Disease relapse in relation to lymph node sampling in lung carcinoid patients.

The predictive value of extent of per-operative lymph node (LN) sampling in relation to disease relapse in patients with pulmonary carcinoid (PC) is unknown. Furthermore, post-surgery follow-up recommendations rely on institutional retrospective studies with rather short follow-up. We aimed to address these short-comings by examining the relation between LN sampling and relapse in a population-based cohort with long-term follow-up. By combining the Dutch nation-wide pathology and cancer registries, all patients with surgically resected PC (2003-2012) were included in this analysis (last update 2020). Extent of surgical LN dissection was scored for number of LN sampled, location (hilar/mediastinal), and completeness of resection according to European Society of Thoracic Surgeons (ESTS) guidelines. Relapse free interval (RFI) was evaluated using Kaplan Meier and multivariate regression analysis. 662 patients were included. Median follow-up was 87.5 months. Relapse occurred in 10% of patients, mostly liver (51.8%) and locoregional sites (45%). Median RFI was 48.1 months (95% CI 36.8-59.4). Poor prognostic factors were atypical carcinoid, pN1/2 and R1/R2 resection. In 546 patients LN dissection data could be retrieved; at least one N2 LN was examined in 44% and completeness according to ESTS in merely 7%. In 477 cN0 patients, 5.9% had pN1 and 2.5% pN2 disease. In this population-based cohort, relapse occurred in 10% of PC patients with a median RFI of 48.1 months thereby underscoring the necessity of long-term follow-up. Extended mediastinal LN sampling was rarely performed but systematic nodal evaluation is recommended as it provides prognostic information on distant relapse.

The optimal treatment for patients with stage I non-small cell lung cancer: minimally invasive lobectomy versus stereotactic ablative radiotherapy - a nationwide cohort study.

OBJECTIVES: The aim of the Early-Stage LUNG cancer (ESLUNG) study was to compare outcomes after minimally invasive lobectomy (MIL) and stereotactic ablative radiotherapy (SABR) in patients with stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this retrospective cohort study, patients with clinical stage I NSCLC (according to TNM7), treated in 2014-2016 with MIL or SABR, were included. 5-year overall survival (OS) and recurrence-free survival (RFS) were calculated and compared between patients treated with MIL and a propensity score (PS)-weighted SABR population with characteristics comparable to those of the MIL group. RESULTS: 1211 MIL and 972 SABR patients were included. Nodal upstaging occurred in 13.0 % of operated patients. 30-day mortality was 1.0 % after MIL and 0.2 % after SABR. After SABR, the 5-year regional recurrence rate (18.1 versus 14.2 %; HR 0.74, 95 % CI 0.58-0.94) and distant metastasis rate (26.2 versus 20.2 %; HR 0.72, 95 % CI 0.59-0.88) were significantly higher than after MIL, with similar local recurrence rate (13.1 versus 12.1 %; HR 0.90, 95 % CI 0.68-1.19). Unadjusted 5-year OS and RFS were 70.2 versus 40.3 % and 58.0 versus 25.1 % after MIL and SABR, respectively. PS-weighted, multivariable analyses showed no significant difference in OS (HR 0.89, 95 % CI 0.65-1.20) and better RFS after MIL (HR 0.70, 95 % CI 0.49-0.99). CONCLUSION: OS was not significantly different between stage I NSCLC patients treated with MIL and the PS-weighted population of patients treated with SABR. For operable patients with stage I NSCLC, SABR could therefore be an alternative treatment option with comparable OS outcome. However, RFS was better after MIL due to fewer regional recurrences and distant metastases. Future studies should focus on optimization of patient selection for MIL or SABR to further reduce postoperative mortality and morbidity after MIL and nodal failures after SABR.

Challenges and controversies in resectable non-small cell lung cancer: a clinician's perspective.

