Virtual Library

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Background:
To date the nodal status is considered one of the most important indicators of prognosis for resectable NSCLC. The latest edition of lung TNM does not include any changes to N descriptors, but several changing proposals are under evaluation: IASLC proposed a subclassification of pN1-N2 based on the number of nodal station involved (pN1a, pN1b; pN2a1, pN2a2, pN2b). The number of positive lymph nodes and the lymph node ratio were also proposed as prognostic indicators of resected NSCLC. The aim of this study was to compare overall survival (OS) and Disease Free Interval (DFI) of pN2a1 (“skip” metastasis) to pN1b and pN2a2-pN2b.

Method:
A retrospectively analysis of 155 patients who underwent a complete resection and a systematic lymph node dissection for T1/T2 N1-N2 NSCLC (VII TNM edition) between 2006 and 2010 was conducted. Patients who underwent induction therapies or extended resections were excluded. All patients were restaged with the new IASLC proposal. OS, DFI and risk factors of pN1b, pN2a and pN2b patients were analysed.

Result:
An overall mean number of 16 (DS 8,4) lymph nodes were resected: 7,18 (DS 4,2) from the hilum and 8,72 (DS 5,9) from the mediastinum. After restaging all cases with new IASLC proposal we observed: 48 (30,9%) pN1b, 26 (16,8%) pN2a1, 63 (40,7%) pN2a2 and 18 (11,6%) pN2b. With a median follow up of 93 months, the median overall survival of the entire cohort was 27 months. pN2a1 had a significant better overall survival when compared with the other three groups (p=0,042). 1, 3 and 5-year survival for pN1b, pN2a1, pN2a2 and pN2b were 75%, 90%, 81% and 71%; 46%, 53%, 37% and 24%; 24%, 45%, 26% and 19% respectively. A number of more than 5 positive lymph nodes and a lymph node ratio >50% were independent prognostic factors of a worse survival (p=0,004 and p=0,035).

Conclusion:
Our data supports the new IASLC proposal for the revision of N descriptors. Patients with skip lymph node metastasis (pN2a1) have a significant better prognosis compared both to other pN2 groups and to pN1b. Moreover, we confirmed the important prognostic value of the number of the involved lymph node, which should be considered as well in the next edition of the lung cancer staging system.

Background:
Completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) patients are considered to be a heterogeneous population. The heterogeneity applies to tumor cells but to the microenvironment as well. Mounting evidence suggests that tumor infiltrating lymphocytes (TILs) are of clinical importance. Hence, we aimed to evaluate the role of the immune microenvironment as an immunoscore in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.

Method:
All patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection in our hospital from 2005 to 2012 were retrospectively reviewed. Tissue microarrays were constructed by the surgical pathology specimens from primary lung tumors. For each specimen, we selected two cores from the tumor center (CT) and two cores from invasive margin (IM) region. Densities of immune cell subpopulations (CD3+, CD45RO+, and CD8+ TILs) were evaluated using immunohistochemistry with image analysis workstation (Vectra 3.0). Immunoscore is based on the numeration of two lymphocyte populations: CD45RO+ memory lymphocytes and CD8+ cytotoxic cells, quantified within the CT and IM. The immunoscore (I) provides a score ranging from I0 when low densities of both cell types are found in both regions, to I4 when high densities are found in both regions. The results were correlated with tumor recurrence and patient survival.

Result:
Of the eligible 357 patients, 288 patients with well-established lung tumor samples were obtained and included in the analysis. The median follow-up duration was 54.9 months (range, 23.9-132 months) for the living patients. The 5-year distant metastasis-free survival (DMFS) and overall survival (OS) rates were 26% and 34%, respectively. In univariate analyses, densities of CD3+ cells were associated with neither OS nor DMFS, whereas CD45RO+ cells in IM were prognostic for DMFS (P=0.02) and OS (P=0.05). Combining CD45RO and CD8+ TILs (CT plus IM), the immunoscore(I) significantly increased the prognostic impact. Of the 288 patients, there were 68 (24%) with I0, 64 (22%) I1, 58 (20%) I2, 48 (17%) I3, and 50 (17%) I4. Five-year DMFS and OS rates were 17% and 28% for the group with low immune score (N=190, I0-2), compared with 42% and 45% for the group with high immune score (N=98, I3-4), respectively (DMFS P<0.001; OS P=0.001). Multivariate analyses showed that the immunoscore had independent effects on DMFS (P<0.001) and OS (P<0.001).

Conclusion:
The immunoscore in NSCLC may provide powerful prognostic information, including the prediction of DMFS and OS, and thus facilitate clinical decision making regarding systemic therapy in patients with completely resected stage IIIA(N2) NSCLC.

Background:
Completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) patients are a heterogeneous population, with 5-year survival rates ranging from 10% to 30%. The aim of this study was to investigate the relationship between the predominant subtype according to the new IASLC/ATS/ERS pathologic classification and prognosis in completely resected stage IIIA(N2) lung adenocarcinoma.

Method:
The medical records of 179 consecutive patients with completely resected stage IIIA(N2) NSCLC were reviewed between January 2005 and July 2012. According to the new pathologic classification, each tumor was reviewed using the comprehensive histological subtyping while recording the percentage in 5% increments for each histological component. Adenocarcinoma was divided into lepidic predominant, papillary predominant, acinar predominant, micropapillary predominant and solid-predominant. The predominant pattern was defined as the pattern with the largest percentage. To compare progression-free survival (PFS) and overall survival (OS) time between difference subtypes in lung adenocarcinomas, log-rank test was used for univariate analysis, and cox regression was used for multivariate analysis.

Result:
The median follow-up time was 42.7 months (range, 4.4–96.7months). The median PFS and OS time was 19.6 and 45.5 months, respectively. The 5-year PFS and OS rates were 16.4% and 34.6%, respectively. Patients with micropapillary and solid predominant tumors had poorer PFS (p=0.027) and OS (p=0.003) as compared to those with other subtypes predominant tumors. Micropapillary and solid predominant tumors were also significantly associated with an increased risk of locoregional recurrence (P=0.025), while not significantly associated with distant metastasis (P=0.21) than other subtypes predominant tumors. Multivariate analysis revealed that the new classification, chemotherapy, clinical N stage and LN ratio were independent prognostic factors for OS. Figure 1



Conclusion:
In patients with completely resected stage IIIA(N2) NSCLC, the predominant subtype according to new IASLC/ATS/ERS classification was an independent prognostic factor. It is valuable of screening out high risk patients to receive postoperative adjuvant therapy.

Background:
There is no large scale study of the initial surgery for patients with cN2 disease who received positron emission tomography (PET). We investigated the outcomes of initial surgery for patients with cN2 disease who had received PET, by conducting a multi-institutional retrospective study.

Method:
Clinical data for 143 patients who had cN2 disease and underwent initial surgery at 12 Japanese institutions in Thoracic Surgery Study Group of Osaka University (TSSGO) between January 2006 and December 2013 were collected. After reviewing all the data for eligibility, completeness, and consistency, 8 cases were excluded. The remaining 135 cases were feasible for analysis. Among these patients, 98 received PET and were analyzed.

Result:
The median follow-up was 56.5 months (2-110 months). The median age was 67 (35-80) years. There were 71 males and 27 females. The histology was adenocarcinoma (n=66), non-adenocarcinoma (n=33). The tumor location was the right upper lobe and left upper segment (n=66, 67.3%), and the others (n=32, 32.6%). Of 98 patients, 85 (86.7%) had clinical single N2 disease and 80 (81.6%) had no mode of spread lesion and 90 (91.8%) underwent lobectomy. The 5-year relapse free survival (RFS) rate and the 5-year overall survival (OS) rate for patients with cN2 were 34.6% and 46.6%. There were 24 patients (24.9%) with cN2pN0,1 and 74 patients (75.5%) with pN2. Of 74 patients with cN2pN2 disease, 42 (59.5%) had pathological single N2 disease and 40 (54.0%) underwent adjuvant chemotherapy. The 5-year RFS for the patients with cN2 in the cN2pN0,1 and cN2pN2 groups were 62.2% and 26.0%, respectively (p=0.0025). The 5-year OS for the patients with cN2 in the cN2pN0,1 and cN2pN2 groups were 74.8% and 40.0%, respectively (p=0.029). Moreover, we provided the following 3 criteria: primary tumor in right upper lobe or left upper segment, N2 disease with regional mode of spread, and patients who did not undergo pneumonectomy. 60 patients who fulfilled all of these criteria were regarded as specific group. The 5-year OS for the patients with cN2 in the specific group and non-specific group was 55.8% and 32.0%, respectively (p=0.024).

Conclusion:
Among patients with cN2 disease, those with pN2 disease were more in number in our study than in previous reports. Our patients with cN2pN2 had better survival compared with those in previous reports. In particularly, patients with clinical N2 disease in specific group have a favorable prognosis. An initial surgery may be considered as a treatment option for these patients.

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Background:
Both cisplatin (CDDP)+S-1 and CDDP+pemetrexed (PEM) can be given at full systemic doses with thoracic radiotherapy (TRT) in locally advanced non-small cell lung cancer (NSCLC), and CDDP+PEM is one of the standard chemotherapy regimens in patients with advanced non-squamous (non-sq) NSCLC. This multicenter, randomized, open-label, phase II study (SPECTRA) compared the efficacy and safety of the two above-mentioned promising regimens combined with TRT in patients with unresectable locally advanced non-sq NSCLC.

Method:
Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. If the 2-year PFS rate is assumed to be 25% in the inferior therapy group and 15% higher in the superior therapy group of this study, the sample size needed for selection of the optimum treatment group at a probability of approximately 95% will be 51 cases/group with the Simon’s selection design. The sample size was set at 100 patients.

Result:
Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n=17 (33%)/n=17 (34%); stage IIIB, n=21 (40%)/n=20 (40%); ECOG PS of 1, n=14 (27%)/n=14 (28%); never smoker, n=12 (23%)/n=12 (24%); and adenocarcinoma, n=47(90%)/n=45(90%). Completion rate of TRT (60Gy) and chemotherapy (4 cycles) was 92%/98% and 73%/86%, respectively. Response rate was 60%/64%. Grade 3 or higher toxicities included febrile neutropenia (12%/2%), anorexia (8%/16%), diarrhea (8%/0%), esophagitis (6%/8%), pneumonia (4%/4%), neutropenia (38%/52%), anemia (8%/12%), thrombocytopenia (4%/6%), and hyponatremia (12%/12%). Grade 1 radiation pneumonitis was observed in 8 (15%)/2 (4%) patients on the basis of the data collected 30 days or less after the discontinuation of protocol treatment. No treatment-related death was observed. The data on PFS and overall survival are immature.

Conclusion:
Response rate was similar between the two arms. Toxicities were tolerable and manageable in both arms; however febrile neutropenia was more frequently observed in the CDDP+S-1 arm. We will present the updated safety data of this study at the conference. Survival data will be analyzed in late 2018.

Background:
CRT is a standard for patients with Stage III non-small cell lung cancer (NSCLC). Veliparib (V) is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following chemotherapy or radiation induced damage. A phase 2 study indicated favorable efficacy of V vs placebo when added to P/C in advanced NSCLC (Ramalingam et al. Clin Cancer Res. 2016). Based on these results, a phase 1/2 trial was initiated to study the safety and efficacy of V/P/C-based CRT in the treatment of Stage III NSCLC.

Method:
Patients without prior NSCLC therapy suitable for definitive CRT received V plus C AUC 2 + P 45 mg/m[2] weekly + 60 Gy over 6-9 weeks. V was escalated from 60 mg BID to a maximum planned dose based on prior studies of 240 mg BID via 3+3 design with over-enrollment allowed followed by consolidation therapy of V 120 mg BID + C AUC 6 + P 200 mg/m[2] for up to two 21-day cycles.

Result:
Thirty-nine patients (median age 66; 14 male) have been enrolled to date into dosing cohorts at 60 mg (7), 80 mg (9), 120 mg (7), 200 mg (8), and a maximum planned dose of 240 mg (8). Median tumor volume at screening was 81 cc (16-555 cc). PK of V was dose proportional. CRT or V required dose reduction for 0 or 1 patient, respectively. Four (10%) patients discontinued study during CRT. No DLTs were observed and an MTD has not been identified. The most common any-grade AEs were esophagitis (23), nausea (22), fatigue (20), neutropenia (19), and thrombocytopenia (19). 27 SAEs occurred including 12 SAEs with reasonable attribution to V but outside the DLT window including G3/4 febrile neutropenia (2), G3 dehydration (1), G3 vomiting (1), G3 esophagitis (1), G3 radiation esophagitis (1), G3 esophageal stricture (1), G3 intractable N/V (1), G3 aspiration pneumonia (1), G3 radiation pneumonitis (1), G4 sepsis (1), and G5 sepsis during consolidation (1). Of 29 patients evaluable for tumor assessment, best response was CR (2), PR (22), SD (3), and PD (2).

Conclusion:
V/P/C-based CRT followed by V/P/C consolidation therapy is a tolerable regimen for the treatment of Stage III NSCLC. The RPTD for V during CRT is 240mg BID. A randomized placebo-controlled phase 2 extension of this study is planned. Clinical trial information: NCT02412371

Background:
Pathological staging (pTNM) after lung resection provides the most reliable data for staging non-small cell lung cancer (NSCLC) and predicting long-term survival. However, the survival rate of patients who undergo direct surgical treatment (pTNM) may differ from those who undergo lung resection after induction treatment due to locally advanced lung cancer (ypTNM). In this study we aim to compare the survival rate of pTNM versus ypTNM.

Method:
In this study, we retrospectively reviewed the prospectively recorded data of the patients undergoing surgery (segmentectomy or more) for NSCLC between 2006 and 2016. The patients were staged according to the 8th edition of TNM staging and divided into two groups. Group 1: patients who underwent direct surgical resection (n:450), Group 2: patients who received induction treatment before surgical resection for locally advanced NSCLC (n:345). We compared the survival rates and additional factors that affected the survival rates.

