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Abstract:
Tobacco use is the single most preventable cause of death and disease, especially of lung cancer. Approximately 1.6 million people in the WHO European Region die of tobacco-related diseases every year and the Region has the highest proportion of deaths (16%) attributable to tobacco use. Globally, Europe also has the highest prevalence of tobacco smoking among adults (28%), including one of the highest smoking prevalence rates among women (19%). In the meantime it is wellknown that a wide range of political decisions can stop the tobacco epidemic and reduce substantially smoking. According to the first health treaty in history, the WHO Framework Convention on Tobacco Control, following strategies are the most effective: raising cigarette prices through higher cigarette taxe and combating illicit trade of cigarettes, protecting from secondhand smoke through comprehensive smoke-free air laws, enforcing bans on advertising, promotion and sponsorship, placing warnings (pictures and text as big as possible) on tobacco packages and communicate the warnings through media/educational programmes and finally offering greater access to smoking cessation services. WHO Europe has established a database on countries of the WHO European region showing the effects of the reduction in smoking prevalence as a result of implementing tobacco control policies. This presentation will analyse the current situation in this Region and showing the lessons learnt from past years with regards to future prevention of smoking.

Abstract:
Up to now strategies of tobacco control, which were successful in Australia, North America and Western Europe, have been introduced only in few Central European countries. Implementing the EU Tobacco Product Directive Austria extended existing smoking bans, advertising bans and mailing bans for tobacco products to e-cigarettes. Still missing is an enforced smoking ban without exceptions in the hospitality industry, an advertising ban and display ban at point of sale, ban of vending machines, increase of age limit for buying any cigarettes and tobacco products to 18 years, enforcement of age control by regular test purchases, ban of free cigarettes (still allowed for introduction of new sorts), extension of warnings and ban of aromas to cigars and pipes, smoke-free hospitals and health care centers, smoke-free school premises without exceptions, smoke-free playgrounds and cars carrying children, smoke-free public transportation including stations, increase of tobacco tax earmarked for tobacco prevention (up to now only the quitline has regular funding), stop of state funding for media violating article 13 FCTC, enforcement of article 5.3 FCTC (transparency law), obligatory TV air time (e.g. 90 min/month like in Turkey) for promotion of non-smoking, inclusion of smoking prevention and cessation in the curricula of health professionals, covering of counseling for smokers by health insurance, more frequent surveys on smoking prevalence, including cotinine tests for risk groups (pregnant women) and opinion leaders (journalists, health care workers), scientific evaluations of efficacy and effectiveness of smoking prevention and smoking cessation programs. Other Central European countries are facing similar problems. 13 of 16 federal states of Germany, the Czech Republic, Slovakia and most cantons of Switzerland did not succeed to pass and enforce smoking bans without exceptions in the hospitality industry. Germany is still violating the EU tobacco advertising ban and the Czech Republic recently failed to ban the use of water-pipes and e-cigarettes in enclosed spaces. Austria was the only Central European state, which ratified the FCTC smuggling protocol up to now. Switzerland did not even ratify FCTC and was abused by the tobacco industry as a base to sue and intimidate small countries like Uruguay for their progress in tobacco control. The Swiss government prepared amendments for the tobacco law without considering the EU tobacco directive. Tighter restrictions on tobacco advertising will probably be eliminated from the Swiss law. A ban of sponsoring by tobacco companies was not even considered within Switzerland. Lobbies in the Federal parliament and the government were able to block also comprehensive smoking bans. Fortunately, the country offers other political tools to progress, namely that counties can go for better policies, and Federal “initiatives” can be launched to bring issues to the ballots. In fact, 8 out of 26 Swiss Counties successfully adopted comprehensive smoking bans with no exemption. The Swiss parliament, however, was not even enabled to raise minimum prices of tobacco. If the Track-and-Tracing-System of TPD-II is not joined, Switzerland might become a platform for international tobacco smuggling. In restaurants smaller than 80 square meters employers can still choose to permit smoking. The largest progress of tobacco control in Switzerland was due to a tobacco prevention fund, financed from tobacco taxes (2.6 Rappen per pack of cigarette sold) since 2004. This fund finances also tobacco monitoring and smoking cessation (training of professionals). Swiss health insurance covers both counseling and pharmaceutical support of smoking cessation. The largest progress of tobacco control in Central Europe was seen in Hungary, which received the WNTD reward by WHO in 2013 and improved its ranking by the European Cancer Leagues from place 27 in 2010 to place 11 in 2013. Only in Hungary there is a total ban on smoking in all enclosed public places (except prisons and psychiatric wards) since 2012, and tobacco shops (reduced from 40 000 to 6 045) must not be entered below age 18. There is no tobacco advertising outside these shops, no vending machine for cigarettes and plain packaging was introduced in 2016. The main obstacle against improvement of tobacco control in the EU is corruption of certain politicians and media by the tobacco industry and the subsidiarity principle in public health. The Green Paper of the EU “Towards a Europe free from tobacco smoke” showed policy options. 