Virtual Library

Background:
Visceral pleural invasion (VPI) is reported to be associated with poor prognosis in non-small cell lung cancer (NSCLC). However, whether a tumor size larger than 3cm with VPI should be upgraded to the next T stage remains unclear. In addition, few studies have clarified the impact of VPI according to nodal status, and whether degree of VPI (PL1, PL2) affects survival is controversial. The objective of this study was to evaluate the influence of VPI and also develop a prognostic nomogram.

Methods:
We retrospectively reviewed the SEER database from 2004 to 2011. Inclusion criteria were defined as: first and only primary NSCLC treated with lobectomy; staging as T1-3N0-2M0, no other non-size-based T factors except VPI. Tumors were divided into 10 groups: A, 0-2cm, non-VPI; B, 0-2cm, VPI; C, 2-3cm, non-VPI; D, 2-3cm, VPI; E, 3–5cm, non-VPI; F, 3–5cm, VPI; G, 5–7cm, non-VPI; H, 5–7cm, VPI; I, >7cm, non-VPI; J, >7cm, VPI. Kaplan-Meier overall survival (OS) curves were compared using the log-rank test. A Cox proportional hazard model was used, and identified independent prognostic factors were entered into the nomogram.

Results:
A total of 26,315 patients were finally identified, 5,941 patients (22.6%) had VPI. VPI showed an adverse impact in all tumor size groups in N0 status (p<0.001). Cox regression showed that VPI is an independent risk factor (HR 1.25; 95%CI 1.19-1.31). In N0 status, the survival rates were significantly different between B with C and D with E groups (p<0.001), whereas not significantly between F with G (p=0.405) and H with I (p=0.506). In N1 and N2 status, only the A and B groups showed a distinct survival impact (p=0.001). Between 2010 and 2011, 5,632 patients performed the elastic stain for differentiating the degrees of VPI, and survival was not significantly different between PL1 and PL2 (p=0.568). The C-index of the nomogram was 0.68. The calibration curves showed optimal agreement between nomogram prediction and actual observation of OS.Figure 1



Conclusion:
The presence of VPI, rather than the extent (PL1, PL2) has an adverse impact on NSCLC patients and N0 status. In a future TNM staging system, VPI should lead to upstaging to the next T category in current 3-7cm tumors. VPI is more aggressive in early-stage tumors, while its prognostic impact in node positive and locally invasive tumors is less significant. We further established and validated a nomogram to provide individual prediction of OS. The nomogram could be helpful for clinicians in decision making.

Background:
Our previous reports highlighting the significance of presence of micropapillary (MIP) (JNCI 2013), STAS- spread of tumor through alveolar spaces (JTO 2015), and predominant solid (SOL) (Modern Pathol 2011) histological subtype as poor prognostic markers in stage I lung adenocarcinomas (ADC) are reproduced by others. In this study, we hypothesized that presence of STAS, MIP or SOL patterns (≥5%) in small stage I lung ADC (≤2 cm) is a marker of invasion and poor prognosis, and can influence the recurrence patterns based on the type of surgical resection – lobectomy (LO) versus limited resection (LR).

Methods:
All available tumor slides from patients with therapy-naive, surgically resected small (≤ 2cm), solitary stage I lung ADC were reviewed (1995-2011; n = 909). STAS was defined as isolated tumor cells within alveolar spaces separate from the main tumor. MIP and SOL patterns were considered present in the tumor when it comprised ≥5% of the overall tumor. Cumulative incidence of recurrence (CIR; any types, locoregional or distant) was estimated using a cumulative incidence function. Differences in CIR between groups were assessed using Gray’s method.