Result:
Postoperative histopathological investigation revealed ypT0N0 in 66 patients (complete response, group 2), stage 1 in 310 patients (group 1 n=211, group 2 n= 99) stage 2 in 223 patients (group 1 n=133, group 2 n= 90), stage 3 in 177 patients (group 1 n=100, group 2 n= 77), stage 4 in 19 patients (group 1 n=6, group 2 n= 13). Five year survival rate in all patients was 59,4% (group 1= 64,6%, group 2= 52,7%, p=0,001). Five year survival rate was 69,7% for complete response group. For patients with stage 1 disease survival rates were 81,9% for group 1 and 63,5% for group 2 (p=0,001). Patients with stage 2 had 5 year survival rates of 55,9% for group 1 and 45,9% for group 2 (p=0,11). Patients staged 3 and 4 had 5 year survival rates of 44,8% for group 1 and 34,4% for group 2 (p=0,10).

Conclusion:
This study revealed that survival rates varied between the patients who underwent direct surgery (pTNM) and the patients who underwent induction treatment before lung resection for locally advanced NSCLC. We recommend that the IASLC should examine the ypTNM stage in more detail in order to achieve more accurate results.

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Background:
NVALT-11 randomized trial showed that PCI reduced the proportion of stage III NSCLC patients with symptomatic BM from 28 % to 5 % (Groen ASCO 2017). Here, we report on the toxicity.

Method:
We randomized between PCI or observation in radically treated stage III NSCLC. Primary endpoint: incidence of symptomatic brain metastases; secondary endpoints: OS, toxicity and quality of life.

Result:
Between 2009 and 2015 a total of 195 pts were registered, 175 were randomized, 87 received PCI and 88 pts were in the observation arm. Median follow up: 48.5 months (95% CI, 39-54). Neurological adverse events (AE) of all grades that occurred more frequently in the PCI vs. the observation arm: cognitive disturbance (18 vs. 2 pt; p< 10[-4]) and memory impairment (25 vs. 7 pt; p<10[-3]). No significant difference in G3-4 cognitive disturbance and memory impairment. Non-neurological AE of all grades that were more frequent in the PCI arm: alopecia (36 vs. 5 pt; p<10[-6]), fatigue (55 vs. 29 patients; p<10[-4]), nausea (30 vs. 15 patients; p=0.01), anorexia (6 vs. 0 patients; p=0.01) and dysphagia (11 vs. 2 pt; p=0.01). Of the G3-4 AE, only fatigue was significantly more present in the PCI arm (13 vs. 2 pt, p < 0.01). Scored as treatment-related, neurological toxicities of all grades that occurred more frequently in the PCI vs. the observation arm: cognitive disturbance (7 vs. 0 pt; p=0.01), dizziness (7 vs. 0 pt; p=0.01) and memory impairment (14 vs. 0 pt; p<10[-4]). No significant differences in G3-4 toxicities, with only one patient reporting severe cognitive disturbance in the PCI group. Scored as treatment-related, non-neurological toxicities of all grades that were more frequent in the PCI arm: alopecia (26 vs. 1 pt; p<10[-6]), fatigue (19 vs. 2 patients; p<10[-4]), nausea (16 vs. 0 patients; p<10[-5]), headache (19 vs. 1 pt; p<10[-5]), rash (8 vs. 0 pt; p<0.01) and vomiting (9 vs. 0 pt; p<0.01). No significant differences in G3-4 toxicities, with 3 patients reporting severe fatigue, 2 nausea and 1 vomiting, all in the PCI group. Overall Qol was worse in the PCI arm 3 months post-treatment, but was similar to observation thereafter.

Conclusion:
PCI related symptoms were mainly grade 1-2 memory and cognitive disturbances and fatigue. G3-4 toxicities were very rare. QoL was only temporarily affected by PCI. The side effects of PCI should be balanced against deteriorating BM symptoms and the lack of OS benefit (Groen ASCO 2017).

Background:
There are no clinically validated biomarkers to identify patients with locally advanced NSCLC who benefit from trimodality therapy (TMT) (i.e. neoadjuvant chemoradiation (NAT) followed by surgery). In this study, we evaluate radiomic (i.e. computer extracted imaging) features of tumor phenotype as potential predictors of pathological response.

Method:
123 patients with stage III NSCLC who received TMT were selected for this study. Of these, 33 patients including those with distant metastasis at presentation and those without baseline pre-NAT CT scans were excluded. Lung tumors were retrospectively contoured on 3D SLICER software by an expert reader. A total of 1542 radiomic features (textural and shape) were extracted from intra and peritumoral region using the MATLAB® 2016a platform (Mathworks, Natick, MA). A random forest (RF) machine classifier was trained with the most predictive features identified on the training set (n=45) and then validated on an independent test set (n=45). The primary endpoint of our study was pathological response defined as the percentage of the residual viable tumor.

Result:
90 patients with NSCLC were included for analysis with a median age of 64 years (38−88), and 54.4 % men. Tumor histology was predominantly adenocarcinoma (71.1%), stage IIIA (94.4%), with positive N2 nodes (91.1%). Pathological response was achieved in 36 (40%) patients; labeled responders (R) and the rest 54 (60%) were labeled non-responders (NR). No statistically significant difference was found in clinical characteristics. We identified five radiomic features (intratumoral and peritumoral textural patterns) predictive of pathological response (Area under Receiver Operating Characteristic (ROC) Curve = 0.7806, RF classifier). Figure 1



Conclusion:
Texture features extracted from within and around the lung tumor on CT images were predictive of pathological response to NAT. Additional validation of these quantitative image-based biomarkers is warranted for accurate early identification of responders who could be potentially spared surgery.

Background:
Response criteria for 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for thoracic malignancies include European Organization for Research and Treatment of Cancer (EORTC) criteria, Positron Emission tomography Response Criteria In Solid Tumors 1.0 (PERCIST), PeterMac Metabolic Visual Criteria and Deauville Criteria. It is unknown which criteria have the highest prognostic value in NSCLC.

Method:
Between 2004 and 2016, three NSCLC prospective trials included patients treated with radical radiotherapy (RT) or chemoRT with baseline and post-treatment FDG-PET imaging. For each patient, the four FDG-PET response criteria were reported retrospectively and blinded to outcome. Responses to therapy were categorized as complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD) or progressive metabolic disease (PMD) and correlated with subsequent survival using Cox proportional hazard models, c-statistic, r[2] and Akaike information criterion (AIC).

Result:
Eighty-seven NSCLC patients underwent FDG-PET before and after radical RT (n=7) or chemoRT (n=80). Follow-up FDG-PET scans were performed at a median of 89 days (range 47-123 days) after RT. After a median follow-up of 49 months, median survival after PET response imaging was 28 months. Both qualitative response criteria (PeterMac and Deauville) showed perfect agreement (kappa = 1.0). Both semiquantitative criteria (EORTC and PERCIST) showed almost perfect agreement (kappa = 0.96). All four response criteria showed statistically significant associations with overall survival. The PeterMac and the Deauville criteria showed stronger survival associations (AIC=357.9) compared to EORTC (AIC=362.3) and PERCIST (AIC=362.6). The two qualitative criteria also performed better in the distinction between CMR and non-CMR (HR = 1.9, CI 1.0-3.4, p=0.047) versus EORTC (HR=1.2, CI 0.6-2.3, p=0.566) and PERCIST (HR 1.2, CI 0.6-2.3, p=0.548). Only 1, 4 and 6 patients had SMD in respectively PeterMac/Deauville, EORTC and PERCIST. Figure 1



Conclusion:
The visual PeterMac and Deauville criteria showed stronger predictive capacity than EORTC and PERCIST criteria, especially for distinguishing CMR from non-CMR.

Background:
Micropapillary and solid subtypes of lung adenocarcinoma have significantly worse outcomes and survival after surgical resection for early-stage disease. These subtypes have recently been shown to have higher locoregional and metastatic progression after definitive stereotactic radiation therapy (SBRT) as well. However, the potential impact of histologic subtype on locally advanced disease treated with definitive concurrent or sequential chemoradiation (CRT) has not been previously explored. We sought to identify high-risk subtype patients treated with CRT, and compare their outcomes with those not known to have high-risk histologic subtypes.

Method:
We identified 249 consecutive patients with stage IIIA-B lung adenocarcinoma who had undergone CRT at our institution from 2008 to 2015. All patients had pathology reviewed by pathologists at our institution with subspecialty expertise in thoracic pathology. Twenty-five patients had elements of micropapillary and/or solid subtype on core biopsy, according to the 2015 World Health Organization classification. The remaining 224 patients were considered non-high-risk (8 patients had core biopsy with no high-risk subtypes identified; 216 patients either did not undergo core biopsy or did not have subtyping performed). Local, nodal, regional, and distant failure were estimated using cumulative incidence (CI) curves and compared using the log-rank test. Time to each event was measured from the date of diagnosis until the event of interest or the last follow-up visit.

Result:
With median followup of 19.7 months, there was a trend towards greater 2-year CI of local failure in the high-risk vs. non-high-risk group (40.7% vs. 26.7% p=0.060). The 2-year CI of nodal, regional, and distant failure in high-risk versus non-high-risk groups was 30.9% vs. 32.6% (p=0.576), 24.7% vs. 20.1% (p=0.468), and 63.9% vs. 59.8% (p=0.272), respectively, though statistical power was limited due to the small number of known high-risk patients.

Conclusion:
Though only a limited proportion of patients had demonstrated high-risk subtypes in this cohort, there was a trend towards earlier local failure in locally advanced adenocarcinoma patients treated with definitive concurrent or sequential chemoradiation, similar to what has been observed for early-stage tumors treated with SBRT. Hence, high-risk histologic subtype may be a prognostic factor for early treatment failure in locally advanced adenocarcinoma patients treated with CRT. We suggest that core biopsies, which are required for histologic subtyping, should be obtained more often in these patients, to allow for further study of the hypothesis that histologic subtype predicts outcomes after definitive chemoradiation.

Background:
The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating response to treatment. Selumetinib, an inhibitor of MEK, has been shown to enhance the effect of radiotherapy (RT) in preclinical studies.

Method:
Single-arm, single-centre, open-label phase I trial. Patients with stage III non-small cell lung cancer (NSCLC) not suitable for concurrent chemo-radiotherapy or stage IV with dominant thoracic symptoms. Patients were recruited to a dose-finding stage (based on the Fibonacci 3+3 design; maximum number =18) followed by the recruitment of an expanded cohort (n=15). Oral Selumetinib (AZD6244, ARRY-142886) was administered at a starting dose of 50mg twice daily commencing 7 days prior to RT, then in combination with thoracic RT for 6-6.5 weeks (60-66Gy in 30-33 fractions). The primary objective was to determine the recommended Phase II dose.

Result:
From 06/10-02/15, 21patients enrolled. Median age 63 years (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%):IV 5(24%). Mean GTV 64cm[3] (range 0.8–223.7). In the dose-finding stage, 2 out of 6 patients experienced dose-limiting toxicities (DLT) but only one DLT (G3 diarrhoea) was attributable to treatment. Despite meeting criteria for escalation, trial management group elected to treat patients on the expanded cohort (n=15) at the starting dose. All 21 patients completed RT as planned and received induction chemotherapy. Compliance rate of Selumetinib was >80%. Common adverse events are listed-see table. There were 2 survivors (24 & 26months) at analysis. The median survival was 9.7 months and 2-year survival was 24%. The main cause of disease progression was distant metastases in 16/21 (76%).

Conclusion:
The combination of thoracic RT and Selumetinib is feasible and associated with an acceptable toxicity profile. However our efficacy results, based on 21 patients, suggest that this combination should not be pursued in a subsequent phase II trial.

Acute Toxicity (CTCAE v4.0) (during treatment and including up to 3 months post treatment)
Toxicity	Grade	N = 21 (%)
Acneiform rash	0 1 2 3	4 (19.04%) 7 (33.33%) 9 (42.86%) 1 (4.76%)
AST[1] increased	0 1 3	17 (80.95%) 3 (14.29%) 1 (4.76%)**
Diarrhoea	0 1 2 3	5 (23.81%) 13 (61.90%) 2 (9.52%) 1 (4.76%)*
GGT[2] increased	0 1 2 3	16 (76.19%) 2 (9.52%) 2 (9.52%) 1 (4.76%)
Haemoptysis	0 1	19 (90.48%) 2 (9.52%)
Maculo-papular rash	0 1 3	16 (76.19%) 4 (19.05%) 1 (4.76%)
Mucositis	0 1 2	18 (85.71%) 2 (9.52%) 1 (4.76%)
Nausea	0 1 2	11 (52.38%) 9 (42.86%) 1 (4.76%)
Radiation dermatitis	0 1 2 3	8 (38.10%) 7 (33.33%) 5 (23.81%) 1 (4.76%)
Radiation oesophagitis	0 1 2 3	3 (14.29%) 2 (9.52%) 15 (71.43%) 1 (4.76%)
Radiation pneumonitis	0 1 2	15 (71.43%) 0 6 (28.57%)
Late Toxicity (follow up from 3+ months onwards)
Toxicity	Grade	N = 21 (%)
Pneumonitis	0 1 2	16 2 (9.52%) 3 (14.29%)
Pulmonary fibrosis	0 1	19 2 (9.52%)
Radiation oesophagitis	0 2	19 (90.48%) 2 (9.52%)
* patient stopped drug on day 49 **patient stopped drug on day 29 abbreviations: 1) AST, Aspartate aminotransferase 2) GGT; Gamma-glutamyltransferase

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Abstract:
The extent of pulmonary resection for peripheral, non-small cell lung cancer (NSCLC) has been defined as "lobe", based on the results of clinical experiences and a randomized trial in 1980's. At present, the possibility of lesser resection such as wedge/segmental resection needs to be evaluated from a updated, scientific viewpoint. For these reasons, JCOG (Japan Clinical Oncology Group) has been prospectively deploying series of clinical trials each for different target lesions to define the proper extent of the parenchymal resection for NSCLC, JCOG 0804, 0802, and 1211. Among these, the most important study is JCOG 0802, in which the non-inferiority of segmentectomy was compared with lobectomy in terms of overall survival for patients with diameter ≤ 2 cm invasive peripheral NSCLC. As a second endpoint, the postoperative pulmonary function was also compared to demonstrate the functional superiority for lesser resection. Between Aug 10, 2009 and Oct 21, 2014, 1,106 patients were enrolled. No mortality was noted. Complications (grade ≥ 2) occurred in 26·2% for lobectomy and 27·4% for segmentectomy. Multivariate analysis indicated a pack-year (PY) smoking >20 (vs. none) as a predictor of postoperative complications (grade ≥ 2), and a complex segmentectomy (vs. lobectomy) and PY > 20 as a predictor of pulmonary complications. The final analyses on the prognostic non-inferiority (primary endpoint) will be available after 2020. Through such series of prospective studies, the proper extent of pulmonary resection for NSCLC is to be defined from prognostic and functional viewpoints. Therefore, especially for JCOG 0802 study, both of two endpoints must meet the hypothetical criteria for lesser resection to be judged as appropriate. We should realize that a true progress in the surgical oncology might be achieved only by a prospective, collaborative comparison as an applied science.