24 ministers of health voted on November 30, 2009 in favor of implementing the WHO- FCTC until 2012, but not the representatives of Austria, Czech Republic and Slovak Republic. Up to now the implementation of FCTC and the EU Council Recommendation on Smoke-free Environments is voluntary. All countries of Central Europe except Switzerland ratified the FCTC treaty, but nonsmoker’s protection follows article 8 only in Hungary. In Central and Eastern Europe tobacco taxes and cigarette prices are much lower than in Northern and Western Europe. In a European ranking according to tobacco price increase by taxes, smoking restrictions at work and in public places, consumer information, tobacco advertising bans, health warnings and access to smoking cessation therapy, Austria, Germany, Cyprus, Czech Republic, Greece and Lithuania had the poorest score and would need help by more advanced EU members to reach Western standard. In summary, tobacco control in Central Europe needs enforcement of FCTC, in particular article 5.3, to stop interference of tobacco industry; application of strategies formulated by WHO (Monitor tobacco use & prevention, Protect from passive smoking, Offer help to quit, Warn about dangers, Enforce bans on ads & promotion, Raise tobacco tax) and the World Bank (Curbing the Epidemic: Governments and the Economics of Tobacco Control); financing of tobacco prevention and cessation by tobacco taxes; comprehensive bans on advertising, promotion and sponsorship of tobacco products and e-cigarettes (including ban of vending machines, display ban at point of sales, plain packaging, stop of state funding for media violating article 13 FCTC); enforcement of smoke-free public places (without exceptions for hospitality industry), workplaces, schools, kindergartens, playgrounds, public transportation and private cars carrying minors and promotion of nonsmoking by schools and media campaigns.

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The rapid development of molecular biology in recent years has allowed us to understand the main molecular steps involved in the development and progression of lung cancer. The identification of molecular alterations in specific tumor genes that function as key drivers for neoplastic growth has laid the foundations for new therapeutic approaches with targeted agents. An accurate detection of target mutation is mandatory for an efficient treatment. The main limitation of targeted therapies is the occurrence of acquired resistance that makes cancer unresponsive to treatment. In many cases, through the acquisition of additional (secondary) mutations the tumor is able to acquire the heterogeneity which may enable it to adapt to various conditions of the microenvironment, including those determined by the effect of treatment with specific drugs. New generation drugs are constantly under development to overcome tumor resistance and increase survival of lung cancer patients. In this process, a constant monitoring of the mutational status of the tumor is required. Different types of genetic alterations are involved in tumor development, progression, and induction of resistance, including single nucleotide variants, indels, amplifications, fusions etc. Mutation detection before first line treatment is usually performed on tissue or cytological samples. Resected tumor samples, biopsies and cytological specimens are available in about 25%, 35% and 40% of NSCLC patients, respectively. At progression, a re-byopsy should be obtained to detect the emergence of resistance-inducing mutations. Transbronchial tissue biopsy is the most common sampling method used for re-biopsy. However, several factors limit the success rate of re-biopsy, such as the performance status of the patient, the difficulty of accessing some tumor sites, and the invasiveness of sampling methods. When the amount and/or quality of the biological material is insufficient for molecular analysis, circulating free DNA (cfDNA) can represent a valid alternative in selected patients. Liquid biopsies have several advantages over tissue or cells: they are less invasive, can be repeated over time, and have a more rapid turnaround time. However, there are some critical issues that must be considered: 1) the possibility to detect a mutation in cfDNA is dependent on several clinicopathological parameters, including tumor type, tumor burden, and particularly tumor stage (a locally advanced tumor has a significantly lower probability to spread mutant DNA in the blood than a metastatic tumor); 2) a large amount of wild-type DNA circulates in the plasma with only trace amounts of the mutant allele; therefore, the analysis of genetic aberrations in cfDNA is challenging, requiring well standardized pre-analytical/analytical protocols and dedicated techniques with high sensitivity and specificity. Different technologies/protocols are required for the detection of these genetic aberrations. Robust and sensitive molecular biology techniques are nowadays available to detect mutations in driver genes before initiating a targeted treatment or to identify the emergence of secondary mutations at disease progression. The use of multimarker assays, and in particular next generation sequencing, is progressively becoming popular, allowing on one hand to reduce the working time, costs per single assay, and the amount of nucleic acids required for testing and increasing, in the other hand, throughput and overall quality. Recently, semi-quantitative or quantitative detection methods for the assessment of genetic aberrations in cfDNA have been developed with a number of potential clinical implications. An accurate quantification of mutated alleles in cfDNA during the first days of treatment could: a) complement or replace more expensive and invasive methods to assess response in treated patients; b) represent a new way to compare the effectiveness of different drug; c) be an additional tool to evaluate the best treatment regimen for patients. In addition, a periodic quantification of the mutation burden during all the treatment time could allow an early detection of resistance-inducing mutations for possible changes to therapy.

