Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions.

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.

Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes. METHODS: We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally). RESULTS: A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P = 0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population. CONCLUSIONS: In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.).

Thoracic irradiation as consolidation therapy in patients with extensive-stage small cell lung cancer.

PURPOSE OF REVIEW: Small cell lung cancer (SCLC) is marked by an exceptionally high proliferative rate and poor prognosis. Given its high propensity to metastasize, nearly two-thirds of SCLC patients are diagnosed with extensive-stage (ES) disease when surgery is not a treatment option anymore. Over several decades, only minimal changes have been made in the therapeutic armamentarium of ES-SCLC. Recently, however, several new therapeutic avenues were defined, thus renewing the hope for patients with this recalcitrant cancer. Here, we present an overview of the most current therapeutic advances in ES-SCLC focusing in particular on consolidative thoracic radiation therapy (cTRT) and chemo-immunotherapy. RECENT FINDINGS: The incorporation of immunotherapy in the standard-of-care of ES-SCLC patients and the resulting outcomes are both a remarkable hallmark of progress and a disappointment. Indeed, chemo-immunotherapy with or without cTRT and prophylactic cranial irradiation contributes to longer survival outcomes with minimal toxicity rates in well selected and properly monitored patients. Nevertheless, the gain in overall survival is still modest relative to that seen in many other solid tumors. SUMMARY: Despite the encouraging results, further clinical trials are needed to determine the efficacy and safety of these therapeutic approaches, and moreover, to identify new predictive biomarkers of response.

Nationwide lung cancer screening with low-dose computed tomography: implementation and first results of the HUNCHEST screening program.

OBJECTIVES: Lung cancer (LC) kills more people than any other cancer in Hungary. Hence, there is a clear rationale for considering a national screening program. The HUNCHEST pilot program primarily aimed to investigate the feasibility of a population-based LC screening in Hungary, and determine the incidence and LC probability of solitary pulmonary nodules. METHODS: A total of 1890 participants were assigned to undergo low-dose CT (LDCT) screening, with intervals of 1 year between procedures. Depending on the volume, growth, and volume doubling time (VDT), screenings were defined as negative, indeterminate, or positive. Non-calcified lung nodules with a volume > 500 mm3 and/or a VDT < 400 days were considered positive. LC diagnosis was based on histology. RESULTS: At baseline, the percentage of negative, indeterminate, and positive tests was 81.2%, 15.1%, and 3.7%, respectively. The frequency of positive and indeterminate LDCT results was significantly higher in current smokers (vs. non-smokers or former smokers; p < 0.0001) and in individuals with COPD (vs. those without COPD, p < 0.001). In the first screening round, 1.2% (n = 23) of the participants had a malignant lesion, whereas altogether 1.5% (n = 29) of the individuals were diagnosed with LC. The overall positive predictive value of the positive tests was 31.6%. Most lung malignancies were diagnosed at an early stage (86.2% of all cases). CONCLUSIONS: In terms of key characteristics, our prospective cohort study appears consistent to that of comparable studies. Altogether, the results of the HUNCHEST pilot program suggest that LDCT screening may facilitate early diagnosis and thus curative-intent treatment in LC. KEY POINTS: • The HUNCHEST pilot study is the first nationwide low-dose CT screening program in Hungary. • In the first screening round, 1.2% of the participants had a malignant lesion, whereas altogether 1.5% of the individuals were diagnosed with lung cancer. • The overall positive predictive value of the positive tests in the HUNCHEST screening program was 31.6%.

Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.

BACKGROUND: An earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival. METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary end points were progression-free survival (as assessed by blinded independent central review) and overall survival. Secondary end points included the time to death or distant metastasis, the time to second progression, and safety. RESULTS: Of the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events. CONCLUSIONS: Durvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

Access to Novel Drugs for Non-Small Cell Lung Cancer in Central and Southeastern Europe: A Central European Cooperative Oncology Group Analysis.

BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune-oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries. MATERIAL AND METHODS: The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries. RESULTS: Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies-even for ALK inhibitors and checkpoint inhibitors in first-line-there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries. CONCLUSION: The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making.

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. RESULTS: Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. CONCLUSIONS: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial.

BACKGROUND: Erlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection. METHODS: 651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS). RESULTS: 62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9-15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation. CONCLUSIONS: Our study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01609543.

[Immunotherapy for lung cancer]. / A tüdõrák immunterápiája.