Abstract:
Until the beginning of the new century limited resection for pathologically proven, early-stage lung cancer was not frequently applied in Europe. The main reason for this practice were the results of the randomized phase III trial of the Lung Cancer Study Group published in 1995, showing that for peripheral, clinical T1N0 tumors, lobectomy yields better locoregional control with less recurrences compared to sublobar resection (1). This study was very influential in Europe. A majority of thoracic surgeons adopted the principle that lobectomy was the minimally acceptable lung volume to be resected for patients with an early-stage bronchogenic carcinoma and a low cardiopulmonary risk. Limited resection for lung cancer was only considered for elderly persons, patients with severe chronic obstructive pulmonary disease precluding lobectomy, patients with a high comorbidity score and limited life expectancy due to debilitating disease. Quite a substantial variation in practice is observed, not only within countries but also when comparing North America and Europe. In an interesting analysis of the thoracic surgical databases of the Society of Thoracic Surgeons (STS) and European Society of Thoracic Surgeons (ESTS), some important differences were discovered regarding the daily practice of lung resections performed during the period 2010-2013 (2). Patients in the STS database were more frequently operated by video-assisted thoracic surgery (VATS) compared to the ESTS dataset (63% versus 22%), and were more likely to undergo sublobar resection (43% versus 31%). However, most of the sublobar resections were wedge resections. Anatomical segmentectomies were more frequently performed in the ESTS database than in the STS dataset (7.4% versus 3.9%). For the ESTS patients 30-day mortality of wedge resections was lower compared to the STS data (0.1% versus 1.9%); however, mortality for lobectomy was higher (2.6% versus 1.4%) (2). With the start of European screening studies, although not at the scale of the National Lung Screening Trial, a new clinical problem arose for thoracic surgeons, namely how to deal with small pulmonary nodules and how to limit the false-positive rate? Thoracic surgical issues of screening were addressed in a recent paper by a task force of the ESTS (3). Recommendations were made for implementation of CT screening in Europe focussing on the training of thoracic surgeons, their clinical profile and the use of minimally invasive thoracic surgery. In general, it has been clearly demonstrated that the main goal of surgery for an invasive lung cancer is to obtain a complete resection which is a major prognostic factor. This mostly implies a lobectomy for tumors > 2cm, and at least a lobe-specific systematic nodal dissection as defined in 2005 by a working group of the International Association for the Study of Lung Cancer (IASLC) (4). Unfortunately, quite a lot of resections have to be considered uncertain due to the fact that the required number of lymph nodes, especially mediastinal, have not been removed for further pathological analysis (5). The new adenocarcinoma classification published in 2011 by a common task force of the IASLC , American Thoracic Society (ATS) and European Respiratory Society (ERS) and accumulating phase II data mainly coming from Japan, had important surgical implications (6). As new entities, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were introduced and the confusing term bronchioloalveolar cell carcinoma (BAC) is not used anymore. This clearly resulted in a paradigm shift and the concept of sublobar resection was reconsidered for smaller, early-stage lung cancers < 2cm. Anatomical segmentectomy is generally preferred to wide wedge resection because of concerns of local recurrence (7). Regarding the overall oncological results several meta-analyses have been performed. Their results are somewhat conflicting but overall, good long-term results are described for tumors until 2 cm treated by segmentectomy when no lymph node invasion is present. However, for small, early-stage lung cancer no high-level evidence is currently available and the reported evidence should be interpreted with caution. As most studies were not randomized, there was probably a clear selection bias regarding comorbidity, histology and tumor size. Recent guidelines and evidence from a randomized trial indicate that small nodules of ≤10 mm or ≤500 mm[3] that are clearly 100% pure ground-glass opacities (GGO) on chest CT may be considered as AIS or MIA, and hence may be suitable for close follow-up or sublobar resection rather than a formal lobectomy (8). Subcentimeter lung cancers, currently T1a disease, represent a specific subgroup as they comprise the smallest lesions. It should also be emphasized that for subsolid lesions the current tumor size is determined by the solid or invasive part only which represents a major change in the 8[th] TNM (tumor, node, metastasis) classification (9). For thoracic surgeons another important topic is the accuracy of intraoperative frozen section analysis to determine the intraoperative extent of resection. Recent studies show that a concordance rate of more than 80% can be reached between the frozen section and definitive pathological report (10) . However, AIS and MIA are more difficult to diagnose on frozen section and accuracy becomes less for lesions below 10 mm, which represent the main category to be considered for sublobar resection. This implies that a second intervention to perform a completion lobectomy may be indicated in patients with poor prognostic histological features who initially underwent a limited resection for a presumably low-malignant lesion. In conclusion, sublobar resection is currently more often applied in European countries but more high-level evidence on long-term oncological results is required to refine its indications and make this procedure a generally accepted intervention, not only by thoracic surgeons but also by thoracic oncologists and pulmonary physicians. References 1. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 1995; 60:615-22; discussion 22-3. 2. Seder CW, Salati M, Kozower BD, Wright CD, Falcoz PE, Brunelli A, et al. Variation in Pulmonary Resection Practices Between The Society of Thoracic Surgeons and the European Society of Thoracic Surgeons General Thoracic Surgery Databases. Ann Thorac Surg. 2016; 101:2077-84. 3. Pedersen JH, Rzyman W, Veronesi G, D'Amico TA, Van Schil P, Molins L, et al. Recommendations from the European Society of Thoracic Surgeons (ESTS) regarding computed tomography screening for lung cancer in Europe. Eur J Cardiothorac Surg. 2017; 51:411-20. 4. Rami-Porta R, Wittekind C, Goldstraw P, International Association for the Study of Lung Cancer Staging C. Complete resection in lung cancer surgery: proposed definition. Lung Cancer. 2005; 49:25-33. 5. Verhagen AF, Schoenmakers MC, Barendregt W, Smit H, van Boven WJ, Looijen M, et al. Completeness of lung cancer surgery: is mediastinal dissection common practice? Eur J Cardiothorac Surg. 2012; 41:834-8. 6. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011; 6:244-85. 7. Sihoe AD, Van Schil P. Non-small cell lung cancer: when to offer sublobar resection. Lung Cancer. 2014; 86:115-20. 8. van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, Vernhout R, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009; 361:2221-9. 9. Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2016; 11:1204-23. 10. Yeh YC, Nitadori J, Kadota K, Yoshizawa A, Rekhtman N, Moreira AL, et al. Using frozen section to identify histological patterns in stage I lung adenocarcinoma of

Abstract:
Since its first report by Churchill and Belsey in 1939, and its evolution in lung cancer management described by Jensik in 1973 (Figure), pulmonary segmentectomy use for early lung cancer diagnosis and treatment has remained controversial. Definitive answers must wait regarding the results of the JCOG and Alliance randomized trials before true standards for surgical care for the lung cancer less than 2 cm are determined. Nevertheless, sublobar resections including wedge resection and segmentectomy are being adopted at an increasing rate compared to its use in previously published large databases (SEER, 5%; ACS NSQIP, 4%). Proper preoperative teaching and intraoperative performance of the technical aspects of sublobar resection are now becoming priorities for general thoracic resident and fellow training in an era where minimally invasive techniques are becoming increasingly the standard of care. General thoracic surgeons must have meticulous attention to detail in performing these resections in order to decrease the likelihood of collateral damage to neighboring segments as well as to minimize local recurrence whether there are performing the operation open, hybrid, standard VATS, uniportal VATS, or robotic. The technical aspects of sublobar resection begin before the patient goes to the operating room, and prime objectives in planning these resections include (1) expertise in the segmental anatomy for that particular patient (2) location and size of the nodule with relation to adjoining segmental bronchovascular components (3) careful study and possible supplementation of high resolution computerized tomography with newer 3-D methods to define the spatial relationships of the nodule and segments (4) pre- and intraoperative methods for locating the nodule if there is suspicion that parenchymal palpation will fail (5) whether to perform wedge resection first or proceed directly to anatomic segmentectomy (6) defining and managing the fissure between segments and recognizing when extended segmentectomy is possible or whether to convert to lobectomy and (7) to use other intraoperative strategies to avoid technique related complications. Preoperative planning includes careful examination of the CT scan in the axial, coronal and sagittal plans in order to get a first appreciation of the depth, size, segmental anatomy and relationship of the nodule bronchovascular elements. Three-dimensional reconstruction can be as simple as navigational bronchoscopy planning images, or newer techniques for total 3-D pulmonary reconstruction which are in development (1). When there is a question of whether up front segmentectomy is to be performed and a part solid or non-solid nodule may not be palpable, intraoperative localization techniques such as navigation bronchoscopy(2) or placement of fiducials/microcoils (3) can be very useful. When there is no preoperative histologic diagnosis, whether a wedge or segmentectomy is performed initially will depend on the location and depth of the lesion as well as the fitness of the patient. Segmentectomy for initial diagnosis with intraoperative frozen section of both the primary lesion and suspicious level 13 and 14 stations can be prudent, especially if wedge resection could compromise performing the segmentectomy(4). In order to avoid positive margins, meticulous attention to detail with compulsive dissection and skeletonizing of the bronchovascular elements must be performed. If it is difficult to preserve the margin in a single segment resection, an extended resection of the parenchyma of adjacent segments or bisegmentectomy can be performed(5). There is controversy regarding the chance for loco-regional recurrence for segmentectomy especially in cases of pure solid lesions or segmentectomies which involve portions of the basilar segments or right upper lobe (6-8). Defining the fissure and the method with which it is divided can be one of the most important yet challenging portions of the operation. A variety of methods to define the fissure have evolved including inflation of the residual lung after segment occlusion, selective inflation of the segment to be removed, or the use of indocyanine green to define the intersegmental vein (4, 5), and the fissure can be divided either with stapling alone or in combination with harmonic scalpel(9). A variety of fibrin sealants are available to decrease postoperative fistulae. With regard to the optimal approach, to date there have been no studies which show any superiority regarding conventional VATs or uniportal VATs for segmental resection, or any difference between the VATs approaches and robotic segmentectomy (10). A recent meta-analysis of over 7438 patients revealed a trend towards increased conversion to open with VATs, while postoperative complications, operation time, length of stay, chest tube duration, and number of lymph nodes were comparable(11). Figure 1 Reference List (1) Yao F, Wang J, Yao J, Hang F, Lei X, Cao Y. Three-dimensional image reconstruction with free open-source OsiriX software in video-assisted thoracoscopic lobectomy and segmentectomy. Int J Surg 2017;39:16-22. (2) Zhao ZR, Lau RW, Yu PS, Wong RH, Ng CS. Image-guided localization of small lung nodules in video-assisted thoracic surgery. J Thorac Dis 2016;8:S731-S737. (3) Donahoe LL, Nguyen ET, Chung TB, Kha LC, Cypel M, Darling GE, et al. CT-guided microcoil VATS resection of lung nodules: a single-centre experience and review of the literature. J Thorac Dis 2016;8:1986-94. (4) Landreneau RJ, D'Amico TA, Schuchert MJ, Swanson SJ. Segmentectomy and Lung Cancer: Why, When, How, and How Good? Semin Thorac Cardiovasc Surg 2017;29:119-28. (5) Oizumi H, Kato H, Endoh M, Inoue T, Watarai H, Sadahiro M. Techniques to define segmental anatomy during segmentectomy. Ann Cardiothorac Surg 2014;3:170-5. (6) Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. Locoregional recurrence after segmentectomy for clinical-T1aN0M0 radiologically solid non-small-cell lung carcinoma. Eur J Cardiothorac Surg 2017;51:518-25. (7) Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. The oncological outcomes of segmentectomy in clinical-T1b lung adenocarcinoma with a solid-dominant appearance on thin-section computed tomography. Surg Today 2016;46:914-21. (8) Ueda K, Tanaka T, Hayashi M, Tanaka N, Li TS, Hamano K. What proportion of lung cancers can be operated by segmentectomy? A computed-tomography-based simulation. Eur J Cardiothorac Surg 2012;41:341-5. (9) Kuroda H, Dejima H, Mizumo T, Sakakura N, Sakao Y. A new LigaSure technique for the formation of segmental plane by intravenous indocyanine green fluorescence during thoracoscopic anatomical segmentectomy. J Thorac Dis 2016;8:1210-6. (10) Veronesi G, Cerfolio R, Cingolani R, Rueckert JC, Soler L, Toker A, et al. Report on First International Workshop on Robotic Surgery in Thoracic Oncology. Front Oncol 2016;6:214. (11) Liang H, Liang W, Zhao L, Chen D, Zhang J, Zhang Y, et al. Robotic Versus Video-assisted Lobectomy/Segmentectomy for Lung Cancer: A Meta-analysis. Ann Surg 2017.