The treatment landscape of resectable early-stage non-small cell lung cancer (NSCLC) is transforming due to the approval of novel adjuvant and neoadjuvant systemic treatments. The European Medicines Agency (EMA) recently approved adjuvant osimertinib, adjuvant atezolizumab, adjuvant pembrolizumab, and neoadjuvant nivolumab combined with chemotherapy, and the approval of other agents or new indications may follow soon. Despite encouraging results, many unaddressed questions remain. Moreover, the transformed treatment paradigm in resectable NSCLC can pose major challenges to healthcare systems and magnify existing disparities in care as differences in reimbursement may vary across different European countries. This Viewpoint discusses the challenges and controversies in resectable early-stage NSCLC and how existing inequalities in access to these treatments could be addressed.

Survival difference between patients with single versus multiple metastatic lymph nodes and the role of histology in pathological stage II-N1 non-small cell lung cancer.

BACKGROUND: Previous studies investigating whether metastatic lymph node count is a relevant prognostic factor in pathological N1 non-small cell lung cancer (NSCLC), showed conflicting results. Hypothesizing that outcome may also be related to histological features, we determined the prognostic impact of single versus multiple metastatic lymph nodes in different histological subtypes for patients with stage II-N1 NSCLC. METHODS: We performed a retrospective cohort study using data from the Netherlands Cancer Registry, including patients treated with a surgical resection for stage II-N1 NSCLC (TNM 7th edition) in 2010-2016. Overall survival (OS) was assessed for patients with single (pN1a) and multiple (pN1b) metastatic nodes. Using multivariable analysis, we compared OS between pN1a and pN1b in different histological subtypes. RESULTS: After complete resection of histologically proven stage II-N1 NSCLC, 1309 patients were analyzed, comprising 871 patients with pN1a and 438 with pN1b. The median number of pathologically examined nodes (N1 + N2) was 9 (interquartile range 6-13). Five-year OS was 53% for pN1a versus 51% for pN1b. In multivariable analysis, OS was significantly different between pN1a and pN1b (HR 1.19, 95% CI 1.01-1.40). When stratifying for histology, the prognostic impact of pN1a/b was only observed in adenocarcinoma patients (HR 1.44, 95% CI 1.15-1.81). CONCLUSION: Among patients with stage II-N1 adenocarcinoma, the presence of multiple metastatic nodes had a significant impact on survival, which was not observed for other histological subtypes. If further refinement as to lymph node count will be considered for incorporation into a new staging system, evaluation of the role of histology is recommended.

Prognostic Implication of KRAS G12C Mutation in a Real-World KRAS-Mutated Stage IV NSCLC Cohort Treated With Immunotherapy in The Netherlands.

Introduction: With the approval of G12C inhibitors as the second line of treatment for KRAS G12C-mutated NSCLC, and the expanding research regarding targeting KRAS, it is key to understand the prognostic implication of KRAS G12C in the current first line of treatment. We compared overall survival (OS) of patients with stage IV KRAS G12C-mutated NSCLC to those with a KRAS non-G12C mutation in a first-line setting of (chemo)immunotherapy. Methods: This nationwide population-based study used real-world data from The Netherlands Cancer Registry. We selected patients with stage IV KRAS-mutated lung adenocarcinoma diagnosed in 2019 to 2020 who received first-line (chemo-)immunotherapy. Primary outcome was OS. Results: From 28,120 registered patients with lung cancer, 1185 were selected with a KRAS mutation, of which 494 had a KRAS G12C mutation. Median OS was 15.5 months (95% confidence interval [CI]: 13.6-18.4) for KRAS G12C versus 14.0 months (95% CI:11.2-15.7) for KRAS non-G12C (p = 0.67). In multivariable analysis, KRAS subtype was not associated with OS (hazard ratio = 0.95, 95% CI: 0.82-1.10). For the subgroup with programmed death-ligand 1 at 0% to 49% who received chemoimmunotherapy, median OS was 13.3 months (95% CI: 10.5-15.2) for G12C and 9.8 months (95% CI: 8.6-11.3) for non-G12C (p = 0.48). For the subgroup with programmed death-ligand 1 more than or equal to 50% who received monoimmunotherapy, the median OS was 22.0 months (95% CI: 18.4-27.3) for G12C and 18.9 months (95% CI: 14.9-25.2) for non-G12C (p = 0.36). Conclusions: There was no influence of KRAS subtype (G12C versus non-G12C) on OS in patients with KRAS-mutated stage IV NSCLC treated with first-line (chemo)immunotherapy.

