Objectives: Targeted therapies in the management of patients with lung cancer provide significantly better outcome compared to chemotherapy. Detection of the anaplastic lymphoma kinase (ALK) gene... Show moreObjectives: Targeted therapies in the management of patients with lung cancer provide significantly better outcome compared to chemotherapy. Detection of the anaplastic lymphoma kinase (ALK) gene rearrangement has great predictive value for treatment with small molecule tyrosine kinase inhibitor (crizotinib and alectinib commonly). Fluorescent in situ hybridisation (FISH) assay is a basic diagnostic test designed for detecting ALK gene rearrangements. Although being considered as gold standard method by IASLC's guideline, it is often regarded as difficult and error prone. Our aim was to examine a unique atypical ALK FISH pattern, revealed during a systematic large-scale monitoring, which carries the great risk of misinterpretation, hence may result in loss of patients eligible for targeted therapy.Materials and Methods: Tissue and cytology samples from nearly one thousand patients with advanced stage non-small cell lung cancer (NSCLC, n = 996) were routinely examined by ALK FISH and immunohistochemistry (Ventana ALK-D5F3-CDx assay). Anchored Multiplex PCR based Next Generation Sequencing (AMP-NGS) was used to detect fusion gene transcripts in ambiguous cases.Results: Fifty-nine (5,9%) of the cases were positive with ALK FISH test. Three cases showed atypical pattern with a significantly reduced sized red (3') signal and complete loss of green signals. Digital signal measurement confirmed this finding, showing consistent attenuation of 3' signals throughout the tumours. In all three cases AMP-NGS and ALK IHC verified the presence of a fusion gene and expressed oncoprotein, respectively.Conclusion: Approximately 5% of the 59 ALK positive cases exhibited atypical attenuated isolated 3' signal pattern. The immunohistochemistry and AMP-NGS examinations helped to clarify the presence of oncoprotein and the fusion gene, respectively. Our results emphasize the importance of extensive exploration of the genetic background of any unexpected FISH finding to avoid false diagnosis. This enables clinicians to indicate the adequate therapy with higher efficiency for patients suffering from NSCLC. Show less
ObjectivesResection is the standard treatment for stage I non-small cell lung cancer (NSCLC) in operable patients. Stereotactic body radiotherapy (SBRT) is recommended for inoperable patients. A... Show moreObjectivesResection is the standard treatment for stage I non-small cell lung cancer (NSCLC) in operable patients. Stereotactic body radiotherapy (SBRT) is recommended for inoperable patients. A shift from surgery to SBRT is expected in elderly patients due to increased frailty and competing risks. We assessed the current influence of age on treatment decision-making and overall survival (OS).Materials and methodsWe performed a retrospective cohort study using data from patients with clinical stage I NSCLC diagnosed in 2012–2016 and treated with lobectomy, segmentectomy, wedge resection, or SBRT, retrieved from the Netherlands Cancer Registry. Patient characteristics and OS were compared between SBRT and (sub)lobar resection for patients aged 18−79 and ≥80 years.Results and Conclusion8764 patients treated with lobectomy (n = 4648), segmentectomy (n = 122), wedge resection (n = 272), or SBRT (n = 3722) were included. In 2012–2016, SBRT was increasingly used for octogenarians and younger patients from 75.3% to 83.7% and from 30.8% to 43.2%, respectively. Five-year OS in the whole population was 70% after surgery versus 39% after SBRT and 50% versus 27% in octogenarians. After correction for age, gender, year of diagnosis, and clinical T-stage, OS was equal after lobectomy and SBRT in the first 2 years after diagnosis. However, after >2 years, OS was better after lobectomy than after SBRT.SBRT is the prevailing treatment in octogenarians with stage I NSCLC. While surgery is associated with better OS than SBRT, factors other than treatment modality (e.g. comorbidity) may have had a significant impact on survival. The wider application of SBRT in octogenarians likely reflects the frailty of this group. Registries and trials are required to identify key determinants of frailty in this specific population to improve patient selection for surgery or SBRT. Show less
Immunotherapy has obtained a secure place in the treatment of metastatic non-small cell lung cancer (NSCLC) and has made a great impact on prognosis of responders. Unfortunately, not all NSCLC... Show moreImmunotherapy has obtained a secure place in the treatment of metastatic non-small cell lung cancer (NSCLC) and has made a great impact on prognosis of responders. Unfortunately, not all NSCLC patients derive benefit from this treatment. Several immune escape mechanisms have been postulated, explaining failure of tumor immune attack. A better understanding of these mechanisms helps us to seek treatment strategies to overcome resistance to immunotherapy. Radiotherapy has immunomodulatory qualities capable of enhancing the anticancer immune response by tackling a number of these tumor escape mechanisms. In this review, we focus on mechanisms of off-target effects of radiotherapy, the so-called abscopal effect, by describing the current role of immune checkpoint inhibitors (ICIs) in NSCLC, the possible reasons for its failures and evidence on how radiotherapy may be able to counteract these mechanisms. An oversight of pre-clinical and clinical data supporting augmentation of abscopal events by radiotherapy when combined with ICIs is presented. As much remains unclear regarding optimal dose, fractionation, target volume or timing of radiation therapy, future research will need to focus on implementing data from pre-clinical and translational findings in the development of new clinical trials in order to help optimizing the potential of the combination of immunotherapy with radiotherapy. Show less
