Virtual Library

Background:
Amplification of ERBB2 in EGFR-mutant lung cancers is a reported mechanism of acquired resistance to tyrosine kinase inhibitor (TKI) therapy. Comprehensive genomic profiling (CGP) of NSCLC tumors shows mutation of ERBB2, most often affecting the encoded HER2 receptor at residue S310, is also prevalent, particularly in the context of EGFR L858R.

Methods:
CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,887 consecutive cases of lung cancer. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes. Short variants (SV) include base substitutions or indels.

Results:
A total of 2,516 (16.9%) samples featured EGFR alterations, including amplification (amp) and SV. Of these, 2.9% (73/2,516) harbored alterations in ERBB2 (amp and/or SV). 18 samples (0.7%) harbored SV alterations in ERBB2, 14 of which were mutations at S310. ERBB2 S310 mutations were most often found with EGFR L858R. The ratio of observed to expected mutation at HER2 S310 in EGFR-mutated lung cancers was 2.12, and the ratio for HER2 S310 in combination with EGFR L858R was 5.03. The co-occurrence of HER2 S310 and EGFR L858R was highly significant (p<0.00005). The combination of EGFR and ERBB2 alterations was more common in women. The ratio of male:female patients with any lung cancer in this dataset was 1:1.1, whereas the ratio of male:female with any EGFR alteration was 1:1.7 and for both EGFR and ERBB2 alterations (amp or SV) was 1:3.4. Patients with a combination of EGFR and ERBB2 alterations have been shown to respond to treatment with the pan-ERBB inhibitor afatinib, or combinations of afatinib with the HER2-targeted therapy trastuzumab.

Conclusion:
Short variant alterations in ERBB2 may be an additional mechanism for tumors to acquire resistance to treatment with EGFR-targeted TKIs. Mutations at residue S310, in the extracellular domain of HER2, are the most common ERBB2 SV observed in EGFR-mutant lung cancer, and are significantly associated with EGFR L858R. The co-occurence of alterations in ERBB2 and EGFR is far more common in women than in men. Treatment with the pan-ERBB inhibitor afatinib, alone or in combination with agents targeting HER2, has been shown to benefit patients with lung cancer harboring mutations in both EGFR and ERBB2.

Background:
Combined inhibition of HER2 and mTOR is synergistic in models of HER2 (or ERBB2)-mutant lung cancers. PUMA-NER-4201 is an adaptive, multinational, randomized phase II study comparing the pan-HER inhibitor neratinib (Puma Biotechnology) ± the mTOR inhibitor temsirolimus in patients with advanced HER2-mutant lung cancers. In stage 1 of the study, neratinib + temsirolimus met predefined criteria for expansion into stage 2 [Besse et al. ESMO 2014].

Methods:
Patients with stage IIIB/IV locally determined HER2-mutant cancers were randomized to receive oral neratinib 240 mg once daily ± intravenous temsirolimus 8 mg once weekly (escalated to 15 mg/week after a 3-week cycle if tolerated) with loperamide prophylaxis. Primary endpoint: overall response rate (RECIST v1.1). Secondary endpoints: duration of response, progression‑free survival, overall survival, toxicity assessments (NCI-CTCAE, v4.0). ClinicalTrials.gov: NCT01827267.

Results:
Of 62 randomized patients, 60 received ≥1 dose of neratinib: neratinib alone (n=17); neratinib + temsirolimus (n=43). Baseline characteristics: male/female 32%/68%; median age 66 years; never smokers 60%; adenocarcinoma 98%. HER2 (or ERBB2) mutation type: exon 20 insertions 93.5%; missense substitutions 3.2%; unspecified 3.2%. The most common HER2 allelic variant was A775_G776insYVMA. Exploratory biomarker analysis from available tumor and plasma samples will be presented at the meeting. Efficacy and safety results are shown in the table. With loperamide prophylaxis, the incidence of grade 3 diarrhea was 12% with neratinib and 14% with neratinib + temsirolimus, which lasted for a median duration of 1.5 (interquartile range, 1.0‒2.0) days and 4.0 (interquartile range, 2.0‒16.0) days, respectively. Figure 1



Conclusion:
Neratinib (240 mg/day) + temsirolimus (8 or 15 mg/week) produced responses lasting 2 to 18+ months in 19% of patients with HER2‑mutant lung cancers. Correlative data will be presented at the meeting. Diarrhea was manageable with loperamide prophylaxis.

Background:
There is still an unmet need for targeted drugs in non small cell lung cancer (NSCLC) patients with HER2 mutation. Pyrotinib is an oral tyrosine kinase inhibitor targeting both HER-1 and HER-2 receptors. This phase II trial is designed to evaluate the safety and efficacy of pyrotinib in patients with HER2 mutant advanced NSCLC.

Methods:
A single arm prospective phase II trial was undergone to evaluate the efficacy and safety of Pyrotinib in patients with HER2 mutant advanced NSCLC in a single center of Shanghai Pulmonary Hospital, Tongji University(NCT 02535507). Pyrotinib was administrated 320mg or 400mg orally once a day. Next generation sequencing or ARMS was used to identify the patients with HER2 mutation. The primary endpoint was objective response rate and the secondary endpoints were side effect, progression free survival and overall survival.

Results:
From Jul 15 2015 to Jul 21, 2016, 11 patients with her2 mutated advanced NSCLC were enrolled into this study. Among them, the median age was 58 years old, 6 were male, 4 were smoker, ECOG PS 0/1/2 were 5/6 and all of them were adenocarcinoma. None of them received pyrotinib as the first line therapy and the median previous anti-cancer regimen was 2. 9 patients had the details variants of HER2 mutation including 7 with exon 20 776YVMA, 1 with exon 20 770AYVM and 1 with 2326G>ATTT. All of them evaluated the response, including 54.5% with partial response(6/11), 27.3% with stable disease(3/11) and 18.2% with progressive disease(2/11). 1 patient got response to pyrotinib after progressed from afatinib. 5 patients were still on the study and the median PFS was 6.2 months. Side effects were mild including 4 with grade I/II diarrhea, 2 with grade II fatigue, 2 with grade I rash and 1 with dispnea.

Conclusion:
Pyrotinib showed promising results about the ORR and PFS together with mild toxicity in patients with HER2 mutant advanced NSCLC, further multicenter large scale phase II study is initiated to validate the results in this study.

Abstract not provided

Background:
P53 mutations are common in lung cancer, and have also been described in EGFR mutated patients The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.

Methods:
484 patients diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing, hybrid cage next generation sequencing. P53 mutations were detected by Sanger Sequencing and either Miseq or hybrid cage NGS. Clinical characteristics including smoking status were available for more than 97%.

Results:
484 consecutive patients were studied. The overall EGFR M+ rate was 17.8% (86/484) in all patients, 84.9% (73/86) showing common mutations of exon 19 or 21. In 21/86 (24.4%) patients’ p53 analysis was not successful. P53 disruptive mutations were demonstrated in 24.6% (16/65) of successfully tested patients, and p53 non-disruptive mutation occurred in 27.7% (18/65) whereas p53 WT configuration was found in 47.7% (31/65). Median OS was 28 months in p53 disruptive mutation and 44 month in p53 WT compared to 23 months in p53 non-disruptive mutation (p<0.023). PFS on 1[st] line TKI therapy was 14 months in p53 disruptive mutation, 27 months in p53 WT and 10 months in p53 non-disruptive mutation (p<0.040). Similar results were shown in the EGFR common mutation subgroup. 11/16 (68.8%) patients with a disruptive p53 M+ and 25/29 (86.2%) patients with a p53 WT constellation achieved an objective response on the 1[st] line TKI therapy compared to 7/13 (53.8%) patients with a non-disruptive p53 status. The patients with an unknown p53 status achieved an objective response on the 1[st] line TKI therapy of 82.4.8% (14/17).

Conclusion:
Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 M+ status. P53 mutational status is predictive when disruptive and non-disruptive p53 M+ are differentiated. A p53 WT constellation has a positive effect on OS and PFS. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.

Background:
KRAS is the most frequently mutated oncogene in Non-Small Cell Lung Cancer (NSCLC) and its role as prognostic and predictive biomarker remains widely debated. Unfortunately, KRAS direct targeting strategies have been unsuccessful and no approved target therapy exists for KRAS-mutant-NSCLC. This pilot study evaluated the activated signaling architecture of advanced NSCLC harbouring a KRAS mutation to better characterize the signaling network driving this subgroup of pulmonary malignancies.

Methods:
Twenty Stage IV Formalin-fixed, paraffin-embedded (FFPE) NSCLCs were collected from chemo-naïve patients at S. Maria della Misericordia Hospital (Perugia, Italy). Ten tumors were KRAS-wild-type (KRAS-WT) and ten were KRAS-Mutant (KRAS-MUT). Whole-tissue lysates were obtained for all samples. Signaling network analysis was performed using the Reverse Phase Protein Array (RPPA) platform to quantitatively evaluate the expression/activation of 148 key proteins and phosphoproteins involved in cellular growth, survival, proliferation, apoptosis, autophagy, inflammation, invasion and cell motility. Wilcoxon Rank-Sum Test was used to compare the signaling architecture of KRAS-MUT and KRAS-WT tumours. All p-values <0.05 were considered significant. Non-parametric correlation analysis was performed to explore the signaling interconnection within each group of patients. Only correlations with p<0.0001 were considered significant.

Results:
This preliminary analysis revealed a statistically significant different activation level of 20 proteins between the KRAS-MUT and KRAS-WT samples. Five of the proteins that were statistically different in the KRAS-MUT group are involved in the inflammatory immunoresponse (ASK1 S83 p<0.01, Axl Y702 p=0.01, Stat2 Y690 p<0.01, Tyk2 Y1054/Y1055 p=0.01 and Twist p<0.01) and six in cell cycle control and DNA repair (ATM S1981 p=0.01; Bcl-xL p=0.03; Cleaved Caspase 3 D175 p=0.02; Histone H3 S10 p<0.01; p53 S15 p<0.01; p27 T187 p=0.04). The analytes that were statistically significant were all lower in the KRAS-MUT group compared to the WT (except for p27 T187 which decreased in the KRAS-MUT group compared to KRAS-WT). Pair-wise correlation analysis of the signaling proteins showed an overall more complex protein-protein interaction network and pathway activation (included AKT/mTOR signaling pathway) in the KRAS-MUT population with high number of statistically significant correlations compared to the KRAS-WT group.

Conclusion:
This pilot study indicated that the effect of KRAS mutation status on protein signaling in NSCLC was an alteration of the immunoresponse axis and DNA repair network. If validated in a larger cohort of patients, these results could have important clinical implications for stratification KRAS-MUT advanced NSCLC patients towards more efficacious targeted treatment and to identify new therapeutic targets based on multi-targets/multi-pathways KRAS inhibitory approach. (AIRC-supported study).

Background:
Activating mutations in the KRAS proto-oncogene define a prevalent and clinically heterogeneous molecular subset of lung adenocarcinoma (LUAC). We previously identified three major subgroups of KRAS-mutant LUAC on the basis of co-occurring genetic events in TP53 (KP), STK11/LKB1 (KL) and CDKN2A/B (KC) and reported that LKB1-deficient tumors exhibit a “cold” tumor immune microenvironment, with reduced expression of several immune checkpoint effector/mediator molecules, including PD-L1 (CD274). Here, we extend these findings and examine the clinical outcome of co-mutation defined KRAS subgroups to therapy with immune checkpoint inhibitors.

Methods:
We conducted a single-institution analysis of clinical and molecular data (PCR-based next generation sequencing of panels of 50, 134 or 409 genes) prospectively collected from patients enrolled into the MD Anderson Lung Cancer Moon Shot GEMINI database. KRAS-mutant LUAC were separated into KP, KL and K (wild-type for TP53 and STK11) groups. The log- rank test and Fisher’s exact test were used for comparison of progression-free survival (PFS) and objective response rate (ORR) respectively between the groups. In addition, automated IF-based enumeration of lymphocyte subsets was performed in 40 surgically resected LUAC (PROSPECT cohort) with available whole exome sequencing data.

Results:
Among 229 patients with KRAS-mutant LUAC who consented to the protocol we identified 35 patients with metastatic disease (17 KP, 6 KL, 12 K) that received immunotherapy with nivolumab (N=29), pembrolizumab (N=3), nivolumab/urelumab (N=1) and durvalumab/tremelimumab (N=2) and had robust clinical outcome data. There was no impact of different KRAS alleles (G12C/G12V/G12D) on PFS (P=0.6149, log-rank test) or ORR to immune checkpoint inhibitors (P=0.88, Fisher’s exact test, 2x3 contingency table). In contrast, co-mutation defined KRAS subgroups exhibited significantly different median PFS to immunotherapy (KP: 18 weeks, KL: 6 weeks, K: 16 weeks, P=0.0014, log-rank test). Objective responses were observed in 9/17 (52.9%) KP and 3/12 (25%) K tumors compared to 0/6 (0%) KL tumors (P=0.049, Fisher’s exact test, 2x3 contingency table). In the PROSPECT cohort of surgically resected LUACs with available whole exome sequencing data, somatic mutation in STK11 was associated with reduced intra-tumoral densities of CD3+ (P=0.0016), CD8+ (P=0.0125) and CD4+ (P=0.0036) lymphocytes.

Conclusion:
Mutations in STK11/LKB1 are associated with an inert tumor immune microenvironment and poor clinical response of KRAS-mutant LUAC to immune checkpoint blockade. The mechanism that underlies this phenotype and strategies to overcome it are under investigation. The impact of additional co-mutations on the immune profile and response of KRAS-mutant LUAC to immunotherapy is also being explored.

Abstract not provided

Background:
Comprehensive genomic profiling (CGP) can discover novel therapy targets in NSCLC. Amplification of RICTOR, encoding a component of the MTORC2 complex, has recently been identified as a targetable alteration leading to clinical benefit.

Methods:
CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,698 consecutive cases of NSCLC, comprising lung adenocarcinoma, squamous cell carcinoma (SCC) or NSCLC not otherwise specified (NOS). Tumor mutational burden (TMB) was determined on 1.1 Mb of sequenced DNA. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes.

Results:
747 (5.0%) NSCLC featured RICTOR amplification (amp). There were 380 (51%) male and 367 (49%) female patients with a mean age of 64.1 years (range 18-88 years). The primary tumor was analyzed in 333 (45%) cases and a metastasis biopsy in 414 (55%) cases. Genes most frequently co-altered with RICTOR amp included TP53 (79.5%) and FGF10 (64.6%), which is located close to RICTOR on chromosome 5 and is frequently co-amplified. Several known oncogenes in NSCLC were mutated at significantly higher rates in tumors with RICTOR amp, including EGFR (22%), MET (8.4%), ERBB2 (7%), as well as FGFR1 (5%), FGFR3 (1.4%), and FGFR4 (1.6%). 42.2% of tumors with RICTOR amp did not harbor additional alterations in KRAS or genes indicated in the NCCN guidelines. KRAS GA were identified in 19.6% of RICTOR amp tumors, compared with 29.8% of all NSCLC, but this difference was not statistically significant. Mean TMB in RICTOR amp tumors was intermediate (14.9 mut/Mb), and is higher than the overall average for NSCLC (9.2 mut/Mb). The number of RICTOR-amplified tumors with high TMB (>20 mut/Mb) was 23%, higher than the rate for non-RICTOR amp NSCLC (12.9%). Examples of patients with RICTOR amplification within late stage NSCLC responding to MTOR inhibitors will be presented.

Conclusion:
RICTOR amplification, when compared to other non-EGFR known drivers of NSCLC, is a relatively frequent clinically relevant GA that has been shown to respond to MTOR inhibitors. The co-occurrence of RICTOR amplification with mutation of known oncogenic drivers suggests a possible mechanism of acquired resistance to therapy that should be explored further. Tumors with RICTOR amp more often have higher levels of TMB than other NSCLC. Further study of RICTOR amp as a therapy target NSCLC in a clinical trial setting appears warranted.

Background:
Lung cancer is the leading cause of death among cancers. There is broad evidence that immune cells are involved in the growth and development of these malignancies. CD26/DPP4 (dipeptidyl peptidase 4) is a transmembrane glycoprotein, that is constitutively expressed on hematopoetic cells, but also found on lung epithelial and endothelial cells. We found previously that the activity of CD26/DPP4 of lung cancer patients at early stages is four times higher than in normal tissue. Here, we tested if CD26/DPP4-inhibition is able to modulate lung cancer growth in mice.

Methods:
An orthotopic lung tumor model was employed by sc. injections of the mouse lung cancer (Lewis Lung Carcinoma (LLC)) and a human lung adenocarcinoma cell line (H460). These were developed in mice C57BL6 (n=18) and CD1-nude mice (n=20) respectively. The CD26/DPP4-inhibitor Vildagliptin was given in drinking water of 50mg/kg daily dose. Tumor growth was evaluated by wet weight of tumor mass at 2 weeks. Histological assessments included TUNEL, immunohistochemistry (IHC) of CD3, B220, F4/80 and NKp46. IL-10, Arginase, IL-12, NKp46, NK1.1, IFN-g, Granzyme, and Perforin 1 were analyzed by RT-PCR. In vitro analysis of surfactant protein (SP) expression in LLC and H460 were performed by western blotting. For a proof of concept, macrophage ablation was performed by clodronate-liposome during Vildagliptin treatment.