Survival of patients with KRAS G12C mutated stage IV non-small cell lung cancer with and without brain metastases treated with immune checkpoint inhibitors.

INTRODUCTION: Few data is available on whether brain metastases (BM) influence survival in patients with stage IV KRAS G12C mutated (KRAS G12C+ ) non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI) +/- chemotherapy ([chemo]-ICI). METHODS: Data was retrospectively collected from the population-based Netherlands Cancer Registry. The cumulative incidence of intracranial progression, overall survival (OS) and progression free survival (PFS) was determined for patients with KRAS G12C+ stage IV NSCLC diagnosed January 1 - June 30, 2019, treated with first-line (chemo)-ICI. OS and PFS were estimated using Kaplan-Meier methods and BM+ and BM- groups were compared using log-rank tests. RESULTS: Of 2489 patients with stage IV NSCLC, 153 patients had KRAS G12C+ and received first-line (chemo)-ICI. Of those patients, 35% (54/153) underwent brain imaging (CT and/or MRI), of which 85% (46/54) MRI. Half of the patients with brain imaging (56%; 30/54) had BM, concerning one-fifth (20%; 30/153) of all patients, of which 67% was symptomatic. Compared to BM-, patients with BM+ were younger and had more organs affected with metastasis. Around one-third (30%) of patients with BM+ had ≥5 BM at diagnosis. Three quarters of patients with BM+ received cranial radiotherapy prior to start of (chemo)-ICI. The 1-year cumulative incidence of intracranial progression was 33% for patients with known baseline BM and 7% for those without (p = 0.0001). Median PFS was 6.6 (95% CI 3.0-15.9) and 6.7 (95% CI 5.1-8.5) months for BM+ and BM- (p = 0.80), respectively. Median OS was 15.7 (95% CI 6.2-27.3) and 17.8 (95% CI 13.4-22.0) months for BM+ and BM- (p = 0.77), respectively. CONCLUSION: Baseline BM are common in patients with metastatic KRAS G12C+ NSCLC. During (chemo)-ICI treatment, intracranial progression was more frequent in patients with known baseline BM, justifying regular imaging during treatment. In our study, presence of known baseline BM did not influence OS or PFS.

Real-world treatment patterns and survival of patients with ROS1 rearranged stage IV non-squamous NSCLC in the Netherlands.

INTRODUCTION: Rearrangement of c-ros oncogene 1 (ROS1) is a rare gene alteration in patients with stage IV non-squamous non-small cell lung cancer (NSCLC). Molecular testing for ROS1 is recommended to enable primary treatment with tyrosine kinase inhibitors (TKI). Aim of this study was to describe real-world treatment patterns and survival for patients with ROS1 in the Netherlands. METHODS: All non-squamous NSCLC stage IV patients, diagnosed 2015-2019, were identified from the population-based Netherlands Cancer Registry (N = 19,871). For patients with ROS1 rearrangements (ROS1+ ) who received first line TKI, additional information about progression and second-line treatment was retrieved by active follow-up. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimators. RESULTS: A total of 67 patients (0.43%) were diagnosed with a ROS1+ NSCLC. Systemic treatment was administered in 75% which was most often TKI (n = 34) followed by chemotherapy (n = 14). Two-year OS for patients receiving upfront TKI versus other systemic treatment was 53% (95% CI 35-68) and 50% (95% CI 25-71), respectively. For patients receiving TKI, median OS was 24.3 months. Survival was inferior in case of brain metastasis (BM) at diagnosis (5.2 months). One in five patients receiving TKI as a first line treatment had BM at diagnosis, of the remaining 22 another 9 developed BM during follow up. PFS was also inferior for patients with BM at diagnosis with a median PFS of 4.3 months versus 9.0 without BM. CONCLUSION: In this real-world population of ROS1+ NSCLC patients, only half received primary treatment with TKI. Overall survival and PFS during TKI were disappointing, mainly related to brain metastasis. TKI treatment with agents that have intra-cranial activity may be beneficial in this patient population and our results confirm the importance of performing an MRI of the brain as part of the standard diagnostic work up in patients with ROS1+ NSCLC.