Veggel, B. van; Santos, J.F.V.M.R.; Hashemi, S.M.S.; Paats, M.S.; Monkhorst, K.; Heideman, D.A.M.; ... ; Langen, A.J. de 2020
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... Show moreObjectives: 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 %. Show less
Smit, H.J.M.; Aerts, J.; Heuvel, M. van den; Hiltermann, T.J.N.; Bahce, I.; Smit, E.F.; ... ; NVALT Immunotherapy Register 2020
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... Show moreObjective: 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+. Show less
Joosten, P.J.M.; Dickhoff, C.; Noort, V. van der; Klomp, H.M.; Diessen, J.N.A. van; Dahele, M.; ... ; Hartemink, K.J. 2020
Objectives: Locoregional recurrence and persistent/progressive disease after curative-intent definitive chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is challenging to manage, as... Show moreObjectives: Locoregional recurrence and persistent/progressive disease after curative-intent definitive chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is challenging to manage, as salvage options are limited. Selected patients might be candidates for resection. This study evaluated the outcomes of patients after salvage surgery for locoregional recurrence, focusing specifically on morbidity and mortality after salvage pneumonectomy.Materials and methods: This retrospective study included patients from 2 tertiary referral hospitals who underwent salvage pulmonary resection for locoregional recurrence or disease persistence/progression >12 weeks after completion of curative intent high dose (>60 Gy) CRT. Disease-free (DFS) and overall survival (OS) were estimated and the influence of patient and treatment characteristics on these endpoints was assessed.Results: A total of 30 patients treated between 2015-2017 were identified with a median age of 60 years (range 42-72 years), 67 % were male. Median follow-up was 47 months (95 % CI 46-NR). Pneumonectomy was performed in 13/30 (43 %) patients and lobectomy in 17/30 (57 %). Median DFS and OS after pneumonectomy/lobectomy were 14/6 and NR/17 months, respectively. 30 and 90-day mortality for pneumonectomy/lobectomy were 0/12 % and 0/24 % respectively. More favorable survival was seen after pathologically radical resection, i.e. R0, and when surgery was performed more than 12 months after completion of CRT.Conclusion: Salvage surgery, including pneumonectomy is associated with acceptable outcomes in selected patients with recurrent or persistent/progressive NSCLC after curative-intent high dose CRT. Patients should be assessed for the probability of an R0 resection, and patients with a locoregional recurrence more than 12 months after treatment with CRT may benefit most from salvage surgery. Show less
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... Show moreObjective: 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. Show less
ObjectivesOrganization and governance of national healthcare might play an important role in decision-making and outcomes in patients with lung cancer. Both Denmark and the Netherlands have a high... Show moreObjectivesOrganization and governance of national healthcare might play an important role in decision-making and outcomes in patients with lung cancer. Both Denmark and the Netherlands have a high level of healthcare but a different financial coverage, governance and level of centralization. By using both national databases we analyzed the consequences of these differences on patterns of care and outcomes with a focus on morbidity, mortality and clinical staging.Materials and methodsGeneral numbers on both healthcare systems were requested. All patients who had surgery for lung cancer from 2013 to 2016 were included. Mortality, morbidity and clinical staging were analyzed for patients with NSCLC without metastases, only one operation and no neo-adjuvant therapy.ResultsIn 2016 annual budget as share of gross national product was 10.4% for both countries. In Denmark 4 hospitals performed lung surgery in 2016, compared to 43 hospitals in the Netherlands. We included 4030 Danish and 8286 Dutch patients. In the subgroup 30-day mortality was 1.5% in Denmark compared to 1.9% in the Netherlands. The percentage of patients with a complicated course was 24.4% and 34.8% respectively (p < 0.05). Accuracy between cTNM and pTNM was 53.0% in Denmark and 52.9% in the Netherlands.ConclusionSurgery for lung cancer is at a high level in both countries, reflected by low mortality-rates. Centralization has been implemented successfully in Denmark, which might explain the lower rate of patients with a complicated post-operative course, although different definitions preclude firm conclusions. In both countries correct clinical staging of lung cancer remains a challenge. Show less
Kuijvenhoven, J.C.; Crombag, L.; Breen, D.P.; Berk, I. van den; Versteegh, M.I.M.; Braun, J.; ... ; Annema, J.T. 2017
After the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or... Show moreAfter the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or progression. We conducted a systematic review of the literature for the activity, effectiveness and toxicity of second line treatment. The results are presented according to the class of drugs: chemotherapy and targeted or biological agent. (C) 2015 Elsevier Ireland Ltd. All rights reserved. Show less