Results:
Vildagliptin treatment significantly reduced the tumor growth of both, LLC and H460 in mice. IHC showed macrophages (F4/80+) and NK cells (NKp46+) to be significantly increased by Vildagliptin within tumors, while TUNEL stain and IHC of T- and B cell infiltration did not show any difference. Gene expression levels of anti-inflammatory markers (IL-10, and Arginase) were unchanged, while the pro-inflammatory cytokine IL-12 was significantly elevated. The NK cell markers NKp46, NK1.1, IFN-g, Granzyme and Perforin 1 were significantly upregulated within the tumor by Vildagliptin, indicating that inhibition of CD26/DPP4 recruits NK cells into the tumor. Furthermore, we found enhanced SP expressions in lung cancer cell lines by Vildagliptin treatment in vitro. Macrophage ablation with clodronate-liposome in Vildagliptin treated mice reversed the tumor size significantly.

Conclusion:
The Inhibition of CD26/DPP4 decreased lung cancer growth in primary models of mouse and human lung cancer and increased inflammatory macrophages and NK cell cytotoxicity within those tumors. Furthermore, an increased expression of SP by Vildagliptin treatment in lung cancer cell lines suggests that surfactant production in lung cancer activates macrophages to fight against lung cancer via the recruitment of macrophages and NK cells.

Background:
Our laboratory has translated (NCT02414269, NCT02792114) mesothelin (MSLN), a cancer-antigen, targeted chimeric antigen receptor (CAR) T-cell therapy to solid tumors including for lung adenocarcinoma (ADC) patients. The goal of this study is to investigate the anti-tumor efficacy of MSLN CAR T cells against lung ADC with heterogenous MSLN expression, and further develop mechanistic insights to potentiate the therapy.

Methods:
Human CAR T cells transduced with M28z, MSLN CAR with CD28 costimulation, were tested in vitro (cytotoxicity by [51]Cr release assay, proliferation, cytokine secretion, LFA-1/ICAM-1 [lymphocyte function associated antigen-1/intercellular adhesion molecule 1] adhesion assay, and flow cytometry) and in vivo (tumor and T-cell bioluminescence imaging [BLI], survival) against low-, high- or a mixture (50:50 or 70:30) of MSLN-expressing A549 human lung ADC.

Results:
MSLN CAR T cells demonstrate antigen-intensity dependant cytotoxicity against both low- and high- MSLN-expressing A549 cells with additive bystander cytotoxicity against [51]Cr-labelled low-MSLN A549 cells in the mixture both in vitro (Figure Panel A) and in vivo (22 days delay in tumor progression by low-MSLN A549 cells). Flow cytometry demonstrated ICAM-1 overexpression on low-MSLN A549 cells when treated with effector cytokine-rich supernatant collected by exposure of CAR T cells to high-MSLN A549 cells (Panel B), LFA-1 expression by MSLN-activated CAR T cells (Panel B). Activated CAR T cells adherence to ICAM-Fc coated plates compared to controls (Panel C). LFA-1/ICAM-1 expression promoted adherence of antigen-activated CAR T cells to low antigen-expressing tumor cells (Panel D), which is inhibited in the presence of LFA-1 blocking antibody (Panel E). Figure 1



Conclusion:
We provide a mechanistic reason for the antigen-specific, bystander efficacy of CAR T cells against low-antigen expressing lung cancer cells. Strategies to augment LFA-ICAM interactions between CAR T cells and cancer cells can effectively translate mesothelin-targeted CAR T-cell therapy against heterogenous antigen-expressing solid tumor, lung cancer.

Abstract not provided

Background:
Diagnosis of peripheral pulmonary lesions with ultrathin bronchoscopy (UTH) has fewer complications than transthoracic needle aspiration (TTNA). However, diagnostic yield with UTH is lower. Virtual bronchoscopic navigation (VBN) might increase diagnostic performance of UTH. The main objective was to compare diagnostic yield of UTH with and without VBN.

Methods:
Prospective case-control study paired 1:2 for lesion size and localization, bronchus sign, sex and final diagnosis. LungPoint (Broncus, USA) was used to plan and navigate based upon online image analysis, putting endoscopic and virtual images in correspondence. Fluoroscopy was used in all. Sampling included bronchial washing and brushing (if no direct vision) or biopsy (if lesion directly visualized). Statistical analyses R-3.2.3.

Results:
Total of 63 patients (VBN and non-VBN, 21:42). Clinical characteristics in table 1. Diagnostic yield was 75% vs 43.9% (p=0.029). Factors associated to positive diagnosis in table 2. Further diagnostic techniques were needed in 14% vs 52% (p=0.001). No differences seen in procedure duration or complications. Figure 1 Figure 2





Conclusion:
VBN significantly improves the diagnostic yield of ultrathin bronchoscopy for diagnosing peripheral pulmonary lesions, especially those located in the utmost periphery and fluoroscopically not visible. Therefore, use of VBN reduces the need for further diagnostic procedures. Funded by La MaratóTV3-20133510, FIS-ETES PI09/90917, FUCAP and SEPAR.

Background:
Electromagnetic navigation bronchoscopy (ENB) may aid in accessing smaller, more peripheral lesions and hence facilitate earlier diagnosis. ENB may also provide a safer alternative to transthoracic biopsy, and allow adequate tissue capture for molecular testing, diagnosis, staging, and localization for surgery in a single anesthetic event. However, usage patterns, safety, and performance remain largely unexplored in a prospective, multicenter study.

Methods:
NAVIGATE is a global, prospective, multicenter study of ENB using the superDimension™ navigation system (Medtronic, Minneapolis). A pre-specified 1-month interim analysis was conducted on the first 1,000 primary cohort subjects enrolled at 29 centers in the United States and Europe. Enrollment and 2-year follow-up are ongoing.

Results:
One-month follow-up was completed in 933/1,000 subjects. Of 1,000 procedures, ENB was intended for lung biopsy in 96.4%, to place fiducial markers in 21.0%, and for dye marking in 1.7% (multiple indications in 34.9%). Lymph node biopsies were attempted in 33.4% of procedures (322/334 using linear endobronchial ultrasound [EBUS]). General anesthesia was used in 79.7% and radial EBUS in 54.3%. Among 1,129 lung lesions, fluoroscopy was used in 90.1% and rapid on-site pathology evaluation in 683/1035 (66.0%). Median lesion size was 20.0 mm (interquartile range 16.0 mm). Most lesions were in the peripheral (62.6%) or middle (30.1%) lung thirds. A bronchus sign was present in 48.4% and 6.3% were ground glass. Navigation was subjectively considered successful in 1,036 lesions (91.8%). Site-reported pathology results were read as malignant in 452 lesions (43.6%), including 38.1% with primary lung cancer. Of 247 lesions with adenocarcinoma or unspecified non-small-cell lung cancer, 70 (28.3%) were sent for molecular testing with adequate tissue in 56/70 (80.0%). Primary lung cancer clinical stage was 52.9% I; 10.7% II, 18.9% III, and 17.3% IV. Preliminary non-malignant results were obtained in 444 lesions (42.9%). An additional 140 lesions (13.5%) were read as inconclusive. Longer follow-up is required to calculate the true negative rate and diagnostic yield. ENB-related pneumothorax was 4.9% (49/1,000) overall and 3.2% Grade ≥2 based on the Common Terminology Criteria for Adverse Events scale. The ENB-related Grade ≥2 bronchopulmonary hemorrhage and Grade ≥4 respiratory failures rates were 1.0% and 0.6%.

Conclusion:
Interim 1-month results suggest a low adverse event rate in the largest prospective, multicenter ENB study conducted to date. Continued enrollment and 2-year follow-up will elucidate the real-world utilization patterns, diagnostic yield, factors contributing to successful diagnosis, and the impact of ENB on lung cancer management.

Background:
Development of drugs that target molecular pathways in lung cancer has made it increasingly important for diagnostic sampling to yield sufficient material for genotyping. At the same time, minimally invasive sampling techniques such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) result in smaller volume cytological specimens. It has been shown that at least 3 EBUS-TBNA passes per lesion are sufficient for cytological subtyping. However, the number of passes needed for mutational subtyping is unclear. We sought to determine the adequacy of a single EBUS-TBNA for genotyping clinically actionable mutations.

Methods:
Patients undergoing EBUS-TBNA for diagnosis of lung cancer were prospectively recruited. Paired samples from the same target lesion were obtained. The “reference” sample was the routine diagnostic specimen consisting of ≥3 passes, whereas the “study” sample comprised a single pass. DNA was extracted from both samples and subjected to quantitative and qualitative assessment. Sequencing for EGFR, KRAS, BRAF mutations was performed in adenocarcinoma/non-small cell lung cancer not otherwise specified (NSCLC-NOS) cases.

Results:
Samples were obtain in 41 patients. Cytological diagnosis was adenocarcinoma/NSCLC-NOS in 25 (61.0%), squamous cell carcinoma in 10 (24.4%), small cell lung cancer in 5 (12.2%), and carcinoid in 1 (2.4%) case. DNA extraction yielded a mean of 4.03μg, well above the minimum required quantity for targeted sequencing of 10ng (Table 1). DNA quality measured by DNA Integrity Number could be calculated in 35 (85%) cases with a mean of 8.9, where >7 is acceptable for sequencing (Table 1). Sequencing results of adenocarcinoma/NSCLC-NOS cases show mutations in EGFR in 6, KRAS in 8, BRAF in 1 case. Wild type was demonstrated in 6 cases. Molecular analysis of the corresponding study samples is proceeding.

Abstract not provided

Background:
Idiopathic pulmonary fibrosis (IPF) is associated with an increased risk of lung cancer (LC) independent of the effect of cigarette smoking. The prognosis of IPF-associated LC (IPF-LC) is known to be worse than the lone IPF or LC mainly due to the complications accompanying LC treatment with no established or standardized consensus. However, despite recent progress in the understanding of pathogenesis and the treatment of LC in general population based on the advances in molecular genomics, the pathogenesis or molecular profiles of IPF-LC has been largely unknown to date.

Methods:
We assessed genomic profiles of IPF-LC using targeted exome-sequencing (OncoPanel version 2) in 35 matched tumor/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling were performed using GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively. Copy number analysis was conducted using CNVkit with focal events determined by GISTIC 2.0, and pathway analysis (KEGG) using DAVID.

Results:
Germline mutations in TERT (rs2736100,n=33) and CDKN1A (rs2395655,n=27) linked with IPF risk were detected in most samples. A total of 410 somatic mutations were identified with an average of 11.7 per tumor including 69 synonymous, 177 missense, 17 nonsense, 1 nonstop, 11 splice-site mutations, and 135 small coding indels. Spectra of the somatic mutations revealed predominant C→T transitions despite extensive smoking histories across most study subjects, suggesting more associations with APOBEC3B-related mutagenesis in the process of IPF-LC development, rather than smoking. TP53 (22/35,62.9%) and BRAF (6/35,17.1%) genes were found significantly mutated in IPF-LC. Recurrent focal amplifications in 3 chromosomal loci (3q26.33, 7q31.2, and 12q14.3), and 9p21.3 deletion were identified, and genes associated with JAK-STAT signaling pathway were significantly amplified in IPF-LC (P=0.012).

Conclusion:
IPF-LC is genetically characterized by the presence of somatic mutations reflecting viral and immune-related mutagenic processes in the background of specific germline mutations, and is associated with potentially targetable alterations such as BRAF mutations.

Background:
Chronic obstructive pulmonary disease (COPD) and lung cancer are associated through tobacco. COPD is underdiagnosed in the general population. Patients with lung cancer suffer from dyspnea and hospitalization for respiratory complications, and underdiagnosis of COPD could confer worse symptoms and morbidity. Using Institute for Clinical Evaluative Sciences (ICES) data, we assessed the diagnosis of COPD in the lung cancer population in Ontario, Canada.

Methods:
Cancer registry, hospital ICD-10 codes, physician billing data, and vital statistics were abstracted in an anonymized manner from ICES. COPD was defined using the validated ICES-derived COPD cohort and spirometry use was assessed through billing codes. Cancer stage was available from cancer registry data. Analysis was conducted using ICES’s confidential, analytic virtual environment using SAS v9.3 in the population age >39 years. The local ethics board approved the study.

Results:
From 2004-2014, 90,783 individuals were diagnosed with lung cancer and 608,347 individuals diagnosed with COPD. Of individuals with lung cancer, 52.7% were male, median age at diagnosis was 65-69 years, and 82.8% have died. Of individuals with COPD, 51% were male, median age at diagnosis was 60-64 years, and 24.7% have died. The diagnosis of COPD was made at a rate of 8.7 persons per 1000 person-years. Among individuals having COPD, 48.4% underwent spirometry. 30.2% of individuals with lung cancer were also diagnosed with COPD and 60.8% underwent spirometry at any time. Among those with a diagnosis of both lung cancer and COPD, 73.6% underwent spirometry. For individuals with registry recorded stage data, 12,110 persons had stage I-II lung cancer, of whom 90.7% had spirometry and 55.9% had a diagnosis of COPD. Conversely, among 31,392 persons with stage III-IV lung cancer, 54.6% had spirometry and 46% were diagnosed with COPD (p<0.001 vs early stage for both).

Conclusion:
The diagnosis of COPD is not based on spirometry in half of cases. More patients with early stage lung cancer underwent spirometry and a higher rate of spirometry was associated with more diagnosis of COPD. Increased use of spirometry may improve the accuracy of a COPD diagnosis and may increase the diagnosis of COPD in advanced stage lung cancer, allowing improved dyspnea management in this population.

Background:
Lung cancer screening (LCS) with chest CT scans in high-risk smokers has been demonstrated to save lives. Medicare and private insurers now cover these scans for beneficiaries under specific criteria. However, most smokers will die of comorbid smoking-related diseases rather than lung cancer itself. Important information about comorbid conditions is available on screening chest CT scans, but the prevalence of these comorbidities has not been comprehensively assessed.

Methods:
COPDGene subjects from the Phase 1 visit who met USPSTF criteria for LCS (age > 55, >30 pack years smoking, current or former smokers within 15 years of smoking cessation or current smokers) were assessed for coronary calcification, emphysema, gas trapping, airway wall thickening and vertebral bone density on standard dose CT scans. A new diagnosis of emphysema, osteoporosis, or cardiovascular disease was assumed when there was no self-report of diagnosis or medication use.

Results:
In 76% of CT scans from LCS-eligible COPDGene subjects, we found abnormal emphysema (>5% low attenuation area @-950 Hounsfield units), airway wall thickening or gas trapping (>20% low attenuation area @-856 Hounsfield units). Osteoporosis was identified in 54% of all CT scans, and abnormal coronary artery calcium was present in 51%. In non-COPD smokers a new diagnosis of emphysema, osteoporosis or coronary calcification was found in 741 (48%) subjects. Overall, 75% of LCS eligible CT scans showed one or more non-cancer diagnoses.

Conclusion:
Enhanced readings of the lung cancer screening scans could identify individuals with previously undiagnosed osteoporosis, atherosclerotic heart disease, emphysema and COPD. Identification and treatment for these conditions may reduce morbidity and mortality, improve quality of life and enhance smoking cessation.

Abstract not provided

Background:
Radiation pneumonitis is a major toxicity after the thoracic radiotherapy, with no method available to accurately predict the individual risk. This was a prospective study to evaluate the exhaled nitric oxide as a predictive biomarker for radiation pneumonitis in the patients received the thoracic radiotherapy

Methods:
A total of 68 patients with lung cancer or esophageal cancer, who received the thoracic radiotherapy, were enrolled in the present study. Each patients underwent the exhaled nitric oxide measurement before the radiotherapy and at the end of radiotherapy. Pneumonitis toxicity was scored using the Common Terminology Criter

Results:
Of the 68 patients, 65 were evaluable. The pneumonitis toxicity grade were grade 3 for 6, grade 2 for 11 and grade0-1 for48. The exhaled NO measured before radiotherapy and at the end of radiotherapy were 23.05±9.59 (range 10-53) and 22.89±8.60(range 11-60) ppbs.For the exhaled NO ratio, the AUC is 0.879 (95%CI0.774-0.984). The accuracy of predicting the symptomatic patients was identified “good” according to the predictive ability criteria and the optimal cutoff value was tested as 1.305. For the exhaled at the end of RT, the AUC is 0.774 (95%CI 0.656-0.892). The accuracy of predictive the symptomatic patients was evaluated “fair” ,The optimal cutoff value was identified 19.5 ppbs.

Conclusion:
The exhaled nitric oxide ratio>1.305 or the exhaled nitric oxide at the end of radiotherapy>19.5ppbs was found to have a closely relation with radiation pneumonitis.

Background:
Detection of EGFR mutations using cell-free DNA in plasma has recently emerged as a novel diagnostic approach to lung carcinoma. This “liquid biopsy” (LB) may also be useful for monitoring disease activity in EGFR-mutated tumors as well as in the management of EGFR-tyrosine kinase inhibitor (TKI) therapy. We present data collected in one year of use and report on applicability and diagnostic value in daily clinical practice.