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Abstract:
The diagnostic and management strategies for stage IIIA-N2 non-small cell lung cancer (NSCLC), which represents locally advanced disease with involvement of ipsilateral mediastinal lymph nodes, remain controversial despite results from several randomized controlled trials [1-2]. There are various reasons for this ongoing debate. First, stage IIIA-N2 represents a very heterogeneous patient population ranging from incidental discovery of positive N2 nodes during lung resection, to single mediastinal nodal involvement and bulky N2 disease where individual lymph nodes are hard to identify. In this setting, the precise diagnostic algorithm remains controversial. Currently, patients with proven or suspected lung cancer are mainly staged by integrated positron emission tomography – computed tomography (PET-CT). However pathological proof of nodal involvement should be obtained by a minimally invasive or invasive technique due to a relatively high rate of false positive nodes, owing to mainly inflammation [3]. Secondly, the optimal restaging strategy after induction therapy is heavily debated. Thirdly, specific controversy relates to the role of surgery versus radiotherapy and the precise extent of resection after induction therapy. Randomized trials included different subsets of N2 disease making the interpretation of results quite difficult. As a result of the limitations of available data heated discussions have been taking place for several decades on the optimal treatment strategy for this subset of patients. When N2 disease is detected during thoracotomy, this is referred to as incidental, unsuspected, unforeseen or “surprise” N2 [4]. When found intraoperatively, a resection should be performed as long as it can be complete. Adjuvant chemotherapy prolongs survival and is currently recommended in this setting. However the role of radiotherapy remains controversial and is currently evaluated in the randomized LungART trial (NCT00410683) [5]. In quite a large subgroup of patients, N2 disease is suspected on PET-CT scanning and subsequently confirmed by minimally invasive or invasive staging techniques. Although the term “potentially resectable N2” is often utilized, no precise, internationally accepted definition is available. Most patients in this sub-group will be treated by concurrent chemo-radiotherapy alone or induction therapy followed by surgery or definitive radiotherapy. Whether induction chemo-radiotherapy yields better results than chemotherapy alone was studied in the recently published, randomised trial NCT00030771 of the Swiss Cancer League [6]. No significant differences were found. However, this study was not adequately powered to show non-inferiority between the two strategies. There are different restaging techniques to evaluate response after induction therapy. In contrast to imaging or functional studies, remediastinoscopy provides pathological evidence but is technically more difficult and less accurate than mediastinoscopy done prior to induction treatment [3]. An alternative approach consists of the use of minimally invasive staging procedures to obtain an initial proof of mediastinal nodal involvement. Mediastinoscopy is subsequently performed after induction therapy to evaluate response [3]. In patients with proven mediastinal downstaging after induction who can preferentially treated by lobectomy, surgical resection may be recommended. Whether radiotherapy yields similar results has not been established yet. One of the reasons is that in patients undergoing chemo-radiotherapy pathology to evaluate response is not available making comparison with surgery quite difficult. A recent meta-analysis tried to better clarify the outcome of surgery compared to radiotherapy after induction treatment in patients with N2 disease [7]. Six trials including a total of 868 patients were included. Main outcome was overall survival. The authors concluded that when bimodality treatment is applied, both surgery and radiotherapy options are valid with a pooled hazard ratio for mortality in the surgery group of 1.01 (p not significant). In contrast, in trimodality regimens results support surgical resection as part of multimodality management with a pooled hazard ratio for mortality in the surgery group of 0.87 indicating a 13% relative improvement in overall survival (p= 0.068). In the recently published ESPATUE trial, patients with resectable stage IIIA-N2 