Denial is a well-known phenomenon in clinical oncology practice. Yet whether the impact of denial on patient well-being is beneficial or harmful remains unknown. The purpose of the current study is... Show moreDenial is a well-known phenomenon in clinical oncology practice. Yet whether the impact of denial on patient well-being is beneficial or harmful remains unknown. The purpose of the current study is to investigate the relationship between denial and social and emotional outcomes in a large sample of lung cancer patients over an extended time period. Denial and social and emotional outcomes were measured in 195 newly diagnosed lung cancer patients. Four assessments were conducted over 8 months. The level of denial was measured using the Denial of Cancer Interview. Patient-reported social and emotional outcomes were measured using the EORTC-QLQ-30 and the HADS. Patients with a moderate or increasing level of denial over time reported better social outcomes (role functioning: p = 0.0036, social functioning: p = 0.027) and less anxiety (p = 0.0001) and depression (p = 0.0019) than patients with a low level of denial. The overall quality of life was better among lung cancer patients who displayed either moderate or increasing levels of denial compared with those who displayed low levels of denial (p < 0.0001). A certain level of denial in lung cancer patients can have a protective effect on social and emotional outcomes. Clinicians should take this into account when providing information about the illness and its prognosis. (C) 2010 Elsevier Ireland Ltd. All rights reserved. Show less
Background: According to current guidelines, transesophageal ultrasound-guided fine needle aspiration (EUS-FNA) can be performed as an alternative for surgical staging to confirm mediastinal... Show moreBackground: According to current guidelines, transesophageal ultrasound-guided fine needle aspiration (EUS-FNA) can be performed as an alternative for surgical staging to confirm mediastinal metastases in patients with non-small cell lung cancer (NSCLC). To date however, data regarding the routine use of EUS-FNA in the preoperative staging of unselected patients with NSCLC are limited. Aims and objectives: (1) To evaluate the diagnostic value of EUS-FNA in consecutive, patients with NSCLC regardless of nodal size at CT. (2) To determine the impact of EUS-FNA on the prevention of surgical staging procedures. (3) To assess the accuracy of mediastinal staging by combining EUS-FNA and mediastinoscopy. (4) To investigate whether a subgroup of patients exists that can be accurately staged by EUS-FNA alone. Methods: 152 consecutive operable patients with proven or suspected NSCLC who underwent EUS-FNA were retrospectively analyzed. In the absence of mediastinal metastases, mediastinoscopy and/or thoracotomy with lymph node dissection was performed. Results: The prevalence of mediastinal metastases was 49%. Sensitivity, negative predictive value (NPV) and accuracy of EUS-FNA for N2/N3 disease were 74%, 73% and 85% respectively, whereas these values for the combined staging of EUS-FNA and mediastinoscopy were 92%, 85% and 95%. Additional surgical staging in patients staged NO at EUS-FNA reduces the false negative EUS-findings by 55%. The NPV of EUS-FNA for left-sided tumors was 68%. EUS-FNA prevented surgical staging procedures in 60 of 152 patients (39%). No major complications occurred during EUS-FNA. Conclusion: Routine use of EUS-FNA in unselected patients with NSCLC reduces the need for surgical staging procedures in nearly half of patients. Additional surgical staging in patients without nodal metastases at EUS-FNA reduces the false negative EUS-FNA findings considerably regardless of the location of the primary lung tumor. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Show less
Although denial in cancer patients is often seen in clinical practice, studies relating denial to physical outcomes are lacking. The present study aims to investigate patterns of denial among lung... Show moreAlthough denial in cancer patients is often seen in clinical practice, studies relating denial to physical outcomes are lacking. The present study aims to investigate patterns of denial among lung cancer patients and connect these to their physical outcomes. Denial was measured longitudinally in 195 consecutive newly diagnosed lung cancer patients. Four assessments were conducted over an 8-month period. Patient-reported physical outcomes were measured with a generic and disease-specific quality of life measure. Medical data were provided by the patients' chest physicians. Three patterns of denial over time were identified in lung cancer patients: patients displayed either low, moderate or increasing denial. Male lung cancer patients were found to deny at a moderate level more often. A moderate or increasing level of denial was consistently related to improved patient-rated physical outcomes. Lung cancer patients displaying more denial reported a better overall perception of health and better physical functioning. They complained less about fatigue, nausea and vomiting, appetite loss, dysphagia and pain in arm and shoulder than low deniers. Other symptoms did not differ among denial classes. Denial in lung cancer patients may well be an adaptive mechanism and have to be respected in clinical practice. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Show less