Abstract:
In the early 2000s, the revolution in computer-driven radiotherapy technology enabled exquisitely precise direction of radiation beams to specific tumor targets. The advent of 4-dimensional computed tomography (CT), MRI and on-board image-guided intensity-modulated radiotherapy (IMRT), stereotactic ablative radiotherapy (SABR), particle therapy have equipped radiation oncologists with novel tools to tightly conform ablative radiation doses to targets while avoiding inadvertent irradiation of surrounding critical normal structures. SABR, also called stereotactic body radiation therapy (SBRT), as a non-invasive curative therapy, achieves >90% local control, improves survival with minimal toxicity and has become standard therapy in medical inoperable peripheral located stage I NSCLC (1, 2). Particularly for elderly patient, SABR’s effectiveness based on lung cancer-specific survival and progression-free survival is the same in the elderly (>75 year old) as it is the average age population (<75 year old). It also poses no increased toxicity. Compared to historical outcomes with surgery in the elderly, SABR outcome is considered comparable for stage I disease but has less morbidity (3). The pattern of failure study showed that the dominant failure of SABR in stage I NSCLC is distant metastasis (10 to 20%), followed by regional lymph node recurrence (10 to 15%) and then local failure ( 5 to 10%) (4). Up to 1 in 6 patients who received SABR for early-stage NSCLC may develop isolated local-regional recurrence that could be salvaged with definitive treatment. The first long-term results for the largest group of salvaged patients with local-regional recurrence after SABR (n=103) was reported in ASCO 2017 annual meeting (Brooks et al, ASCO 2017 oral presentation in Chicago). 912 patients with clinically early-stage I-II NSCLC from MDACC were treated with SABR with isolated local recurrence (LR, n = 49) or regional recurrence (RR, n = 53). Salvage was performed in 79.6% of LR and 90.6% of RR patients. Median follow-up from time of initial SABR was 57.2 months. 5-year OS was 52% for LR and 27.8% for RR patients. Of LR and RR patients, those receiving salvage had significantly better 5-year OS compared to those not receiving salvage (57.9% LR, 31.1% RR, 0% no salvage; p = 0.006). 5-year OS for LR salvaged patients was not statistically different from patients with NR (53.5% NR, p = 0.92) and 5-year OS for salvaged RR was lower than that of NR (p=0.022). 60% patients never recurred after salvage but subsequent DM occurred in 27.6% of local-regional recurrent patients at a median of 10.5 months. No salvaged patient experienced grade 5 toxicity. There is debate about what is the optimal treatment for operable stage I NSCLC. Majority of the population-based retrospective propensity-matched studies have indicated that SABR has effectiveness comparable to that of surgery for this population, with reported 3-year overall survival rates of 48-91% and local control rates of 85-96% that is significantly better than conventional radiotherapy (5). A pooled analysis of two prospective randomized trials for operable patients showed a better overall survival rate at 3 years for SABR than for surgery (6); however, the efficacy, pattern of failure, and toxicity reported were mostly based upon relatively short follow-up and patient’s number is small; therefore, larger studies with longer follow up are needed and are ongoing around the world. Recently, a phase II prospective study investigating SABR for early-stage NSCLC with median follow-up of 7 years demonstrated outstanding OS of 47% with low rates of local (8%), regional (14%) and distant failure (14%) 7 years after SABR, comparable to those of surgery but with lower toxicity (7). Second malignancy remains one of the most common issues with longer follow-up (21%), again consistent with surgical data. There are two major limitations of SABR in treating early stage NSCLC. First, critical nearby normal tissue dose constraints such as esophagus, bronchial tree, brachial plexus, heart, major vessels etc. may limit the ablative dose that could be safely delivered (8); second, the efficacy of SABR is reduced and toxicity is increased with increasing size of the lesion, particularly when the lesion is >5 cm (9). Most of outstanding clinical outcome with SABR reported in the literature are based on lesions less than 5 cm, typically <3 cm, and not close/next to critical normal structures. Finally, we need to keep in mind that cancer is a biological disease, not just a technologic challenge. As our ability to control local tumors improves with the use of new technology, the importance of systemic disease control grows in parallel—after all, in most cases it is metastatic disease that kills the patient. During the past decade, the development of genomic profile–based targeted therapy and immune checkpoint pathway– based immunotherapy has revolutionized the management of stage IV lung cancer. More and more data indicated that cancer cells killed by radiation release tumor-associated antigens and immunoregulatory cytokines, thereby functioning as a kind of cancer-specific vaccine in situ; they further activate tumor-specific systemic immune responses to eradicate tumors even outside the radiation field (the abscopal effect). These effects seem to be more prominent when the radiation used with immunotherapy involves giving high (ablative) doses, a type of therapy for which we coined the term “I-SABR” (immunotherapy and stereotactic ablative radiotherapy, 10). I-SABR protocols are underway for both early-stage disease and advanced cancer. In summary: SABR/SBRT, a novel non-invasive approach with low toxicity, achieves outstanding clinical outcome and is the standard treatment in medical inoperable stage I NSCLC. It remains controversial whether SABR should be used for operable early stage NSCLC and more randomized studies are ongoing. The dominant pattern of failure after SABR is distant metastasis, followed by regional or intra-lobar failure. Patient with isolated local/regional recurrence should be salvaged aggressively and long-term surveillance is crucial to detect early recurrence and the secondary lung cancer. Combined SABR with systemic therapy such as immunotherapy may further improve the efficacy and cure rate. REFERENCES 1. Timmerman R, et al. Jama. 2010;303(11):1070-6. 2. Onishi H, et al. Cancer. 2004;101(7):1623-31. 3. Brooks ED,et al. Int J Radiat Oncol Biol Phys. 2017;98(4):900-907 4. Senthi S, et al. Lancet Oncol. 2012;13(8):802-9. 5. Shirvani SM, et al JAMA Surg. 2014;149(12):1244-53. 6. Chang JY, et al.Lancet Oncol. 2015;16(6):630-7. 7. Sun B, et al. Cancer. 2017. E-pub ahead of print 8. Timmerman R, et al. JCO. 2006;24(30):4833-9. 9. Tekatli H,et al. J Thorac Oncol. 2017;12(6):974-982. 10. Bernstein MB, el al. Nat Rev Clin Oncol. 2016;13(8):516-24

Abstract:
Neuroendocrine tumors (NET) of the lung comprise approximately 20% of all primary lung carcinomas overall and consist primarily of four malignancies: Typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma(SCLC) using 2015 World Health Organization (WHO) nomenclature. The four tumors have historically been regarded as a spectrum; however, there are significant differences between TC/AC and LCNEC/SCLC on many levels. Additionally, while most TC and AC arise de novo, a small percentage of cases with arise in the setting of diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH), a rare pre-neoplastic condition. DIPNECH has not been associated with the development of LCNEC or SCLC. TC and AC, comprise 1-2% of primary lung cancers with the vast majority being TC. Both TC and AC may occur in either a central or peripheral location, with central tumors resulting in symptoms related to obstruction while peripheral tumors are often asymptomatic and discovered incidentally. TC is considered a “low grade” or “well-differentiated” tumor; however, 5-20% of TC are associated with regional lymph node or distant metastases. AC, considered an “intermediate grade” or “moderately-differentiated” tumor, is associated with metastases in up to 40% of cases. The five and 10 year survival for TC is approximately 90% whereas it drops to 70% and 50% for AC. By current WHO criteria, TC is defined as a neuroendocrine tumor greater than 5mm in size with fewer than 2 mitoses per 2mm[2] and lacking necrosis, whereas AC is defined as a neuroendocrine tumor with 2-10 mitoses per 2mm[2] or necrosis. As mitotic activity and necrosis may be focal, the distinction between TC and AC can generally not be made on a small sample. Both tumors classically show an organoid or trabecular pattern of growth and are composed of a relatively uniform population of round to oval cells with granular nuclear chromatin, but may show a wide range of histologic growth patterns, particularly in TC. Given that the main feature distinguishing AC from TC is mitotic activity, one would expect that proliferation markers such as Ki-67 would be of potential value in discriminating these two tumors. Numerous studies have attempted to evaluate this parameter with various cut offs being proposed; however, ultimately there is too much overlap between the Ki-67 scores of TC and AC for it to be reliably useful in discriminating between the two tumors. The Ki-67 score can be useful in separating high-grade from low-grade tumors on small distorted biopsies, and some studies have shown it to have utility as a prognostic marker in TC/AC. As such it may be used to potentially guide treatment and is included as a parameter in the European Neuroendocrine Tumor Society (ENETS) guidelines. Surgery remains the only curative treatment option for TC/AC but there is a lack of consensus in regard to treatment of un-resectable or metastatic disease. Results of the RADIANT-4 trial have led to the approval of everolimus for advanced TC/AC. There is additional evidence that somatostain analogs may be useful in selected patients. Molecular analysis of TC and AC demonstrate distinctly different molecular profiles compared to the high grade NET’s, with MEN1 alterations found essentially exclusively in carcinoids whereas alteration of RB1 cell cycle regulation genes and the PI3K/AKT/mTOR pathway were found less frequently in TC/AC and enriched in the higher grade tumors. TC/AC also tend to show frequent mutations of chromatin remodeling genes, as well as mutations of PSIP1 and ARID1A. Actionable mutations such as EGFR mutations and ALK rearrangements are not found in TC/AC and thus far evaluation of PD-L1 in carcinoids has been negative, suggesting a lack of a role for current targeted therapy or immunotherapeutic agents used in non-small cell lung carcinomas (NSCLC). Several clinical trials are either ongoing or currently recruiting to evaluate the efficacy of several small molecular inhibitors. LCNEC was originally described in 1991 and was initially included as a subtype of large cell carcinoma in subsequent WHO classification, but in the current WHO it is classified as a type of neuroendocrine carcinoma. The tumor is defined as a tumor with neuroendocrine morphology with large cell morphology and greater than 10 mitoses/2mm[2], although most cases have substantially higher mitotic rates. By definition, tumors must show evidence of neuroendocrine differentiation, usually identified by immunohistochemical methods. While distinction of LCNEC from SCLC may appear straightforward on the surface, in reality LCNEC can be heterogeneous and the distinction is not always clear cut. Currently, there is no immunostain or other definitive test to discriminate between the two and distinction ultimately rests of subjective evaluation of the tumor morphology. The extreme rarity of this tumor, combined with the tumor heterogeneity and resultant subjectivity inherent in classification has likely contributed to conflicting reports in the literature regarding prognosis, although it is generally agreed that LCNEC is a high-grade tumor with a poor prognosis. Similarly, variable results have been reported in regard to the responsiveness of LCNEC to treatment regimens typically used for SCLC leading to a lack of consensus regarding whether LCNEC should be managed similar to SCLC or similar to other non-small cell carcinomas. Molecular studies have additionally shown variable results. The majority of studies have shown overlapping features with SCLC. Some studies, however, have shown alterations characteristic of other tumor types, most notably occasional EGFR, ALK and KRAS mutations even in the absence of an overt mixed adenocarcinoma component, which have not been found in SCLC. Interestingly, in 2016, Rekhtman, et al, evaluated 45 LCNEC and pared normal tissue by NGS with 241 cancer gene analysis. This study demonstrated that LCNEC, while having some commonly altered genes, largely fell into two major and one minor subset (SCLC-like, NSCLC-like and a small number of “carcinoid like” tumors). These findings may explain the variability of results in treatment trials and may indicate that more comprehensive analysis of this rare groups of tumors may yield more optimal treatment strategies.

Abstract:
Given that large cell neuroendocrine carcinoma (LCNEC) of the lung is rare and histological diagnosis from small samples is difficult, no large-scale clinical trials has yet evaluated the optimal chemotherapy for LCNEC. In a retrospective study of 45 consecutive patients with advanced LCNEC, response rates for small cell lung cancer (SCLC; n=11) and non-small cell lung cancer (NSCLC; n=34) regimen groups receiving first-line chemotherapy were 73% and 50% (P=0.19), median progression-free survival (PFS) was 6.1 and 4.9 months (P=0.41), and median overall survival (OS) was 16.5 and 9.2 months (P=0.19), respectively. SCLC regimens included platinum plus paclitaxel (PTX) and irinotecan plus platinum, while NSCLC regimens included pemetrexed, erlotinib, and gemcitabine[1]. A second retrospective study of the efficacy of first-line chemotherapies in 22 consecutive patients with advanced LCNEC reported an objective response in five of nine patients receiving CDDP+irinotecan (56%) and in three of five receiving carboplatin (CBDCA)+PTX (60%) [2]. Of the two prospective phase II studies of platinum-based chemotherapies for LCNEC (Table), a French study (GFPC 0302) used a chemotherapy regimen comprising CDDP+etoposide (ETP), while a Japanese study used CDDP+irinotecan. Objective response rate (ORR) was about 40% and median PFS was 5 to 6 months in both studies. Central pathological reviews in both studies demonstrated that about a quarter of patients had SCLC or undifferentiated NSCLC [3, 4]. Everolimus is an oral mTOR inhibitor that has been approved for the treatment of well-differentiated neuroendocrine tumors of the lung. A recent phase II study of CBDCA+PTX+everolimus as first-line chemotherapy for advanced LCNEC was discontinued prematurely due to low recruitment after enrolling only 49 patients versus a planned sample size of 71. Among them, ORR was 45%, disease control rate was 74%, median PFS was 4.4 months, and median OS was 9.9 months [5]. Ongoing studies include a randomized phase II study comparing CBDCA+ETP and CBDCA+PTX for advanced LCNEC and a randomized phase II/III study of CDDP+ETP with or without veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with extensive stage SCLC or metastatic LCNEC.

Study	GFPC 0302	Japanese study	German study
Regimen	CDDP+ETP	CDDP+Irinotecan	CBDCA+PTX+Everolimus
N	42	44	49
ORR (%) (95%CI)	38	55 (39-70)	45 (31-60)
Median PFS (months) (95%CI)	5.2 (3.1-6.6)	5.9 (5.5-6.3)	4.4 (3.2-6.0)
Median OS (months) (95%CI)	7.7 (6.0-9.6)	15.1 (11.2-19.0)	9.9 (6.9-11.7)

Reference 1. Sun JM, Ahn MJ, Ahn JS, et al. Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer 2012;77:365-370. 2. Fujiwara Y, Sekine I, Tsuta K, et al. Effect of platinum combined with irinotecan or paclitaxel against large cell neuroendocrine carcinoma of the lung. Jpn J Clin Oncol 2007;37:482-486. 3. Niho S, Kenmotsu H, Sekine I, et al. Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study. J Thorac Oncol 2013;8:980-984. 4. Le Treut J, Sault MC, Lena H, et al. Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study. Ann Oncol 2013;24:1548-1552. 5. Christopoulos P, Engel-Riedel W, Grohe C, et al. Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial. Ann Oncol 2017.

