Real-World Treatment Patterns and Survival Outcomes for Patients with Non-Metastatic Non-Small-Cell Lung Cancer in Sweden: A Nationwide Registry Analysis from the I-O Optimise Initiative.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with ~40-50% of patients diagnosed with non-metastatic disease (stages IA-IIIC). The treatment landscape is evolving rapidly as immunotherapies and targeted therapy are introduced in the non-metastatic setting, creating a need to assess patient outcomes prior to their introduction. This real-world study using Swedish National Lung Cancer Registry data examined outcomes (overall survival (OS) and time to next treatment or death (TTNTD)) and treatment patterns for adults diagnosed with non-metastatic NSCLC. Baseline characteristics and OS from diagnosis were described for all patients; OS, treatment patterns, and TTNTD from treatment start were described for the treatment subgroup (patients diagnosed from 2014 onwards), stratified by disease stage and initial treatment. OS and TTNTD were described using the Kaplan-Meier estimator. The overall population (2008-2019) included 17,433 patients; the treatment subgroup included 5147 patients. Median OS (interquartile range) overall ranged from 83.3 (31.6-165.3) months (stage I patients) to 10.4 (4.3-24.2) months (stage IIIB patients). Among the treatment subgroup, median OS and TTNTD were longest among patients receiving surgery versus other anticancer treatments. These findings provide a baseline upon which to evaluate the epidemiology of non-metastatic NSCLC as newer treatments are introduced.

A successful shift from thoracotomy to video-assisted thoracoscopic lobectomy for non-small cell lung cancer in a low-volume center.

OBJECTIVES: Although video-assisted thoracoscopic surgery (VATS) lobectomy has become the gold standard for pulmonary resections of non-small-cell lung cancer (NSCLC), lobectomy is still performed via thoracotomy in many European and North American centres. VATS lobectomy was implemented overnight from thoracotomy in our low-volume centre in early 2019, after 1 senior surgeon undertook observership VATS-training overseas, and immediately became the mainstay of surgical treatment for NSCLC in Iceland. We aimed to investigate our short-term outcomes of VATS lobectomy. METHODS: This was a retrospective study on all pulmonary resections for NSCLC in Iceland 2019-2022, especially focusing on VATS lobectomies, all at cTNM stage I or II. Data were retrieved from hospital charts, including information on perioperative complications, mortality, length of stay and operation time. RESULTS: Out of 204 pulmonary resections, mostly performed by a single senior cardiothoracic surgeon, 169 were lobectomies (82.9%) with 147 out of 169 (87.0%) being VATS lobectomies. Anterolateral thoracotomy was used in 34 cases (16.7%), including 22 lobectomies (64.7%), and 5 (3.4%) conversions from VATS lobectomy. The median postoperative stay for VATS lobectomy was 4 days and the average operating time decreased from 155 to 124 min between the first and last year of the study (P < 0.001). The rate of major and minor complications was 2.7% and 15.6% respectively. One year survival was 95.6% and all patients survived 30 days postoperatively. CONCLUSIONS: The implementation of VATS lobectomy has been successful in our small geographically isolated centre, serving a population of 390 000. Although technically challenging, VATS lobectomy was implemented fast for most NSCLC cases, with short-term outcomes that are comparable to larger high-volume centres.

Real-world analysis of MET exon 14 mutations in non-small cell lung cancer: a retrospective study from two Swedish hospitals.