Similarly to other malignancies, immune checkpoint inhibitor therapy is a revolutionary, effective new treatment possibility for lung cancer. In lung cancer carcinogenesis is related mainly to tobacco smoking with high somatic mutation rate and immunogenicity. The PD-1 inhibitor nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab is a labelled indication in second line setting in advanced nonsmall cell lung cancer (NSCLC). Avelumab and durvalumab have promising activity as well. Based on the data of KEYNOTE 024 trial, pembrolizumab is approved in first line setting for cases with ≥50% PD-L1 expression. In this selected patient population, progression-free survival has doubled, and overall survival was significantly better in pembrolizumab-treated patients compared to those receiving standard of care. Pembrolizumab treatment became a new first line standard of care in advanced NSCLC. There are numerous ongoing clinical trials in lung cancer with immune checkpoint inhibitors in combination with cytotoxic chemotherapy, targeted agents, or in adjuvant setting.

[Self defense instead of offense - Immunotherapy in lung cancer]. / Támadás helyett önvédelem - Immunterápia tüdõrákban.

Lung cancer is the leading cause of cancer death worldwide and also in Hungary, therefore new therapeutic strategies are of great importance. Among immunotherapeutic approaches immune checkpoint inhibition appears to be the most promising. Recent studies have shown efficacy of immunotherapy, especially in squamous cell lung cancer, which is a big step forward in the treatment of this histological subtype. Unlike in the molecularly targeted therapies, the patient selection method has not yet been developed, although some studies indicate the predictive value of tumor cell PD-L1 immunopositivity, especially in lung adenocarcinoma. Introduction of immunotherapy carries challenge for clinicians regarding the radiological assessment of therapeutic efficiency as well as the management of side effects of new profile. The favorable results of recent studies, however, provide hope in this malignancy still presenting a major therapeutic challenge.

[Excerpts from the collaborative lung cancer research program of Semmelweis University, the National Institute of Oncology and Korányi Institute of TB and Pulmonology (2010-2015)]. / Szemelvények a Semmelweis Egyetem, az Országos Onkológiai Intézet és az Országos Korányi Tbc és Pulmonológiai Intézet együttmûködésén alapuló tüdõrák-kutatási programból.

Lung cancer places a significant socio-economic burden on the Hungarian population. This overview summarizes the findings of collaborative translational lung cancer research efforts of three Hungarian flagship academic institutions, the Semmelweis University, the National Institute of Oncology and the National Koranyi Institute of TB and Pulmonology. With regards to the molecular factors regulating tumor angiogenesis, we identified the prognostic significance of apelin and erythropoietin receptor (EPOR) expression in non-small cell lung cancer (NSCLC). Furthermore, the impact of KRAS mutation subtypes and ERCC1 (excision repair cross-complementation group 1) expression on the response to platinum-based chemotherapy have been studied. We also described the epidemiology and predictive power of rare EGFR (epidermal growth factor receptor) mutations in a large Hungarian patient cohort. Lastly, the expression of molecular factors associated with NSCLC progression was studied specifically in brain metastatic matched cases series. These preclinical and clinical studies provide clinically relevant information that hopefully will contribute to the improvement of lung cancer patient care.

Association between event-free survival and overall survival after neoadjuvant treatment for non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: We wanted to evaluate if event-free survival (EFS) is a reliable surrogate for overall survival (OS) in patients with resectable non-small cell lung cancer (r-NSCLC) receiving neoadjuvant therapy. We conducted a systematic literature review and meta-analysis to investigate the statistical association between EFS and OS. RESEARCH DESIGN AND METHODS: Electronic databases were searched on 30 July 2021 to identify sources reporting both EFS and OS data in patients with stage I-IIIB r-NSCLC receiving neoadjuvant therapy. Correlation and regression analyses evaluated the association between the effect of treatment on EFS and OS using log-hazard ratios (HRs). Sources in which the entire population had epidermal growth factor receptor mutations were excluded from the analyses. RESULTS: We identified 74 sources, of which 8 reported EFS and OS HRs from randomized controlled trials. Based on these, we found a positive linear correlation and a strong association between EFS and OS log-HRs (weighted Pearson's correlation coefficient r = 0.864; 95% confidence interval 0.809-0.992; P = 0.006; random-effects meta-regression, R2 = 0.777). CONCLUSIONS: We found a strong association between treatment effects for EFS and OS, indicating that improvements in EFS are likely to be predictive of improvements in OS. EFS may therefore be a reliable surrogate for OS after neoadjuvant therapy in r-NSCLC.