and selected stages IIIB NSCLC were included [2]. No significant differences were found between the control arm consisting of induction chemotherapy followed by definitive chemo-radiotherapy, and the experimental arm administering induction chemotherapy followed by chemo-radiotherapy with a dose of 45 Gy, followed by surgical resection. Both treatment options are considered acceptable strategies for these highly selected patients with a relatively good prognosis. North American (American College of Chest Physicians 2013) [8] and European guidelines (European Society of Medical Oncology 2015) [1] recommend that in NSCLC patients with N2 involvement the treatment plan should be made with the input of an experienced multidisciplinary team. The ESMO guidelines include induction chemotherapy followed by surgery, induction chemoradiotherapy followed by surgery, or concurrent definitive chemoradiotherapy as possible treatment strategies for potentially resectable stage IIIA-N2 However bulky N2 disease is mostly treated with chemo-radiotherapy as these patients do not qualify for surgical resection due to extensive extracapsular involvement [1]. Furthermore complete resection, which is a major prognostic factor, is mostly not achievable in this subset of N2 disease. The standard of care in patients with good performance status is concurrent chemoradiotherapy [1]. Of particular interest to thoracic surgeons is the relatively new concept of “salvage” surgery after full-dose chemo-radiotherapy in stage IIIA-N2 NSCLC [9, 10]. These patients present with recurrent or progressive locally advanced disease, in some cases complicated by an infected cavity, rendering surgical resection technically difficult. Furthermore, a systematic nodal dissection may be challenging, especially when bulky lymph nodes were initially present. In conclusion, although randomised controlled trials are available, no definite answer can be provided regarding the optimal strategy for staging, restaging and treatment of the different subsets of stage IIIA-N2 disease. Every patient with locally advanced NSCLC should be discussed within a multidisciplinary tumour board including radiation oncologists and thoracic surgeons who have a large experience with major lung resections. The best available diagnostic and treatment strategies should be discussed with the patient. Salvage surgery should be reserved for those centres having a large experience in thoracic surgery where a dedicated team is available as management of these patients requires multidisciplinary cooperation preoperatively, intraoperatively and postoperatively. References 1. Eberhardt WE, De Ruysscher D, Weder W, Le Péchoux C, De Leyn P, Hoffmann H et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol 2015; 26:1573-88. 2. Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V et al. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA-N2 and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol 2015; 33:4194-201. 3. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014; 45:787-98. 4. Van Schil P. Stage IIIA-N2 non-small-cell lung cancer: from “surprise” involvement to surgical nightmare. Eur J Cardiothorac Surg 2016; 49:1613-4. 5. Le Péchoux C, Dunant A, Faivre-Finn C, Thomas PA, Pourel N, Lerouge D et al. Postoperative radiotherapy for pathologic N2 non-small cell lung cancer treated with adjuvant chemotherapy: need for randomized evidence. J Clin Oncol 2015; 33:2930-1. 6. Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S et al. Induction chemo-radiotherapy in stage IIIA/N2 non-small cell lung cancer: a phase 3 randomised trial. Lancet 2015; 386(9998):1049-56. 7. McElnay PJ, Choong A, Jordan E, Song F, Lim E. Outcome of surgery versus radiotherapy after induction treatment in patients with N2 disease: systematic review and meta-analysis of randomised trials. Thorax 2015; 70:764-8. 8. Ramnath N, Dilling TJ, Harris LJ, Kim AW, Michaud GC, Balekian AA et al. Treatment of stage III non-small cell lung cancer: diagnosis and management of lung cancer, 3[rd] ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013; 143 (5 Suppl): e314-30S. 9. Van Schil P. Salvage surgery after stereotactic radiotherapy: a new challenge for thoracic surgeons. J Thorac Oncol 2010; 5:1881-2. 10. Schreiner W, Dudek W, Sirbu H. Is salvage surgery for recurrent non-small-cell lung cancer after definitive non-operative therapy associated with reasonable survival? Interact Cardiovasc Thorac Surg 2015; 21: 682-4.