Overall survival in advanced epidermal growth factor receptor mutated non-small cell lung cancer using different tyrosine kinase inhibitors in The Netherlands: a retrospective, nationwide registry study.

Background: Clinical guidelines advise osimertinib as preferred first line treatment for advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with deletions in exon 19 (del19) or exon 21 L858R mutation. However, for first-line osimertinib the real world overall survival (OS) in mutation subgroups remains unknown. Therefore, the aim of this study was to evaluate the real-world OS of those patients treated with different generations of EGFR-tyrosine kinase inhibitors (TKI), and to identify predictors of survival. Methods: Using real-world data from the Netherlands Cancer Registry (NCR) we assessed patients diagnosed with stage IV NSCLC with del19 or L858R mutation between January 1, 2015, and December 31, 2020, primarily treated with then regularly available TKIs (including osimertinib). Findings: Between January 1, 2015, and December 31, 2020, 57,592 patients were included in the NCR. Within this cohort we identified 1109 patients, 654 (59%) with del19 and 455 (41%) with L858R mutations, respectively; 230 (21%) patients were diagnosed with baseline brain metastases (BM). Patients were treated with gefitinib (19%, 213/1109), erlotinib (42%, 470/1109), afatinib (15%, 161/1109) or osimertinib (24%, 265/1109). Median OS was superior for del19 versus L858R (28.4 months (95% CI 25.6-30.6) versus 17.7 months (95% CI 16.1-19.5), p < 0.001. In multivariable analysis, no difference in survival was observed between various TKIs in both groups. Only in the subgroup of patients with del19 and baseline BM, a benefit was observed for treatment with osimertinib. Interpretation: In this nationwide real-world cohort, survival of Dutch patients with advanced NSCLC and an EGFR del19 mutation was superior versus those harboring an L858R mutation. Osimertinib performed only better as first-line treatment in patients with del19 and BM. Funding: None.

The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R): Real-World Data on Stage III Non-Small Cell Lung Cancer Patients Treated With Curative Chemoradiation.