Methods:
EGFR Mutations were analyzed using the semi-quantitative Roche cobas® EGFR Mutation Test v2, comprising 42 mutations. Cell free DNA was extracted from EDTA-Blood with the Qiagen QIAsymphony circulating DNA Kit. LB was initially used for follow-up of known EGFR-mutated tumors and/or in patients under TKI-therapy. Subsequently, we introduced routine LB testing in the primary diagnostic workup of lung cancer patients.

Results:
From July 2015 to June 2016 we performed a total of 92 liquid biopsies in 77 patients (60% male, mean age 65y) in whom EGFR mutations could be detected in 10 cases (13%). EGFR status from histological samples was available in 40 patients, in 14 (18%) of them mutations were reported. Compared to histological EGFR status, LB reached a sensitivity and specificity of 0.57 and 0.96, respectively. A total of 9 patients had multiple LB testing during follow-up. Three of them initially had detectable mutations by LB, which turned undetectable upon tumor-specific treatment. Two patients remained EGFR-positive during follow-up despite of therapy, whereas four patients remained negative throughout follow-up and therapy. Resistance mutations under TKI-therapy were not observed. Primary LB (before initiation of any tumor-specific therapy) was obtained from 47 patients (72% male, mean age 66y). EGFR mutations by LB were detected in 2 patients (4%; 1 Ins. Exon-20, 1 L858R), while histology revealed EGFR mutations in 2 out of 22 patients (9%; both L858R). Comparison yielded a sensitivity of 0.5 and a specificity of 0.95 for LB.

Conclusion:
Testing for EGFR mutations using cell-free DNA has been established as a new powerful tool in the field of pulmonary oncology. Apart from sole detection of EGFR mutations, especially the application of LB in following patients over time will provide valuable new opportunities in clinical routine and decision making

Background:
Photodynanic therapy (PDT), is a treatment modality for many cancers, and uses a tumor-specific photosensitizer and laser irradiation. PDT is recommended as a treatment option for centrally located early lung cancer. The detection of peripheral lung cancers is increasing, and stereotactic body radiotherapy (SBRT) and percutaneous thermal ablation are emerging as alternatives to surgical resection, but PDT has not been a modality. Recently, we have developed a new minimally invasive laser device using a 1.0 mm in diameter composite-type optical fiberscope (COF), which could transmit laser energy and images for observation in parallel. In this study, we aimed to develop a new endobronchial treatment for peripheral cancer using PDT and a 1.0 mm in diameter composite-type optical fiberscope (COF), and we evaluated the feasibility of PDT using COF for peripheral lung cancer.

Methods:
This phase I study enrolled patients with peripheral lung cancers (primary tumor< 20 mm, stage IA), which were definitively diagnosed by bronchoscopic modalities using radial-probe endobronchial ultrasound (EBUS) and guide sheaths. We conducted irradiation using a diode laser (664 nm) and optical fiberscope (COF), four hours after the administration of NPe6 40 mg/m2. Before performing PDT, we evaluated the tumor lesions using EBUS through the guide sheaths for peripheral small lesions. Then, we introduced the COF into the peripheral lung cancer, observed the lesions and irradiated of red light 664 nm (120 mW, 50 J/cm2).

Results:
Three patients met our criteria, and 2cases were adenocarcinoma and 1 case squamous cell carcinoma. We were able to observe the cancer lesions at the peripheral lung by the COF, and feasibly irradiated. Two weeks and 3 months after NPe6-PDT, there was no morbidity including pneumothorax, pneumonia, skin photosensitivity.

Conclusion:
The 1.0 mm COF was a very useful device of NPe6-PDT for peripheral lung cancers, and PDT using the COF was a feasible and non-invasive treatment. Now, we have started phase II study of PDT using the COF for peripheral lung cancers. In the future, for non-invasive adenocarcinoma such as AIS, NPe6-PDT using COF will play an important role.

Abstract not provided

Background:
Incidental stage IIIA non-small cell lung cancer (NSCLC) cases have positive N2 mediastinal lymph node involvement discovered at the time of surgery, resulting in stage reclassification. These patients represent a small group within the stage III patient spectrum with limited data regarding their outcome. This study’s aim is to characterize the survival of incidental stage IIIA disease and compare these outcomes to patients diagnosed with stage II and IIIA disease.

Methods:
Using the Glans-Look Lung Cancer database and electronic patient charts, a retrospective review identified patients consulted at the Tom Baker Cancer Center from 1999 to 2012 who were defined as incidental stage III NSCLC. Their outcome was compared with stage II patients who underwent resection and stage IIIA patients treated with concurrent chemotherapy and radiation (CCR). These groups were selected for comparison because they represent patients who received the recommended standard of care for their respective diagnosis. A Kaplan-Meier analysis was conducted to compare overall survival (OS) among the groups.

Results:
Fifty-eight incidental stage III NSCLC patients were identified: median age was 63 years (SE ±10.3), 46.6% male, and 63.8% received adjuvant therapy. There were 225 individuals treated with CCR; median age 64 years (SE ±9.0), 56.0% male. The stage II group contained 248 individuals, the median age was 64 years (SE ±10.2), 53.6% were males, and 30.6% received adjuvant therapy. The OS of the incidental group was 47.4 months (95% CI 20.0-74.7). The OS for patients treated with CCR only was 24.0 months (95% CI 20.8-27.2) and 55.3 months (95% CI 43.7-66.9) for stage II resected cases. There was a significant difference in OS between CCR-treated stage IIIA and incidental cases (p = .001) but not between stage II and incidental (p = .264). The five-year survival rates were 44.6% (SE ±6.5) for incidental IIIA, 21.0% (SE ±2.7) for CCR-treated IIIA, and 46.9% (SE ±3.2) for resected stage II.

Conclusion:
This study demonstrates that incidental stage IIIA-N2 patients are a distinct group whose median OS closely resembled stage II patients. The benefit of resection for stage IIIA patients suggests that the traditional influence of stage in dictating treatment is changing. Further investigation is needed to identify which stage IIIA patients benefit the most. Ongoing analysis will include a comparison of progression-free survival between the three groups, impact assessment of post-operative treatment on OS, and a description of the diagnostic process evolution over time leading to an incidental N2 diagnosis.

Background:
Complete histopathological response or downstaging has been reported as a good prognostic factor for locally advanced non-small cell lung cancer (NSCLC) patients who received neoadjuvant therapy and underwent surgical resection. However, it is yet to be known if the prognosis of pStage I patients is similar to that of ypStage I cases. In this study we aimed to compare the long-term survival following surgical excision between locally advanced NSCLC that have been downstaged to stage I after neoadjuvant therapy versus stage I NSCLC treated by direct surgery.

Methods:
In this is multi-centered study we retrospectively analyzed the medical data of NSCLC patients undergoing surgery (segmentectomy or more) between January 1998 and December 2014. According to the histopathological results patients with Stage 1 (T1-2aN0) disease (n=427) were included into the study. Patients were divided into two groups Group 1: patients who underwent direct surgical resection without any preoperative therapy (n=291), Group 2: Patients who had locally advanced disease (T3-4N0-1 or T1-3N2) and received neoadjuvant treatment (chemotherapy or chemoradiation) for locally advanced NSCLC (n=136). The survival rates and effecting factors were analyzed.

Results:
All but 64 patients were male with a mean age of 60y (20-87y). According to tumor type; 192(45%) patients had squamous cell carcinoma, 158(37%) adenocarcinoma and 77 (18%) patients NSCLC. Neoadjuvant treatment consisted of chemotherapy in 89 (65,4%) and chemoradiation in 47(34,5%) patients. Histopathological investigation of the resected specimen revealed stage Ib (T2aN0) in 205 patients (group 1; n=140, group 2;n= 65, p=0,95). Overall morbidity rate for all patients was 30,9% (132/427) with 1.8% mortality. Five year survival rate in all patiens was 71% (77% in group I and 57% in group 2). The difference was statistically different between the groups, p<0,001.

Conclusion:
This study showed that survival of patients after surgical excision was different in ypStage 1 compared to pStage 1. Histopathological staging does not reflect to the survival figures. Our impression is that IASLC recommendations for staging of NSCLC should be subdivided or revised according to ypTNM staging following neoadjuvant treatment.

Background:
In IIIa(N2) Non-small cell lung cancer (NSCLC), various strategies to cure have been tried but the major cause of mortality is still the recurrence. Therefore, understanding of the dynamics of recurrence is important to improve the treatment outcome. We investigated the timing and patterns of recurrence after treatment of IIIA(N2) NSCLC with trimodality treatment (neoadjuvant chemoradiotherapy and surgery).

Methods:
An institutional database of consecutive patients between 1997 and 2013 (N = 574) was reviewed retrospectively. Eligible patients had pathologically proven N2 disease of NSCLC and completion of a planned trimodality treatment. First events involving the development of loco-regional recurrence, distant metastases or both were considered. The hazard rate function was used to evaluate the dynamics of recurrence.

Results:
The 5-year overall survival rate was 47% and the 5-year recurrence free survival rate was 29%. Among the 299 patients (52.1% of total) who experienced recurrence, 26 (8.7%) had loco-regional recurrences, 248 (82.9%) had distant metastases, and 25 (8.4%) had both. The most frequent sites of distant metastases were lung (n=102, 41%), brain (n=63, 25%), and bone (n=63, 25%). The hazard rate function for the overall recurrence revealed the peak at approximately 8 months after surgery then the down-slope pattern before 38 months. A similar risk pattern was found in distant metastasis but low and steady risk pattern was detected in loco-regional recurrence. In distant metastases, similar patterns were found in individual organs, however, earlier peak at approximately 5 months presented in brain metastasis. A comparison of histology showed that adenocarcinoma exhibited higher recurrence hazard rate of distant metastasis than squamous cell carcinoma with similar pattern of recurrence (p=0.03). The status of nodal clearance after induction therapy exhibited that ypN2 patients (n= 229, 39.9%) had highest hazard rate (p=0.03). The recurrence hazard rate of ypN0 was the least, but the extent was not smaller, they showed approximately one of third of ypN2 at peak.

Conclusion:
The hazard rate of loco-regional failure after trimodality therapy was low. But the hazard rate of distant metastasis was considerably high yet and shifted to left with the peak within 12 moths after surgery. This study guides the intensive surveillance immediate after completion of trimodality therapy to identify risk groups of early recurrence and to develop therapeutic strategy.

Abstract not provided

Background:
In all current non-small cell lung cancer (NSCLC) guidelines it is advised to screen all stage III patients for brain metastases, preferably by magnetic resonance imaging (MRI), or otherwise a contrast-enhanced computed tomography (CE-CT). Access to MRI can be problematic and a dedicated brain CE-CT can be incorporated in the staging [18]Fluodeoxoglucose-positron-emission-tomography ([18]FDG-PET)-CT scan. The additive value of a brain MRI after a dedicated brain CE-CT scan is unknown.

Methods:
In this observational prospective multicentre study all consecutive stage III NSCLC patients scheduled for treatment with curative intent from three Dutch hospitals who underwent a dedicated brain CE-CT incorporated in the staging [18]FDG-PET and an additional brain MRI were included. Patients with another primary tumour within 2 years of NSCLC diagnosis were excluded. Data regarding patient characteristics and imaging results were collected. Primary endpoint was the percentage of patients diagnosed with brain metastases on MRI without suspect lesions on CE-CT. 118 patients were needed to show a clinically relevant considered difference of 2%.

Results:
Between December 14[th] 2012 and July 15[th] 2016, 264 consecutive patients had an extracranial stage III NSCLC based on [18]FDG-PET. 111 out of these 264 patients (42.0%) were excluded because of no dedicated brain CE-CT 57 (51.4%) had only a low dose CT for attenuation correction, 54 (48.6%) had a CE-CT but without dedicated brain imaging protocol). Fourty (26.1%) of the remaining 153 patients were excluded because of asymptomatic brain metastases on dedicated CE-CT brain (N=8), second primary (N=6) or no brain MRI (N=26). 113 stage III patients were included (updated results of 118 patients will be presented). 57.5% of the included patients were male; mean age was 67.0 years, 84.1% had WHO PS 0-1, 60.2% had stage IIIA (before MRI brain) and 42.5% had an adenocarcinoma. Median time (range) between [18]FDG-PET-CE-CT and MRI was 2.0 (0.0 -8.1) weeks. 5/113 (4.4%) patients had a solitary brain metastasis on MRI despite no suspect brain lesions on CE-CT. In retrospect, in one of these five patients a solitary brain metastasis could be identified on the [18]FDG-PET–CE-CT.

Conclusion:
Although asymptomatic brain metastasis were detected in staging CE-CT, MRI brain is in daily practice clinically relevant superior to a CE-CT in screening for brain metastases in stage III NSCLC

Background:
Tumor-infiltrating lymphocytes (TILs) and tumor budding were all the markers of tumor microenvironment. This study aimed to explore the potential association of tumor microenvironment with brain metastases (BM) in patients with completely resected stage IIIA(N2) NSCLC.

Methods:
301 consecutive patients with pathological stage IIIA(N2) NSCLC who underwent complete surgery were reviewed between January 2005 and July 2012. Full-face hematoxylin and eosin-stained sections from surgical specimens for each case were evaluated for the density of TILs. Patients were stratified into TIL- and TIL+ groups based on pathologic evaluation. Tumor budding was defined as single cancer cells and clusters composed of up to four cancer cells. According to the number of tumor budding per field, the cases were classified into two groups: grade 1, up to five budding foci; and grade 2, six or more budding foci. The relationship between tumor microenvironment and BM at the initial presentation was analyzed.

Results:
Brain was the most common site of distant failure, and 92.5% BM developed in 3 years after the complete resection. 53 (17.6%) patients had BM as the first failure. Although, univariate analysis showed that TIL was not significantly associated with an increased risk of developing BM as the first site of failure in 3 years (P=0.196), a higher density of TILs was associated with improved postoperative survival time (P=0.058). Patients with the tumor budding >5 experienced increased BM in 3 years versus patients with the tumor budding ≤5 (P=0.068). Multivariate analysis showed that adenocarcinomas and multiple N2 stations were significantly associated with the high risk of BM as the initial site of failure in 3 years. Figure 1



Conclusion:
In patients with completely resected stage IIIA(N2) NSCLC, tumor budding >5 had a tendency to experience more BM. TIL seems to be a potential role in predicting survival of patients in completely resected stage IIIA(N2) NSCLC.

Background:
Type 2 Diabetes Mellitus (T2DM) has been associated with an increased risk of relapse and mortality in several cancer locations, but the prognostic value of T2DM or its metabolic control (MC) in patients (pts) with stage III non-small cell lung cancer (NSCLC) have not been studied yet. The purpose of this study is to evaluate the influence of T2DM and its MC on the prognosis of pts with NSCLC treated with concurrent chemoradiotherapy (cCT-RT).

Methods:
170 pts with NSCLC stage III treated with cCT-RT at the Catalan Institute of Oncology from 2010-2014 were retrospectively reviewed. The overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier method and multivariate Cox model was adjusted by: age, histology, stage, ECOG PS and smoking history.

Results:
Patient characteristics: median age 64y (37-87), male 87%; ECOG≤1 92%; smoking history: current 49%, former 46%, never 5%; histology: adenocarcinoma 34%, squamous 43%, NOS 23%. Platinum doublet CT: Cisplatin 64%, Carboplatin 36%. RT between 60-70 Gys: 94%. At a median follow-up of 38 months (m), 108 patients relapsed (63%), mPFS; 13m (95% CI 10-16) and mOS: 28m (95% CI 22-34). 54 pts (32%) had been diagnosed with T2DM before NSCLC diagnosis. In the overall population mean baseline glycemia was 6.75 mmol/L (3-17). OS and PFS were significantly shorter in patients with T2DM (mOS 17m vs 31m, p=0,005; mPFS 10m vs 16m; p =0,003). T2DM pts were classified into 3 groups of MC based on glycated hemoglobin (HbAc1) before treatment: good MC (HbAc1 <7%), n=26pts; moderate MC (HbAc1 between 7.1-8.5%), n=18pts and poor MC (HbAc1 >8.6%), n=10pts. Poor MC was significantly associated with shorter mOS (11m) as compared with moderate MC (20m) and good MC (28m; p=0.029). T2DM pts treated with insulin had shorter mOS (8m vs 20m; p=0.002) and mPFS (7m vs 12m; p=0.002) than non-insulin treated pts. However there were no differences based on whether pts were taking metformin or not. T2DM was not associated with higher risk of treatment toxicity (pneumonitis or esophagitis). In the multivariate analysis, baseline glycemia and T2DM were both independent prognostic factors for OS (HR 1.2; IC95%1.17-1.3 and HR 1.51; IC95% 1.02 -2.27, respectively).

Conclusion:
Our data suggest that T2DM and poor MC is associated with worse prognosis in pts with stage III NSCLC treated with cCT-RT. Optimal control of T2DM and prevention of hyperglicaemia might benefit those pts, and further studies are warranted.