Results:
Figure 1 The association of outcomes with the presence of STAS, MIP, or SOL patterns is shown in the table. The risk of developing any types of recurrence was significantly higher in patients with both STAS and MIP positive tumors than others (P < 0.001); and the risk of developing any types of recurrence was significantly lower in patients with both STAS and SOL negative tumors than others (P < 0.001). In the LR group, STAS, MIP and SOL patterns were independent prognostic factors for any types of recurrence (HR: 4.5, 1.4, and 1.3, respectively), locoregional recurrence (HR: 5.2, 1.3, and 1.3, respectively), and distant recurrence (HR: 3.1, 1.4, and 1.2, respectively).



Conclusion:
Tumor STAS, presence of MIP and SOL patterns are independent risk factors of recurrence especially in the LR group of small stage I lung ADC patients. Importantly, of these factors, tumor STAS was the strongest predictor of locoregional recurrence in this group. These results suggest that the identification of STAS in small lung ADC may identify LR patients who need further management, one of which may be completion lobectomy.

Background:
Recent advancements in surgical and radiotherapy techniques for early stage NSCLC have demonstrated improved outcomes in clinical trials and case series. However, their impact on large populations remains poorly studied. We therefore analyzed Department of Veterans Affairs (VA) data to evaluate temporal trends in survival within a large integrated healthcare system during the decade these techniques were introduced.

Methods:
Using VA Central Cancer Registry and vital status data, patients diagnosed with stage I-II NSCLC between 1/1/2001-12/31/2010 were identified. Patient characteristics assessed included age, race, stage, histology, Charlson comorbidity index, specific comorbid conditions, and smoking status. Descriptive and chi-square statistics were used to compare patient characteristics and outcomes.

Results:
18,442 patients were identified with stage I-II NSCLC. The primary modality of treatment was surgery in 10,754 (58%), radiotherapy in 3,708 (20%), and another or no therapy in 3,980 (22%). Patients treated with surgery were younger (median age 66 vs 72%, p<0.0001), were more likely to have a comorbidity index of 0 (28% vs 18%, p<0.0001), and were less likely to have COPD (41% vs 58%, p<0.0001), diabetes (22% vs 25%, p=0.0026), peripheral vascular disease (16% vs 20%,P<0.0001), and coronary vascular disease (9 vs 12%,p<0.0001). Surgery patients were more likely to be current (52% vs 45%, p<0.0001) and less likely to be former (39% vs 45%,p<0.0001) smokers. Equal percentages of surgery and radiation patients were black (14% vs 15%) and white (86% vs 85%). Compared to radiotherapy, surgery patients were more likely to have earlier stage disease (stage I: 79% vs 70%, p<0.0001), and adenocarcinoma (45% vs 22%, p<0.0001). The number of stage I-II NSCLC patients treated with radiotherapy or surgery increased by 50% (667 to 1,001) and 35% (1,845 to 2,496), respectively. The percentage treated each year with surgery increased from 56% in 2001 to a peak of 61% in 2004-2005, decreasing back to 56% in 2010. Inversely, the percentage treated each year with radiation decreased from 21% in 2001, to 17% in 2005 and increased to 24% in 2010. The use of other/no therapy remained unchanged. The Southern region comprised almost half of all treated lung cancer diagnoses (46%), followed by the Midwest (21%), the West (17%), and the Northeastern Region (14%). Between 2001-2010, the number of patients receiving therapy (radiation or surgery) increased each year (p=0.0017). The 4-year survival rate was 54% for surgery patients and 19% for radiotherapy patients (p<0.0001), which varied based on stage (stage I: 58% vs 22%; stage II: 41% vs 13%, respectively). Between 2001-2010, patients treated with either surgery or radiotherapy had a 12% absolute improvement in 4 year OS, representing a 100% survival improvement with radiotherapy (12% to 24%) and a 24% improvement with surgery (49% to 61%).

Conclusion:
The Department of Veterans Affairs is treating increasing numbers of patients with stage I-II NSCLC. Following a decade when advanced technologies were introduced for surgery and radiotherapy, survival rates have improved significantly for both treatment modalities. The largest gains were observed among patients treated with radiotherapy with a doubling of 4-year survival.