Covid-19-fertozés klinikai jelentosége tüdorák és egyéb malignus mellkasi daganatok esetén.

The COVID-19 pandemic has posed significant challenges to healthcare systems worldwide. Patients with cancer, and particularly those with lung malignancies, represent a highrisk group for COVID-19 since they are more susceptible to infection and have a higher risk of severe outcomes. However, the restructuration of the healthcare environment, the development of guidelines for treatment and surveillance, and the improvement of vaccination coverage allowed adequate patient shielding and continuity of oncological care of cancer patients. By shedding light on the characteristics of COVID-19 patients with thoracic malignancies, recent studies also contributed to the development of personalized therapeutic strategies. Accordingly, several determinants were identified to predict disease outcomes. These include the ECOG performance status, the levels of C-reactive protein, neutrophils and procalcitonin, the disease stage, and the presence of pneumonia. COVID-19 vaccines are safe in patients with lung cancer. In order to obtain adequate immunization, the booster dose is recommended in these patients.

Underlying reasons for post-mortem diagnosed lung cancer cases - A robust retrospective comparative study from Hungary (HULC study).

Objective: The Hungarian Undiagnosed Lung Cancer (HULC) study aimed to explore the potential reasons for missed LC (lung cancer) diagnosis by comparing healthcare and socio-economic data among patients with post-mortem diagnosed LC with those who were diagnosed with LC during their lives. Methods: This nationwide, retrospective study used the databases of the Hungarian Central Statistical Office (HCSO) and National Health Insurance Fund (NHIF) to identify patients who died between January 1, 2019 and December 31, 2019 and were diagnosed with lung cancer post-mortem (population A) or during their lifetime (population B). Patient characteristics, socio-economic factors, and healthcare resource utilization (HCRU) data were compared between the diagnosed and undiagnosed patient population. Results: During the study period, 8,435 patients were identified from the HCSO database with LC as the cause of death, of whom 1,203 (14.24%) had no LC-related ICD (International Classification of Diseases) code records in the NHIF database during their lives (post-mortem diagnosed LC population). Post-mortem diagnosed LC patients were significantly older than patients diagnosed while still alive (mean age 71.20 vs. 68.69 years, p<0.001), with a more pronounced age difference among female patients (difference: 4.57 years, p<0.001), and had significantly fewer GP (General Practitioner) and specialist visits, X-ray and CT scans within 7 to 24 months and 6 months before death, although the differences in GP and specialist visits within 7-24 months did not seem clinically relevant. Patients diagnosed with LC while still alive were more likely to be married (47.62% vs. 33.49%), had higher educational attainment, and had more children, than patients diagnosed with LC post-mortem. Conclusions: Post-mortem diagnosed lung cancer accounts for 14.24% of total lung cancer mortality in Hungary. This study provides valuable insights into patient characteristics, socio-economic factors, and HCRU data potentially associated with a high risk of lung cancer misdiagnosis.

Lung cancer in never smokers.

Lung cancer in never smokers (LCINS) is the seventh leading cause of death among solid tumors. The main risk factor for lung cancer is smoking; however, approximately 15% of lung cancer patients have never smoked. LCINS is more frequent in women, irrespective of geographical location, nevertheless, the highest incidence has been found in South-East Asia. The histological incidence of adenocarcinoma is higher in the group of never smokers than squamous cell carcinoma. There is a familial clustering of lung cancer that is more pronounced in never smokers, where the family history was associated with an increased risk. Genome-wide association studies identified certain chromosomal aberrations in LCINS. Furthermore, the oncogenic mutation pattern is distinct in nonsmoking patients: activating mutations of EGFR or anaplastic lymphoma kinase are more frequent. The etiology of LCINS includes several environmental factors as well, such as environmental tobacco smoke, viral and hormonal factors, a variety of pulmonary diseases and certain occupational exposures. It is now established that EGFR-tyrosine kinase inhibitor treatment (erlotinib and geftinib) in lung cancer is more effective in LCINS, owing to the higher incidence of EGFR mutation in nonsmokers. Despite the growing body of information on LCINS in recent years there is a need to further investigate the pathogenesis of this particular lung cancer. Future studies on LCINS should try to tackle the issues of prevention, early diagnosis and the exploration of novel therapeutic targets to combat lung cancer disease.