INTRODUCTION: Chemoradiotherapy (CRT) is the standard of care in inoperable non-small-cell lung cancer (NSCLC) patients, favoring concurrent (cCRT) over sequential CRT (seqCRT), with adjuvant immunotherapy in responders. Elderly and frail NSCLC patients have generally been excluded from trials in the past. In elderly patients however, the higher treatment related morbidity of cCRT, may outweigh the possible lower tumor control of seqCRT. For elderly patients with locally advanced NSCLC real-world data is essential to be able to balance treatment toxicity and treatment outcome. The aim of this study is to analyze acute toxicity and 3-month mortality of curative chemoradiation (CRT) in patients with stage III NSCLC and to analyze whether cCRT for elderly stage III NSCLC patients is safe. METHODS: The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R) is a national lung cancer audit that started in 2013 for patients treated with curative intent radiotherapy. All Dutch patients treated for stage III NSCLC between 2015 and 2018 with seqCRT or cCRT for (primary or recurrent) stage III lung cancer are included in this population-based study. Information was collected on patient, tumor- and treatment characteristics and the incidence and severity of acute non-hematological toxicity (CTCAE-4 version 4.03) and mortality within 3 months after the end of radiotherapy. To evaluate the association between prognostic factors and outcome (acute toxicity and mortality within 3 months), an univariable and multivariable analysis was performed. The definition of cCRT was:radiotherapy started within 30 days after the start of chemotherapy. RESULTS: Out of all 20 Dutch departments of radiation oncology, 19 centers participated in the registry. A total of 2942 NSCLC stage III patients were treated with CRT. Of these 67.2% (n = 1977) were treated with cCRT (median age 66 years) and 32.8% (n = 965) were treated with seqCRT (median age 69 years). Good performance status (WHO 0-1) was scored in 88.6% for patients treated with cCRT and in 71.0% in the patients treated with seqCRT. Acute nonhematological 3-month toxicity (CTCAE grade ≥3 or radiation pneumonitis grade ≥2) was scored in 21.9% of the patients treated with cCRT and in 17.7% of the patients treated with seqCRT. The univariable analysis for acute toxicity showed significantly increased toxicity for cCRT (P = .008), WHO ≥2 (P = .006), and TNM IIIC (P = .031). The multivariable analysis for acute toxicity was significant for cCRT (P = .015), WHO ≥2 (P = .001) and TNM IIIC (P = .016). The univariable analysis for 3-month mortality showed significance for seqCRT (P = .025), WHO ≥2 (P < .001), higher cumulative radiotherapy dose (P < .001), higher gross tumor volume total (P = .020) and male patients (p < .001). None of these variables reached significance in the multivariable analysis for 3-month mortality. CONCLUSION: In this national lung cancer audit of inoperable NSCLC patients, 3-month toxicity was significantly higher in patients treated with cCRT (21.9% vs. 17.7% for seqCRT) higher TNM stage IIIC, and poor performance (WHO≥2) patients.The 3-months mortality was not significantly different for tested parameters. Age was not a risk factor for acute toxicity, nor 3 months mortality.

Mutation-tailored treatment selection in non-small cell lung cancer patients in daily clinical practice.

OBJECTIVES: The number of targeted drugs in non-small cell lung cancer (NSCLC) is ever-expanding and requires testing of an increasing number of predictive biomarkers. We present a comprehensive real-world evaluation of molecular testing and treatment selection in stage IV NSCLC patients in the Netherlands from 2017 to 2019. MATERIALS AND METHODS: Molecular pathology reports of NSCLC patients were collected from the Dutch Pathology Registry in time intervals between Oct-2017 and April-2019 (N = 5,038 patients) to study diagnostic yield. Linkage between the Dutch Pathology Registry and the Netherlands Cancer Registry enabled studying molecular testing rates for stage IV NSCLC initially diagnosed in 2017-Q4 (N = 1,193) and application of targeted therapy in stage IV NSCLC patients with potentially druggable alterations reported between Oct-2017 and June-2018 (N = 401). RESULTS: Predictive molecular testing was performed in 85.0% of adenocarcinomas, 60.4% of NSCLC-not otherwise specified (NOS) and 17.4% of squamous cell carcinomas. Testing rates were highest for EGFR and ALK (adenocarcinoma: 82.7% and 80.7%, respectively). Incidence of molecular driver alterations (i.e. EGFR, KRAS, ALK, ROS1, BRAF, MET, ERBB2, FGFR1) was 61.1% for adenocarcinomas, 42.3% for NSCLC-NOS, and 24.7% for squamous cell carcinomas. Therapeutically relevant alterations were detected at a higher frequency by NGS- versus non-NGS-approaches (adenocarcinoma: 62.4% versus 56.5%, respectively (P = 0.004)) due to a lower failure rate, more comprehensive testing and higher sensitivity. Uptake of treatment with a registered targeted therapy in eligible patients varied per actionable target, i.e. EGFR: 85.8%, ALK: 74.7%, ROS1: 33.7%, BRAF: 51.5%. Treatment with agents in clinical studies/compassionate use was lower, i.e. MET: 22.8%, HER2: 18.9%, RET: 6.7%. CONCLUSION: Real-world data show NGS-based approaches to be superior to non-NGS. Uptake of molecular testing and the corresponding targeted treatments was less than expected based on guidelines and even more so for trials, off-label use and compassionate use, indicating less than optimal access to rational treatment options.

