Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of... Show moreGastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (<= 10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835.A neoadjuvant treatment regimen of anti-PD-L1 monotherapy followed by anti-PD-L1 plus chemotherapy was well tolerated and led to a major pathologic response rate of 70% in patients with resectable gastric or gastroesophageal junction adenocarcinoma. Show less
Cattaneo, C.M.; Battaglia, T.; Urbanus, J.; Moravec, Z.; Voogd, R.; Groot, R. de; ... ; Scheper, W. 2023
Cancer neoantigens that arise from tumor mutations are drivers of tumor-specific T cell responses, but identification of T cell-recognized neoantigens in individual patients is challenging.... Show moreCancer neoantigens that arise from tumor mutations are drivers of tumor-specific T cell responses, but identification of T cell-recognized neoantigens in individual patients is challenging. Previous methods have restricted antigen discovery to selected HLA alleles, thereby limiting the breadth of neoantigen repertoires that can be uncovered. Here, we develop a genetic neoantigen screening system that allows sensitive identification of CD4+ and CD8+ T cell-recognized neoantigens across patients’ complete HLA genotypes. Show less
Gruijs, M.; Zeelen, C.; Hellingman, T.; Smit, J.; Borm, F.J.; Kazemier, G.; ... ; Egmond, M. van 2023
Circulating tumor cells (CTCs) have been detected in many patients with different solid malignancies. It has been reported that presence of CTCs correlates with worse survival in patients with... Show moreCirculating tumor cells (CTCs) have been detected in many patients with different solid malignancies. It has been reported that presence of CTCs correlates with worse survival in patients with multiple types of cancer. Several techniques have been developed to detect CTCs in liquid biopsies. Currently, the only method for CTC detection that is approved by the Food and Drug Administration is CellSearch. Due to low abundance of CTCs in certain cancer types and in early stages of disease, its clinical application is currently limited to metastatic colorectal cancer, breast cancer and prostate cancer. Therefore, we aimed to develop a new method for the detection of CTCs using the Attune NxT-a flow cytometry-based application that was specifically developed to detect rare events in biological samples without the need for enrichment. When healthy donor blood samples were spiked with variable amounts of different EpCAM+EGFR+ tumor cell lines, recovery yield was on average 75%. The detection range was between 1000 and 10 cells per sample. Cell morphology was confirmed with the Attune CytPix. Analysis of blood samples from metastatic colorectal cancer patients, as well as lung cancer patients, demonstrated that increased EpCAM+EGFR+ events were detected in more than half of the patient samples. However, most of these cells showed no (tumor) cell-like morphology. Notably, CellSearch analysis of blood samples from a subset of colorectal cancer patients did not detect CTCs either, suggesting that these blood samples were negative for CTCs. Therefore, we anticipate that the Attune NxT is not superior to CellSearch in detection of low amounts of CTCs, although handling and analysis of samples is easier. Moreover, morphological confirmation is essential to distinguish between CTCs and false positive events. Show less
In't Veld, S.G.J.G.; Arkani, M.; Post, E.; Antunes-Ferreira, M.; D'Ambrosi, S.; Vessies, D.C.L.; ... ; Wurdinger, T. 2022
Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising... Show moreCancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening. Show less
Ruiter, J.C. de; Diessen, J.N.A. van; Smit, E.F.; Noort, V. van der; Damhuis, R.A.M.; Hartemink, K.J.; ESLUNG Grp 2022
OBJECTIVES: A minimally invasive lobectomy (MIL) is the standard treatment for stage I non-small cell lung cancer (NSCLC) in medically operable patients. Stereotactic ablative radiotherapy (SABR)... Show moreOBJECTIVES: A minimally invasive lobectomy (MIL) is the standard treatment for stage I non-small cell lung cancer (NSCLC) in medically operable patients. Stereotactic ablative radiotherapy (SABR) is recommended for inoperable patients and has been proposed as a potential alternative for operable patients as well. Here, we present the results of a feasibility study in preparation for a nationwide retrospective cohort study, comparing outcomes between both treatment modalities. METHODS: In this retrospective cohort study, data from patients with clinical stage I NSCLC treated with MIL or SABR in 2014-2015 were retrieved from databases from 12 Dutch hospitals. Progression-free survival (PFS), overall survival (OS) and lung cancer-specific survival (LCSS) were compared between MIL and SABR. RESULTS: A total of 597 patients with clinical stage I NSCLC treated with MIL (n = 356) or SABR (n = 241) were included. In total, 106 (30%) patients had died in the MIL group and 142 (59%) in the SABR group. After MIL and SABR, unadjusted 5-year PFS was 63% and 30%, OS was 72% and 38% and LCSS was 81% and 76%, respectively. Propensity score-weighted analyses did not show significant differences between MIL and SABR in OS [hazard ratios (HR) 0.74 (95% confidence interval (CI) 0.43-1.29)], PFS [HR 0.74 (95% CI 0.42-1.32)] or LCSS [HR 0.81 (95% CI 0.42-1.59)]. CONCLUSIONS: Unadjusted analyses revealed superior OS and PFS for MIL and similar LCSS, but this feasibility study was not sufficiently powered to demonstrate significant differences using propensity score methodology. Therefore, this study is currently being extended to include more than half of Dutch hospitals in order to enlarge the population to >= 1880 patients, not only to determine the best treatment for patients with stage I NSCLC overall, but also to assess the preferred treatment for patient groups with specific characteristics. Show less
OBJECTIVES: Persistent air leak (PAL; >5days after surgery) is the most common complication after pulmonary resection and associated with prolonged hospital stay and increased morbidity.... Show moreOBJECTIVES: Persistent air leak (PAL; >5days after surgery) is the most common complication after pulmonary resection and associated with prolonged hospital stay and increased morbidity. Literature is contradictory about the prevention and treatment of PAL. Variation is therefore hypothesized. The aim of this study is to understand the variation in the incidence, preventive management and treatment of PAL.METHODS: Data from the Dutch Lung Cancer Audit for Surgery were combined with results of an online survey among Dutch thoracic surgeons. The national incidence of PAL and case-mix corrected between-hospital variation were calculated in patients who underwent an oncological (bi)lobectomy or segmentectomy between January 2012 and December 2018. By multivariable logistic regression, factors associated with PAL were assessed. A survey was designed to assess variation in (preventive) management and analysed using descriptive statistics. Hospital-level associations between management strategies and PAL were assessed by univariable linear regression.RESULTS: Of 12382 included patients, 9.0% had PAL, with a between-hospital range of 2.6-19.3%. Factors associated with PAL were male sex, poor lung function, low body mass index, high American Society of Anesthesiologists (ASA) score, pulmonary comorbidity, upper lobe resection, (bi)lobectomy (vs segmentectomy), right-sided tumour and robotic-assisted thoracic surgery. Perioperative (preventive) management of PAL differed widely between hospitals. When using water seal compared to suction drainage, the average incidence of PAL decreased 2.9%.CONCLUSIONS: In the Netherlands, incidence and perioperative (preventive) management of PAL vary widely. Using water seal instead of suction drainage and increasing awareness are potential measures to reduce this variation. Show less
Joosten, P.J.M.; Dickhoff, C.; Noort, V. van der; Smeekens, M.; Numan, R.C.; Klomp, H.M.; ... ; Hartemink, K.J. 2021
Objectives: Chemoradiotherapy (CRT) has been the backbone of guideline-recommended treatment for Stage IIIA non-small cell lung cancer (NSCLC). However, in selected operable patients with a... Show moreObjectives: Chemoradiotherapy (CRT) has been the backbone of guideline-recommended treatment for Stage IIIA non-small cell lung cancer (NSCLC). However, in selected operable patients with a resectable tumour, good results have been achieved with trimodality treatment (TT). The objective of this bi-institutional analysis of outcomes in patients treated for Stage IIIA NSCLC was to identify particular factors supporting the role of surgery after CRT.Methods: In a 2-centre retrospective cohort study, patients with Stage III NSCLC (seventh edition TNM) were identified and those patients with Stage IIIA who were treated with CRT or TT between January 2007 and December 2013 were selected. Patient characteristics