BACKGROUND: Real-World evidence on mesenchymal-epithelial transition exon 14 skipping mutations (METex14) in lung cancer remains limited. With an incidence of 3-4% across histological subtypes, METex14 is now an actionable target for MET inhibitors (METi) in advanced lung cancer, demonstrating response rates between 30-70%. Yet, its role in early stages and sensitivity to immune checkpoint inhibitors (ICIs) is still under exploration. MATERIAL AND METHODS: We conducted a retrospective analysis of the clinical data of lung cancer patients presenting with METex14 across all stages. These patients were treated at two Swedish University Hospitals: Karolinska and Skåne, between the years 2014 and 2022. RESULTS: We identified a total of 63 patients, of which 50 met the inclusion criteria. The median overall survival (OS) with corresponding 95% confidence intervals (95% CI) according to the stage was not reached (NR) for stage I, NR for stage II, 15 months (95% CI, 5.4-24.6) for stage III, and 17 months (95% CI, 9.2-NR) for stage IV. The median OS for stage IV patients who received a METi was 17 months (95% CI, 9.5-NR) vs. 10 months (95% CI, 6.2-NR) in patients without METi (p = 0.92; Hazard Ratio [HR] = 1.07). The median OS for stage IV patients who received ICIs was 18 months (95% CI, 16.5-NR) vs. 6 months (95% CI, 2.5-NR) in patients without ICIs (p = 0.15; HR = 0.47). The median OS for stage IV patients who received chemotherapy was 17 months (95% CI, 9.7-NR) vs. 10 months (95% CI, 4.5-NR) in patients without (p = 0.97; HR = 0.98). CONCLUSIONS: Our data suggest limited survival benefits from METi, ICIs, and chemotherapy for METex14 lung cancer patients. While not statistically significant, these findings underscore the need for larger trials for validation. Identifying effective treatments for this challenging lung cancer subtype remains a priority.

Prevalence, molecular markers, and outcome of bronchial squamous carcinoma in situ in high-risk subjects.

Bronchial squamous carcinoma in situ (CIS) is a preinvasive lesion that is thought to precede invasive carcinoma. We conducted prospective autofluorescence and white light bronchoscopy trials between 1992 and 2016 to assess the prevalence, molecular markers, and outcome of individuals with CIS and other preneoplastic bronchial lesions. Biopsies were evaluated at multiple levels and selected biopsies were tested for aneuploidy and DNA sequenced for TP53 mutation. Thirty-one individuals with CIS were identified. Twenty-two cases of CIS occurred in association with concurrent invasive carcinomas. Seven of the invasive tumors were radiographically occult. In two cases, CIS spread from the focus of invasive carcinoma into contralateral lung lobes, forming secondary invasive tumors. In nine cases, CIS occurred as isolated lesions and one progressed to invasive squamous carcinoma at the same site 40 months after discovery. In a second case, CIS was a precursor of carcinoma at a separate site in a different lobe. In seven cases CIS regressed to a lower grade or disappeared. High level chromosomal aneusomy was often associated with TP53 mutation and with invasive carcinoma. CIS most often occurs in association with invasive squamous carcinoma and may extend along the airways into distant lobes. In rare cases, CIS may be observed to directly transform into invasive carcinoma. CIS may be indicative of invasive tumor at a separate distant site. Isolated CIS may regress. Molecular changes parallel histological changes in CIS and may be used to map clonal expansion in the airways.

Establishment of mountain birch (Betula pubescens ssp. tortuosa) on a glacial outwash plain: Spatial patterns and decadal processes.

Most of the Earth's surface has now been modified by humans. In many countries, natural and semi-natural ecosystems mostly occur as islands, isolated by land converted for agriculture and a variety of other land-uses. In this fragmented state, long-distance dispersal may be the only option for species to adapt their ranges in response to changing climate. The order of arrival of species may leave a lasting imprint on community assembly. Although mostly studied at and above the species level, such priority effects also apply at the intraspecific level. We suggest that this may be particularly important in subarctic and arctic ecosystems. Mountain birch (Betula pubescens ssp. tortuosa) is characterized by great intraspecific variation. We explored spatio-temporal patterns of the first two mountain birch generations on a homogeneous, early successional glacial outwash plain in SE Iceland that was the recipient of spatially extensive long-distance dispersal ca. 30 years ago. We evaluated the decadal progress of the young population by remeasuring in 2018, tree density and growth form, plant size, and reproductive effort on 30 transects (150 m2) established in 2008 at four sites on the plain and two adjacent sites ca. 10 km away. All measured variables showed positive increases, but contrary to our predictions of converging dynamics among sites, they had significantly diverged. Thus, two of the sites (only 500 m apart) could not be distinguished in 2008, but by 2018, one of them had much faster growth rates than the other, a higher growth form index reflecting more upright tree stature, greater reproductive effort, and much greater second-generation seedling recruitment. We discuss two hypotheses that may explain the diverging dynamics, site-scale environmental heterogeneity, and legacies of intraspecific priority effects.