Minimally invasive lobectomy versus stereotactic ablative radiotherapy for stage I non-small cell lung cancer.

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) 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.

Surgery without preoperative histological confirmation of lung cancer: what is the current clinical practice?

BACKGROUND: There are discordances in the guidelines regarding the need to acquire histological diagnosis before surgical treatment of (presumed) lung cancer. Preoperative histological confirmation is always encouraged in this setting to prevent unnecessary surgery or when sublobar resection for small-sized tumors is considered. The aim of this retrospective cohort study was to assess the proportion of patients undergoing lung cancer resection in the Netherlands without preoperative pathological confirmation, based on the intraoperative pathological diagnosis (IOD) rate, and to determine characteristics that may influence IOD frequency. METHODS: Data on 10,226 patients, who underwent surgical treatment for lung cancer from 2010 to 2015, were retrieved from the Netherlands National Cancer Registry. We registered an IOD when the date of diagnosis equaled the date of the first surgical intervention. Tabulations and multivariable logistic regression were used to identify predictive parameters for IOD. RESULTS: 36% of surgical procedures were classified as IOD, and decreased with increasing tumor size and extent of surgery (57% for segmentectomy, 39% for lobectomy and 11% for pneumonectomy). IOD was more frequently observed in adenocarcinoma (41%), varied between hospitals from 13% to 66% and was less common when patients were referred from a hospital where thoracic surgery was not performed. Previous history of cancer did not affect IOD. CONCLUSIONS: More than one-third of patients with suspected lung cancer in the Netherlands was operated without preoperative histological confirmation. There was significant variation in IOD rates between different hospitals, which deserves further detailed analysis when striving for uniform surgical quality of care for patients with lung cancer.

A Nationwide Study on the Impact of Routine Testing for EGFR Mutations in Advanced NSCLC Reveals Distinct Survival Patterns Based on EGFR Mutation Subclasses.

EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, with the overall objective to characterize the landscape of clinically actionable EGFR mutations and determine the role and clinical relevance of uncommon and composite EGFR mutations. Non-squamous NSCLC patients diagnosed in 2013, 2015 and 2017 were identified in the Netherlands Cancer Registry (NCR) and matched to the Dutch Pathology Registry (PALGA). Overall, 10,254 patients were included. Between 2013-2017, the uptake of EGFR testing gradually increased from 72.7% to 80.9% (p < 0.001). Multi-gene testing via next-generation sequencing (increased from 7.8% to 78.7% (p < 0.001), but did not affect the number of detected EGFR mutations (n = 925; 11.7%; 95% confidence interval (CI), 11.0-12.4) nor the distribution of variants. For patients treated with first-line EGFR inhibitors (n = 651), exon 19 deletions were associated with longer OS than L858R (HR 1.58; 95% CI, 1.30-1.92; p < 0.001) or uncommon, actionable variants (HR 2.13; 95% CI, 1.60-2.84; p < 0.001). Interestingly, OS for patients with L858R was similar to those with uncommon, actionable variants (HR 1.31; 95% CI, 0.98-1.75; p = 0.069). Our analysis indicates that grouping exon 19 deletions and L858R into one class of 'common' EGFR mutations in a clinical trial may mask the true activity of an EGFR inhibitor towards specific mutations.

Stage I non-small cell lung cancer: Treatment modalities, Dutch daily practice and future perspectives.