Abstract not provided

Background:
This study aims to compare efficacy and safety of two widely used combinations of cisplatin (P) in this setting: as etoposide (E) and vinorelbine. This last, in its oral formulation (oV) which has achieved comparable results as the IV formulation and patients (pts) prefer it.

Methods:
Pts between 18-75years, with histologically proven untreated and unresectable locally-advanced NSCLC (LA-NSCLC), adequate respiratory function, V20≤35% and ECOG-PS 0-1, were randomized 1:1 to oV-P arm: 2 induction cycles (cy) of oV-P followed by 2 cy more with RT; or to E-P arm: 2 cy of E-P concomitants to RT. Both arms with a total radiation dose of 66Gy administered 2 Gys daily. Primary endpoint was progression free survival (PFS) by RECIST 1.1. Secondary endpoints: overall response rate (ORR), overall survival (OS) and safety. With α-error of 0.05 (one-tailed test) and 0.1 β-error, median PFS unacceptable for the oV-P arm of 10 months (m) (p0) and a very acceptable of 15 m (p1), 122 eligible pts were required.

Results:
140 pts from 23 institutions of SLCG were randomized between 08/2011-12/2014. 134 pts were treated (66 in oV-P and 68 in E-P arms). Results based on this 134 pts are presented. Median age 62 years [39-76]; PS 0/1, 45%/55%; current smoker 51%; squamous cell 51%; stage IIIB 54%. 244 and 131 cy were given in the oV-P and E-P arms, respectively. All irradiated pts in oV-P arm received at least 60Gy, 7 pts in the E-P arm received less than 60Gy (4 due to toxicity). 1 pt (1.5%) in oV-P arm and 12 pts (17.6%) in E-P arm presented esophagitis G3/4 (p=0.002). 121 confirmed eligibility for efficacy analysis. ORR were 39 (64%) and 40 pts (67%) in the oV-P and E-P arms, respectively (p=0.889). After 16 m [1-43] of follow-up, 66% pts progressed and 43% pts died. Median PFS is 11.4 m (IC95%; 6-17) in oV-P arm and 11.8 m (IC95%; 7-16) in E-P arm (p=0.374).

Conclusion:
Both regimens achieve similar efficacy however oV-P has less toxicity, especially esophagitis G3/4. Further follow-up is needed for the survival analysis.

Background:
Concurrent chemoradiotherapy (CCRT) is the standard treatment (TRT) for stage 3 NSCLC. Elderly patients (pts) are common, may have increased toxicity,& poorer results from CCRT

Methods:
Individual patient data (IPD) from NCTN phase 2/3 trials of CCRT for stage 3 NSCLC from 1990-2012 was collected. We compared the overall survival (OS), progression-free survival (PFS), & adverse events (AE’s) for pts age ≥70 years (yrs) (elderly) vs. <70 yrs (younger). Unadjusted & adjusted Hazard Ratios (HRs) for survival time & their confidence intervals (CIs) were estimated by single-predictor & multivariable Cox models. Unadjusted & adjusted Odds Ratio (OR) for AE’s & their CIs were obtained from single-predictor & multivariable logistic regression models

Results:
IPD from 16 trials were analyzed; 2,768 pts were younger & 832 were elderly. Median OS & PFS for elderly & younger pts are in the table. In the unadjusted & multivariable models elderly pts had worse OS (HR=1.23; 95%CI =1.13-1.35, and 1.20; 95%CI=1.10-1.32, respectively). In the unadjusted & multivariable models, elderly & younger pts had a similar PFS (HR=1.02; 95% CI=0.94-1.11 and 1.01, 95% CI=0.92-1.10, respectively). Elderly pts had a higher rate of grade ≥3 AE’s in the unadjusted & multivariable models (OR=1.25; 95% CI=1.00-1.57 and 1.30; 95%CI=1.03-1.62, respectively). A lower percentage of elderly pts compared to younger completed TRT (47% and 57%, respectively; P<0.0001) & higher percentage stopped due to AE’s (20% and 13%; P<0.0001). Grade ≥ 3 AE’s (occurring at a rate ≥ 2.5%) with a higher rate in the elderly: neutropenia, dyspnea, fatigue, anorexia, vomiting, dehydration, hypoxia, hypotension, & pneumonitis (P<0.05).

Background:
Nimotuzumab, a humanized IgG~1~ monoclonal anti-EGFR antibody, is approved and widely used in patients (pts) with head and neck cancer or malignant glioma in combination with radiotherapy (RT) in several countries. On in-vitro and in-vivo experiments using NSCLC cell lines, nimotuzumab showed a radio-sensitizing effect.

Methods:
This phase II study evaluated the tolerability and efficacy of nimotuzumab in combination with concurrent CRT in pts with unresectable locally advanced NSCLC. All eligible pts received concurrent thoracic RT (60 Gy, 2 Gy/day, 6 weeks from day 1) and 4 cycles of chemotherapy (cisplatin 80 mg/m[2] on day 1, vinorelbine 20 mg/m[2] on days 1 and 8) once every 4 weeks as scheduled. Nimotuzumab (200 mg) was administrated once a week from cycle 1 to 4. The primary endpoint was tolerability in combination with concurrent CRT, which was measured by the percentage of pts who completed 60 Gy of RT within 8 weeks, completed 2 cycles of chemotherapy and received more than 75% of nimotuzumab.

Results:
Of 40 pts enrolled between June 2009 and May 2010, 39 eligible pts received the study treatment. The pts characteristics were as follows: 62 years (median); male/female, 34/5; stage IIIA/B, 21/18; PS0/1, 25/14. Thirty-four pts met the criteria for treatment tolerability, and 38 pts completed 60 Gy of RT within 8 weeks. Infusion reaction, >grade 3 skin rash, >grade 3 radiation pneumonitis, or >grade 4 nonhematological toxicity were not observed. The 3-year and 5-year overall survival rates for the 39 pts were 66.4% and 58.4%, respectively. The median PFS was 16.9 months, and the 5-year PFS rate for pts with squamous cell carcinoma (Sq; n = 16) was 50%, while that for pts with non-squamous cell carcinoma (non-Sq; n = 23) was 13.7%. In terms of the first relapse site, in-field relapse rates were low for both Sq (4/16; 25%) and non-Sq (4/23; 17%). However, the distant relapse rate was significantly higher for non-Sq (15/23; 65%) than that for Sq (4/16; 25%). Cytologic or histologic specimens were examined for the expression of EGFR protein/mutations using the EGFR IHC/FISH methods in 20 pts. EGFR 2+/3+ expression was shown more frequently in sq (8/10) than non-sq (4/10). EGFR mutation was observed in only 2 pts with non-sq.

Conclusion:
Addition of nimotuzumab to the concurrent CRT in this setting was well tolerated with clinical benefit to the patients. The low in field relapse rates may be attributed to the radio-sensitizing effect of nimotuzumab.

Abstract not provided

Abstract:
Background: Lung cancer and its treatment have a major physical impact, as well as emotional, social, psychological, spiritual, functional and practical challenges and consequences, both for the patient and his relatives. While coping with the disease they become aware of vulnerability and mortality, they are balancing hope and the realisation of mortal danger(1). Preconceptions which patients are harbouring could be an important factor at coping with the lung cancer. Both smokers (or former smokers) and non-smokers are being stigmatised, and lung cancer is connected with stereotype representation of incurable disease(2). Life is never the same as before the diagnosis. In the comprehensive approach to lung cancer, team work is of paramount importance. Beside the standard oncological treatment, for the patient there is a benefit of an early palliative care. This benefit beside better quality of life (due to better quality of life, less depression and less aggressive treatment) confers also an increase of survival(3). Here, the nurse is an important member of comprehensive care team, and is the one spending the greatest amount of time at bedside. Methods: We reviewed the literature and the current clinical practice. Results: In operationalising psychosocial care in oncology many authors are advocating so called tiered approach(4,5). Providing psycho-social support to lung cancer patients is the task of all medical workers included in the multidisciplinary care. And all cancer patients have the basic psycho-social needs, such as informational needs, basic emotional support, adequate communication, screening of needs on on-going basis and the symptom management. Patients experiencing more profound distress or have more unmet needs, should be directed into the specialist care provided by the mental health professionals or other professionals needed. At the psycho-social care of the lung cancer patients entering the treatment, there should be an emphasis on the adequate patient information concerning the disease, planned treatment, side effects and their management, the possibilities of patient’s contribution to the treatment, and also patients’ fears and existential issues should be addressed. It is important for the patient to get as many information as he deems necessary, being careful about the pace the information is given. Despite the amount of information offered in media in the recent time – many of them unfortunately also untested – many patients in their search for information prefer getting information in one-to-one communication with health provider, in relation with whom they are experiencing confidence, safety, care and professionalism(1). It is important to present the information, at the same time accurate and still preserving the hope even in the face of the odious situation, thus giving the patient and his relatives emotional support and strengthening their functional coping strategies. Therefore, medical professionals should develop good communication skills; these are proven to be associated with less unmet needs(6)by the patient and also with the increase of informed decisions regarding treatment(7). In patients with poorer communication skills, assertiveness support can help with the communication with the medical professionals but also with the relatives. The cognitive behavioural therapy strategies can take a pivotal place. Cognitive interventions are focused on the way of thinking about a situation and through it influences the behavioural and emotional response, like cognitive restructuration, helping the patient in development of positive alternative to negative thought, or distraction, changing the patient focus. Behavioural interventions, such as relaxation techniques, can help controlling physiological responses in stressful situations. An important place in the support of patient’s psycho-social needs is taking into consideration emotional and social support. In addition to patient’s relatives, friends and peers, medical workers represent an integral part of it. In the patient’s preparation for treatment, it is important to recognize those experiencing more profound distress or having more unmet needs, thus needing more help. Research has shown that cancer patients are experiencing more physical problems - the most common are pain, dyspnoea, fatigue, cough(8) - and also have more unmet needs than other patients. In excess of 80 % of lung cancer patients are experiencing some degree of psychological distress. This is more than other cancer type patients are experiencing. Depression estimates are ranging between 11 and 44 % and the fear of recurrence is ranging from 5 % up to the 89 %(8). The severity of distress is varying through the process of treatment and rehabilitation; the time of diagnosis is a period during which more patients are entering psycho-social treatment than later during treatment(1,5). With the aim of early recognition of patients with more profound distress, screening procedures are being implemented. Beside different questionnaires, International Psycho-Oncology Society is striving to implement the distress thermometer with 10 grades(9). The psycho-social interventions, performed by mental health professionals are proven to increase wellbeing, improve adjustment and coping, and reduce distress in people with cancer. In the field of psycho-oncology, the most commonly used methods are cognitive behavioural therapy, learning of relaxation skills, psycho education, and also partnership and family therapy(4). Providing psycho-social treatment for patients with more profound distress is connected with multiple challenges. Beside patient recognition and implementation of screening programmes, the next challenge is patient’s compliance, as psychological treatment can for a patient still be stigmata. Despite limited evidence of its efficacy patients prefer emotional and social help from the nurse than from allied professionals, because their medical expertise is seen as an advantage(5). In many healthcare systems the availability of psycho-social treatment, to the patient who needs it in the proper time, and the development of required resources, still in many cases underutilised, is the next challenge. This, despite proven ethical, emotional as well as economic benefits of psycho-social treatment. Conclusion:The nurse is playing one of the crucial roles in comprehensive treatment of lung cancer patients. She is indispensable in providing psycho-social support to the lung cancer patients, preparing to enter treatment. She is providing the basic psycho-social support, such as patient’s need for relevant information, basic emotional support, communication, screening for needs on an ongoing basis, symptom management. She is also pivotal in recognizing patients, experiencing more profound distress or has more unmet needs and can run a screening programme. REFERENCES: 1. Missel M, Pedersen JH, Hendriksen C, Tewes M, Adamsen L. Diagnosis as the First Critical Point in the Treatment Trajectory: An Exploration of Operable Lung Cancer Patients’ Lived Experiences. Cancer Nurs. 2015;38(6):E12-21. 2. Pujol J-L, Mérel J-P, Roth C. How preconceptions about lung cancer treatment interact with medical discourse for patients who accept chemotherapy? Psychooncology. 2016 Jul 23 [cited 2016 Aug 21]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/27449209 Accessed August 20, 2016 3. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733–42. 4. Hutchison SD, Steginga SK, Dunn J. The tiered model of psychosocial intervention in cancer: a community based approach. Psychooncology. 2006;15(6):541–6. 5. Brebach R, Sharpe L, Costa DSJ, Rhodes P, Butow P. Psychological intervention targeting distress for cancer patients: a meta-analytic study investigating uptake and adherence. Psychooncology. 2016;25(8):882–90. 6. Walling AM, Keating NL, Kahn KL, Dy S, Mack JW, Malin J, et al. Lower Patient Ratings of Physician Communication Are Associated With Unmet Need for Symptom Management in Patients With Lung and Colorectal Cancer. J Oncol Pract. 2016;12(6):e654-69. 7. Janssens A, Kohl S, Michielsen T, Van Langendonck S, Hiddinga BI, van Meerbeeck JP. Illness understanding in patients with advanced lung cancer: curse or blessing? Ann Palliat Med. 2016;5(2):135–8. 8. Pozo CLP, Morgan MAA, Gray JE. Survivorship issues for patients with lung cancer. Cancer Control. 2014;21(1):40–50. 9. Bultz BD. Guide to implementing screening for distress, the 6th vital sign: Background, recommendations, and implementation. Cancer Journey Action Gr. 2009;(May):4–43.

Abstract:
Purpose: To develop a cost-effective preoperative patient teaching program that includes a patient teaching video along with written material that improves patient satisfaction, decreases patient anxiety, decreases readmission rates associated with post-operative complications, and optimizes overall outcomes of thoracic surgery patients. Overview: Patients undergoing surgery usually have little knowledge of what to expect during the preoperative, postoperative, and recovery period following thoracic surgery. Multiple studies have shown that good quality preoperative teaching increases patient satisfaction, improves patient outcomes, and decreases patient readmission rates following surgery. Although the benefit of preoperative education is widely recognized in the literature, finding the resources available to provide efficient and effective teaching is a challenge. Patients who are diagnosed with a suspicious lung nodule or lung cancer are usually overwhelmed when attempting to navigate through the health care system. During the initial surgical visit a battery of studies and often additional diagnostic procedures are ordered for staging and surgical clearance. The details of the surgery are discussed and the surgical consent is obtained. The patient and family are inundated with so much information that pre-operative teaching is not effective at this time. Further, in outpatient health care settings there is a finite amount of time within a visit for a provider to promote all of the pre-operative patient education. It has been the experience of this thoracic surgery practice that providing the patients and families an opportunity to undergo pre-operative teaching in another setting, such as in their own homes, typically results in increased retention of the information, and patients do better not only in the pre-operative period but in the post-operative and recovery stages as well. Developing a well-designed preoperative teaching program requires a multidisciplinary approach and utilization of resources already available to build upon and promote better programs that optimize patient and caregiver learning and retention. Pre-operative education and teaching is not just to provide information, but also to help patients acquire the knowledge needed to change behaviors and to promote better health. Individuals within the care team with particular interest in patient education should be utilized in helping to develop an effective preoperative teaching program. Collaborating with nurses and advanced practice providers across the care continuum is ideal: these members of the team have both the knowledge base and the access to patients and their families needed to provide effective patient education. Method: “A Patient’s Guide to Thoracic Surgery” is a thoracic teaching manual that was customized to fit our thoracic patient population. It was developed by a group of nurses and advanced practice providers who were interested in developing thoracic patient education at our institution. The booklet includes basic information concerning how to prepare for thoracic surgery, as well as what to expect before and after the surgery. Our thoracic team saw the need for additional education and developed a patient education video, “A Patient’s Guide to Thoracic Surgery Video” that includes pre-operative teaching, what to expect after surgery, and after discharge. The video was funded by a grant that our hospital provides annually, funding various projects that support research, education, and clinical care. The team wrote a script and worked with the hospital IT department to create the video. Patients receive both the pre-operative teaching booklet and video during the initial office visit and the major points of the teaching material are reviewed at this time. The patient is instructed to read through the information and watch the video at their convenience. They are also encouraged to call the office to discuss what they learned and answer any questions they may have. The outpatient nurse practitioner calls and sometimes meets with the patients at least once again prior to surgery to review the patients’ pre-operative studies, update their pre-operative paperwork, and to answer any questions or concerns about their upcoming surgery. The patients are asked if they have read through the material and watched the video. During this encounter, updates on smoking cessation and exercise are documented and discussed. Following surgery, additional teaching is done by the nursing staff and the teaching video and discharge instructions are again reviewed. Furthermore, the patient is phoned for a “day after discharge” call by a thoracic team member to check on the patient’s progress and answer any questions the patient or family may have. The patients and their families are seen in the office for a post-operative visit usually 2-3 weeks after discharge. A 10 question “Thoracic Video Patient Satisfaction Survey” is completed during this initial post-op visit. This survey asks the patients to rate the educational video on content and how helpful they felt the video was in preparing them for surgery and for what to expect after surgery. Results: A “Thoracic Video Satisfaction Survey” has been given to all patients undergoing thoracic surgery at Penn Presbyterian Medical Center; Philadelphia, Pennsylvania over the past several months. Preliminary results have shown that since the implementation of the thoracic teaching video in conjunction with the written material there has been an increase in patient’s satisfaction and a decrease in anxiety associated with thoracic surgery Conclusion: Providing patients with multi-format education materials and the ability to review them on their own time has proven successful at achieving the stated goals. Moving forward we intend to build upon this resource to improve the patient education program at our institution. Additionally, we hope to conduct a formal research project in conjunction with other institutions such as the University of Maryland to continue to develop thoracic patient education and to help identify which programs work best in promoting patient education and changing behaviors in the thoracic surgery population.