Chromosomal Aberrations in Blood Lymphocytes as Predictors of Respiratory Function After Stereotactic Lung Irradiation.

Due to the profound difference in radiosensitivity of patients and various side effects caused by this phenomenon, a radiosensitivity marker is needed. Prediction by a marker may help personalise the treatment. In this study, we tested chromosomal aberrations (CA) of in vitro irradiated blood as predictor of pulmonary function decrease of nonsmall cell lung cancer (NSCLC) patients and also compared it with the CAs in the blood of irradiated patients. Peripheral blood samples were taken from 45 lung cancer patients before stereotactic radiotherapy (SBRT) and immediately after the last fraction and 3, 6, 9, 12, 15, 18, 21, and 24 months later. Respiratory function measurements were performed at the same time. Diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1s), and FEV1s/FVC (FEV1%) were monitored. Metaphase preparations of lymphocytes were made with standard procedures, and chromosome aberrations were analysed. In our cohort, the 36-month local relapse-free survival was 97.4%, and the distant metastasis-free survival was 71.5% at 36 months. There was no change in the mean of the pulmonary function tests (PFTs) after the therapy. However, there was a considerable variability between the patients. Therefore, we subtracted the baseline and normalised the PFT values. There were significant decreases at 12-24 months in relative FEV1s and relative FEV1%. The tendentious decrease of the PFTs could be predicted by the in vitro chromosome aberration data. We also found connections between the in vitro and in vivo CA values (i.e., dicentrics plus rings after 3 Gy irradiation predicts dicentric-plus-ring value directly after the radiotherapy/V54 Gy (p = 0.001 24.2%)). We found that-after further validation-chromosome aberrations resulted from in vitro irradiation before radiotherapy can be a predictive marker of pulmonary function decrease after lung irradiation.

Afatinib in EGFR TKI-naïve patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer: Interim analysis of a Phase 3b study.

OBJECTIVES: Randomized controlled trials have demonstrated that afatinib is a suitable treatment option for patients with epidermal growth factor receptor mutation-positive (EGFRm +) non-small cell lung cancer (NSCLC). However, such studies often exclude patients treated in routine clinical practice. We report interim results from a Phase 3b, open-label, multicenter, single-arm, exploratory trial, in which afatinib was investigated in a real-world setting. MATERIALS AND METHODS: Patients with EGFRm + tyrosine kinase inhibitor (TKI)-naïve NSCLC received afatinib 40 mg orally, once-daily, until disease progression, or voluntary withdrawal. Primary objective was safety. RESULTS: Overall, 479 patients received afatinib: median age 65 years, 8 % of patients had an ECOG performance status ≥ 2, 17 % had brain metastases, and 13 % had tumors containing uncommon mutations only. All but one patient (99.8 %) had an adverse event (AE). Treatment-related AEs (TRAEs; any/grade ≥ 3) occurred in 97 %/44 % of patients; most common were diarrhea (87 %/16 %) and rash (51 %/11 %). AEs leading to afatinib dose-reduction were reported in 258 patients (54 %), and 37 patients (8 %) discontinued treatment due to a TRAE. Objective response rate was 45.5 %, median duration of response was 14.1 months (95 % CI: 12.2-16.4). Overall median time to symptomatic progression and progression-free survival were 14.9 months (95 % CI: 13.8-17.6) and 13.4 months (95 % CI: 11.8-14.5), respectively, in the overall population and 19.3 months (95 % CI: 15.6-21.8) and 15.9 months (95 % CI: 13.9-19.1) in patients with EGFR exon 19 deletions. CONCLUSIONS: Afatinib administration in routine clinical practice was well tolerated with no new safety signals and demonstrated promising efficacy in patients with EGFRm + NSCLC. TRAEs were generally manageable with tolerability-guided dose reductions. Overall, these data independently support findings from randomized controlled trials of afatinib in EGFRm + NSCLC.

Age and Gender Specific Lung Cancer Incidence and Mortality in Hungary: Trends from 2011 Through 2016.