Background:
Institution-driven survival disparities persist among non-small cell lung cancer (NSCLC) patients who receive curative-intent surgical resection. Recently, the Commission on Cancer (CoC) established an institutional quality surveillance measure: the proportion of resected stage IA–IIB NSCLC with examination of ≥10 lymph nodes. We examined the potential impact of this measure on long-term patient survival.

Methods:
We analyzed all stage IA-IIB NSCLC resections in the Mid-South Quality of Surgical Resection cohort, a patient-level database of all lung cancer resections performed in 11 institutions in 5 Dartmouth Hospital Referral Regions in Eastern Arkansas, Northern Mississippi, and Western Tennessee from 2004-2013. We recorded pathologic staging details. Patients receiving pre-operative therapy were excluded. A trend analysis of quality and survival disparities was performed based on a Cox proportional hazard model, adjusted for age and pathologic stage.

Results:
Of 1,877 eligible patients, 77% were stage I and 23% stage II. The median number of lymph nodes retrieved during surgery was 6 (interquartile range [IQR]: 3-10). The CoC quality measure was achieved in 27.8% of cases. Conversely, 11% of resections had no lymph nodes examined (pNX). The proportion of cases meeting the CoC criteria increased from 18.8% in 2004 to 50% in 2013 (p<0.001). Large variations among institutions existed, ranging from 14% to 55% of institutional cases meeting the CoC measure. Compared to pNX resections, resections with at least one lymph node examined yielded some survival benefit (Hazard ratio (HR): 0.71, 95%CI: 0.54-0.93, p=0.014). Likewise, Patients with 10-12 lymph nodes examined had 43% overall survival benefit (HR: 0.57, 95%CI: 0.40-0.81, p=0.002), but survival did not significantly improve compared with 4-6 (the median) lymph nodes harvested (p=0.48). However, the survival benefit improved as more lymph nodes were examined, reaching an optimal point of a 72% benefit when 19-21 lymph nodes were harvested (HR: 0.28, 95%CI: 0.11-0.68, p=0.005). Compared with 4-6 lymph nodes, the survival benefit was 17% (p=0.06) (Figure 1). Furthermore, for those with any mediastinal lymph nodes sampled during the surgery, the survival benefit was 17% (HR: 0.82, 95%CI: 0.71-0.96, p=0.015). Figure 1



Conclusion:
Only 28% of NSCLC resections achieved the CoC measure, with large variations among institutions, but the overall rate of attainment has increased over time. Compared with no lymph nodes examined, meeting the CoC criteria provided a 43% overall survival benefit. However, more stringent measures, such as examining 20 lymph nodes (72%) or requiring mediastinal lymph node examination (17%), will have even greater survival impact.

Abstract not provided

Background:
Lower rates of surgical resection for early-stage lung cancer among blacks compared to whites are well-documented and have persisted for decades. It is suggested that the survival disparity is largely due to lower rates of surgery among blacks and that equivalent outcomes are possible for blacks and whites with similar treatment. The objectives of this work were to utilize a decade of data to evaluate trends in receipt of treatment among blacks and whites and examine the impact of race on survival outcomes.

Methods:
We used data from a national cohort of patients in the Veterans Administration diagnosed with Stage I-II non-small cell lung cancer (NSCLC) between 2001 and 2010. Chi-square statistics were used to compare treatment and outcomes by race. Cox proportional hazards models estimated hazard ratios (HR) with 95% confidence intervals (95%CI).