Abstract:
Ethical decision making is very important in the context of treatment of cancer patients. These decisions can lead to withdrawal or withholding of life-sustaining therapy, or change the goal of the therapy from curative to palliative. “Do-not-reanimate” or “allow-natural-death” orders are also part of ethical decision making. Sometimes pain treatment is adapted or palliative sedation is started. It is necessary to make these decisions to ensure dignity at the end-of-life, which is a human right. Ethical decision making is usually done state-of-the-art in the context of Palliative Care, which means dialogue with the patient, the next of kin and other health-care-professionals involved in the treatment. The decision making process is structured, documented and can be replicated for everyone. Most of the time, these decisions are made by physicians only, without a dialogue, especially in Austria in hospitals or nursing homes. Sometimes patients are involved, but more often only their relatives. Physicians rarely ask other health-care-professionals for their opinion. End-of-life-decision-making seldom occurs as a structured well documented process. But the fact, that by law physicians have to take the final decision, does not prevent them from listening to and involving the perspective of the different persons concerned. If the discussion stops with the question “Who is allowed to decide?” then decisions would only be made because of having legal authority and not because of ethical reasons. (Vanlaere & Gastmans, 2008, Arndt, 2007) From an ethical perspective these decisions are often decisions between the autonomy of patients and the care of health care professionals. It is crucial to preserve the dignity of the suffering human being. It is a challenge to make reasonable ethical decisions in a context characterized by strong pressure for efficient and flexible organisational structures on the one side and complex values on the other side. (Gastmans & Vanlaere, 2005). It is not always clear what is right and what is wrong, or what is good and what is bad. Sometimes health care professionals, especially physicians, try to avoid these decisions by not to deciding anything, but avoidance is also a decision. Ethical decision making is much more difficult, if the suffering person cannot express his wishes anymore. Then, physicians and other health care professionals, who are included in the decision-making-process, have to find out the person`s wishes. It is very important that ethical decision making is based on indication for treatment, futility and the wish of patient. (Bundeskanzleramt, 2015) Ethical decision making should include all persons involved – physician, patient, relatives, nurses and also, if appropriate pastor or other religious leader, social workers and other health care professionals. The involvement of patients and – if they wish – their next of kin is necessary. Austrian medical guidelines (Valentin et al. 2004) recommended that nurses and other members of the multidisciplinary team had to be involved in such decisions. The decision making process should be structured, documented and - depending on the context – regularly evaluated. Several models exist for ethical decision making and help to guide and structure the dialogues. Individual ethical case conferences could be part of clinical ethical counseling, which also includes ethical education and providing guidelines. (Zentrale Ethikkommission, 2006). Examples of such decision-making-models are the model of Gastmans and Vanlaere (Vanlaere & Gastmans, 2008) based on the personalism and care-ethic, the Nijmwegener-model of Steinkamp and Gordijn (Steinkamp, 2012) and the model of Arndt (2007). Decision-making-models are not simply checklists. Health care professionals have to use them with empathy in the context of their own experience and values. (Körtner, 2012). General guidelines could deviate from frequently arising problems, but there always would be individual cases, which represent marginal cases because they burst all limits (Körtner, 2012). By using decision-making-models health care professionals have to be alert, not to use those strictly according to the written instructions. The sensitivity for the individual and his special situation has to be preserved. A discussion or counselling, where all persons concerned make a choice together according to their values and principles, is the best guarantee for a well-grounded ethical decision and gives more sense of security for a good result. Nevertheless, there is no guarantee for a right or good action. (Körtner, 2012). Because of the emotional burden of end-of-life-decisions, these models are also helpful to include all important aspects. The participants of these dialogues have to respect the values of the others and to see the situation from their point of view. Using decision-making-models guarantees to involve all relevant individuals. Furthermore, the decision making process becomes repeatable and visible. Finally, it is important to mention that ethical-decision-making can’t be reduced to using decision-making-models. Ethical thinking is a result of dynamic mutual reactions between emotions, intuition, standardization and rational reasoning. (Van der Arend & Gastmans, 2009) The role of nurses in this decision making process and also in the realization of these decisions is rarely recognized. But nurses play an important role in ethical decision making - as national (Ruppert et al., 2012) studies show. Nurses have the closest relationship to the patient compared to all health care professionals. They communicate daily with patients, know their problems, emotions, understand the social context and values. Furthermore, nurses execute the end-of-life-decisions, by, for example, not calling the rescue team. Therefore, it is very important, that nurses reflect and create actively their role in the ethical decision making process. They have to know which end-of-life-decisions are available and legal in the country where they work. Furthermore, they need knowledge in nursing ethics and ethical frame conditions of their organisations. Nurses have to become part of the ethical-decision-making; especially, if discussing ethical problem with the help of decision-making-models becomes routine because this has a vital impact on the daily nursing practise. Then nurses get used to reflect their acts, the values and principles laying behind and to involve the perspectives, values and norms of other individuals. If decision-making is consciously trained, it has a positive impact on situations, where reflection isn’t possible. (Arndt, 2007) Literature: Arndt, Marianne (2007): Ethik denken. Maßstäbe zum Handeln in der Pflege. Stuttgart: Thieme Verlag, 2. Unveränderte Auflage. Bundeskanzleramt (2015): Sterben in Würde. Empfehlungen zur Begleitung und Betreuung von Menschen am Lebensende und damit verbundene Fragestellungen. Stellungnahme der Bioethikkommission. Gastmans, Chris & Vanlaere, Linus (2005): Cirkels van zorg. Ethisch omgaan met ouderen. Leuven: Ten Have. Körtner, Ulrich (2012): Grundkurs Pflegeethik. Wien: Facultas Verlag, 2. Auflage. Ruppert Sabine; Heindl Patrik & Kozon Vlastimil (2012): Rolle der Pflege bei ethischen Entscheidungen. In: Imago Hominis 19 (2), S. 97-105. Steinkamp, Norbert (2012): Methoden ethischer Entscheidungsfindung im Pflegealltag. In: Monteverde Settimio (Hrsg.): Handbuch Pflegeethik. Ethisch denken und handeln in den Praxisfeldern der Pflege. Stuttgart: W. Kohlhammer Verlag, S. 175-192. Valentin, Andreas; Druml, Wilfred & Steltzer, Heinz (2004): Konsensuspapier der Intensivmedizinischen Gesellschaften Österreichs (2004): Empfehlungen zum Thema Therapiebegrenzung und -beendigung an Intensivstationen. In: Wiener Klinische Wochenschrift, 116/21-22: 763-767. Van der Arend, Arie & Gastmans, Chris (2009): Ethisch zorg verlenen. Handboek voor de verpleegkundige beroepen. Baarn: Hbuitgevers, 4. korrigierte Druck, 5. Auflage. Vanlaere, Linus & Gastmans, Chris (2008): Een goed gesprek voor een zo goed mogelijke zorg. Een zorgethische en personalistische overlegmethode. In: Tijdschrift voor Gezondheitdszorg en ethiek 18(2), S. 45-49. Zentrale Ethikkommission bei der Bundesärztekammer (2006): Ethikberatung in der klinischen Medizin. Deutsches Ärzteblatt 103 (24): A1703-1707.

Abstract not provided

Background:
About 10% of non-small cell lung cancer (NSCLC) patients with EGFR mutations will develop leptomeningeal metastasis (LM) either at initial diagnosis or during treatment. LM is a devastating complication of NSCLC associated with poor prognosis. The median overall survival is 4.5-11 months, with ~60% death due to LM or LM together with systemic lesions. However, the underlying mechanisms of the metastasis process are still poorly understood.

Methods:
we performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF) and matched normal controls from 11 EGFRm+ NSCLC patients with LM. Among them, 2 patients had LM at initial diagnosis, and 8 patients developed LM during 1[st] generation EGFR-TKI treatment, while such clinical information was missing for 1 patient.

Results:
The status of EGFR active mutations was the same in the primary tumor and CSF of all the patients, except one whose EGFR mutation was undetectable in the primary site probably due to low sequence coverage. In total, there were 8 patients with EGFR L858R, 1 with 19Del, and 2 with L858R & 19Del dual mutation. One patient also had de novo EGFR T790M in the primary site. None of the CSF samples showed EGFR T790M mutation, suggesting that it was not the resistance mechanism for the 8 patients who developed LM during TKI treatment. PIK3CA E545K and H1047L, and PTEN R130Q were identified in primary site and/or CSF of 6 patients. Although with small sample size, this ratio is much higher than what was reported in general EGFR L858R or 19Del positive lung adenocarcinoma patient population (~2% from 4 datasets), implicating that alternations in PI3K pathway may associate with LM risk. Interestingly, in 9 of the 11 patients, only 0.9%-7.8% of variants in CSF samples overlapped with those in primary site, suggesting tumor heterogeneity, divergence and clonal evolution during LM development. Moreover, when we cataloged the recurrent CSF-unique somatic genomic alterations existing in >5 patients, we identified genes involved in DNA repair pathway, cell cycle regulation and epigenetic reprogramming (NPM1, RAD50, MRE11A, POLE, CHEK1, XPC, KMT2B, KMT2C, KMT2D, and ATRX).

Conclusion:
In summary, our study has shed light on the genomic variations of LM and paved the way for potential therapeutic approaches to this unmet medical need.

Background:
Leptomeningeal metastases (LM) occur in almost 5% of non-small cell lung cancer (NSCLC) patients (pts) and are associated with a poor prognosis. To date, no prospective study has identified active chemotherapy for NSCLC pts with LM. In retrospective studies, EGFR-TKI treatment is reported to be effective in the treatment of LM. We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of erlotinib in pts with LM.

Methods:
NSCLC pts with cytologically confirmed LM were eligible and received erlotinib 150mg daily. Overall cytological response rate (ORR; defined “number of pts who achieves complete remission in CSF / number of all pts”), time to LM progression (TTP), overall survival (OS) and pharmacokinetics were analyzed. Under the null hypothesis, the regimen would be rejected if confirmed ORR was 5% or less. This study was closed because of low accrual with only 21 of required 32 pts (66 %) accrued.

Results:
From Dec 2011 to May 2015, 21 pts (17 pts with EGFR mutation) were enrolled. CSFs available for EGFR mutation analysis (N=17) were all EGFR T790M negative. ORR was 30 % (95%CI 12 -54 %). Median TTP was 2.3 months. Median OS was 3.1 months. Significantly longer TTP and OS were observed in EGFR-mutant than in EGFR-wild type (P=0.0054 and P<0.0001, respectively). Seven pts survived longer than 6 months. CSF penetration rate (Mean + SD) was 3.3 + 0.8 %. There was no correlation between CSF concentration and clinical efficacy.

Conclusion:
Erlotinib treatment for LM is active, especially in EGFR-mutant. Our findings suggest that erlotinib could represent a treatment option for EGFR mutated pts. CSF penetration in LM patients is equivalent to those in previous reports. Table1. Summary of ORR, TPP and OS

Background:
Central nervous system (CNS) metastasis, such as brain metastasis and leptomeningeal carcinomatosis (LMC), occurs frequently in EGFR mutant lung cancer. EGFR-TKIs are generally effective to CNS metastasis in EGFR mutant lung cancer patients who are naïve to TKI treatment. Nevertheless, progression of CNS lesions are frequently observed during EGFR-TKI treatment. Brain metastases are manageable by concomitant use of EGFR-TKI and local intervention, including whole brain irradiation and stereotactic radiotherapy. There is, however, no established therapy for LMC, which is resistant to first and second generation EGFR-TKIs. Therefore, novel and effective therapies need to be developed for managing LMC in EGFR mutant lung cancer patients who become refractory to these EGFR-TKIs. The purpose of this study is to clarify the mechanism of EGFR-TKI resistance in LMC and establish novel therapeutic strategy.

Methods:
We examined EGFR mutations, including T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 LMC and 20 extracranial lesions (e.c., lung metastasis and malignant pleural effusions) of EGFR mutant lung cancer patients who became refractory to EGFR-TKI treatment. To clarify molecular mechanisms of acquired EGFR-TKI resistance in LMC, we utilized in vivo imaging model of LMC with EGFR mutant lung cancer cell line PC-9/ffluc and induced acquired resistance to gefitinib by continuous oral treatment.

Results:
We found that all 32 re-biopsy specimens had the same baseline EGFR mutations and that T790M was less frequent in LMC specimens than extracranial specimens (8% vs 55%). Compared with subcutaneous tumors, T790M was less frequent in LMC which acquired resistance to gefitnib. We further established PC-9/LMC-GR cells from the gefitinib-resistant LMC model and found that PC-9/LMC-GR cells were intermediately resistant to gefitinib and osimertinib (3[rd] generation EGFR-TKI). While EGFR-T790M was negative, MET copy number gain associated MET activation was involved in the gefitinib resistance in PC-9/LMC-GR cells. Moreover, combined use of EGFR-TKI and crizotinib, having inhibitory activity against MET, dramatically regressed LMC which already acquired resistance to gefitinib or osimertinib.

Conclusion:
These findings suggest that combined use of MET inhibitors may be promising for controlling LMC which acquires resistance to EGFR-TKIs including osimertinib.

Abstract not provided

Background:
Afatinib (AFA) is an effective treatment in advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutation. However, there were few reports about the cerebrospinal fluid (CSF) penetration rate and the efficacy for central nervous system (CNS) metastasis. Therefore, we conducted the study to evaluate the CSF penetration rate and efficacy of AFA in NSCLC patients harboring EGFR mutation with leptomeningeal carcinomatosis (LC).

Methods:
Eligibility criteria included performance status (PS) 0-3, aged 20 years or older, pathologically proven NSCLC, harboring EGFR mutation, with LC, adequate organ function, and written informed consent. Patients received AFA (40mg/body every day). We analyzed the blood and CSF level of AFA before administrating AFA on the eighth day. The primary endpoint was the CSF penetration rate. Secondary endpoints included objective response rate (ORR), progression free survival (PFS), overall survival (OS), and safety profile.

Results:
A total of 11 patients were enrolled. And we could analyze the blood level in10 patients and the CSF level in 8 patients. Median patients-age was 66 years old. All patients were adenocarcinoma. In EGFR mutation status, 5 patients had exon 19 deletion, 3 had L858R and 3 had minor (exon18) mutation. The patients with PS 2 were 3 patients and PS 3 were 4 patients. Almost all patients received AFA after third-line or more line chemotherapy. The blood level was the Median 88.2 ng/ml (range: 30.4-373), the CSF level was Median 1.4 ng/ml (range: 0.39-2.85) and the CSF penetration rate was Median 1.65% (range: 0.1-9.25). The ORR is 27.3%, and two of three petients with exon 18 mutation showed the partial response. Median OS was 3.8 months (95%CI: 1.1-13.1) and median PFS was 2.0 months (95%CI: 0.6-5.8). Hematological toxicity was mild, however we have to take care of severe diarrhea and skin toxicities, especially in patients with poor PS.

Conclusion:
The median CSF penetration rate (1.65%) of AFA were higher than the penetration rate in previous case report. Although the efficacy for EGFR mutation positive patients with LC was moderate, the promising efficacy for the patient with LC harboring EGFR exon 18 mutation was demonstrated. And we have to take care of diarrhea and skin toxicities, especially in the patients with poor PS.

Background:
Patients treated with crizotinib often experience disease progression in the brain. Brigatinib, an investigational next-generation ALK inhibitor, is being evaluated in an ongoing phase 1/2 trial (Ph1/2) and an ongoing pivotal phase 2 trial (ALTA).

Methods:
In Ph1/2, patients with advanced malignancies, including ALK+ NSCLC, received 30–300 mg brigatinib per day. In ALTA, patients with crizotinib-resistant advanced ALK+ NSCLC received 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Efficacy (in both trials) and safety (in ALTA) are reported for ALK+ NSCLC patients with brain metastases at baseline.