OBJECTIVES: Several treatment modalities are available for patients with stage I non-small cell lung cancer (NSCLC). Over the past decade, these treatment modalities have been further investigated and might have changed current treatment regimens. In this review we present an overview of the treatment options, developments and future perspectives for stage I NSCLC. Furthermore, we describe the current use of these treatment modalities in the Netherlands. MATERIALS AND METHODS: A bibliographical search was performed in PubMed and the Cochrane Library for publications concerning treatment modalities for stage I NSCLC. In addition, evidence-based guidelines of the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) were studied. RESULTS: The guideline-recommended treatment for operable stage I NSCLC patients is a lobectomy with systematic lymph node dissection. Inoperable patients or those refusing surgery are offered stereotactic ablative radiotherapy (SABR). Percutaneous ablation, such as radiofrequency ablation, is a non-surgical minimally invasive technique offered to those who are ineligible for surgery or SABR. The role of systemic therapy is currently limited. However, the efficacy of immunotherapy is being investigated in clinical trials. In the Netherlands, an increasing use of SABR and a relative decrease in resection rates have been observed. CONCLUSION: Surgery and SABR are currently the prevailing treatment modalities for stage I NSCLC patients. Despite optimization of treatment regimens, survival of patients with stage I NSCLC remains to be improved. Future studies are required to optimize treatment strategies, but also to investigate factors influencing treatment decision-making for patients with stage I NSCLC.

Age-related treatment patterns for stage I NSCLC in three European countries.

INTRODUCTION: Surgery is the preferred treatment for patients with early-stage non-small cell lung cancer (NSCLC) while stereotactic body radiation therapy (SBRT) may be applied in patients with major comorbidity or high age. We evaluated the association between age and treatment utilization for early-stage NSCLC in patients diagnosed in 2015-2016 in three European countries. PATIENTS AND METHODS: Information was retrieved from population-based registries in England, Norway and the Netherlands. Treatment patterns and two-year overall survival rates for 105,124 patients with clinical stage I were analysed by age-group. RESULTS: Surgical resection rates were higher in Norway (55%) and England (53%) than in the Netherlands (47%), and decreased with increasing age. SBRT use was highest in the Netherlands (41%), followed by Norway (29%) and England (12%). In the Netherlands, SBRT was the prevailing treatment in patients aged 70 years or older. In octogenarians, the proportion not receiving curative intent treatment was 53% in England, versus 35% in Norway and 22% in the Netherlands. Two-year survival rates were better for surgery than for SBRT and slightly better in Norway. CONCLUSION: In patients aged 70 years or older, the proportion not receiving any curative treatment remains substantial, and differs significantly between countries. Measures to address these disparities are needed.

Preoperative Biopsy Diagnosis in Pulmonary Carcinoids, a Shot in the Dark.

INTRODUCTION: The preferred treatment for pulmonary carcinoids (PCs) is lobectomy, and parenchyma-sparing approaches might be considered for typical carcinoids (TCs). Treatment decisions are based on a preoperative biopsy diagnosis. Following the WHO criteria (2015), definitive diagnosis is only feasible postoperatively, thereby hampering preoperative treatment decisions. Here, we determined whether the final carcinoid classification on a resection specimen can be predicted by a preoperative biopsy. METHODS: We searched all stage I to III patients with a final carcinoid diagnosis who underwent a curative resection and of whom both a preoperative biopsy and paired resection specimen were available (2003-2012) using the Dutch Pathology Registry (PALGA) and the Netherlands Cancer Registry (IKNL). Pathology report conclusions of the biopsy-resection specimen were compared. RESULTS: Paired biopsy-resection specimens in combination with clinical data were available from 330 patients. 57% (189 of 330) of the patients exhibited discordance between the preoperative biopsy and paired resection diagnosis, including 36% (44 of 121) preoperatively diagnosed TC, 40% (six of 15) atypical carcinoid (AC), and 65% (103 of 158) not-otherwise-specified (NOS) carcinoids. A quarter of preoperatively diagnosed TC and NOS was reclassified as AC on the resection specimen. Preoperatively diagnosed ACs exhibited the highest relapse rates (40%, 6 of 15). Preoperatively diagnosed TC and NOS patients who were reclassified as ACs exhibited higher relapse rates as compared to nonreclassified TCs and NOS (3% versus 1%, and 16% versus 6%). CONCLUSIONS: We provide evidence that carcinoid classification on preoperative biopsies is imprecise, as is also stated by the current WHO classification. We advise clinicians to interpret the preoperative biopsy diagnosis with caution in deciding the extent of surgery (e.g., parenchyma-sparing versus non-parenchyma-sparing).