A gene expression-based single sample predictor of lung adenocarcinoma molecular subtype and prognosis.

Disease recurrence in surgically treated lung adenocarcinoma (AC) remains high. New approaches for risk stratification beyond tumor stage are needed. Gene expression-based AC subtypes such as the Cancer Genome Atlas Network (TCGA) terminal-respiratory unit (TRU), proximal-inflammatory (PI) and proximal-proliferative (PP) subtypes have been associated with prognosis, but show methodological limitations for robust clinical use. We aimed to derive a platform independent single sample predictor (SSP) for molecular subtype assignment and risk stratification that could function in a clinical setting. Two-class (TRU/nonTRU=SSP2) and three-class (TRU/PP/PI=SSP3) SSPs using the AIMS algorithm were trained in 1655 ACs (n = 9659 genes) from public repositories vs TCGA centroid subtypes. Validation and survival analysis were performed in 977 patients using overall survival (OS) and distant metastasis-free survival (DMFS) as endpoints. In the validation cohort, SSP2 and SSP3 showed accuracies of 0.85 and 0.81, respectively. SSPs captured relevant biology previously associated with the TCGA subtypes and were associated with prognosis. In survival analysis, OS and DMFS for cases discordantly classified between TCGA and SSP2 favored the SSP2 classification. In resected Stage I patients, SSP2 identified TRU-cases with better OS (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18-0.49) and DMFS (TRU HR = 0.52; 95% CI = 0.33-0.83) independent of age, Stage IA/IB and gender. SSP2 was transformed into a NanoString nCounter assay and tested in 44 Stage I patients using RNA from formalin-fixed tissue, providing prognostic stratification (relapse-free interval, HR = 3.2; 95% CI = 1.2-8.8). In conclusion, gene expression-based SSPs can provide molecular subtype and independent prognostic information in early-stage lung ACs. SSPs may overcome critical limitations in the applicability of gene signatures in lung cancer.

Clinical Utility of Targeted Sequencing in Lung Cancer: Experience From an Autonomous Swedish Health Care Center.

OBJECTIVES: Mutation analysis by massive parallel sequencing (MPS) is routinely performed in the clinical management of lung cancer in Sweden. We describe the clinical and mutational profiles of lung cancer patients subjected to the first 1.5 years of treatment predictive MPS testing in an autonomous regional health care region. METHODS: Tumors from all patients with lung cancer who had an MPS test from January 2015 to June 2016 in the Skåne health care region in Sweden (1.3 million citizens) were included. Six hundred eleven tumors from 599 patients were profiled using targeted sequencing with a 26-gene exon-focused panel. Data on disease patterns and characteristics of the patients subjected to testing were assembled, and correlations between mutational profiles and clinical features were analyzed. RESULTS: MPS with the 26-gene panel revealed alterations in 92% of the 611 lung tumors, with the most frequent mutations detected in the nontargetable genes TP53 (62%) and KRAS (37%). Neither KRAS nor TP53 mutations were associated with disease pattern, chemotherapy response, progression-free survival, or overall survival in advanced-stage disease treated with platinum-based doublet chemotherapy as a first-line treatment. Among targetable genes, EGFR driver mutations were detected in 10% of the tumors, and BRAF p.V600 variants in 2.3%. For the 71 never smokers (12%), targetable alterations (EGFR mutations, BRAF p.V600, MET exon 14 skipping, or ALK/ROS1 rearrangement) were detected in 59% of the tumors. CONCLUSION: Although the increasing importance of MPS as a predictor of response to targeted therapies is indisputable, its role in prognostics or as a predictor of clinical course in nontargetable advanced stage lung cancer requires further investigation.

Improved long-term survival following pulmonary resections for non-small cell lung cancer: results of a nationwide study from Iceland.