Abstract:
Carcinoid tumors of the lung belong to a broad group of neoplasms called neuroendocrine tumors (NETs). These tumors are highly heterogeneous and represent a broad spectrum of phenotypes and clinical behavior. Often, the clinical behavior of these tumors corresponds with their underlying pathologic features. For example, in those tumors deemed as “typical carcinoid/NETs”, clinical behavior is often very indolent. At the other end of the spectrum, NETs can present as small cell lung cancer (SCLC) which is characterized by virulent and highly metastatic behavior. Those tumors deemed as “atypical carcinoid/NETs” usually have an intermediate clinical phenotype. Lung NETs are rare: the annual incidence rate is estimated to be approximately 1 in 100,000. In those patients whose lung NETs are no longer surgically resectable and/or have metastasized distantly, the treatment goals are principally disease control and symptom palliation. Because of their rarity, there are very limited prospective Level 1 data to guide optimal management of lung NETs. Treatment recommendations are often based on extrapolation from clinical experience in gastrointestinal NETs (specially pancreatic NET), subset analyses from other NET trials, anecdotal reports (case series), and expert opinion (e.g., consensus panels). Thus, the optimal management strategy for Lung NETs is not yet fully defined. Systemic therapy options range from somatostatin analog therapy, mTOR inhibitor therapy, and cytotoxic chemotherapy. Somatostatin analog therapy is offered in selected patient subsets that have slowly progressing disease and whose tumors express somatostatin receptors as detected by nuclear medicine scanning (Octreoscan). Somatostatin analog therapy is only modestly efficacious, with disease stabilization as the expected clinical benefit. Inhibition of the mTOR with everolimus has demonstrated efficacy in randomized trials. In the RADIANT-2 trial of everolimus+octreotide vs. placebo+octreotide in NETs, a small subset of patients with lung NETs (n=44) was analyzed. This showed an improvement in progression free survival with everolimus+octreotide vs. the control arm (median PFS 8.8 months vs 2.8; Hazard Ratio (HR) = 0.62; p=0.1). Subsequently, the phase III RADIANT-4 trial of everolimus vs placebo in non-functional lung and GI NETs was conducted. In this trial, approximately 30% of the 302 randomized patients had lung NETs. RADIANT-4 showed a PFS and overall survival (OS) benefit in favor of everolimus (PFS HR=0.39, p<0.0001; OS HR=0.64, p=0.037). More recently, a randomized phase II trial (LUNA) of pasitreotide alone, everolimus alone, or the combination showed a trend for improved PFS for the combination arm (PFS at 9 months was 39.0% for pasitreotide alone, 33.3% for everolimus alone, and 58.5% for the combination). In patients who are not candidates for somatostatin analog therapy or everolimus, or have failed these therapies, cytotoxic chemotherapy is often considered. The most commonly used regimens include platinum-etoposide (similar to that employed for SCLC) and temozolomide. Response rates to chemotherapy are reportedly much lower in lung NETs (vs SCLC) in retrospective studies; for example, platinum-etoposide is reported to yield response rates of 20-30% in lung NETs compared to rates greater than 50% in SCLC. It is thought that tumor responses are possibly influenced by the degree of tumor de-differentiation. Other agents with anecdotal activity include 5FU, capecitabine, oxaliplatin, and anthracyclines. Prospective trials of systemic therapy in lung NETs are essential to define the optimal standards of care. Selected References: 1. Hendifar, AE et al. J Thor Oncol 2016; 12(3):425-436 2. Yao, J. et al. Lancet 2016; 387: 968-77 3. Fazio N, et al. Chest 2013; 143(4):955-962

Abstract:
In the 1970s, pulmonary neuroendocrine tumors were classified into three histologically defined categories: typical carcinoid (TC), atypical carcinoid (AC) and small cell lung carcinoma (SCLC) [1]. In 1999, the World Health Organization (WHO) classified large cell neuroendocrine carcinoma (LCNEC) as a fourth neuroendocrine tumor of the lung. Although LCNEC was classified as a variant of large cell carcinoma in 1999 [2], it was classified as a neuroendocrine tumor in 2015. To date, for neuroendocrine tumors of the lung, the major categories of morphologically identifiable neuroendocrine tumors are TC, AC, LCNEC, and SCLC. Analyses of molecular markers revealed that low-grade TC and intermediate-grade AC exhibit a low proliferative rate compared with high-grade LCNEC and SCLC [3], and TC and AC have different genetic alterations from high-grade LCNEC and SCLC [4]. Analyses of their genetic alterations show that neuroendocrine lung tumors may represent a spectrum ranging from low-grade TC and intermediate-grade AC to highly malignant LCNEC and SCLC tumors [4]. TC is classified as a malignant epithelial tumor of the lung [2, 5]. However, the overall survival rate is better for TC than for AC [5, 6], and the frequency of lymph node metastases in TC is lower than in high-grade LCNEC and SCLC [6]. Therefore, some investigators have advocated limited resection in patients with TC [7]. Some reports revealed that sublobar resection was noninferior to lobectomy for survival in patients with TC tumor [7]. However, other reports advised that radical oncologic surgery with radical node dissection was needed, and segmental and other limited procedures had to be avoided because of the high frequency of lymph node involvement and multicentric forms [8]. Moreover, preoperative diagnoses and/or diagnoses from intraoperative frozen sections are often difficult for differentiating AC from TC, because small amounts of necrosis or few mitoses are sometimes unclear in those specimens. A randomized controlled trial is the best method to compare surgical efficacy. However, it may be impractical due to the rarity of carcinoid tumors. Moreover, AC has a poorer prognosis and a higher frequency of lymph node metastases than TC. Therefore, sublobar resection for TC might be the optimal surgical method because of lung preservation and lower mortality than lobectomy; however, limited resection for TC remains an area of controversy. Several reports [9] revealed that the clinical behavior, morphology, and prognosis of LCNEC were similar to those of SCLC, even though there might be several clinicopathological differences between SCLC and LCNEC in peripheral, small-sized, and high-grade neuroendocrine tumors [10]. Because it is difficult to diagnose patients with LCNEC pre-operatively, and most cases have been diagnosed postoperatively from surgically resected specimens, many reports on LCNEC have referred to surgical cases, of which the majority [9] revealed that patients with LCNEC had poor prognoses. Even patients with pathological stage I LCNEC have had poor prognoses, with five-year survival rates of 27-67% [9]. In patients with LCNEC who underwent radical surgery and complete resection, many recurrent tumors were observed as distant metastases [10]. Therefore, surgery alone is not sufficient to treat patients with LCNEC, and subsequent adjuvant therapy may be necessary [10]. Although there were high response rates with platinum-based and SCLC-based chemotherapies in patients with LCNEC, almost all patients had only partial responses [9, 10]. Patients with LCNEC may not be able to expect complete responses with platinum-based and SCLC-based chemotherapies compared with patients with SCLC, even though these chemotherapies are as effective as adjuvant treatment. Therefore, patients with advanced-stage LCNEC had a poor prognosis because they could not always achieve a complete response. Although the indication for surgery is limited to stage I in patients with SCLC, surgery and adjuvant chemotherapy may achieve satisfactory results in terms of survival for patients with LCNEC with not only stage I but also stage II/III [10]. Therefore, surgical indications for patients with LCNEC may not be limited to clinical stage I cases, and surgery with adjuvant chemotherapy should be attempted for resectable LCNEC. References [1] Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg. 1972;64:413-21. [2] Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, editors. Histological Typing of Lung and Pleural Tumours. World Health Organization International Histological Classification of Tumors, XIII, 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999. [3] Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg. 1996;62:798-810. [4] Onuki N, Wistuba II, Travis WD, Virmani AK, Yashima K, Brambilla E, Hasleton P, Gazdar AF. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer. 1999;85:600-7. [5] Travis W.D, Brambilla E, Müller-Hermelink H.K, Harris C.C (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. IARC Press:Lyon 2004. [6] Iyoda A, Hiroshima K, Baba M, Saitoh Y, Ohwada H, Fujisawa T. Pulmonary large cell carcinomas with neuroendocrine features are high grade neuroendocrine tumors. Ann Thorac Surg. 2002;73:1049-54. [7] Fox M, Van Berkel V, Bousamra M II, Sloan S, Martin RC II. Surgical management of pulmonary carcinoid tumors: sublobar resection versus lobectomy. Am J Surg. 2013;205:200-8. [8] Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F, Daddi G. Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg. 2004;26:813-7. [9] Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T. Pulmonary large cell neuroendocrine carcinoma- its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg. 2007;84:702-7. [10] Iyoda A, Makino T, Koezuka S, Otsuka H, Hata Y. Treatment options for patients with large cell neuroendocrine carcinoma of the lung. Gen Thorac Cardiovasc Surg. 2014;62:351-6.

Abstract:
Lung Neuroendocrine Tumors (NETs) are rare neoplasms derived from the neuroendocrine cells of the bronchopulmonary epithelium. They represent about 25% of all the neuroendocrine tumors, and no more than 2%-3% of all the primary tumors of the lung. Their incidence has recently increased by approximately 6% per year, probably due to the improved awareness as well as for the diffusion of lung cancer screening programs worldwide. NETs’ incidence now ranges from 0.2 to 2 per 100,000 individuals per year in the United States. Their rarity, along with the lack of randomized clinical trials, make lung NETs’ global management still questioned, especially in case of advanced diseases, and only few clinical recommendations currently exist. In 2012, during the Annual Meeting in Essen (Germany), the European Society for Thoracic Surgeons (ESTS) created a new Working Group (WG) specifically dedicated to the Lung NETs. The Steering Committees was composed by the following Thoracic Surgeons: Pier Luigi Filosso (Torino, Italy-Chair), Pascal Alexandre Thomas (Marseille, France), Mariano Garcia-Yuste (Valladolid, Spain), Eric Lim (London, UK), Federico Venuta (Rome, Italy), Alessandro Brunelli and Konstantinos Papagiannopoulos (Leeds, UK), Hisao Asamura (Tokyo, Japan). The aim of this WG was to create a group of physicians expert on Lung NETs in order to improve scientific knowledge on such rare neoplasms, and disseminate it among the scientific community. A specific database was rapidly designed, to retrospectively collect data of patients operated for lung NETs, and it was sent to all the ESTS Members who expressed their interest to this project. Moreover, a survey concerning lung NETs’clinical management was prepared and its results were recently published (Future Oncol. 2016;12:1985-1999). Up to now, 2040 operated NETs patients have been collected amongst 17 high-volume International Thoracic Surgery Institution worldwide. This retrospective database was used for several studies about lung NETs clinical behavior and outcome. In particular, the outcome and prognostic factors of two aggressive lung NETs: atypical carcinoids (ACs) and large-cell neuroendocrine carcinomas (LCNCs) were the object of the first publication (Eur.J.Cardiothorac Surg. 2015;48:55-64). For ACs, age (P<0.001), tumour size (P=.015) and sub-lobar resections (P=0.005) were independent negative prognostic factors; for LCNCs, only pTNM stage III tumors (P=0.016) negatively affected outcome in the multivariate analysis. Local recurrences and distant metastases were statistically more frequent in LCNCs (P=0.02), as expected. A prognostic model of survival for typical carcinoids (TCs) was the matter of the second publication (Eur.J.Cardiothorac Surg. 2015;48:441-447): an analysis of 1109 TC patients was performed. A prediction model for mortality, evaluating age, gender, previous malignancies, peripheral tumour location, TNM stage and ECOG PS was elaborated, and the final model showed a good discrimination ability with a C-statistic equal to 0.836 (bootstrap optimism-corrected 0.806). Moreover, this model has been recently validated by Cattoni and Coll. The treatment of biologically aggressive/advanced lung NETs was recently investigated in a paper published by the Journal of Thoracic Disease (J.Thorac. Dis. 2015;7:S163-S171). Surgery, whenever feasible, remains the mainstay of treatment, and chemo/radiotherapy should be reserved to progressive diseases. In case of resected N1-N2 carcinoids, a "watch and see" policy and a close clinical/radiological follow-up is also recommended. Surgery alone is not sufficient to treat high-grade NETs (e.g.: LCNC): adjuvant CT is suggested even in early stages. Platinum-Etoposide regimen demonstrated to be the most effective; Irinotecan and other biological drugs are also regarded to be very promising. The management of advanced lung NETs should be tailored by multidisciplinary teams including Medical and Radiation Oncologists, Surgeons, Pathologists, Pulmonologists, Endocrinologists, Interventional Radiologists; patients’ prognosis is mainly dependent on tumor grade and its anatomical extent. Large-cell neuroendocrine carcinoma (LCNC) is a rare tumor characterized by an aggressive biological behaviour and poor prognosis; its optimal treatment is still under debate. Some recent reports indicate that adjuvant chemotherapy (CT) may have a beneficial effect on survival. Data from 400 patients with resected LCNC were analyzed. The 3- and 5-year survival rates were 54.1% and 45%, respectively. With the multivariable model, increasing age, ECOG ≥2 and advanced TNM stage were indicators of poor prognosis. Weak evidence of a higher overall survival in patients receiving adjuvant CT (adjusted hazard ratio 0.73; 95% confidence interval: 0.56-0.96, P  = 0.022) was also observed (Eur.J.Cardio-Thorac.Surg. 2017;52:339-345). In Stage I TCs (SITCs) non-anatomical resections (wedge) are sometimes advocated because of their indolent behavior. An analysis on effect of surgical procedure on SITC patients’ survival was therefore done (Eur.J.Cardiothorac.Surg. 2017 submitted paper). Eight-hundred seventy-six SITC patients (569 females,65%) were included in this study; the 5-year OS rate was 94.3% (95%CI:92.2 –95.9). At univariable analysis, wedge resection resulted to be associated with a poor prognosis (5-year OS 82%,95%CI:0.71-0.89,P<.001) compared to other anatomical resections. At multivariable score-adjusted analysis, wedge resection confirmed to be an independent predictor of poor prognosis (HR2.17,95%CI: 1.19-3.96,P=.012). Since 2106, a lung NETs prospective database is active through the official ESTS European Database, and up to now, more than 150 new cases have been collected. Through this new platform, very easy to be used, we are confident to collect, in few years, more data especially on possible tumor recurrences and their treatment, as well as on the role of emerging biological drugs used in the adjuvant setting in advanced diseases. An active participation of Medical/Radiation Oncologists to this scientific project would be also desirable. The active role of the most important Scientific Societies could strongly support the success of this scientific project.