Objective: No assessment was conducted describing the age and gender specific epidemiology of lung cancer (LC) prior to 2018 in Hungary, thus the objective of this study was to appraise the detailed epidemiology of lung cancer (ICD-10 C34) in Hungary based on a retrospective analysis of the National Health Insurance Fund database. Methods: This longitudinal study included patients aged ≥20 years with LC diagnosis (ICD-10 C34) between January 1, 2011 and December 31, 2016. Patients with different cancer-related codes 6 months before or 12 months after LC diagnosis or having any cancer treatment other than lung cancer protocols were excluded. Results: Lung cancer incidence and mortality increased with age, peaking in the 70-79 age group (375.0/100,000 person-years) among males, while at 60-69 age group for females (148.1/100,000 person-years). The male-to-female incidence rate ratio reached 2.46-3.01 (p < 0.0001) among the 70-79 age group. We found 2-11% decrease in male incidence rate at most age groups, while a significant 1-3% increase was observed in older females (>60) annually during the study period. Conclusion: This nationwide epidemiology study demonstrated that LC incidence and mortality in Hungary decreased in younger male and female population, however we found significant increase of incidence in older female population, similar to international trends. Incidence rates peaked in younger age-groups compared to Western countries, most likely due to higher smoking prevalence in these cohorts, while lower age LC incidence could be attributed to higher competing cardiovascular risk resulting in earlier mortality in smoking population.

Improvement in Lung Cancer Survival: 6-Year Trends of Overall Survival at Hungarian Patients Diagnosed in 2011-2016.

Objective: Lung cancer is one of the most common cancers worldwide and its survival is still poor. The objective of our study was to estimate long-term survival of Hungarian lung cancer patients at first time based on a nationwide review of the National Health Insurance Fund database. Methods: Our retrospective, longitudinal study included patients aged ≥20 years who were diagnosed with lung cancer (ICD-10 C34) between January 1, 2011 and December 31, 2016. Survival rates were evaluated by year of diagnosis, patient gender and age, and morphology of lung cancer. Results: 41,854 newly diagnosed lung cancer patients were recorded. Mean age at diagnosis varied between 64.7 and 65.9 years during study period. One- and 5-year overall survival rates for the total population were 42.2 and 17.9%, respectively. Survival was statistically associated with gender, age and type of lung cancer. Female patients (n = 16,362) had 23% better survival (HR: 0.77, 95% confidence interval (CI): 0.75-0.79; p < 0.001) than males (n = 25,492). The highest survival rates were found in the 20-49 age cohort (5Y = 31.3%) and if the cancer type was adenocarcinoma (5Y = 20.5%). We measured 5.3% improvement (9.2% adjusted) in lung cancer survival comparing the period 2015-2016 to 2011-2012 (HR: 0.95 95% CI: 0.92-0.97; p = 0.003), the highest at females <60 year (0.86 (adjusted HR was 0.79), interaction analysis was significant for age and histology types. Conclusion: Our study provided long-term Lung cancer survival data in Hungary for the first time. We found a 5.3% improvement in 5-year survival in 4 years. Women and young patients had better survival. Survival rates were comparable to-and at the higher end of-rates registered in other East-Central European countries (7.7%-15.7%).

Increase in the Length of Lung Cancer Patient Pathway Before First-Line Therapy: A 6-Year Nationwide Analysis From Hungary.

Objective: This study aimed to examine the characteristics of the lung cancer (LC) patient pathway in Hungary during a 6-years period. Methods: This nationwide, retrospective study included patients newly diagnosed with LC (ICD-10 C34) between January 1, 2011, and December 31, 2016, using data from the National Health Insurance Fund (NHIF) of Hungary. The following patient pathway intervals were examined: system, diagnostic and treatment interval by age, gender, tumor type, study year and first-line LC therapy. Results: During the 6-years study period, 17,386 patients had at least one type of imaging (X-ray or CT/MRI) prior to diagnosis, and 12,063 had records of both X-ray and CT/MRI. The median system interval was 64.5 days, and it was 5 days longer among women, than in men (68.0 vs. 63.0 days). The median system interval was significantly longer in patients with adenocarcinoma compared to those with squamous cell carcinoma or small cell lung cancer (70.4 vs. 64.0 vs. 48.0 days, respectively). Patients who received surgery as first-line treatment had significantly longer median system intervals compared to those receiving chemotherapy (81.4 vs. 62.0 days). The median system interval significantly increased from 62.0 to 66.0 days during the 6-years study period. Conclusion: The LC patient pathway significantly increased in Hungary over the 6-years study period. There were no significant differences in the length of the whole LC patient pathway according to age, however, female sex, surgery as first-line treatment, and adenocarcinoma were associated with longer system intervals.