BACKGROUND: We studied the outcome of pulmonary resection with curative intent for non-small cell lung cancer (NSCLC) in a nationwide study covering a 24-year period, focusing on survival. METHODS: All patients who underwent pulmonary resection for NSCLC in Iceland in the period 1991-2014 were reviewed for demographics, TNM stage and survival. Median length of follow-up was 45 months. Three 8-year periods were compared, overall survival was estimated, and prognostic factors for survival were identified. RESULTS: Altogether, 652 surgical resections were performed on 644 individuals (52% females): 492 lobectomies (75%), 77 pneumonectomies (12%), and 83 sublobar resections (13%). Mean age increased from 65 to 68 yrs during the study period (P=0.002). The number of cases operated at stage IA increased substantially between the first and last periods (29% vs. 37%; P<0.001). Survival improved from 75% to 88% at 1 year and from 38% to 53% at 5 years (P<0.001). Independent prognostic factors for mortality were advanced TNM stage (HR =2.68 for stage IIIA vs. I), age (HR =1.04), ischaemic heart disease (HR =1.26), any minor complication (HR =1.26), and sublobar resection (HR =1.33), but surgical margins free from tumour growth (HR =0.59) and treatment during the latter two eight-year periods were predictors of lower mortality. The best survival was seen between 2007 and 2014 (HR =0.61, 95% CI: 0.48-0.78; P<0.001). CONCLUSIONS: Survival of patients who have undergone pulmonary resection for NSCLC has improved significantly in Iceland. This may be explained by the increased number of patients diagnosed at lower stages and improved preoperative staging, with fewer understaged patients.

Resection rate and operability of elderly patients with non-small cell lung cancer: Nationwide study from 1991 to 2014.

OBJECTIVES: An increasing number of elderly patients are diagnosed with non-small cell lung cancer (NSCLC). We compared the surgical resection rate, operability and survival in this age group (≥75 years) to younger patients using centralized databases in Iceland. METHODS: The study population comprised all patients diagnosed with NSCLC in Iceland from 1991 to 2014. A total of 140 elderly patients (≥75 years) with NSCLC underwent pulmonary resection and were compared with 550 surgically resected patients less than 75 years, with respect to resection rate, short and long-term survival and complications of surgery. Reasons for exclusion from surgery were registered for elderly surgical candidates (stages IA-IIB). RESULTS: Surgical resection rate in the elderly group was 18% compared to 32% in the younger age group ( P < 0.001). The most frequent reasons for not operating on elderly patients in stages IA-IIB were poor pulmonary function (58%), heart disease (17%) or multiple comorbidities (17%). The rate of major complications following surgery was comparable in the elderly versus the younger age group, 13 vs 11%, respectively ( P = 0.578). The same was true for 30 day mortality (2 vs 1%, P = 0.397). Five-year overall survival was 40% vs 44% ( P = 0.019) and cancer-specific survival 51% vs 50% ( P = 0.802). CONCLUSIONS: Elderly patients with resectable NSCLC according to stage are frequently excluded from surgery due to comorbid conditions. Although the operated patients may represent a selected group, their favourable 30-day and long-term survival indicate that more elderly patients with NSCLC could be operated on.

Smoking during pregnancy: A population-based study.

AIMS: Tobacco is a major cause of disease and mortality in modern times. The risk of smoking in pregnancy is a serious threat to the development and future health of an unborn child. The aim of this study was to explore the epidemiological factors associated with smoking during pregnancy in a primary healthcare setting. METHODS: All 856 maternity records at the Glaesibaer Health Care Centre in Reykjavik during 2006-2013 were reviewed and information on smoking habits investigated. RESULTS: The records showed that in 108 (12.2%) pregnancies, women smoked at first visit and 63 stopped smoking in early pregnancy, leaving 45 (5.3%) mothers smoking throughout the whole gestational period. The mean age of the smoking women was 27.8 years and for the non-smokers 29.7 years. Low social status (odds ratio (OR) = 2.66; 95% confidence interval (CI): 1.19-5.96), previous mental health diagnosis (OR = 2.7; 95% CI: 1.3-5.6), and unstable relationship with a partner (OR = 3.78; 95% CI: 2.1-7.0) were associated with smoking. Smoking fewer cigarettes was associated with a 0.04-unit lower risk of smoking during pregnancy (OR = 0.04: 95% CI: 0.02-0.08). CONCLUSIONS: Our results indicated that the women who smoked during pregnancy were often heavy smokers and living without a partner. They were younger, had worse mental health, and a lower social status than those pregnant women who did not smoke. Bearing in mind the consequence of smoking in pregnancy, this subgroup should get increased assistance to quit smoking before and during early pregnancy, as well as appropriate medical and social support.