Results:
In Ph1/2 and ALTA, 50/79 (63%; IRC-assessed) and 154/222 (69%; investigator-assessed) of ALK+ NSCLC patients, respectively, had baseline brain metastases. In Ph1/2 (n=50), median age was 53 years, 76% received prior chemotherapy, and 8% were crizotinib-naive. In ALTA (n=154), median age was 52 years; 75% received prior chemotherapy. As of November 16, 2015, 25/50 (50%) patients were receiving brigatinib in Ph1/2; as of February 29, 2016, 101/154 (66%) patients were receiving brigatinib in ALTA. For patients with measurable lesions, confirmed iORR was 53% in Ph1/2 and 42%/67% in ALTA A/B (Table). Among patients with only nonmeasurable lesions (Ph1/2, n=31; ALTA A/B, n=54/n=55), 35% had confirmed complete resolution of lesions in Ph1/2; 7%/18% had confirmed complete resolution in ALTA A/B. For all evaluable patients with baseline brain metastases, median intracranial PFS was 15.6 months in Ph1/2 (n=46) and 15.6/12.8 months in ALTA A/B (n=80/n=73). Most common treatment-emergent adverse events in ALTA in patients with baseline brain metastases (n=151 treated): nausea (A/B, 32%/43%), headache (30%/30%), diarrhea (18%/36%), cough (21%/30%), vomiting (25%/26%); grade ≥3 (excluding neoplasm progression): increased blood CPK (1%/11%), hypertension (4%/7%), increased lipase (3%/3%), pneumonia (1%/4%).

Conclusion:
Brigatinib has demonstrated substantial clinical activity in ALK+ NSCLC patients with brain metastases in both Ph1/2 and ALTA.

Background:
BRAF mutations occur in around 3% of non-small cell lung cancers (NSCLC) and V600E accounts for 50%. BRAF V600E is an attractive molecular target for cancer tyrosine kinase treatment, but ideal treatment is still not defined.

Methods:
A case of a patient with BRAF-mutated non–small cell lung cancer (NSCLC) detected by NGS Ion torrent technology who presented with LM disease and was treated with the selective BRAF inhibitor vemurafenib is described.

Results:
58 years old, female, non-smoker, who presented in the emergency department with pericardial effusion. Pericardial fluid cytology confirmed adenocarcinoma TTF1 positive. Multi-organ metastatic disease was diagnosed (bone, lung and thyroid) without EGFR mutation or ALK-EML4 translocation. Four cycles of chemotherapy with pemetrexed and carboplatin were done. She started with refractory headache and vomiting, brain CT and MRI showed no evidence of metastasis, a lumbar puncture confirmed malignant cells in the cerebrospinal fluid. A BRAF V600E was detected by NGS, Ion Torrence PGM technology in the initial tumour sample and in plasma circulating free DNA. An off-label treatment with vemurafenib 960 mg q12hr was offered to the patient, with clinical improvement and radiologic lung stability. At month 2 of treatment, the patient developed respiratory insufficiency with lung infiltrates and Influenza A virus was identified in a nasal swab. Vemurafenib was temporary suspended and re-introduced until 720 mg q12h and maintained until disease progression (large volume pleural effusion with positive cytology), at month 6 of vemurafenib tretament. Third line treatment is being planned.

Conclusion:
The authors highlight the importance of using a multiplex screening strategy to detect targetable mutations in advanced lung cancer patients. The application of next generation sequencing to the tumour and plasma cfDNA allowed the detection of a BRAF-V600E mutation. The improvement of neurologic symptoms and disease control achieved with vemurafenib supports vemurafenib´s efficacy. Care should be taken to the possibility of occurring lung toxicity.

Abstract not provided

Abstract:
In the United States of America (USA), the public is dangerously uninformed about lung cancer, our nation’s second leading cause of death behind heart disease[1]. Lung cancer accounts for more deaths than any other cancer[2]; more than breast, prostate and colon cancer combined! An estimated 220,000 new cases of lung cancer will be diagnosed the USA in 2016[3] resulting in 158,080 deaths or about 27% of all cancer deaths 2016[4]. Ready access to effective and comprehensive medical care at a reasonable cost is the key to our well-being. This is especially true for lung cancer. For lung cancer patients, access takes many forms, to include diagnosis, treatment and financial support for care and treatment. Regardless, for lung cancer patients, time is of the essence, making quick, effective and affordable access to care critical. This discussion will focus on four areas that affect access to care for lung cancer be it at the diagnostic stage or the treatment and care stage: (1) Stigma: At the outset, the negative bias against lung cancer may weigh against early access to treatment[5]. 68% of advanced cancer patients who have never received cancer care are lung cancer patients6. Cancer patients, healthcare professionals, caregivers and the general public are all equally likely to have a negative bias toward lung cancer[7]. (2) Timely diagnosis: The good news is that thanks to advances in technology, early detection screening using spiral CT has been shown to reduce lung cancer deaths by 16% to 20% ( in a defined population), compared to standard chest x-rays among adults[8]. Yet, only 16% of people will be diagnosed in the earliest stage, when the disease is most treatable[9 ]and at best, early diagnosis is usually the serendipitous result of some other unrelated procedure. Aside from the lack of public awareness that anyone with a set of lungs may be at risk for lung cancer, there remains no standard effective diagnostic tool for lung cancer. The development of affordable diagnostic tools using biomarkers in airway epithelial cells, sputum, blood, breath, and urine for early diagnosis and prediction of high risk individuals is critical. (3) Current and evolving treatment options: Once again, the good news is that treatment options for lung cancer patients are rapidly improving. In the last two years more treatments have been approved by the United States Food and Drug Administration (FDA) for the treatment of lung cancer than had been approved in the prior ten years. Most of the discoveries and associated clinical trials are happening at academic centers yet 80% of lung cancer patients are treated at their local community hospital. New and life savings treatments along with clinical trials are happening so quickly that it is sometimes challenging for these advancements to reach the treating physician thereby limiting ready access of these new treatments to the patient. (4) Cost of treatment and care: The Patient Protection and Affordable Care Act (PPACA), commonly called the Affordable Care Act (ACA) or Obamacare, is a United States federal statute signed into law by President Barack Obama on March 23, 2010. In April 2016, Gallup reported that the percentage of adults who were uninsured dropped from 18% in the third quarter of 2013 to 11% in the first quarter of 2016. Although individual insurance coverage has improved, the rapid pace of discovery and FDA approval of treatments, insurance payors and federal medical care assistance programs have not necessarily kept pace with these advancements in both testing and treatments by not providing insurance coverage, leaving lung cancer patients without the financial ability to pay for needed care. Various organizations such as ESMO, ASCO, ICER and others are attempting to compare drug prices to overall patient benefit through programed algorithms in order to assist payors and patients in treatment decision making. These are often long and laborious projects which may be out of date by the time the recommendations are published, and impede quick access to treatment and care Patients and patient advocates are in a strategically advantageous position to affect change in these four areas in order to provide greater access to care for all lung cancer patients. 1 http://www.medicalnewstoday.com/articles/282929.php#top_10_leading_causes_of_death_in_more_detail 2 http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf 3 American Cancer Society. Cancer Facts & Figures 2016. Atlanta: American Cancer Society; 2016. 4 http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf 5 LoConte NK, Else-Quest NM, Eickhoff J, Hyde J, Schiller JH. Assessment of Guilt and Shame in Patients With Non-Small-Cell Lung Cancer Compared With Patients With Breast and Prostate Cancer. Clinical Lung Cancer. 2008;9(3):171-8. 6 http://thelungcancerproject.org/#need-for-change 7 http://thelungcancerproject.org/#need-for-change 8 http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf 9 http://seer.cancer.gov/statfacts/html/lungb.html

Abstract not provided

Abstract:
Patient Advocacy Track Access to Care: Malaysia Recently The Systemic Anti-Cancer Therapy (SACT) dataset collated by Public Health England reported the assessment of factors affecting 30-days mortality in national patient population. Although, the report was impressive, only 3% of lung cancer patient treated with curative intent died within 30 days of starting chemotherapy and 10% for palliative treatment. There was a vast disparity among some hospitals. This concluded that clinical decision making in can certainly impact on cancer mortality(Wallington et al., 2016). In the similar context, clinical decision making in Malaysia and the South East Asia (SEA) are hugely influenced by the affordability factor which can directly influence mortality rates. The clear evidence is seen in Globocan 2012 data. SEA despite having the lowest prevalence for all cancers combined has a highest mortality to incidences ratio when compare with countries which have universal health coverage with better access to innovative care. Figure 1 To understand why the clinical decision making in Malaysia or the SEA region is hugely influenced by the affordability factor we must first dive in the health-care systems in southeast Asia (SEA). There is an enormous social, economic and political diversity within and across the countries in SEA which is formed by its history, geography and position as a major trade route. All these have had contributed not only to the diverse population but also to the wide-ranging nature of its health systems which are at varying stages. This highly diverse health-care system, range from dominant tax-based financing to social insurance and high out-of-pocket payments across the regions. For example, The World Health Report 2006 estimated that the total private finance sources account for 41.8% of total health expenditure in Malaysia which is likely affect the equity of financing because private health payments might impose disproportionate financial burden on households (“WHO | The World Health Report 2006 - working together for health,” 2013). A subsequent analysis showed private health expenditure has dominant role in financing healthcare in five of the seven countries in the SEA, contributing more than 70% of the total spending on health in Laos and Cambodia. This urge for health-financing reform and there are multiple model which are considered by varies government. Among them are financial protections through payroll-financed social health insurance or tax-funded arrangements for formal employment. However, this approach still challenges the informal and the rest of the population with countries such as the Philippines and Vietnam(Tangcharoensathien et al., 2011) A reformed health-financing with universal coverage will not only decrease the Lung cancer mortality as seen in the developed countries but also hugely impact daily clinical practice and increase quality of services provided to the patients. Bibliography. Globocan. (2012). Fact Sheets by Cancer. Retrieved October 14, 2016, from http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx Tangcharoensathien, V., Patcharanarumol, W., Ir, P., Aljunid, S. M., Mukti, A. G., Akkhavong, K., … Wagstaff, A. (2011). Healthfinancing reforms in southeast Asia: challenges in achieving universal coverage. The Lancet, 377(9768), 863873. http://doi.org/10.1016/S01406736(10)618909 Wallington, M., Saxon, E. B., Bomb, M., Smittenaar, R., Wickenden, M., McPhail, S., … Dodwell, D. (2016). 30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study. The Lancet Oncology, 17(9), 1203–1216. http://doi.org/10.1016/S1470-2045(16)30383-7 WHO | The World Health Report 2006 - working together for health. (2013). WHO.

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2016 World Conference on Lung Cancer Presentation Title: Access to Care: Australia Lung Foundation’s Lung Cancer Patient Pathway In June 2016, Lung Foundation Australia launched an evidence-based, clear and concise guide, the “Lung Cancer Patient Pathway”, for patients with a confirmed lung cancer diagnosis. The guide is available as a printed resource and online resource supported by a micro-site on Lung Foundation Australia’s website and the Lung Cancer Network Australia website and has been distributed to the majority of dedicated lung cancer treatment centers around Australia. Project aims The main aim of producing the Lung Cancer Patient Pathway (LCPP) was to provide newly diagnosed patients with a “one stop” resource that outlines the clinical referral pathways and details the full range of treatment options and supportive care services available to them throughout their lung cancer journey. The LCPP also aims to improve patient health literacy and empower patients with access to evidence based information to support informed decision making and treatment choices, self- management and ultimately, to improve patient outcomes. Project Synergies The LCPP was launched in conjunction with the launch of the Lung Foundation’s Australian Lung Cancer Multi-Disciplinary Team Directory http://lungfoundation.com.au/mdt/. This national directory lists the current (64) dedicated lung cancer multidisciplinary (MDT) services around Australia. It is intended to facilitate referrals of patients to hospitals delivering MDT-based lung cancer management. The creation of this national directory has forged closer relationships between the Lung Foundation and dedicated lung cancer multidisciplinary (MDT) services and provided a mechanism to be able to reach patients at time of diagnosis. Lung Foundation has previously struggled to reach patients early in their cancer journey. Strengthening these relationships with Lung MDT services has led to a systematic distribution of Lung Foundation patient kits including the LCPP info-graph. The Cancer Nurses Society of Australia Winter Congress in May 2016 and Australian Lung Cancer Conference in August 2016 presented opportunities to distribute the printed LCPP in conference delegate bags and at trade exhibitions to more than 550 cancer clinicians and nurses. Sustainability The Lung Foundation will implement the following strategies to ensure the sustainability of this project: · Info-graph will be trialed in Lung Cancer MDTs around Australia · Info-graph will form part of the Lung Cancer Consultative Groups activities · A minimum review period of two years for info-graph and website content · Annual budget allocation for ongoing promotion and dissemination Conclusion The Lung Cancer Patient Pathway project has produced a patient centered resource to empower newly diagnosed patients with current, evidence based information so that they can make informed decisions on treatment options and supportive care services and access the right treatment and care at the right time. This project was managed by Glenda Colburn, Director, Lung Cancer National Program, Lung Foundation Australia. The Lung Cancer patient pathway was made possible via unrestricted education grants. Principal sponsor: Bristol-Myers Squibb Supporting Sponsors: AstraZenea, Boehringer Ingelheim, Cancer Australia, Pfizer, Maurice Blackburn Lawyers, MSD.

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The defining characteristic of the health system in Israel is its governance by the National Health Insurance Law (1995). This law ensures health coverage to every resident of Israel and defines the government's responsibility to provide health services to every person without discrimination. In other words, health insurance is mandatory, and all residents of Israel must be insured. Citizens pay a healthcare tax – 4.8% of income. Private Health Services Patients have the option of seeking private medical care from a physician of their choice, and at their own expense. There are four health funds, where each fund has branches throughout the country and provide its members with all mandated services. The Basket of Health Services, consists of a range of essential medical services, including treatments, medications, and equipment which each health fund is obligated to provide to its members. Its contents are defined by law, but are subject to periodic revision. Therefore, a treatment or medication that was covered at one point may be discontinued, or new items may be added. Every end of a year, new treatments and technologies are submitted to be included to the new health basket. First the physicians rate the proposed new treatments and technologies, then the top ones enter the basket debate, where eventually only some every year enter the health system. In the past years new treatments and technologies could be added until the sum of 300 million NIS, that equals, 80 million dollars. This year the basket fund was increased to 146 million dollars. The problem is that there are many new treatments and that the oncology rating is among all oncological diseases. Last year, four new lung cancer drugs were proposed to the health basket. The Israel Lung Cancer Foundation, advocated in the Israeli Kneset (house of parliament), attended meetings, raised awerness in digital and written media. Eventually 3 new lung cancer drugs were approved including OPDIVO, TAGRISSO and ALECTINIB. This end of year, KYTRUDA and OPDIVO for larger indications were submitted in addition to foundation 1 diagnosis test. This year, the foundation submitted to the health basket the lung cancer screening test, LDCT to be included for population at risk. Clinical studies take place in Israel, although as a very small country with only 8 million people, the number of clinical trials is not large. Companionate programs exist as well. Overall, Israel has a very good health system with good access to targeted therapy and immunotherapy. Drugs for mutations such as ALK and EGFR are approved including immunotherapy for NSCLC.

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There is a growing evidence of direct contributions of nicotine to cancer onset and growth. The list of cancers reportedly connected to nicotine is expanding and presently includes small-cell and non-small-cell lung carcinomas, as well as head and neck, gastric, pancreatic, gallbladder, liver, colon, breast, cervical, urinary bladder and kidney cancers. The mutagenic and tumour-promoting activities of nicotine may result from its ability to damage the genome, disrupt cellular metabolic processes, and facilitate growth and spreading of transformed cells. The nicotinic acetylcholine receptors (nAChRs), which are activated by nicotine, can activate several signaling pathways that can have tumorigenic effects, and these receptors might be able to be targeted for cancer therapy or prevention. There is also growing evidence that the unique genetic makeup of an individual, such as polymorphisms in genes encoding nAChR subunits, might influence the susceptibility of that individual to the pathobiological effects of nicotine. The emerging knowledge about the carcinogenic mechanisms of nicotine action should be considered during the evaluation of regulations on nicotine product manufacturing, distribution and marketing.