Metformin use and lung cancer survival: a population-based study in Norway.

BACKGROUND: We assessed associations between metformin use and survival in a nationwide Norwegian cohort of lung cancer (LC) patients. METHODS: The study linked 22,324 LC patients from the Cancer Registry of Norway diagnosed 2005-2014 with the Norwegian Prescription Database. We estimated associations of pre- and post-diagnostic metformin use with overall survival (OS) and LC-specific survival (LCSS) using multivariable time-fixed and time-dependent Cox regression. RESULTS: Pre-diagnostic metformin use was not associated with improved survival in all patients. Nevertheless, pre-diagnostic metformin use was associated with better LCSS in squamous cell carcinoma (SCC) patients (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.62-0.99) and in patients with regional stage SCC (HR = 0.67; 95%CI 0.47-0.95). Post-diagnostic metformin use was associated with improved LCSS in all patients (HR = 0.83; 95%CI 0.73-0.95), in patients with SCC (HR = 0.75; 95%CI 0.57-0.98), regional stage LC (HR = 0.74; 95%CI 0.59-0.94), and regional stage SCC (HR = 0.57; 95%CI 0.38-0.86). OS showed similar results. Analyses of cumulative use showed a dose-response relationship in all patients, patients with adenocarcinoma and SCC, and with regional and metastatic LC. CONCLUSIONS: Metformin use was associated with improved survival, especially LCSS in patients with regional stage SCC. Further prospective studies are required to clarify the role of metformin in LC treatment.

Risk of second primary malignancies among patients with carcinoid of the lung.

OBJECTIVES: Little is known about the etiology of pulmonary carcinoids (PC). Associations with other types of cancer may identify shared risk factors but results from earlier studies were inconclusive. The aim of the present study was to explore the association between PC and other primary malignancies for identifying risk factors. METHODS: A query of the nationwide Netherlands Cancer Registry generated data about patients diagnosed with PC from 1989 to 2018. The occurrence of second primary malignancies was evaluated separately for year 1 and years 2-30. The expected numbers of second primary malignancies were calculated using incidence reference tables, controlling for age, gender and period. Confidence intervals (95 % CI) for the ratio between observed and expected numbers (SIR: standardized incidence ratio) were calculated using Poisson distributions. RESULTS: In a total of 2933 patients with PC, 425 consecutive primary malignancies were observed in 376 patients. Concomitant diagnoses in the first year mainly comprised lung (n = 59) and renal cancer (n = 14). Metachronous malignancies beyond the first year were most common for breast (n = 50), colorectal (n = 41), prostate (n = 32), and lung cancer (n = 29). Beyond year 1, the overall risk of second primary cancer in patients with PC was similar to the risk within the general population (n = 256, SIR = 1.12, 95 % CI 0.99-1.27). Increased risks were observed for soft tissue sarcoma (n = 5, SIR = 3.52, 95 % CI 1.14-8.22) and GEPNET (n = 4, SIR = 4.30, 95 % CI 1.17-11.01). CONCLUSIONS: Concomitant diagnosis of PC with other cancers is common, reflecting surveillance diagnostics. Apart from MEN-1 family history, no shared risk factors could be identified.

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non-small-cell Lung Cancer.

BACKGROUND: Only a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival. PATIENTS AND METHODS: Information about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals. RESULTS: A total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis. CONCLUSION: Dutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib.

The role of surgery for stage I non-small cell lung cancer in octogenarians in the era of stereotactic body radiotherapy in the Netherlands.

OBJECTIVES: Resection 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 METHODS: We 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 CONCLUSION: 8764 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.