Abstract:
Staging of large cell neuroendocrine carcinoma (LCNEC) was classified based on non-small cell type (TNM stage). The treatment of early stage (I, II) was mainly surgery; the use of neo - adjuvant and adjuvant chemotherapy are in consideration but there's not a standard approach; for stage III which limited to the thoracic area, the role of concurrent chemotherapy and radiotherapy is one of the options. Whether the regimen of chemotherapy should be similar to small cell lung cancer (SCLC) or the regimen of non -small cell lung cancer (NSCLC) is not clear. Most of the data are in favor of SCLC regimen which is Cisplatin plus etoposide; however the data came from retrospective and small numbers of patients, thus there's an unmet need to improve the treatment of LCNEC. Large Cell Neuroendocrine Carcinoma and Small Cell Lung Cancer are both consider high grade neuroendocrine carcinoma of the lung. Small cell is the most frequent type of lung neuroendocrine tumor, occurs around 15% of lung cancer while Large Cell neuroendocrine carcinoma was only about 3% of lung cancer. According to WHO classification in 2004 LCNEC was classified as a variant of large-cell carcinoma; however in 2015 WHO classification LCNEC was classified into a group of neuroendocrine tumor which includes SCLC, typical carcinoid, atypical carcinoid and LCNEC. According to genomic analysis, LCNEC was separated into two groups. Some have genomic characteristic of SCLC and some have genomic characteristic of NSCLC. The new modalities such as anti-angiogenesis and in the case of EGFR mutation the treatment with EGFR inhibitor should be considered. The role of met inhibitors in LCNEC should be explored. Thus there is a long way to go in order to improve the outcome of this rare lung cancer type.

Abstract not provided

Abstract:
Reasons surgeons “quit” cancer operations are typically related to finding additional sites of disease, inability to perform necessary dissection, or disappearance of previously identified disease. In the setting of N2 positive non-small cell lung cancer (NSCLC) the disappearance of disease is not a consideration, so occult sites of disease or inability to perform safe hilar or mediastinal dissection are the most common reasons to back out of an operation once started. Incredibly precise pre-resection imaging has made this an uncommon scenario. Imaging techniques include functional and molecular correlates, and 3 and 4 dimensional reconstructions, which improve detection of very small lesions and appreciation of tumor interactions with adjacent structures. That being said, N2 involvement denotes locally advanced and often aggressive disease and use multimodality treatments and therefore the risk for unexpected findings in the operating room which alter resectability are more frequent than in early stage disease. Occult or unexpected disease encountered by thoracic surgeons in the operating room typically involves the parietal pleura, as occult carcinomatous pleuritis. Additional pulmonary nodules and unanticipated milliary spread are far less common. Pleural studding is defined as M1a disease in the 8[th] edition of AJCC staging. Chemotherapy is the recommended treatment for radiographically identified pleural involvement, but management recommendations are slightly less clear for disease found at the time of surgery. Pulmonary resections are generally contraindicated, but several investigators report favorable outcomes for those who can undergo macroscopic complete resection.[1,2] Carcinomatous pleuritis can escape radiographic detection, the incidence of occult disease at thoracotomy ranges from 1.5% to 4.5% for all lung cancer resections,[3] and is associated with large tumors, non-squamous histology, and lymph node involvement.[2] Carcinomatous pleuritis can escape radiographic detection, the incidence of occult disease at thoracotomy ranges from 1.5% to 4.5% for all lung cancer resections,[] and is associated with large tumors, non-squamous histology, and lymph node involvement. Intraoperative pleural lavage cytology (PLC) is a technique used for detecting subclinical dissemination of malignant cells in the pleural cavity. The boundary between malignant pleural effusion and positive PLC is not particularly well defined and most reports demonstrate a negative impact on prognosis in resected patients, but positive PLC does not upgrade tumors in the current TNM staging system. It also does not preclude resection in a patient with otherwise resectable disease. Similar to pleural studding positive cytology is consistently found to be more common in patients with higher stage and nodal involvement.[4] The presence of bulky N2 disease can greatly increase the complexity of hilar and mediastinal dissection. Modern techniques and intraoperative tools have increased surgeons ability to remove structures once considered unresectable including the spine, carina, and superior vena cava, but direct tumor extension or nodal involvement of the trachea, heart or great vessels can make safe resection impossible. Preoperative imaging typically allows for appropriate planning and decision making about these types of complex resections and controversy exists as to appropriateness of such resections in the setting of N2 disease. Induction therapy can make the pre-operative assessment of involved structures more complicated, differentiation between tumor and treatment effect is not always clear and therefore many surgeons make resection decisions on pre-treatment imaging. A more common scenario in thoracic oncology is that of the patient with marginal pulmonary reserve in whom the hilar resection is complicated by extensive nodal involvement or treatment effect; a pneumonectomy is technically feasible and would result in complete resection, but the patient would not tolerate that extensive a resection. Sleeve resections are used whenever possible, but widespread hilar and mediastinal scarring can sometimes exclude any safe surgery other than a pneumonectomy. The amount of fibrosis and scarring encountered at resection following induction therapy remains unpredictable. It is known to increase with time, which is why resection is recommended within 12 weeks induction therapy, but within that window, it can be quite variable. Review of recent large prospective trials for resectable IIIA NSCLC can help shed light on how frequently and why surgeons cannot complete the planned resection for N2 positive NSCLC. In the recent SAAK trial which compared induction chemotherapy to induction chemoradiotherapy in high volume operative centers in Europe, all patients who were taken to surgery, had a pulmonary resection, but R2 resections occurred in 3% of the trimodality group and 8% of the bimodality, reasons for incomplete resection were not delineated.[5] In the recent report of pooled data from RTOG 0229 and 0839, evaluating surgical outcomes after high dose induction chemo-radiotherapy, 7 of the 99 patients brought to surgery were not resected, 2 due to occult pleural metastasis, 2 because of persistent N2 involvement in patient with limited pulmonary reserve, and 3 were “unresectable”, 2 because complete resection would require a pneumonectomy and they had poor pulmonary reserve and one due to extensive mediastinal fibrosis.[6] These trials were all limited to experienced thoracic surgeons, indicating that the inability to complete a planned resection for IIIA NSCLC remains a rare but real phenomenon even in skilled surgical hands. References 1. Fukuse, T., et al., The prognostic significance of malignant pleural effusion at the time of thoracotomy in patients with non-small cell lung cancer. Lung Cancer, 2001. 34(1): p. 75-81. 2. Iida, T., et al., Surgical Intervention for Non-Small-Cell Lung Cancer Patients with Pleural Carcinomatosis: Results From the Japanese Lung Cancer Registry in 2004. J Thorac Oncol, 2015. 10(7): p. 1076-82. 3. Fukui, T. and K. Yokoi, The role of surgical intervention in lung cancer with carcinomatous pleuritis. J Thorac Dis, 2016. 8(Suppl 11): p. S901-S907. 4. Toufektzian, L., et al., Pleural lavage cytology: where do we stand? Lung Cancer, 2014. 83(1): p. 14-22. 5. Pless, M., et al., Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet, 2015. 386(9998): p. 1049-56. 6. Donington, J., et al. safety and Feasibility of Lobectomy folowing Concurrent Chemotherapy and High Dose Radiation for Stage IIIA NSCLC: Pooled Surgical Results of NRG Oncology RTOG 0229 and 0839. in American Asociation for Thoracic Surgery. 2017. Boston, MA.

Abstract:
Various treatment strategies, including chemotherapy, radiotherapy and surgery have been developed for patient populations with N2 lymph node metastasis, especially clinical stage IIIA-N2 non-small cell lung cancer (cIIIA-N2 NSCLC). For potentially resectable patients, clinical trials including surgical treatment have been published. Among them, EORTC-08941, INT-0139, ESPATUE examined the efficacy of adding surgical treatment with chemotherapy and radiotherapy in randomized design. In the INT-0139 study, surgery after induction chemoradiotherapy (CRT) demonstrated a 7% gain on 5-year survival, however, it failed to show statistical significance mainly because of treatment-related death in patients received pneumonectomy after induction CRT. Although the contribution of surgery was recognized, the additional effect of surgery over CRT has not been confirmed consistently in other trials. On the other hand, trials investigating newer medical treatment and higher radiotherapy dose have been conducted for patients with unresectable stage III NSCLC. In this patient population, so-called third generation cytotoxic agents whose effects were confirmed in patients with advanced disease, including paclitaxel (WJTOG0105), docetaxel (OLCSG 0007), vinorelbine and pemetrexed (PROCLAIM) with platinum have been actively examined but failed to show improvement compared to older agents (etoposide, vindesine and mitomycin C). Furthermore, high-dose radiotherapy (74Gy) with platinum-doublet chemotherapy showed strikingly shorter survival than conventional radiation dose (60Gy) in RTOG-0617. After these continuous efforts, CRT stayed as standard for those patients with unresectable N2 disease. Besides CRT, induction therapy followed by surgery has also come to be recognized as a treatment option for potentially resectable N2 disease in major guideline including ACCP, NCCN and ESMO. However, no clear answer has been provided for the question: what is resectable N2 disease, and what is unresectable N2 disease? To refine the heterogeneity in cIIIA-N2 NSCLC patients and show clues to answer the question of resectable/unresectable, we analyzed the data of consecutive patients with cIIIA-N2 NSCLC diagnosed and treated by CRT in National Cancer Center Hospital, Tokyo, Japan. The appearance of the mediastinal lymph nodes (MLNs) was classified into discrete or infiltrative according to the criteria proposed by the ACCP. In addition, the extent of MLN involvement (MLNI) was classified as limited (close to the primary tumor) or extensive (including upper MLNI in the case of tumors in the lower lobes and vice versa). Those with a discrete appearance of the MLNIs and a limited extent of MLNIs at diagnosis could show favorable survival outcomes by CRT without surgery comparable to the data provided by induction CRT followed by surgery. Meanwhile, immune checkpoint inhibition by PD-1/PD-L1 antibody has been being actively examined as adjuvant for early stage resectable NSCLC patients and consolidation therapy for unresectable stage III NSCLC patients after CRT. The PACIFIC is a phase III randomized clinical trial investigating the efficacy of MEDI-4736 (PD-L1 antibody) as consolidative therapy in patients without progression after definitive CRT. Based on the press release by AstraZeneca, MEDI-4736 showed significant prolongation of progression-free survival, suggesting that there is a possibility of changing standard treatment. Under such circumstances that powerful medical treatment option will be introduced in unresectable N2 disease, there is increasing need for an appropriate guidance to select surgical candidates in potentially resectable population. Now is the time to respond to the question of resectable/unresectable that has not been answered for a long time.

Abstract not provided

Abstract:
What is Resectable N2 Disease, and What is Unresectable N2 Disease: A Surgeon's Viewpoint Jhingook Kim, MD (Samsung Medical Center, Sungkyunkwan University) The poor prognosis of N2 disease is related to the risk of occult systemic metastasis although N2 disease, by definition, is a localized disease. Therefore, multimodal treatment, including systemically chemotherapy and locally surgery or radiotherapy, is often required. However, the optimal multimodal approaches for N2 disease remain controversial. Although definitive concurrent chemoradiotherapy (CCRT) is considered the standard of care, its oncologic efficacy can be limited by the high rate of local failure. Adding surgical resection to this bimodal treatment as a neoadjuvant treatment setting or replacing the radiotherapy with surgery has been attempted and has achieved enhancement of local control and improved survival, but the main concern regarding this approach is the increased risk of postoperative mortality and morbidity. Since 1995, neoadjuvant CCRT followed by surgical resection has been the preferred treatment modality at our institution, and prospectively and consecutively performed for more than 800 medically fit patients with resectable NSCLC with N2 disease. Figure 1 Fig. 1. Summary of treatment scheme Based on the previous analysis of 574 patients (From 1997 to 2013, 59 years of mean age, 444 men), complete resection was obtained in 543 patients (95%) by lobectomy (418 patients; 73%), pneumonectomy (73 patients; 13%) and sleeve resection (25 patients; 4.3%). Postoperative complications and in-hospital mortality occurred in 199 patients (35%) and 21 (3.7%), respectively. Pathologic complete response was achieved in 72 patients (13%) and 304 (53%) experienced mediastinal clearance. The 5-year overall and recurrence-free survival rates were 47 and 29%, respectively, and the median overall survival and recurrence-free survival were 56 months and 18 months, respectively. The 5-year OS rates were 61% in ypN0, 49% in ypN1, and 35% in ypN2 (p = 0.001). The 5-year RFS rates were 45% in ypN0, 23% in ypN1, and 17% in ypN2 (p < 0.001). Older age, advanced pTstage, persistent N2, large cell carcinoma, and pneumonectomy were independent prognostic factors associated with worse OS and poorer RFS. Evidence such as acceptable early postoperative outcomes, satisfactory local control and encouraging long-term survival has supported the need to expand the indication or situation. When investigating the timing and patterns of recurrence after treatment, of 290 patients with recurrence, 25 (8.4%) experienced loco-regional recurrence, whereas 238 (80.4%) had distant metastases. The hazard rate function for overall recurrence revealed a peak at approximately 8 months after surgery and a marked decline after 2 years (figure 2). The peak recurrence frequency of distant metastasis differed at each site, with isolated brain metastases exhibiting the earliest peak (6 months) and a narrow recurrence interval (15 months). Interestingly, the dynamics of recurrence after trimodality therapy varies according to pathologic factors and response to induction therapy (not specifically related with pre-induction presentation), which may mean personalized consideration of the treatment including surgery. Figure 2 FIG 2. Comparison of the recurrence hazard rate according to the site of distant metastasis. Each organ has a different peak of recurrence, although the peaks and shapes of the hazard rate curves were similar between bone and supraclavicular lymph nodes. Therefore, in this session, we will discuss “resect or not to resect” in several specific situations such as 1) for the patients with invasive T3 or resectable T4 2) for the patients with multi-station, bulky lymph nodes (not every) 3) for the patients with central lung cancer with possible sleeve lobectomy 4) for the old patients (>75 year-old) with comorbidity By the rapid development of the medical sciences, especially in cancer medicine, there would be fundamental changes in the diagnosis and management of N2 disease. Especially, improvement in systemic treatment would have critical impact on the surgical role in locally-advanced lung cancer. Moreover, if systemic tumor burden or minimal residual disease could be assessed at the earliest, surgery would be applied with higher benefit, and thus, the survival outcome would be significantly improved. Therefore, there should be more studies of combined local control (surgery) and systemic control (chemo and/or immunotherapy); either as adjuvant, neoadjuvant or salvage purpose; either with or without radiotherapy; participated by thoracic surgeons, to maximize the survival of the patients from dreadful disease. References 1. Kim HK, Cho JH, Choi YS, et al. Outcomes of neoadjuvant concurrent chemotherapy followed by surgery for non-small cell lung cancer with N2 disease. Lung Cancer 2016; 96:56-92 2. Lee J, Kim HK, Park BJ, et al. Recurrence Dynamics after Trimodality Therapy (Neoadjuvant Concurrent Chemoradiotherapy and Surgery) in Patients with Stage IIIA (N2) Lung Cancer. Lung Cancer (submitted)

Background:
Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.