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Introduction Due to general ageing population, many patients with lung cancer are elderly and with frequent underlying co-morbidities. The most frequent co-morbidities associated with lung cancer are cardiac (i.e. coronary artery disease) and pulmonary diseases (i.e. COPD). Cardiac co-morbidity Coronary artery disease (CAD) is present in approximately 10-15% of lung resection candidates. The risk of major adverse cardiac events (MACE) and cardiac mortality is 4-fold higher in patients with previous history of CAD1 and patients with a previous coronary stent procedure within 1 year from lung resection had MACE and mortality rates of 9.3% and 7.7% after surgery, respectively2. Cardiac evaluation is therefore particularly important in this population to optimize their treatment and reduce surgical risk. A specific cardiac risk score was recently developed and is named Thoracic RCRI (ThRCRI). Patients in the highest class of risk had a incidence of MACE of 23% versus only 1.5% in those in the lowest class of risk1. These findings were subsequently validated by a number of independent studies. Detailed evaluation for coronary heart disease is not recommended in patients who have an acceptable exercise tolerance and with low cardiac risk score. For patients whose exercise capacity is limited, those with a ThRCRI > 1.5 or those with known or newly suspected cardiac condition, non-invasive cardiac evaluation is recommended as per AHA/ACC guidelines3 to identify patients needing more invasive interventions. Appropriately aggressive cardiac interventions should be instituted prior to surgery only in patients who would need them irrespective of the planned surgery. However, prophylactic coronary revascularization prior to surgery in patients who otherwise do not need such a procedure does not appear to reduce perioperative risk4. Pulmonary co-morbidity Approximately 20-25% of patients with early stage lung cancer have a concomitant moderate to severe COPD (FEV1<80% and FEV1/FVC ratio < 70%). Many studies have shown the association between FEV1 or predicted postoperative FEV1 (ppoFEV1), and surgical risk. In particular the risk of pulmonary morbidity and mortality has been shown to increase when FEV1 is below 50-60% or ppoFEV1< 30-40%. However, recent evidence has shown that even patients with moderate to severe COPD and lung cancer can undergo safely to lung resection. In these patients, the resection of the most affected parenchyma containing the tumor may determine a minimal loss or even an improvement in respiratory mechanics and elastic recoil, similar to what happens in typical end-staged emphysema patients candidates to lung volume reduction surgery. Nearly one third of COPD patients may actually improve their FEV1 3 months after pulmonary lobectomy for cancer. Therefore, although a reduced FEV1 or ppoFEV1 is associated with increased morbidity and mortality, most recent guidelines recommended against using this parameter alone to exclude patients from surgery even in case of very low values5,6. Patients with idiopathic pulmonary fibrosis (IPF) and lung cancer are a more challenging population to manage. Surgical treatment of these patients is high risk for postoperative acute exacerbations of IPF, which is associated with 80-100% mortality rate. The postoperative mortality rate of these patients has been reported to range between 7 and 18%. Moreover, long-term prognosis of IPF itself affects long term survival following surgery for cancer. Additional fitness tests Carbon monoxide lung diffusion capacity (DLCO) appears to be a more sensitive indicator of poor pulmonary function and more reliably associated with postoperative respiratory complications and mortality. Until recently, DLCO measurement has been mainly reserved to patients with abnormal FEV1. However, recent studies have shown that FEV1 and DLCO are poorly correlated and that more than 40% of patients with normal FEV1 (>80%) may have reduced DLCO. A low DLCO or ppoDLCO is a reliable predictor of cardiopulmonary morbidity and mortality not only in patients with COPD but also in those with normal respiratory function. This is the rationale behind the most recent recommendations to measure DLCO systematically in all lung resection candidates. Cardiopulmonary exercise test: Cardiopulmonary exercise test is the gold standard in preoperative evaluation of lung resection candidates. In addition to the most frequently used parameter, VO2max, it provides several other direct and derived measures that permit, in case of a limited aerobic reserve, to precisely identify possible deficits in the oxygen transport system. Several series have shown that a VO2max>20 mL/kg/min is safe for every extent of resection, whilst values < 10 mL/kg/min are associated with a high risk of potoperative mortality. We recently found that VO2max<12 mL/kg/min was associated with 13% in-hospital mortality rate following open major anatomic lung resections7. A parameter, which has gained recent interest in our specialty is the minute ventilation to carbon dioxide output (VE/VCO2) slope, also named as ventilatory efficiency slope. VE/VCO2 slope can be increased due to either pulmonary or cardiac diseases. Several studies have shown that a value greater than 35 is associated with increased respiratory complications and mortality after lung resection. We found that the mortality rate of patients with VE/VCO2>35 was 7% versus only 0.6% of those with lower values. The association between this parameter and respiratory complications remained the same for patients with and without COPD and for those with VO2max greater or lower than 15 mL/kg/min. VATS and sublobar resections Videoassisted thoracoscopic surgery (VATS) has been recommended as the approach of choice for stage I lung cancer patients. Several studies showed that this approach is associated with lower incidence of complications, shorter hospital stay and in some cases lower mortality rates compared to thoracotomy. The benefits of VATS are particularly evident in patients with poor pulmonary function. Large series found that the difference in pulmonary complication rates after lobectomy by VATS versus thoracotomy was present only in patients with a FEV1<60%. Burt and coll.8 found that patients with ppoFEV1<40% or ppoDLCO<40% and submitted to VATS lobectomy had a markedly reduced incidence of mortality compared to those operated on through thoracotomy (ppoFEV1<40%: 0.7% vs. 4.8%, p=0.003; ppoDLCO<40%: 2% vs. 5.2%, p=0.003). Recent evidences have shown that anatomic segmentectomies provide equivalent oncologic results compared to lobectomy for tumours smaller than 2 cm, whilst preserving much more respiratory function and being associated with lower incidence of postoperative complications9,10. This extent of resection appears therefore ideal for patients with a limited baseline pulmonary function. Selected references 1. Brunelli A, et al. Recalibration of the revised cardiac risk index in lung resection candidates. Ann Thorac Surg. 2010;90(1):199-203. 2. Fernandez FG, et al. Incremental risk of prior coronary arterial stents for pulmonary resection. Ann Thorac Surg. 2013 Apr;95(4):1212-8 3. Fleisher LA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. Circulation 2007: 116(17): 418-499. 4. McFalls EO, et al. Coronary-artery revascularization before elective major vascular surgery. N Eng J Med 2004; 351(27): 2795-2804 5. Brunelli A, et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). Eur Respir J 2009; 34:17-41. 6. Brunelli A, et al. Physiologic Evaluation of the Patient With Lung Cancer Being Considered for Resectional Surgery: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2013 May;143(5 Suppl):e166S-90S 7. Brunelli A, et al. Peak Oxygen Consumption During Cardiopulmonary Exercise Test Improves Risk Stratification in Candidates to Major Lung Resection. Chest 2009; 135:1260-1267. 8. Burt BM, et al. Thoracoscopic lobectomy is associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40% of normal. J Thorac Cardiovasc Surg. 2014 Jul;148(1):19-28 9. Okada M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg. 2006 Oct;132(4):769-75 10. Yano M, et al. Survival of 1737 lobectomy-tolerable patients who underwent limited resection for cStage IA non-small-cell lung cancer. Eur J Cardiothorac Surg. 2015 Jan;47(1):135-42

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In recent years, the number of early stage lung cancers has enormously increased and this tendency is more prominent in octogenarians. Both curability and non-inavasiveness should be required for such situation. Surgery is the standard treatment for early stage lung cancer and VATS lobectomy or sublobar resection have been routinely performed for selected patients to maintain performance status[1)]. Especially, the indication of sublobar resection is considered to be related to the aggressive nature of tumors, thus several studies by HRCT findings and PET-CT were performed to predict the invasive nature as well as clinical stage. In JCOG 0201, 545 case who received lobectomy and mediastinal lymph node dissection due to stage I NSCLC were enrolled prospectively. Pathological non-invasive cancer (both vascular and lymphatic invasion negative) was evaluated by the consolidation/tumor ratio on preoperative HRCT. Adenocarcinoma <2.0 cm with <0.25 consolidation to the maximum tumor diameter (35 patients, 12.1%) revealed pathological non-invasiveness in 98.7% (95% CI: 93.2–100.0%), and this criterion could be used for radiological early lung cancer[2)]. The prognostic study of cases enrolled in JCOG0201 revealed that 5 year OS and RFS survivals of the entire patients were 90.6% and 84.7%, respectively. The 5-year OS of radiologic early and invasive adenocarcinomas were 97.1% and 92.4%, respectively (p=0.259). If the consolidation/tumor ratio lower than 0.5 in cT1a-b was used as a cutoff, the 5-year OS of radiologic early (121 patients, 22.2%) was 96.7% and invasive adenocarcinomas, 88.9% (p<0.01)[3)]. Based on the criteria of radiologic early cancer obtained by JCOG0201, randomised phase 3 trial to evaluate non-inferiority in OS of segmentectomy compared to lobectomy (JCOG0802)[4)]. The maxSUV of the primary tumor on PET/CT could be used as a prognostic marker of early stage lung cancer. Analyses of 610 resected stage IA adecocarcinoma showed that maxSUV and GGO ratio cutoffs to predict recurrence were 2.9 and 25%, respectively. They were also related to nodal metastasis, histological tumor invasiveness and recurrence. The 5-year RFS of cases with maxSUV <2.9 (n=456) was 95%, while cases with maxSUV>2.9 (n=154), 72% (p<0.001)[5)]. Surgical management of early stage lung cancer should be selected by based on the tumor size, GGO ratio and maxSUV to predict the biological malignancy of each case. Streotactic ablative radiotherapy (SABR) has attained importance for efficacy and safety for the treatment of early cancers located in the peripheral lung. There are two representative randomised phase 3 trial (STARS and ROSEL) to compare SABR and surgery. Eligible patients of these studies were T1-2a (<4cm) N0M0 and a total of 58 cases were registered (31 received SABR and 27, surgery). The combined analysis of these two studies revealed that 3 year OS in SABR (95%) was superior to that of surgery (79%) (p=0.037) and RFS at 3 years was similar; 86% in SBRT and 80% in surgery (p=0.54). Only 10% of cases in SBRT group suffered grade 3 toxicity but 44% of surgery group developed grade 3 and 4 toxicities. The pooled analysis of the two studies showed SBRT had similar treatment efficacy to that of surgery in spite of the small sample size[6)]. Japan Clinical Oncology Group evaluated the efficacy and safety of SBRT for operable/inoperable T1N0M0 patients (JCOG 0403). A total of 164 patients (100 inoperable and 64 inoperable) were treated by 48 Gy. The 3 year OS was 59.9% in inoperable patients and 76.5% in operable patients[7)]. Investigations into the effectiveness of SABR for operable patients as well as the optimal indication, dose and fraction should be clarified by prospective manner. SABR has become a radical treatment for inoperable stage I lung cancer. In addition, if operable cases treated by SABR in JCOG0403 show favorable outcome, further comparable trial of SABR versus less invasive surgery should be warranted. References 1) Committee for Scientific Affairs The Japanese Association for Thoracic Surgery, Thoracic and cardiovascular surgery in Japan during 2013 : Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg.2015;63:670-701. 2) Suzuki K, Koike T, Asakawa T, et al.: A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-756 3) Asamura H, Hishida T, Suzuki K, et al. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201 J Thorac Cardiovasc Surg 2013;146:24-30 4) Nakamura K, Saji H, Nakajima R, et.al. A Phase III Randomized Trial of Lobectomy Versus Limited Resection for Small-sized Peripheral Non-small Cell Lung Cancer (JCOG0802/WJOG4607L) Jpn J Clin Oncol 2010;40:271–274 5) Uehara H, Tsutani Y, Okumura S, et al. Prognostic Role of Positron Emission Tomographyand High-Resolution Computed Tomography in Clinical Stage IA Lung Adenocarcinoma Ann Thorac Surg 2013;96:1958–1965 6) Chang JY, Senan S, Paul MA et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: A pooled analysis of two randomized trials. Lancet Oncol 2015;16:630–637. 7) Nagata Y, Hiraoka M, Shibata T, et al. Prospective trial of stereotactic body radiation therapy for both operable and inoperable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group Study JCOG0403. Int J Radiat Oncol Biol Phys 2015;93;989-996.

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In 2030, 60% of all new cancer diagnoses (15/25 million cases) and 80% of cancer related deaths (10/13 million deaths) will occur in low and middle income countries (LMICs) [1]. This explosion in cancer incidence is attributed to prolonged life expectancy in steadily growing populations with high levels of modifiable risk factors such as tobacco/alcohol and unhealthy diets. Despite the significant health burden, LMICs spend less than 10% of the global cancer budget. Cancer therapies are exponentially sprouting in rich countries but LMICs are not proportionally benefitting from this growth. Corruption, lack of infrastructure, poverty, and absence of national cancer policies/goals have hindered the development of quality cancer care programs. Radiotherapy has particularly suffered because of the perceived assumption that establishing quality radiotherapy centers in LMICs is unaffordable, non-sustainable and therefore unattainable and should not be pursued. Currently, up to 90% of LMIC inhabitants lack sufficient radiotherapy access and about 30 countries in Africa do not have a single treatment machine. It is estimated that by 2020, >9000 treatment machines, >10,000 radiation oncologists, and thousands of physicists and therapists are needed to treat patients in LMICs per evidence-based radiotherapy recommendations [2]. Recently, a group of experts with the Lancet Oncology Commission [3] reviewed the current radiotherapy capacity in LMICs and estimated the 20-year burden of cancer requiring radiotherapy and the needed investments to bring radiotherapy capacity in these countries to the needed levels. The published report provides compelling evidence that investment in radiotherapy not only will save millions of lives but will also bring significant economic benefits. The initial capital costs of scaling up radiotherapy may appear prohibitive, but these figures are based on estimations and projections that promise to deliver radiotherapy that is safe, timely, effective, efficient, equitable and patient centered. By aiming at quality care delivery, we can guarantee the highest returns on investments not only in oncologic outcomes but also in curbing loss in health-related productivity and life years. We hereby discuss few strategies to directly or indirectly reduce the capital or operating costs of such an expansion: - Trans-national, public and private partnerships: International organizations (such as the WHO, IAEA, etc) in collaboration with interested academic consultants and national governments should plan the required radiotherapy centers based on individualized national cancer priorities in the setting of a wide cancer care policy. This will require however a significant buy-in from national governments which are expected to establish effective social security systems with universal health coverage, create reliable cancer registries, implement effective cancer preventative and early diagnosis programs and finally promote outreach health literacy programs in real-world settings. Once international investments are coupled to national needs/efforts, minimal wasting of resources and maximal return on investment will be attained. - Centralization and pooling of resources regionally and internationally: This is a crucial step to at least jump start radiotherapy programs especially in the very low income countries where efforts are generally starting from nothing or close to nothing at best. High quality radiotherapy/simulation units donated by and refurbished in developed countries can provide a starting point around which other resources can be pooled. Regional centers can create circles of remote dosimetry/physics support and chart rounds via video conferencing to promote continued education and high quality treatment plans. These regional networks can be also connected to international cancer centers of excellence for further support and collaboration. Tax breaks could be offered to academic institutions or manufacturers in rich countries to participate in this process. - Investing in technology/science adapted to local needs in developing countries: Even if the capital is available, current manufacturing capabilities will not be able to build the required number of machines by 2020 as required. There is thus an immense need for innovative low cost, high quality radiotherapy units. Research and development departments should be offered incentives to create these tools. Optimizing the use of radiation techniques and per-unit activity to adapt to the treatment demands in developing countries will also improve benefit to cost ratio. - Hypofractionation: The number of “radiation fractions per year” is used as a surrogate for radiotherapy demand. Hypofractionation, thus, is a major strategy to optimize radiotherapy utilization and decrease operating costs without compromising outcomes in many cancer sites. For example, in the case of 1000 early breast [4] and 1000 early prostate cancer [5] patients requiring radiotherapy per year, using evidence-based hypofractionated treatments, not necessarily the extremely hypofractionated high-tech stereotactic radiation, would decrease the number of needed treatment machines from 10 to 6 and the number of therapists from 25 to 14. It will also decrease the duration of treatment per patient and thus allow more patients to be treated daily. Despite these benefits, hypofractionation remains widely underutilized even in developed countries [6]. Figure 1 - Investing in building local skills: Skilled radiation oncologists, therapists and physicists are very expensive commodities. While initial external support is crucial, new radiation centers need to eventually become self-sufficient and sustainable. Establishing local training programs should be a national priority in developing countries to decrease the cost of external training and limit brain drain. There is no magic wand to decrease the initial cost of investing in building radiotherapy capabilities but through careful planning and strong collaborations, millions of lives can be saved. Cost is crucial but we should not lose compass of our goal: delivering quality radiotherapy treatments to cure, improve the quality of life and alleviate pain in of millions of patients with cancer who are desperately in need.