as well as tumour parameters were evaluated in relation to outcome and whether or not these variables were predictive for the influence of treatment (TT or CRT) on outcome [overall survival (OS) or progression-free survival (PFS)]. Estimation of treatment effect on PFS and OS was performed using propensity-weighted cox regression analysis based on inverse probability weighting.Results: From a database of 725 Stage III NSCLC patients, 257 Stage IIIA NSCLC patients, treated with curative intent, were analysed; 186 (72%) with cIIIA-N2 and 71 (28%) with cT3N1/cT4N0 disease. One hundred and ninety-six (76.3%) patients were treated by CRT alone (high-dose radiation with daily low-dose cisplatin) and 61 (23.7%) by TT. The unweighted data showed that TT resulted in better PFS and OS. After weighting for factors predictive of treatment assignment, patients with a large gross tumour volume (>120 cc) had better PFS when treated with TT, and patients with an adenocarcinoma treated with TT had better OS, regardless of tumour volume.Conclusions: Patients with Stage IIIA NSCLC and large tumour volume, as well as patients with adenocarcinoma, who were selected for TT, had favourable outcome compared to patients receiving CRT. This information can be used to assist multidisciplinary team decision-making and for stratifying patients in studies comparing TT and definitive CRT. Show less
Joosten, P.J.M.; Langen, A.J. de; Noort, V. van der; Monkhorst, K.; Klomp, H.M.; Veenhof, A.A.F.A.; ... ; Hartemink, K.J. 2021
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... Show moreObjectives: 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. Show less
Winkelman, J.A.; Woude, L. van der; Heineman, D.J.; Bahce, I.; Damhuis, R.A.; Mahtab, E.A.F.; ... ; Dickhoff, C. 2021
Objectives: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with... Show moreObjectives: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with SST in the Netherlands. Material and methods: Data was retrieved from the Dutch Lung Cancer Audit for Surgery (DLCA-S) for all patients undergoing resection for clinical stage IIB-IV SST from 2012 to 2019. Because DLCA-S is not linked to survival data, survival for a separate cohort (2015-2017) was obtained from the Netherlands Cancer Registry (NCR). Results: In the study period, 181 patients had SST surgery, representing 1.03% (181/17488) of all lung cancer pulmonary resections. For 2015-2017, the SST resection rate was 14.4% (79/549), and patients with stage IIB/III SST treated with trimodality had a 3-year overall survival of 67.4%. 63.5% of patients were male, and median age was 60 years. Almost 3/4 of tumors were right sided. Surgery was performed in 20 hospitals, with average number of annual resections ranging from < 1 (n = 17) to 9 (n = 1). 39.8% of resections were performed in 1 center and 63.5% in the 3 most active centers. 12.7% of resections were extended (e.g. vertebral resection). 85.1% of resections were complete (R0). Morbidity and 30-day mortality were 51.4% and 3.3% respectively. Despite treating patients with a higher ECOG performance score and more extended resections, the highest volume center had rates of morbidity/mortality, and length of hospital stay that were comparable to those of the medium volume (n = 2) and low-volume centers (n = 1). Conclusion: In the Netherlands, surgery for SST accounts for about 1% of all lung cancer pulmonary resections, the number of SST resections/hospital/year varies widely, with most centers performing an average of < 1/year. Morbidity and mortality are acceptable and survival compares favourably with the literature. Although further centralisation is possible, it is unknown whether this will improve outcomes. Show less
Joosten, P.J.M.; Langen, A.J. de; Noort, V. van der; Monkhorst, K.; Klomp, H.M.; Veenhof, A.A.F.A.; ... ; Hartemink, K.J. 2021
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... Show moreObjectives: 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. Show less
Voabil, P.; Bruijn, M. de; Roelofsen, L.M.; Hendriks, S.H.; Brokamp, S.; Braber, M. van den; ... ; Thommen, D.S. 2021
An ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer... Show moreAn ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer.Inhibitors of the PD-1-PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation. Show less
Woude, L. van der; Wouters, M.W.J.M.; Hartemink, K.J.; Heineman, D.J.; Verhagen, A.F.T.M. 2021