Results:
Among 18,442 patients with stage I-II NSCLC, the proportion of blacks and whites receiving surgery was 54% and 59% (p ≤ 0.0001), respectively. The black-white difference in surgery rates was 8% in 2001 and 1% in 2010. There was no racial difference in receipt of nonsurgical therapy; however, blacks were more likely than whites to have no treatment (22% vs. 18%, p ≤ 0.0001). Among surgical patients, type of surgical resection was similar by race, the 30-day mortality rate was 2% in both race groups, but 90-day mortality was significantly higher in whites than blacks (6% vs. 3%, p=0.0008). Also, 31% of blacks were diagnosed at the time of surgery compared to 27% of whites (p<0.0001). There was no racial difference in type of nonsurgical treatment, with 86% of all patients who did not have surgery receiving radiation therapy. Among all patients, the 4-year survival rate was 40% in blacks and 39% in whites (p=0.38), and the adjusted HR for blacks compared to whites was 0.91 (95%CI 0.84-0.98) among all patients. Corresponding HRs and 95% CI among patients receiving surgical treatment, nonsurgical treatment, or no treatment were 0.90 (0.83-0.97), 0.83 (0.76-0.91), and 0.91 (0.82-0.996), respectively.

Conclusion:
The racial disparity in receipt of surgery for early-stage lung cancer decreased between 2001 and 2010, with similar rates observed at the end of the study period. Previously reported racial differences in survival outcomes were not observed in this cohort. Despite overall lower surgery rates among blacks, the proportion of black and white patients surviving 4 years was similar although overall survival was slightly better among blacks, and this finding was consistent among patients with and without treatment.

Background:
Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare and distinct type of primary lung cancer which is characterized by Epstein-Barr virus (EBV) infection. The prognostic significance of programmed cell death ligand 1 (PD-L1) in pulmonary LELC remains poorly understood.

Methods:
A total of 113 surgically resected pulmonary LELC in Sun Yat-sen University Cancer Center between January 2008 and December 2012 were included. Paraffin-embedded tumor sections were stained with PD-L1 antibody. H score were calculated by multiplying the percentage of positively stained cells by an intensity score. Tumors with >5% PD-L1 expression were deemed PD-L1 positive. The mRNA level of latent membrane protein 1 (LMP1) were determined by RT-PCR. Univariate and multivariate analyses were performed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS).

Results:
The positive rate of PD-L1 was 74.3%. Patients with PD-L1 (+) tumor were significantly younger than those with PD-L1 (-) (median age, 50 vs 58 years; p = 0.008). High PD-L1 expression (H-score > 30) was associated with impaired DFS (median: 33.8 months vs not reached; p = 0.008) compared with low PD-L1 expression (Figure 1). Multivariate analysis shows that PD-L1 expression level (p = 0.014), N stage (p = 0.039) and M stage (p= 0.024) were independent prognostic factors for DFS. N stage and M stage but not PD-L1 expression level were significantly associated with OS (Figure 2). Also, LMP1 mRNA level was significantly associated with PD-L1 expression level (p < 0.001).Figure 1Figure 2





Conclusion:
Our results reveal higher incidence of PD-L1 expression in pulmonary LELC than common lung cancer, which may be linked to EBV burden. PD-L1 was a negative prognostic factor for DFS but was not associated with OS in surgically resected pulmonary LELC. These findings may provide a rationale for immunotarget therapy in this virus-associated lung cancer.

Background:
Radiologically characteristic ground-glass opacity (GGO) represents a special cohort of pulmonary adenocarcinomas that has been unanimously defined as biologically inert. Lymph node metastasis, however, occurs occasionally in these biologically "indolent" cancers. The incidence and underlying risk factors of nodal metastasis remain unknown.

Methods:
All surgically removed GGO lesions between Jan. 2008 and Dec. 2014 were reviewed from a single treatment institution. Pathologically-confirmed adenocarcinomas with systemic lymph node dissection or sampling were enrolled into the present study. All the lesions were classified into three groups according to the proportion of solid densities: Group I, pure GGO; Group II, 1% to 50%; and Group III, 50% to 100%. Risk factors analysis of lymph node involvement was performed by multivariate logistic regression.