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Cancer incidence and mortality have been increasing in mainland China, making cancer the leading cause of death since 2010 and a major public health problem in the country. Much of the rising burden is attributable to population growth and ageing and to socio-demographic changes. According to the National Central Cancer Registry of China (NCCR), an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in mainland China in 2015, with lung, stomach, esophageal, liver and colorectal cancer being the most five common incident cancers and the leading cause of cancer death, for which radiotherapy always plays an important role in the comprehensive therapy. The earliest record of radiation therapy for cancer in China dates back to the early 1930s. The establishment of the Sino-Belgian Radium Institute in 1931 signified the initiation of modern radiation oncology in China. However, the development of cancer treatment has been hampered by several major wars and political turmoil in the following decades until the late 1970s and early 1980s: the era of national economical reform in mainland China. It was at this point when the academic and research bodies started to focus on the availability of radiation oncology service and their access by cancer patients. In the next over 30 years, China has undergone a period of incredible economic growth and radiation oncology, has clearly improved in terms of equipment and its utilization, although the shortage of facilities and workforce remain to be improved. The Chinese Society of Radiation Oncology (CSTRO) started its survey of the personnel and equipment in radiation oncology in mainland China since 1986. The updated survey results of 2015 were recently compiled and analyzed. Comparison of these crucial data clearly demonstrates the increase in the number of the facilities as well as advances in the quality of service (Figures 1 and 2). Based on the report of the third survey (of 1997) (first English-vision survey published in the International Journal of Radiation Oncology * Biology * Physics), there were 453 radiation oncology centers equipped with 286 linear accelerators, 381 cobalt units, 179 deep X-ray machines, and 302 brachytherapy units. These facilities were staffed with 3,440 physicians, 423 physicists, and 2,245 radiation therapists. It is important to note that less than 1,200 physicians were trained at major cancer centers within the radiation oncology specialty. The rest were of other specialties (e.g., surgeons) and received only several months of “practical training” (i.e., mentorship by experienced radiation oncologist with customized lectures) in a few major cancer centers mostly in major cities such as Beijing, Shanghai, and Guangzhou, rather than formal residency training in radiation oncology. The ratio of medical physicists to radiation oncology centers was less than 1 as well. (Figure 1) The two decades after 1997 signifies a rapid advance in the quality of radiation therapy facilities as well. The number of linear accelerators exhibited a nearly 6-fold increase in these 20 years, and more facilities are now equipped with computerized treatment planning systems (increased from 177 to 1,921) as well. On the other hand, the registered radiation oncology centers were established in most of the major cities, increased to 1,431 (a 210% increase from the 1997 survey), which makes radiotherapy much more easily accessed by cancer patients. The number of radiation oncologists increased to 15841 (a 360% increase). Besides, medical physics, a crucial specialty for the quality and safety of the clinical application of radiotherapy, has substantially improved. The number of trained medical physicists has undergone a nearly 7-fold increase to 3,294 in total. (Figure 2) At the same time period for accelerated development regarding radiation therapy capacity, the population and cancer incidence of mainland China had also increased, which resulted in the radiotherapy remained much insufficient. According to the recently cancer statistics in mainland China, the cancer incidence was 4.29 million in 2015. Given that approximately 50% require RT as part of definitive treatment, around 2.15 million Chinese cancer patients need RT annually. This number is most likely higher, since it does not include recurrent and palliative indications (estimates put this number into the 65-75% range for all malignancies), and cover all the area in mainland China. In fact, the numbers of annual new radiotherapy consultation and daily treatment was 919,339 and 76,612 in 2015. Therefore, only 50% patients who would need radiotherapy received radiotherapy in Mainland China in 2015. The current status is caused by two main reasons. First, the ratio of tele-therapy facility (linear accelerator and Co60 combined) per million was 1.49 in 2015, which are quite low compared to 8.2 in the United States, 7.5 in France, 3.4 in the United Kingdom, and 2-3 recommended by the World Health Organization. Second, the distribution of radiotherapeutic resources is uneven by region. For example, the ratio in Beijing, Tianjin, Shanghai, and Shandong municipalities/province, where are considered regions of better economic development, is 3.07, 3.28, 2.19, and 2.28, respectively. Meanwhile, rural and/or less populous regions such as Tibet are often under 1.00. In conclusion, it is still obvious that cancer patients have limited access to radiotherapy facilities as well as qualified radiation oncologist, though remarkably robust development in all facets of radiation oncology over the last 30 years in mainland China. Clearly, much more effort should be made in regards to access to radiation oncology facilities and their service for cancer patients.Figure 1 Figure 1. The growth radiation therapy equipment in China from 1986 to 2015 based on the2015 CSTRO report by Lang et al. Figure 2 Figure 2. The changes in the configuration of radiotherapy team in China from 1986 to 2015 based on the 2015 CSTRO report by Lang et al. References 1. Gu XZH, Feng NY, Yu Y, et al. Investigation report on the composition of equipment and technical level of radiation therapy team in China. Radiat Oncol China. 1989, 3(1): 41-43. [Published in Chinese] 2. Yin WB, Chen B, Gu XZH, et al. General survey of radiation oncology in China. Chin J Radiat Oncol, 1995, 4(4):271-275. [Published in Chinese] 3. Yin WB, Tian FH, Gu XZH. Radiation Oncology in China: the third survey of personnel and equipment in radiation oncology. Int J Radiat Oncol Biol Phys, 1999, 44(2):239-241. 4. Yin WB, Tian FH. Survey report on national radiation therapy personnel and equipment in 2001. Chin J Radial Oncol, 2002, 11(3): 145-147. [Published in Chinese] 5. Chinese Society of Radiation Oncology (Yin WB, Yu Y, Chen B, et All). Fifth nationwide survey on radiation oncology of China in 2006. Chin J Radial Oncol, 2007, 16(1): 1-5. [Published in Chinese] 6. Chinese Society of Radiation Oncology (Yin WB, Chen B, Zhang CL, et al). The sixth nationwide survey on radiation oncology of continent prefecture of China in 2011. Chin J Radiat Oncol, 2011, 20(6): 453-457. [Published in Chinese] 7. Yin WB, Chen B, Tian FH, et al. The growth of radiation oncology in mainland China during the last 10 years. Int J Radiat Oncol Biol Phys, 2008, 70(3): 795-798. 8. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016, 66(2):115-132.

Abstract not provided

Abstract:
Patients with advanced squamous NSCLC receive first-line chemotherapy with a platin-based doublet. Combining first-line chemotherapy with EGFR-directed monoclonal antibodies has been studied as a strategy to improve outcome of these patients. Anti-EGFR monoclonal antibodies inhibit EGFR-mediated signal transduction and may also act via immunological mechanisms. Several monoclonal antibodies have been studied within clinical trials and data from phase III trials are available for cetuximab and necitumumab (for review see ref. 1). Two randomized phase III trials compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced NSCLC (2, 3). The FLEX trial demonstrated improved overall survival for cetuximab added to chemotherapy in patients with advanced NSCLC and enriched for EGFR expression in their tumors (2). The hazard ratio was 0.87 (p=0.044), median survival times were 11.3 months and 10.1 months, and 1-year survival rates were 47% and 42%, respectively. For patients with squamous cell carcinomas (n=347), the hazard ratio was 0.80 and median survival times were 10.2 months and 8.9 months, respectively. The BMS 099 trial failed to show an improvement in progression-free survival for cetuximab added to carboplatin plus paclitaxel in unselected patients with advanced NSCLC (3). A meta-analysis based on individual patient data from four randomized trials demonstrated a survival benefit for chemotherapy plus cetuximab compared to chemotherapy alone (4). The hazard ratio was 0.88 (95% CI 0.79-0.97; p=0.009). The benefit was greater in patients with squamous NSCLC in whom a hazard ratio of 0.77 (95% CI 0.64-0.93) was seen. Necitumumab has also been studied in combination with first-line chemotherapy in two phase III trials (5, 6). The SQUIRE trial assessed cisplatin plus gemcitabine with or without necitumumab in 1,093 patients with advanced squamous NSCLC (5). Necitumumab was intravenously administered at a dose of 800 mg on days 1 and 8 of every 21 days and was planned to be continued after the end of chemotherapy until disease progression or intolerable toxicity. Necitumumab improved the outcome of chemotherapy. The hazard ratio was 0.84 (95% CI 0.74-0.96; p=0.012). Median survival times were 11.5 months and 9.9 months, and 1-year survival rates were 47.7% and 42.8% for the chemotherapy-plus-necitumab arm and chemotherapy arm, respectively. Progression-free survival and response rates were also improved with the combined treatment. Grade ≥3 adverse events more frequently seen with chemotherapy plus necitumumab compared to chemotherapy were skin rash and hypomagnesemia. Based on these results, necitumumab has been approved as first-line therapy of squamous NSCLC in combination with gemcitabine and cisplatin. In contrast to the SQUIRE trial, the INSPIRE trial was prematurely stopped after enrolment of 634 patients because an interim analysis showed increased thrombo-embolic events and a lack of survival benefit for the combined treatment (6). Research has also focussed on the characterization of predictive biomarkers. Immunohistochemical EGFR protein expression and EGFR FISH positivity were of particular interest. In the FLEX trial, immunohistochemical EGFR expression of tumor cells was prospectively assessed by means of the DAKO pharmDx[TM] kit (7). Membrane staining intensity was divided into no staining, weak staining (1+), intermediate staining (2+), and strong staining (3+). The fractions of cells at the various staining intensities were determined. An immunohistochemistry score (IHC) based on both intensity and frequency of staining was then used for further analysis on the association between EGFR expression levels and clinical outcome. Patients were divided into those with high (IHC score ≥200) and those with low (IHC score <200) EGFR expression. High EGFR expression was seen in 31% of the patients. Among patients with high EGFR expression, patients treated with chemotherapy plus cetuximab had prolonged survival compared to those treated with chemotherapy alone. The hazard ratio was 0.73 (95% CI 0.58–0.93; p=0.011), median survival times were 12.0 and 9.6 months, and 1-year survival rates were 50% versus 37%. Among patients with low EGFR expression, survival times were not different between the two treatment arms. The treatment interaction between EGFR expression levels and treatment effect was statistically significant (p=0.04). The survival benefit achieved by the addition of cetuximab to chemotherapy in patients with high EGFR expression was seen across most subgroups including all major histological subgroups. Among patients with squamous NSCLC and high EGFR expression, the hazard ratio was 0.62 (0.43-0.88) in favour of cetuximab plus chemotherapy compared to chemotherapy alone. The survival benefit by the addition of cetuximab to chemotherapy in patients with high EGFR expression was achieved without an increase in toxicity. In summary, patient selection based on EGFR expression levels resulted in a clinically meaningful improvement in the risk benefit assessment of platinum-based first-line chemotherapy plus cetuximab in patients with advanced NSCLC (7). The SWOG S0819 biomarker validation study indicated that EGFR FISH positivity predicted benefit from cetuximab, particularly in patients with squamous NSCLC (8). Similarly, the benefits from necitumumab appeared to be greater in patients with EGFR FISH positivity or high EGFR expression (5, 9-10). References 1. Pirker R et al. Curr Opin Oncol 2015, 27, 87-93 2. Pirker R et al. Lancet 2009, 373, 1525-31 3. Lynch TJ et al. J Clin Oncol 2010, 28, 911-7 4. Pujol JL et al. Lung Cancer 2014, 83, 211-8 5. Thatcher N et al. Lancet Oncol 2015, 16, 763-74 6. Paz-Ares L et al. Lancet Oncol 2015, 16, 328-37 7. Pirker R et al. Lancet Oncol 2012, 13, 33-42 8. Herbst R et al. J Thorac Oncol 2015, 10, S795 9. Hirsch F et al. J Thorac Oncol 2015, 10, S797 10. Paz-Ares L et al. Ann Oncol 2016, 27, 1573-9

Abstract:
Lung cancer is the leading cause of cancer-related mortality worldwide with 1.59 million deaths in 2012 and, with an estimated 1.8 million new lung cancer cases, it accounts for about 13% of total cancer diagnoses[1]. Non-small cell lung cancer (NSCLC) represents around 85% of all lung cancers with the majority of patients in advanced stages of the disease when diagnosed. Squamous cell carcinoma (SqCC) is the second most common histology in NSCLC accounting for 20-30% of cases[2]. Compared to the most frequent advanced lung adenocarcinoma, for which targeted therapies are available in case of presence of actionable mutations, treatment options for advanced lung SqCC have not changed with the same vividness in the last decade. But, to date, we can definitely say that also for these patients, the research has made progresses and new therapeutic scenarios are now open. Docetaxel and erlotinib were the only standard second-line treatment options for lung SqCC until, in December, 2014, the US Food and Drug Administration (FDA) approved ramucirumab (an anti-VEGFR-2 antibody) in combination with docetaxel, for the treatment of metastatic NSCLC patients who progressed during or after a platinum-based chemotherapy. In March 2015 nivolumab (an immune-checkpoint-inhibitor) was approved, for treatment of patients with metastatic SqCC, who progressed during or after a platinum-based chemotherapy and pembrolizumab (another immune-checkpoint-inhibitor) was approved in October, in the same setting of patients but whose tumors expressed PD-L1 (evaluated with the approved specific companion diagnostic, the PD-L1 IHC-22C3 pharmDx test). Finally, in April 2016, afatinib (an EGFR tyrosine-kinase inhibitor) was approved for treatment of patients with metastatic SqCC progressing after a platinum-based chemotherapy[3][,[4],[5],[6]]. It has been suggested that SqCC patients treated with docetaxel had a poorer survival compared to non-SqCC patients hypothesizing that docetaxel may be less effective in squamous compared with non-squamous lung cancer[7]. This was also evidenced in the phase III study (REVEL), in which squamous and non-squamous NSCLC patients were treated with docetaxel with or without ramucirumab: an OS benefit was seen with ramucirumab-docetaxel in the whole population (10.5 vs 9.1 months, HR 0.86, 95% CI 0.75–0.98, p = 0.023). In those patients who presented squamous cell histology (25%) the OS benefit, when treated with ramucirumab-docetaxel, was 9.5 months (4.4–17.6) vs 8.2 months (3.6–14.9, HR: 0.88, 95% CI 0.69–1.13) in placebo-docetaxel subgroup, while in those with non-squamous disease a better OS was described (11.1 months, Interquartile Range, IQR 5.3–24.3) in the ramucirumab-docetaxel group, vs 9.7 months (4.4–19.6) in the control group (HR 0.83, 95% CI 0.71–0.97), however it needs to be noted that subgroup analyses in this study were not pre-planned[4]. In LUX-Lung 8, a phase III study of second-line afatinib vs erlotinib, which enrolled squamous patients only, OS was 7.9 vs 6.8 months (HR 0.81, 95% CI 0.69–0.95, p = 0.007), in the afatinib subgroup vs erlotinib one[7]. Survival benefits highlighted in these studies when compared to older studies with docetaxel, while statistically significant, evidenced modest developments in the treatment of advanced-stage SqCC, as a consequence, novel therapeutic approaches have been considered and well accepted in the oncology community as well as largely awaited. Research on tumor immunosurveillance led to the development of PD-1 immune-checkpoint-inhibitors, such as nivolumab and pembrolizumab, and the PD-L1 inhibitors atezolizumab (MPDL3280A), durvalumab (MEDI4736) and avelumab (MSB0010718C)[8]. Nivolumab produced response rates equal to 15 to 17% with a median OS of 8.2 to 9.2 months, in phase I and II trials, among previously treated patients with advanced SqCC[5]. Then in the phase III CheckMate 017, Nivolumab induced a median OS of 9.2 months (95% CI, 7.3-13.3) vs 6 months (95% CI, 5.1-7.3) with docetaxel. The results in the docetaxel group were worst than expected. The risk of death was 41% lower with nivolumab than with docetaxel (HR, 0.59; 95% CI, 0.44-0.79; p < 0.001)[5]. PD-L1 expression is largely debated and its specific influence in the squamous population still needs further elucidations, since a total of 83% of the patients who underwent randomization (225 of 272 patients) in this trial had quantifiable PD-L1 expression and PD-L1 was assessed on archival tumor tissue, which may not have reflected its real status at the time of treatment[5]. SqCC is considered the tumor with the second highest amount of molecular aberrations, (eg, FGFR1 amplification, PIK3K3 abnormalities, DDR2 mutations), providing a plausible explanation about heterogeneity of treatment responses and efficacy results in the second-line setting[9]. However, despite the identification of those specific molecular alterations, progress in targeting oncogenic drivers in SqCC still runs behind adenocarcinoma. There is a need to develop predictive and specific molecular biomarkers, that might identify subgroups of patients with lung SqCC that are most likely to benefit from targeted treatments or immunotherapic approaches. In this context Pilotto et al. elaborated a project with the aim to evaluate the molecular profile of resected SqCC in order to identify those immunologic pathways and molecular aberrations potentially able to estimate the probability of disease recurrence (prognostic factors) and to characterize novel biomarkers, whose targeting with specific drugs could potentially limit the oncogenic potential and change the natural history of this disease (predictive factors). Preliminary results of this study were consistent with literature data: several molecular alterations might be identified [PIK3CA, MET, FGFR3, DDR2, FRS2, CDKN2A, SMAD4, PD-L1] and some of them might impact on the biological behavior of SqCC contributing in the determination of patients prognosis[10]. These data will be further presented at WCLC this year. In conclusion, as more treatment options turn out to be available for patients, it will become essential to tailor those choices on patient’s unique molecular characteristics and his own needs, identifying the best sequence of treatments, especially in the era of rising healthcare costs and longer lifespan of advanced lung cancer patients. References [1] WHO Statistics. http://www.who.int/mediacentre/factsheets/fs297/en/ [Accessed on 21 August , 2016]. [2] Travis WD. Pathology of lung cancer. Clin Chest Med 2011; 32: 669–92. [3] Garon EB et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665–73. [4] Brahmer J et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2):123-35. [5] FDA approves Keytruda for advanced non-small cell lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm [Accessed on 21 August , 2016]. [6] Soria JC et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial Lancet Oncol 2015; 16: 897–907. [7] LE Ang Y et al. Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer. OncoTargets and Therapy 2016:9 3187–3195. [8] Melosky B et al. Pointed Progress in Second-Line Advanced Non–Small-Cell Lung Cancer: The Rapidly Evolving Field of Checkpoint Inhibition. J Clin Oncol 2016;34:1676-1688. [9] The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489(7417): 519–525. [10] S. Pilotto et al. Analyzing prognostic outliers to unravel biologically and clinically relevant molecular and immunologic pathways: a model from resected squamous cell lung carcinoma (R-SQCLC). Poster presented at 58 Annual Meeting of the Italian Cancer Society helded in Verona on 5-8 September 2016.

Abstract not provided