Objective: In patients with NSCLC, lymph node metastases are an important prognostic factor. Despite an accurate pre-operative work up, for optimal staging an intrapulmonary-and mediastinal lymph... Show moreObjective: In patients with NSCLC, lymph node metastases are an important prognostic factor. Despite an accurate pre-operative work up, for optimal staging an intrapulmonary-and mediastinal lymph node dissection (LND) as part of the operation is mandatory. The aim of this study is to assess the completeness of LND in patients undergoing an intended curative resection for NSCLC in the Netherlands and to compare performance between open surgery and minimally invasive surgery (MIS).Materials and methods: The intraoperative LND was evaluated in 7460 patients who had undergone a lobectomy for clinically staged N0-1 NSCLC (2013-2018). The LND was considered complete, when three mediastinal (N2) lymph node stations, including station 7, were sampled or dissected, in addition to the lymph nodes from station 10 and 11. A comparison was made between open surgery and MIS.Results: Of 5154 patients, who had MIS, a sufficient intrapulmonary LND was performed in 47.9% and a sufficient mediastinal LND in 58.6%. A complete LND was performed in 31.6%. For 2306 patients who had an open resection, these numbers were 45.0%, 59.0%, and 30.6%, respectively. The overall between hospital variation in a complete LND ranged between 0 and 72.5%.Conclusion: In the Netherlands, a complete LND of both intrapulmonary-and mediastinal lymph nodes is performed only in a minority of patients with clinically staged N0-1 NSCLC, with substantial between hospital variation. No differences were seen between open surgery and MIS. Because of poor performance, completeness of lymph node dissection will be recorded as a mandatory performance indicator in our national audit, to improve the quality of resection.(c) 2020 Elsevier Ltd, BASO The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
BackgroundCheckpoint inhibitors provided sustained clinical benefit to metastatic lung cancer patients. Nonetheless, prognostic markers in metastatic settings are still under research. Imaging... Show moreBackgroundCheckpoint inhibitors provided sustained clinical benefit to metastatic lung cancer patients. Nonetheless, prognostic markers in metastatic settings are still under research. Imaging offers distinctive advantages, providing whole-body information non-invasively, while routinely available in most clinics. We hypothesized that more prognostic information can be extracted by employing artificial intelligence (AI) for treatment monitoring, superior to 2D tumor growth criteria.MethodsA cohort of 152 stage-IV non-small-cell lung cancer patients (NSCLC) (73 discovery, 79 test, 903CTs), who received nivolumab were retrospectively collected. We trained a neural network to identify morphological changes on chest CT acquired during patients' follow-ups. A classifier was employed to link imaging features learned by the network with overall survival.ResultsOur results showed significant performance in the independent test set to predict 1-year overall survival from the date of image acquisition, with an average area under the curve (AUC) of 0.69 (p < 0.01), up to AUC 0.75 (p < 0.01) in the first 3 to 5 months of treatment, and 0.67 AUC (p = 0.01) for durable clinical benefit (6 months progression-free survival). We found the AI-derived survival score to be independent of clinical, radiological, PDL1, and histopathological factors. Visual analysis of AI-generated prognostic heatmaps revealed relative prognostic importance of morphological nodal changes in the mediastinum, supraclavicular, and hilar regions, lung and bone metastases, as well as pleural effusions, atelectasis, and consolidations.ConclusionsOur results demonstrate that deep learning can quantify tumor- and non-tumor-related morphological changes important for prognostication on serial imaging. Further investigation should focus on the implementation of this technique beyond thoracic imaging. Show less
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