Abstract:
Recent Advances in Radiation Treatment Technique for Lung Cancer Lung cancer is the leading cause of cancer-related death in the United States and throughout the world. Advancement of Radiation Treatment have been parallel to imaging capability to target cancer and avoid surrounding normal tissue structure which associated with volume and dose. We can cure most of early lung cancer if it is well staged early cancer and targeted correctly by stereotactic body radiation therapy (SBRT). Because of high dose per fraction, technical aspects and quality assurance to deliver the radiation to the tumor precisely and avoid high dose of radiation to the critical surrounding normal tissue are critical issues organs in addition to controlling tumor motion. Technologic advancements of imaging and radiotherapy to conform the gross target volume(GTV) with tighter margins but adequate clinical targeted volume (CTV) and planning tumor volume (PTV) considering daily set up variations which are supposed to minimize the dose to nearby normal tissues. We have tried to answer higher radiation dose improve survival by the RTOG 0617 which compared overall survival after standard-dose versus high-dose intensity-modulated radiation therapy (IMRT) or three-dimensional conformal radiation therapy (3DCRT) with concurrent chemotherapy +/- cetuximab for patients with inoperable stage III non-small-cell lung cancer. In this open-label randomized, phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0–1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All received concurrent chemotherapy with 45 mg/m2 paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m2) and carboplatin (AUC 6). Radiation dose was prescribed to the PTV and was given in 2 Gy daily fractions with either IMRT or 3DCRT. For patients assigned to receive cetuximab, 400 mg/m2 cetuximab was given on day 1 followed by weekly doses of 250 mg/m2, and was continued through consolidation therapy. 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5–33.3). Median overall survival was 28.7 months (95% CI 24.1–3.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7–25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09–1.76; p=0.004). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2–30.5) compared with 24.0 months (19.8–28.6)in those who did not (HR 1.07, 95% CI 0.84–1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). Severe esophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). This study did not mandate 4D simulation and possibly GTV was not well covered by the dose prescribed. There was higher local failure in the 74 Gy arm because of tighter margin in this group. We assumed from this study that 74 Gy radiation given in 2 Gy fractions with further improvements are expected from the use of charged particle therapy with protons or other particles; randomized comparisons of proton therapy vs. intensity-modulated photon radiation therapy for lung cancer are underway in the United States .A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617. The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P =.005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distance metastasis were not different between IMRT and 3D-CRT. IMRT was associated with fewer grade 3 or greater pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses (P <0 .05), and volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis (P<0.05). Lung V5 was not associated with any toxicity equal or greater than grade 3, whereas lung V20 was associated with increased grade 3 or greater pneumonitis risk on multivariable analysis (P = .026). IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC. We have evidence that severe pneumonitis and esophagitis have been reduced by proton compared to IMRT with concurrent chemotherapy for stage III NSCLC. However it is difficult to do a randomized trials. In conclusion, screening by low dose spiral CT scan for among previous or current smokers to detect early lung cancer. Early lung cancer can be curable by SBRT Lung cancer treatment planning requires 4D simulation. The technical advancement such as IMRT or Proton Treatment compared to 2 or 3 dimensional radiotherapy with concurrent chemotherapy reduced normal tissue toxicity among patients with locally advanced lung cancer which will improve their outcome in future. We are testing this hypothesis by a randomized prospective study.

Abstract:
Dose escalation with conventional fractionation and concurrent platin-based chemotherapy within the RTOG 0617 trial has failed to show a survival benefit. Proton therapy has failed to show a reduction in radiation pneumonitis in comparison to intensity modulated photon radiotherapy at the same total dose according to the NCT 00915005 trial. Randomized trials for comparison of IMRT and 3D conformal radiotherapy are lacking. While randomized trials conducted so far failed to show an increment in survival by newer radiotherapy concepts on one hand, the old standard of giving 60 Gy with conventional fractionation and concurrent chemotherapy consolidated on the other. So where does the hope come from that technological advances in radiotherapy lead to an improved survival in locally advanced lung cancer, if not from randomized trials? It comes from many small precious components that can lead to an increase of loco-regional control by radiotherapy in locally advanced NSCLC, the primary goal of radiotherapy. First of all, the determination of tumor spread has been substantially improved by the introduction of FDG-PET/CT, by systematic mediastinal evaluation with EBUS-TBNA, and by brain MRI. The determination of tumor position during irradiation has been improved by stereoscopic KV imaging during irradiation or real-time magnetic resonance imaging and therefore tumor targeting can be optimized. Volumetric modulated arc therapy can deliver conformal dose distributions within a breath hold of 20 s. With hyperfractionated acceleration and concurrent chemotherapy, high biologically effective doses can be given for patients with locally advanced NSCLC resulting in similar survival and local control rates than with trimodality treatment. Integrated boost radiotherapy controlling dose gradients form gross tumor volume towards organs at risk as the contra-lateral bronchial wall or the esophagus has become feasible and is tested within prospective trials. Immunotherapy and molecular targeted therapies are upcoming as combination partners with radiotherapy in selected tumors. Proper patient selection criteria resulted long term survival as high as 30-45% in multicenter prospective trials in locally advanced NSCLC. These advantages have to be bundled into new radiotherapeutic concepts and tested against the standard of conventional fractionated radiotherapy up to 60 Gy and simultaneous chemotherapy in future well designed randomized trials.