC and etoposide has an additive effect in vitro. We describe a dose finding study for the combination of these drugs., Patients and Methods: NSCLC patients progressive after chemotherapy received gemcitabine (1000 mg/m2 days 1, 8, 15) and one of five etoposide schedules in doses ranging from 60 to 100 mg/m2 per day administered on days 1-3 (schedules 1-2) or 8-10 (schedules 3-5)., Results: 23 patients (median age 59 years) were entered. Number of patients and cycles evaluable for toxicity was 22 and 75. Non-hematological toxicity was mild. In cycle 1 leukocytopenia grade III/IV was observed in 33 and 56% of the patients treated with etoposide 60 and 80 mg/m2 days 1-3 and in 50% treated with etoposide 60 and 80 mg/m2 days 8-10. During cycle 1 thrombocytopenia grade III/IV was observed in 0, 33, 0 and 33% of these patients, respectively. Both patients treated at etoposide 100 mg/m2 days 8-10 experienced febrile leukocytopenia. During cycle 1 single doses of gemcitabine were administered as planned more frequently in patients receiving etoposide 80 mg/m2 per day on days 8-10 compared to etoposide days 1-3 (83 versus 70%). Postponement of combination gemcitabine and etoposide was not necessary. The overall response rate was 21% (95% confidence interval 3-39%) with a median duration of 7.5 + months in this dose finding study., Conclusions: Combined gemcitabine etoposide is feasible in patients with progressive NSCLC. The optimal combination was gemcitabine 1000 mg/m2 per day on days 1, 8 and 15 and etoposide 80 mg/m2 per day on days 8-10 of each 28-day cycle. The response rate of 21% warrants further investigation in patients with advanced NSCLC.

After a remarkable improvement of the very poor prognosis of small cell lung cancer with very simple therapy such as iv and oral cyclophosphamide the role of oral therapy has become minimal. However, since more than a decade results of combination chemotherapy are at a plateau and it is necessary to reconsider the role of simple therapy in patients without the prospect of cure. Oral therapy might be worthwhile because it is probably less effecting the quality of life of the patient and makes it unnecessary to visit the hospital frequently. All drugs available for oral use with known activity against small cell lung cancer are reviewed. The best example of the success of oral therapy is etoposide, other candidates that need to be tested in a modern way are oral cyclophosphamide and hexamethylmelamine. New concepts of prolonged chemotherapy and dose-intensity are easier evaluated by using oral drugs. The discovery of the activity of prolonged oral etoposide is an excellent example how to test a new concept in a very simple way.