Method:
We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).

Result:
In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.

Conclusion:
Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.

Background:
EGFR exon 20 insertions (ins20) comprise 4-10% of EGFR mutations in NSCLC and are refractory to 1[st]/2[nd] generation EGFR TKIs. No effective targeted therapies exist for patients with EGFR ins20. EGFR is a client protein of the molecular chaperone Heat Shock Protein 90 (hsp90). Here, we present the final results of a phase II investigator-initiated trial to assess the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20 (NCT01854034).

Method:
Between 8/2013 and 10/2016, the study enrolled 29 patients with stage IV NSCLC, EGFR ins20 identified on local testing, ECOG PS 0-2, at least one prior line of therapy and no untreated brain metastases. The study was closed on 2/28/17 when the available drug supply was exhausted. Luminespib was given at 70mg/m2 IV weekly. Response was assessed by RECIST 1.1 every 6 weeks; treatment beyond progression was allowed. Dose interruptions and dose reductions were allowed as needed for toxicity management. Primary endpoint was ORR with a target disease control rate (DCR; PR/CR plus SD lasting > 3 mos) of > 20%. Secondary endpoints were PFS, OS, safety and response by EGFR ins20 subtype.

Result:
29 patients (18 female/11 male, median age 60 (range, 31-79)) were enrolled. Median number of prior therapies = 1 (range, 1-5.) 4/29 achieved PR and 1 CR (ORR 5/29; 17%). 15 patients had SD and 9 had PD as their best response. mPFS was 2.9 mos (95% CI, 1.4-5.6,) mOS was 13 mos (95% CI, 4.9-19.5.) DCR was 11/29 (38%). Among 19 patients with baseline PS 0-1 and < 2 prior therapies, ORR = 21% and mPFS = 5.1 mos (95% CI, 2.1-11.8.) The most common luminespib-related toxicities were visual changes (22/29; 76%) diarrhea (21/29; 72%) and fatigue (13/29; 45%). Treatment-related grade 3 toxicities included ocular toxicity (1/29; 3%), hypertension (3/29; 10%) and hypophosphatemia (1/29; 3%). All study treatment was stopped on 2/28/17 due to lack of drug availability; 3 patients were on treatment without progression at study termination.

Conclusion:
The study met its primary endpoint and suggests that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other Hsp90 inhibitors in this population is warranted, as are novel systems to continue drug supply for benefitting patients when availability of experimental compounds is limited.

Background:
HER2 is a potential driver oncogene. HER2-targeted precision therapy has been tested in NSCLC. However, the demographics of HER2-positive NSCLC have not been defined systematically.

Method:
Pts with advanced NSCLC were registered. HER2-IHC and FISH assays were performed with commercial kits. HER2 mutations were identified by the direct sequencing. The aim of this study was to clarify the frequency, characteristics and outcome of HER2-positive NSCLC.

Result:
Of 1,126 tumors screened (Table A), 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 EGFR wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775_G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female pts had HER2 mutant tumors more frequently, while IHC/FISH+ tumors were detected more often in males (Table B). HER2-positive tumors had similar survival outcome to triple negative tumors, but significantly worse prognoses than EGFR-mutant and ALK-positive tumors (p < 0.05 each). The treament info will be presented at the meeting.

A. The Genotype-Specific Subsets*
	HER2 (n = 88)	EGFR (n = 358)		ALK (n = 44)	Triple negative /unknown (n = 662)		Total (n = 1,126)
Age, median Sex (male) Smoking habit Non-Sq Stage III/IV	69 61 (69%) 58 (66%) 78 (89%) 51 (58%)	69 142 (40%) 142 (40%) 351 (98%) 220 (61%)		62 21 (48%) 19 (43%) 44 (100%) 35 (80%)	69 516 (78%) 544 (82%) 503 (76%) 423 (64%)		69 726 (64%) 754 (67%) 951 (84%) 714 (63%)
MST (mo) 1-yr OS rate	17.5 59%	NR 85%		NR 79%	15.1 59%		19.8 67%
B. The Subsets of HER2 aberrations**
	IHC3+ (n = 34)		IHC2+/FISH+ (n = 34)			Mutant (n = 21)
Age, median Sex (male) Smoking habit Non-Sq Stage III/IV	71 27 (79%) 24 (71%) 30 (88%) 17 (50%)		71 27 (79%) 26 (76%) 28 (82%) 21 (62%)			65 8 (38%) 9 (43%) 21 (100%) 14 (67%)
MST (mo) 1-yr OS rate	10.5 46%		16.0 70%			NR 59%

*including 22 pts with HER2-positive tumors with EGFR mutations, 2 with both HER2- and ALK-positive tumors, and 2 had ALK-positive tumors with EGFR-mutations. ** 1 had an IHC2+/FISH+ tumor with mutation.

Conclusion:
This is the first prospective study showing a small fraction of NSCLC possessed HER2 aberrations. HER2-positive tumors had relatively poor prognosis. NSCLCs with HER2 IHC3+ and mutation seem to be distinct subsets.

Abstract not provided

Background:
Somatic BRAF V600E is a National Comprehensive Cancer Network clinical therapeutic target in non-small cell lung cancer (NSCLC), occurring in 6% of tumors from patients with lung adenocarcinoma. However, approximately half of BRAF alterations are non-V600E that do not respond to FDA-approved vemurafenib or dabrafenib. Emerging evidence suggests some non-V600E mutations exhibit clinical response to novel therapeutic agents. We analyzed the landscape of BRAF mutations in a very large cohort of patients with NSCLC who underwent somatic genomic testing utilizing a CLIA-certified/CAP-accredited/NYSDOH-approved 73 gene cell-free circulating tumor DNA (cfDNA) panel which evaluates single nucleotide variants, and selected indels, fusions, and copy number amplifications.

Method:
The Guardant Health laboratory database was queried for cfDNA tests from patients with a diagnosis of NSCLC where a BRAF variant was identified. Literature was queried for a description of the known function of non-V600E BRAF mutations on serine-threonine kinase activity.

Result:
A total of 1,014 BRAF alterations were observed in 914 tests, with 234 unique alterations identified. The majority of variants were observed only once (75.6%; N=177). 43 alterations were synonymous and excluded from analysis. Plasma-detected BRAF amplification was the most common alteration, observed in 484 tests. Of the remaining variants, 33 of 190 had functional consequence reported in the literature (17.4%), 18 with gain of function or predicted gain of function, 13 with loss of function or predicted loss of function and 2 with no effect. BRAF V600E accounted for 51.1% of occurrences of variants with gain of function or predicted gain of function (N=95 occurrences). Recurrent (>10 occurrences) non-V600E gain of function mutations included G469A (13.4%; N=25 occurrences), K601E (8.0%: N = 15 occurrences), and N581S (7.0%; N=13 occurrences). Fourteen additional gain of function variants comprised the remaining 21% of occurrences. Recurrent loss of function BRAF mutations (>10 occurrences) included G466V and D594G.

Conclusion:
This is the largest reported cohort of somatic BRAF alterations in metastatic non-small cell lung cancer. Non-V600E alterations accounted for almost 50% of the gain of function variants. The spectrum of non-V600E alterations was consistent with reports from The Cancer Genome Atlas and prior published results from tissue genomic sequencing. The recurrent non-V600E variants identified in this cohort are emerging therapeutic targets with promising early clinical data. These findings advocate for more comprehensive BRAF genomic profiling and identification of patients eligible for clinical trials targeting these non-V600E classic mutations and demonstrate the ability of plasma-based cfDNA to detect these alterations.

Background:
MET exon 14 alterations occur in ~4% of non-squamous non-small cell lung cancers (NSCLCs). Treatment with the MET inhibitor, crizotinib, achieves confirmed and durable responses in patients with MET exon 14-altered NSCLCs, underscoring the need to test for these drivers (as of August 1, 2016, objective response rate was 39% and median duration of response was 9.1 months). Comprehensive molecular tumor profiling is required to detect MET exon 14 alterations that are highly heterogeneous. The utility of plasma profiling to detect these drivers has not previously been explored in a prospective trial.

Method:
Patients with advanced NSCLCs harboring MET exon 14 alterations by local tumor profiling performed in a CLIA-certified or equivalent environment were treated with crizotinib at 250 mg twice daily on an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195). Objective response was assessed by RECIST v1.0. Prospective plasma profiling of circulating tumor DNA (ctDNA) for MET exon 14 alterations was performed using the PlasmaSELECT64 targeted gene panel (sequencing and analysis output by Personal Genome Diagnostics, Boston MA).

Result:
Plasma samples were obtained for MET exon 14 alteration analysis after study amendment approval in 20 of 52 crizotinib-treated patients, of which 18 samples were deemed sufficient for analysis. MET exon 14 alterations were detected in ctDNA in 11 of 18 patients (61% agreement of plasma ctDNA testing with tumor testing) mapping to the same exon 14 splice site region in 10 of the 11 cases. Of the 11 patients with ctDNA-positive tumors, all were evaluable for response. Of these evaluable patients, a confirmed partial response and stable disease were observed in 2 and 4 patients, respectively.

Conclusion:
MET exon 14 alterations can be detected in plasma ctDNA in a subset of patients with advanced NSCLCs that harbor MET exon 14 alterations by tumor testing. Responses to crizotinib were observed in patients with ctDNA-positive testing for a MET exon 14 alteration. Plasma profiling should be considered as an adjunct to tumor profiling in screening patients for MET exon 14 alterations, pending further confirmation.

Background:
RET fusions are validated therapeutic targets in human lung cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity is limited by a narrow therapeutic index from off-target effects and poor pharmacokinetics (PK). Moreover, MKIs have limited RET inhibition in the central nervous system (CNS), and patients often experience disease progression in the brain. LOXO-292 is a potent and highly selective RET inhibitor, with >100-fold selectivity versus important off-targets, and anti-tumor activity in the brain and periphery in RET-dependent tumor models in vivo.

Method:
Two RET fusion-positive lung cancer patients were treated with LOXO-292: a patient with CCDC6-RET-rearranged lung cancer with acquired resistance to RXDX-105; and a patient with KIF5B-RET-rearranged lung cancer with progressive disease in the brain while on alectinib treated under a single patient protocol with real-time, PK- guided intra-patient dose titration.

Result:
The first patient was enrolled on cohort 1 of the Phase 1 trial (20 mg daily) and was the first lung cancer patient to receive LOXO-292. She achieved a rapid, confirmed partial response (PR) by RECIST 1.1, with a 44% reduction in target lesion size. The second patient, the first to receive LOXO-292 in the setting of brain metastases, achieved a PR with escalating doses of LOXO-292 (20-60-100 mg twice daily) that included target lesion responses in both the lungs and brain (Figure 1), and resolution of cancer-related CNS symptoms. Early clinical experience with LOXO-292 has already established drug exposures that are consistent with significant RET inhibition in vitro and RET-dependent tumor regression in vivo. Importantly, LOXO-292 has been well-tolerated, with the majority of treatment-emergent adverse events reported as Grade 1-2, and none attributed to LOXO-292.

Conclusion:
LOXO-292 has demonstrated proof-of-concept tolerability, significant exposure, and efficacy in two patients with MKI-resistant, RET-dependent cancers, including a patient with progressive brain metastases after alectinib.Figure 1

Background:
MET amplification (METamp) is a known driver and a mechanism of resistance in EGFR-mutated lung cancers treated with targeted therapy. However, development of therapies targeting METamp has been hampered in part due to poor genomic stratification of patients. We investigated the natural distribution of the size of the MET amplicon and associated genomic characteristics.

Method:
Hybrid-capture based comprehensive genomic profiling (CGP) was performed prospectively on DNA isolated from FFPE samples from NSCLC. Tumor mutational burden (TMB) was calculated from 1.1 Mbp of sequenced DNA and reported as mutations/Mb, as previously described (PMID: 28420421).

Result:
We identified 545 NSCLC cases with focal, defined as <20 Mbp (n = 457, 84%), or non-focal (n = 88, 16%) amplification of the MET gene using CGP. Within this set, the size of the MET amplicon ranged from 0.095 – 158 Mbp; 25[th], 50[th] and 75[th] quartiles were 1.63 Mbp, 3.46 Mbp, and 11.66 Mbp, respectively. In cases with focal METamp the median MET copy number was 11, compared to a median of 7 copies for cases with non-focal METamp (P <0.001). Median TMB in cases with focal vs. non-focal METamp was 10.8 and 9.0, respectively (P=0.47). MET exon 14 splice site alterations co-occurred with METamp in 45 cases (8%), of which 80% had focal METamp (median amplicon size of 2.02 Mbp). EGFR mutations co-occurred with METamp in 93 cases (17%) in this dataset, of which 78% had focal METamp (median amplicon size: 3.77 Mbp). In contrast, cases with other co-occurring alterations described in the NSCLC NCCN guidelines (ALK, ROS1 or RET rearrangements, BRAF V600E, or ERBB2 mutations) METamp was more commonly non-focal (3 focal and 6 non-focal cases), with a median amplicon size of 25.5 Mbp. Clinical outcomes will be presented, including a subset of cases in the setting of resistance to EGFR inhibitors.

Conclusion:
The size of the MET amplicon in MET-amplified NSCLCs is largely variable. Focal amplification is associated with a higher estimate of MET copy number. Neither TMB or co-occurring MET or EGFR mutations significantly correlated with size of the MET amplicon; however, other co-occurring known drivers were associated with non-focal METamp. Additional investigation is warranted to determine the clinical significance of the size of the MET amplicon in NSCLC.