Primary adenocarcinoma of the lung--histological subtypes and outcome after surgery, using the IASLC/ATS/ERS classification of lung adenocarcinoma.

Adenocarcinoma is the most common histological type of lung carcinoma. Recently the histologic classification of adenocarcinomas in the lung was modified to better reflect biologic properties and prognosis. We reviewed the histology of all primary lung adenocarcinomas operated on in Iceland during a 20-year period and assessed the impact of histology on survival. This nationwide study included 285 patients (mean age 67 years, 57% female), who underwent resection in Iceland from 1991 to 2010. Tumors were reclassified according to the current IASLC/ATS/ERS classification system. Overall survival was estimated by the Kaplan-Meier method and Cox regression analysis used to evaluate prognostic factors of overall mortality. Acinar predominant adenocarcinoma was the most common histological subtype (46%) followed by solid-predominant (SPA) with mucin production comprised (23%). Non-invasive carcinomas were rare. A difference in survival between the histological adenocarcinoma subtypes was not seen (p = 0.32) and multivariate analysis showed that advanced stage and age predicted worse outcome, but histologic subtyping of adenocarcinoma did not. In this nation-wide study there was not a statistical difference in survival according to adenocarcinoma subtypes and the histological subtype did not predict mortality. Preinvasive and minimally invasive adenocarcinomas were rare.

[Outcome of surgical treatment for Pancoast lung carcinoma in Iceland]. / Árangur skurdmedfedar vid Pancoast-lungnakrabbameini á Íslandi.

OBJECTIVE: Pancoast tumors are lung carcinomas that invade the apical chest wall and surrounding structures. Treatment is complex and often involves surgery together with radio- and chemotherapy. We studied the outcome of surgical resection for Pancoast tumors in Iceland. MATERIALS AND METHODS: A retrospective study including all patients that underwent resection of a Pancoast tumor with curative intent in Iceland in the years 1991-2010. Data on symptoms, complications, TNM-stage, relapse and survival were analyzed. RESULTS: Twelve patients were operated on; 7 on the right lung. Shoulder pain (n=5) and/or chest pain (n=3), cough (n=6) and weight loss (n=5) were the most common presenting symptoms. Adenocarcinoma (n=5) and squamous cell carcinoma (n=4) were the most frequent histological types. Average tumor size was 5,9 cm (range: 2,8-15). Five cases were stage IIB and 7 stage IIIA according to operative staging. In 10 cases (83%) the surgical margins were free of tumor. All patients survived surgery and only one patient suffered a major operative complication, an intraoperative bleeding. In one case induction chemo-radiation prior to surgery was administrated, and 8 patients received postoperative radiotherapy. Recurrent disease was diagnosed in 9 patients; four had local or regional recurrence, four had distant metastases and one patient was diagnosed with both local and distant recurrences simultaneously. Survival at 5 years was 33% and median survival was 27,5 months (range: 4-181). CONCLUSIONS: Operative and short-term outcomes for patients with Pancoast tumors in Iceland are excellent. However, long-term outcomes are not as favorable and recurrence rate is high compared to other studies, possibly due to incomplete preoperative staging and less use of chemo-radiation therapy prior to surgery among these patients.

Resection rate and outcome of pulmonary resections for non-small-cell lung cancer: a nationwide study from Iceland.