Clinical implementation of tumor organoids for personalized medicine requires that pure tumor organoids can be reliably established. Here, we present our experience with organoid cultures from >... Show moreClinical implementation of tumor organoids for personalized medicine requires that pure tumor organoids can be reliably established. Here, we present our experience with organoid cultures from >70 non-small cell lung cancer (NSCLC) samples. We systematically evaluate several methods to identify tumor purity of organoids established from intrapulmonary tumors. Eighty percent of organoids from intrapulmonary lesions have a normal copy number profile, suggesting overgrowth by normal airway organoids (AOs). This is further supported by the failure to detect mutations found in the original tumor in organoids. Histomorphology alone is insufficient to determine tumor purity, but when combined with p63 immunostaining, tumor and normal AOs can be distinguished. Taking into account overgrowth by normal AOs, the establishment rate of pure NSCLC organoids is 17%. Therefore, current methods are insufficient to establish pure NSCLC organoids from intrapulmonary lesions. We discourage their use unless steps are taken to prevent overgrowth by normal AOs. Show less
Introduction | Patients with stage IIIA non-small cell lung cancer (NSCLC) form a heterogenous group; concurrent chemoradiotherapy (CRT) remains the main treatment strategy, stage cT3N1 or cT4N0-1... Show moreIntroduction | Patients with stage IIIA non-small cell lung cancer (NSCLC) form a heterogenous group; concurrent chemoradiotherapy (CRT) remains the main treatment strategy, stage cT3N1 or cT4N0-1 may be eligible for surgery and potentially resectable stage IIIA (N2) NSCLC for neoadjuvant therapy followed by a resection.The reported survival rates after neoadjuvant treatment and resection vary widely. We evaluated treatment patterns and outcome of patients with stage IIIA NSCLC in the Netherlands.Material and Methods | Primary treatment data of patients with clinically staged IIIA NSCLC (according to the 7th edition of the TNM classification) between 2010 and 2016 were extracted from the Netherlands Cancer Registry. Patient characteristics were tabulated and 5-year overall survival (OS) was calculated and reported.Results | In total, 9,591 patients were diagnosed with stage IIIA NSCLC. Of these patients, 41.3% were treated with chemoradiotherapy and 11.6% by upfront surgery without neoadjuvant therapy. 428 patients (4.5%) received neoadjuvant treatment, CRT in 341 patients (80%) and chemotherapy in 87 patients (20%), followed by a resection. The 5-year OS was 26% after chemoradiotherapy, 40% after upfront surgery without neoadjuvant therapy and 54% after neoadjuvant treatment followed by a resection. Clinical overstaging was seen in 42.3% of the patients that were operated without neoadjuvant therapy.Conclusion | In the Netherlands, between 2010 and 2016, 4.5% of patients with stage IIIA NSCLC were selected for treatment with neoadjuvant therapy followed by a resection. The 5-year OS in these patients exceeded 50%, which is better than previously reported, however, outcome might be overestimated due to clinical overstaging. Show less
Introduction: Concurrent chemoradiotherapy remains the main treatment strategy for patients with stage IIIA non-small cell lung cancer (NSCLC); stage cT3N1 or cT4N0-1 may be eligible for surgery... Show moreIntroduction: Concurrent chemoradiotherapy remains the main treatment strategy for patients with stage IIIA non-small cell lung cancer (NSCLC); stage cT3N1 or cT4N0-1 may be eligible for surgery and potentially resectable stage IIIA (N2) NSCLC for neoadjuvant therapy followed by resection. We evaluated treatment patterns and outcomes of patients with stage IIIA NSCLC in The Netherlands. Material and Methods: Primary treatment data of patients with clinically staged IIIA NSCLC between 2010 and 2016 were extracted from The Netherlands Cancer Registry. Patient characteristics were tabulated and 5-year overall survival (OS) was calculated and reported. Results: In total, 9,591 patients were diagnosed with stage IIIA NSCLC. Of these patients, 41.3% were treated with chemoradiotherapy, 11.6% by upfront surgery and 428 patients (4.5%) received neoadjuvant treatment followed by resection. The 5-year OS was 26% after chemoradiotherapy, 40% after upfront surgery and 54% after neoadjuvant treatment followed by resection. Clinical over staging was seen in 42.3% of the patients that were operated without neoadjuvant therapy. Conclusion: In The Netherlands, between 2010 and 2016, 4.5% of patients with stage IIIA NSCLC were selected for treatment with neoadjuvant therapy followed by resection. The 5-year OS in these patients exceeded 50%. However, the outcome might be overestimated due to clinical over staging. 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