Abstract not provided

Abstract:
Small cell lung cancer (SCLC) accounts for 15%–20% of all lung cancers, and the overwhelming majority (>95%) are associated with tobacco exposure. The incidence of all types of lung cancer, including SCLC, has been declining in the United States with the onset of tobacco smoking cessation programs, although this trend took nearly 20 years to become evident among men. Overall survival (OS) rates for patients with lung cancer have also increased by about 5% since the advent of low-dose spiral computed tomography (CT) scanning to detect early lung cancer. The prognosis for patients with SCLC continues to be poor but has improved with the advent of smoking cessation campaigns, more effective chemotherapy agents and radiation planning and delivery techniques, and the use of prophylactic cranial irradiation (PCI) for those who experience a complete response to therapy. Consolidation with chest radiotherapy has improved OS among patients with extensive-stage SCLC who achieved a complete response to chemotherapy. SCLC often presents as bulky symptomatic masses, and mediastinal involvement is common with or without pleural effusion and extrathoracic disease. Extrathoracic spread (i.e., extensive-stage disease) is also quite common, being present in 80%-85% of cases at diagnosis. Brain metastases are present in approximately 20% of patients at diagnosis; roughly half of these metastases are symptomatic and the other half are detected by imaging. Predictors of poor prognosis include poor performance status, older age, and being male. The pathologic subtypes of the disease (small cell carcinoma and combined small cell carcinoma) all carry a similarly poor prognosis. Current guidelines of the U.S. National Comprehensive Cancer Network recommend the use of positron emission tomography (PET), CT scanning, or fused PET/CT scanning of the chest, liver, adrenals, bone, and other areas of concern in the diagnosis and staging of SCLC (NCCN guideline-SCLC 2017) . Thoracic radiotherapy has also become important for improving OS among patients with SCLC who achieved a complete response to chemotherapy. In one prospectively randomized study of 498 patients with extensive-stage SCLC (WHO performance status score 0-2) who achieved complete response to chemotherapy, patients who received consolidation thoracic radiotherapy (30 Gy in 10 fractions) had significantly better 2-year OS rates than did those who did not receive thoracic radiotherapy (13% vs. 3%, P=0.004). Thoracic radiotherapy further improved thoracic-only failure rates (19.8% vs. 46% without, P=0.001) (Slotman B et al, Lancet Oncol 2015;385:36-42). However, many patients with extensive-stage SCLC do not respond to the standard etoposide/cisplatin chemotherapy (Figure 1). Those patients may need to receive molecular-targeted therapies or immunotherapy with the consolidating thoracic radiotherapy. Several histologic and immunohistochemical markers have been evaluated for diagnosing or monitoring treatment response in SCLC, including transcription thyroid factor-1 (positive in >85% of SCLC cases); cytokeratin 7; deletions in chromosome 3; Leu-7; chromogranin A; synaptophysin; myc amplification; and p53 mutations (present in ~75% of cases). Deletions in tumor-suppressor genes are also relatively common and include fragile histidine triad (FHIT) (80%); RAS effector homologue (RASSF1) (>90%); TP53 (>75%); retinoblastoma-1 (RB1) (>90%); and retinoic acid receptor-beta (72%). However, to date no biomarkers have been validated for use in diagnosing SCLC. Moreover, mutations that are often present in non-small cell lung cancer (such as epidermal growth factor receptor [EGFR] mutations and anaplastic lymphoma kinase [ALK]) are rare in SCLC. Several clinicopathologic features have been linked with worse prognosis, including poor performance status, significant weight loss, high lactate dehydrogenase levels, large numbers of metastatic sites, and the presence of paraneoplastic syndromes. Because SCLC has the among the highest rates of somatic driver mutations, and because more than 95% of patients with SCLC are former or current smokers, immunotherapy seems a reasonable approach, as high mutation burdens correlate with good response to chemoradiotherapy and sensitivity to immunomodulators (Peifer M et al., Nat Genet 2012;44(10):1104-10). At MD Anderson Cancer Center, an ongoing phase I/II study of patients with extensive-stage SCLC has been proposed to the NRG as a prospective randomized study (PI J Welsh) (Figure 2). Use of thoracic radiotherapy to consolidate a site at which SCLC is quite likely to recur is reasonable, given that recurrence considerably reduces quality of their life as well as OS. In summary, in most cases SCLC presents as extensive-stage disease, for which outcomes are very poor. Consolidation with thoracic radiotherapy for patients who achieve a complete response to chemotherapy can improve 2-year OS rates. However, less toxic and more effective systemic treatment is also required to derive the greatest benefit from consolidation thoracic radiotherapy. Figure 1(Figure 1) Figure 2(Figure 2)

Abstract not provided

Abstract:
Radiation therapy (RT) has an important role in both limited stage and extensive stage (M1) small cell lung cancer (SCLC), although more recent randomized trial results have led to increasing discussion and opposing views regarding the indications and type and degree of benefit conferred. This is one such debate, in which I am arguing in favour of recommending Prophylactic Cranial Irradiation (PCI) in extensive stage (ES) SCLC. There is no disagreement about the prevalence of brain metastases (BM) in SCLC. There is strong randomized trial evidence that delivery of modest doses of RT, such as 25 Gy in 10 fractions (fr) over 2 weeks, can reduce the incidence of BM. The simplistic explanation is that RT reduces the tumor cell burden and affects the ability of cancer cells to multiply, thus delaying or preventing the progression of microscopic intracranial metastases, and reducing the likelihood, that patient will develop symptomatic metastases – thus the term “prophylactic” brain RT. A meta-analysis [1 ]of previously conducted randomized clinical trials (RCTs) in patients with limited stage (LS) or ES SCLC with response to chemotherapy demonstrated not only a reduction in symptomatic BM (from 58% to 33% at 3 yrs) but also a survival benefit (15.3% to 20.7%). A large RCT [2] in LS SCLC confirmed that 25Gy/10 fr is the optimal dose fractionation, and described the potential negative neurocognitive and quality of life (QOL) impact of PCI [3]. Other studies [4 ]provided further data to inform patients regarding the potential risks and benefits of PCI. The EORTC group conducted a RCT in ES SCLC [5], randomizing 286 patients who had a response to 4-6 cycles of chemotherapy and had no clinical evidence of BM (but who did not have brain imaging to confirm absence of radiological metastases) to PCI vs observation. Their primary endpoint was time to symptomatic BM. A range of fractionation schedules was allowed; 62% of pts were treated with 20 Gy/5fr, 22% with 30 Gy/10-12 fr and only 4% with 25Gy/10 fr. There was a large reduction in symptomatic BM, 16.8% in the PCI group vs 41.3% in the control group (p < 0.001, hazard ratio (HR) 0.27 (95% confidence intervals (CI) 0.16-0.44). Disease-free survival (DFS) was significantly longer in the PCI group (median 14.7 weeks, vs 12 weeks, p = 0.02, HR 0.76 (95% CI 0.59-0.96), as was the overall survival (OS) (median 6.7 mo vs 5.4 mo, p = 0.003). This study let to the more widespread recommendation of PCI to patients with ES SCLC who have responded to chemotherapy. Practice guidelines on management of ES SCLC include PCI in their recommendations. A more recent Japanese RCT [6] randomized patients with ES SCLC who had a response to chemotherapy and no BM on MRI, to PCI (25 Gy/10 fr) vs observation. Follow up MRIs were mandated every 3 mo initially, then q6 mo. If patients were discovered to have radiological brain progression, whole brain RT was utilized regardless of whether they were symptomatic or not. Primary endpoint was OS. The study was closed after interim analysis, as the PCI group was not going to have a superior OS; 224 patients were enrolled in all. There was a reduction in BM in the PCI group, with the cumulative incidence at 6 mo15% vs 46% in the observation arm; at 12 months there was also a difference (33% and 59% respectively). PFS was identical, and there was no significant difference in OS (11.5 mo median OS in the PCI group vs 13.7, p = 0.094, HR 1.27 (95% CI 0.96-1.68)). The study concluded that PCI doesn’t result in longer OS and is thus “not essential for patients with ES SCLC (..) and a confirmed absence of BM, if patients will be followed by periodic MRIs”. Those are indeed very fair conclusions of their data, although it is interesting that some, perhaps many, especially in the medical oncology community, after hearing the presentation at ASCO 2015, seem to have concluded that PCI may be detrimental to survival (given the small and statistically non-significantly longer survival in the observation group). Comments have been made that in the era of staging/ restaging MRIs, there may be no benefit to PCI in ES SCLC, and that perhaps the EORTC study showed improved survival because patients may have had clinically undetected gross metastatic disease (ie not just microscopic disease). That is clearly an incorrect interpretation of the Japanese data, and an assumption that has no proof in terms of the EORTC study. Every study that looked at local control ie ability of PCI to eradicate metastatic disease showed a benefit to RT, whether assessed radiologically or clinically. The incidence of BM in the control arms of the EORTC and Japanese trials was similar, suggesting that patients staged with MRIs did not have a different risk of brain disease than patients staged clinically. Even if restaging MRIs are routinely available in many parts of the world, close surveillance with regular MRIs is not routinely done for ES SCLC; it should be noted that Japan has the highest ratio of MRI to population. A very large proportion of patients in the observation arm of the Japanese study (83%) had whole brain RT for BM – no wonder there was no survival difference as it was really a comparison of early vs late RT. Finally, the risk of systemic disease in ES SCLC is high, so that a treatment that clearly has an impact in reducing brain relapse would be expected to have a relatively small OS benefit. Thus, Japanese study provides valuable data that continue to support the role of PCI in ES SCLC, and emphasize the need for a more realistic and holistic view of the expected role and benefit of RT – ie reducing BM, prolonging survival in some, and aiming to provide good neurological functioning and QOL. Rather than trying to argue against PCI as a strategy, we should continue with attempts to reduce its toxicity, such as through hippocampal sparing techniques [7 ]and to identify groups of patients who are more or less likely to benefit in terms of survival [8], [9]. References: Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 341(7):476-84, 1999. Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomized clinical trial. Lancet. 10(5):467-74, 2009. Le Pechoux C, Laplanche A, Faivre-Finne C, et al. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in intergroup phase III trail (PC I00-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Annals of Oncology 22: 1154-1163, 2011. Wolfson AH, Kyounghwa B, Ritsuko K, et al. Primary Analysis of a phase II randomized trial radiation therapy oncology group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation of chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int. J. Radiation Oncology Biol. Phys Vol 81 (1): 77-84, 2011. Slotman B, Faivre-Finn C, Kramer G, et al. EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 357(7):664-72, 2007. Takahashi T, Takeharu Y, Takashi S, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicenter, randomized, open-label, phase 3 trial. The Lancet Oncology, 18: 663-71, 2017. Gondi V, Paulus R, Bruner DW et al. Decline in tested and self-reported cognitive functioning following prophylactic cranial irradiation for lunc cancer: Pooled secondary analysis of RTOG randomized trials 0212 and 0214. Int J. Radiat Oncol Biol Phys. 86(4): 656-664, 2013. Rule WG, Foster NR, Meyers JP et al. Prophylactic cranial irradiation in elderly patients with small cell lung cancer: Findings from a North Central Cancer Treatment Group pooled analysis. Journal of Geriatric Oncology 6: 119-126, 2014. Farooqi AS, Holliday EB, Allen PK et al. Prophylactic cranial irradiation after definitive chemoradiotherapy for limited-stage small cell lung cancer: Do all patients benefit? Radiotherapy and Oncology 122: 307-312, 2017.

Abstract:
What does prophylactic cranial irradiation (PCI) prevent in ED-SCLC? - Why isn’t the presence of brain metastasis evaluated before performing PCI? Background: In a European trial, prophylactic cranial irradiation (PCI) was performed on patients with extensive-disease small cell lung cancer (ED- SCLC). As a result, PCI was reported to reduce the incidence of symptomatic brain metastasis and to prolong patient survival. However, their treatments were completely different from our routine medical care. For example, they did not perform tests to examine whether there was a metastatic brain tumor before assignment to the PCI group or observation group and, after assignment, symptoms alone were observed and no imaging test was performed. For this reason, in Japan, we corrected this inconsistency of protocol and repeated the trial to determine whether PCI contributes to prolonged survival. Participants and method: Included in the current trial were patients who underwent two or more cycles of platinum-based combination chemotherapy, had achieved at least stable disease (SD), and had no metastatic brain tumor on their MRI. They were randomly assigned to either the PCI group or observation group. Follow-up with brain, chest and abdominal diagnostic imaging tests was performed every three months in both groups. Results: In the first pre-specified interim analysis, it was found that there was no possibility of improving patient prognosis using PCI even if the trial were continued. An independent data monitoring committee therefore terminated the trial. At that time, 224 cases had already been enrolled, with 113 cases assigned to the PCI group and 111 cases to the observation group. Median survival period in the final analysis was 11.6 months for the PCI group and 13.7 months for the observation group (hazard ratio, 1.27; 95% CI, 0.96 to 1.68). There was no statistically significant difference between the groups, but PCI actually tended to make the prognosis somewhat worse or, at least, did not improve prognosis in patients with ED-SCLC.Discussion: The biggest difference between the two trials was whether follow-up assessments were conducted using symptoms or brain MRI. In the current trial, it is impossible to estimate the proportion of asymptomatic brain metastasis cases; however, in the European trial, asymptomatic brain metastasis cases were also included, which means that there were in fact two different subgroups in the PCI group: a subgroup of patients with asymptomatic brain metastasis undergoing therapeutic cranial irradiation and a subgroup of patients without brain metastasis undergoing true PCI. It seems that the survival difference between patients with asymptomatic brain metastasis in the PCI group and in the observation group caused the apparent improvement of survival period. On the other hand, it is conjectured that PCI generated a lot of toxic effects in the patients without brain metastasis and that their survival curve tended to be inferior. PCI is a treatment to prevent new brain metastasis. One year of PCI reduces the incidence of new brain metastasis in no more than 30% of cases. For patients with MRI showing no metastatic brain tumor, needless PCI can be avoided by performing regular brain imaging tests, without impairing survival.

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