BACKGROUND: The proportion of patients with non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent is one measure of effectiveness in treating lung cancer. To the best of our knowledge, surgical resection rate (SRR) for a whole nation has never been reported before. We studied the SRR and surgical outcome of NSCLC patients in Iceland during a recent 15-year period. METHODS: This was a retrospective study of all pulmonary resections performed with curative intent for NSCLC in Iceland from 1994 to 2008. Information was retrieved from medical records and from the Icelandic Cancer Registry. Patient demographics, postoperative tumor, node, metastasis stage, overall survival, and complication rates were compared over three 5-year periods. RESULTS: Of 1530 confirmed cases of NSCLC, 404 were resected, giving an SRR of 26.4%, which did not change significantly during the study period. Minor and major complication rates were 37.4% and 8.7%, respectively. Operative mortality rates were 0.7% for lobectomy, 3.3% for pneumonectomy, and 0% for lesser resection. Five-year survival after all procedures was 40.7% and improved from the first to the last 5-year period (34.8% versus 43.8%, p = 0.04). Five-year survival for stages I and II together was 46.8%, with no significant change in stage distribution between periods. Five-year survival after pneumonectomy was 22.0%, which was significantly lower than for lobectomy (44.6%) and lesser resection (40.7%) (p < 0.005). Unoperated patients had a 5-year survival of 4.8%, as compared to 12.4% for all the NSCLC patients together. CONCLUSION: Compared with most other published studies, the SRR of NSCLC in Iceland is high. Short-term outcome is good, with a low rate of major complications and an operative mortality of only 1.0%. Five-year survival improved significantly over the study period.

[Postoperative complications following lobectomy for lung cancer in Iceland during 1999-2008]. / Fylgikvillar bladnámsadgerda vid lungnakrabbameini á Islandi 1999-2008.

OBJECTIVE: Non small cell lung cancer (NSCLC) is the second most common cancer in Iceland. We studied the indications and surgical outcome of lobectomy for NSCLC in Iceland. MATERIALS AND METHODS: 213 consecutive patients underwent lobectomy for NSCLC between 1999 and 2008. Data on indications, histology, TNM-stage and complications were analysed, and logistic regression used to assess outcome predictors. RESULTS: The majority of patients (60%) were referred because of symptoms, whereas 40% were asymptomatic. Adenocarcinoma (62%) and squamous cell carcinoma (29%) were the most frequent histological types. Operative staging showed that 59.6% of cases were stage I, 17.8% were stage II, 7% were stage IIIA and 14.6% were stage IIIB or IV. Mediastinoscopy was performed in 13.6% of cases. Mean operative time was 128 min., operative bleeding 580 ml and median hospital stay 10 days. Sixteen patients (7.5%) had major complications and 36 (17.5%) had minor complications, such as atrial fibrillation and pneumonia. Twelve patients required reoperation, most often due to bleeding, but two had empyema and one had a bronchopleural fistula. Older patients with high ASA scores and extensive smoking history were at increased risk for complications. No patient died within 30 days of surgery whereas two (0,9%) died within 90 days of surgery. CONCLUSIONS: The results of lobectomy for NSCLC in Iceland are excellent in relation to operative mortality and short term complications.

[Factors predictive of survival after lobectomy for non-small cell lung cancer in Iceland during 1999-2008]. / Forspárbaettir lífshorfa eftir bladnám vid lungnakrabbameini á Islandi 1999-2008.

OBJECTIVE: To study the impact of TNM stage and various preoperative functional parameters on survival in patients who underwent lobectomy for non-small cell lung cancer (NSCLC) in Iceland from 1999 to 2008. MATERIALS AND METHODS: Retrospective study including 213 patients (mean age 66.9 yrs, equal male/female ratio) that underwent lobectomy for NSCLC. Tumors were staged by the TNM staging system, survival was estimated by the Kaplan-Meier method and prognostic factors of survival studied using the Cox proportional hazards regression model. RESULTS: Survival at 1 year was 82.7% and 45.1% at 5 years. Operative mortality at 30 days was 0%. Most tumors were found to be in stage I (59.6%) or stage II (17.8%) and 7% were stage IIIA, whereas 14.6% were in stage IIIB or IV. Using multivariate analysis; advancing stage, increasing tumor size, reduced lung function and history of arrhythmia, predicted worse survival, whereas adenocarcinoma histology was a positive prognostic factor (HR 0.5, p=0.002) when compared to other histological types. CONCLUSIONS: Survival for patients undergoing lobectomy for operable non-small cell lung cancer in Iceland is comparable with other studies. Advanced stage, tumor size, reduced lung function and arrhythmia were negative predictors of survival, but in contrast to many but not all studies adenocarcinoma histology predicted a better prognosis compared to other tumor types.