Results:
Of the 867 patients eligible for this study, there were 566 (65.3%) females and 301 (34.7 %) males. 553 (63.7%) presented as pure GGOs (Group I) and 314 (36.2%) were mixed GGOs, of which 160 (18.5%) were in Group II and 154 (17.8%) group III. Lymph node metastasis was confirmed in 25 patients, including 12 pN1 and 13 pN2 cases. Among these 25 cases, 11 were Group II and 14 were Group III; 13 (13/367) had1-2cm tumors and 12 (12/136) had 2-3cm tumors, which also showed a significant statistical difference (p=0.016). Two of the 25 patients were deceased from lung cancer metastases at postoperative 23rd and 36thmonths, respectively. Statistical analysis revealed three predictors for lymph nodal metastasis: tumor size, preoperative serum carcinoembryonic antigen level, and proportion of the mix density. The ROC curves show cutoff values at 1.1cm, 2.75ng/ml and 21%, respectively.Figure 1

Table1. Independent predictors of lymph node involvement by multivariate analysis

Variables	Odds Ratio	95%CI	P
Tumor size	2.544	1.271-5.092	0.008
GGO status(Ratio)	3.272	1.759-6.089	<0.001
CEA level	9.672	3.805-24.584	<0.001

Conclusion:
Among the majority of "indolent" GGO lesions, lymph node metastasis occurs occasionally at 2.9%. A larger size, mixed GGOs with a higher proportion of solid component, and elevated serum CEA level were associated with a higher preference for nodal metastasis.

Background:
Previously, aerogeneous spread with floating cancer cell clusters (ASFC) was a prognostic factor and significantly related with local recurrence of the surgical margin after metastatic lung tumor (Shiono, Ann Thorac Surg 2005). However, ASFC in surgically resected lung cancer has not been investigated well. Since our institute examined ASFC in resected lung cancer specimens prospectively, we assessed the prognostic impact of ASFC and local recurrence in stage I lung adenocarcinoma cases.

Methods:
From July 2004 to November 2014, a total of 877 lung cancer patients underwent a surgery. Among them, 318 patients with pathological stage I adenocarcinoma cases were reviewed. We investigated the characteristics of ASFC and analyzed the relationship between ASFC and prognosis. The patients who received preoperative treatment or had multiple lung cancers were excluded.

Results:
Median follow-up time was 28 months. Of the 318 patients, 47 (14.8%) patients had ASFC. The local recurrence rate was 11 of 47 (23.4%) cases with ASFC and 10 of 271 (3.7%) cases without (p < 0.01). All 4 cases developing surgical stump recurrence had an ASFC. In patients with ASFC, the ratio of male, smoker, EGFR mutation negative, lymphovascular and pleural invasion were significantly high (p < 0.01). Standardized uptake value (SUV) (p < 0.01) was also significantly higher in ASFC positive cases. Surgical procedure did not influence development of ASFC. Multivariate analysis revealed that the ASFC were significantly related with EGFR negative mutation and lymphovascular invasion. As preoperative predictive factors for ASFC, SUV was a significant predictive factor (p = 0.01). Univariate analysis showed that overall 5-year survival of cases with ASFC was 62.7% and without was 91.1% (p < 0.01) and recurrence free 5-year survival of cases with ASFC was 54.4% and without 87.8% (p < 0.01). Multivariate analysis showed that age, pleural invasion and ASFC were significant prognostic factors for overall survival, and that these factors were significantly related to cancer recurrence after surgery.Figure 1



Conclusion:
In p-stage-I lung adenocarcinoma patients, ASFC was frequently found in invasive lung adenocarcinoma cases. Therefore, characteristics of these lung cancers may develop a poor prognosis. PET scan might have effective radiological examinations to find a lung adenocarcinoma with ASFC.

Abstract not provided

Background:
Population studies suggest that high body mass index (BMI) correlates with a reduced risk of death from lung cancer. The aim of our study was to evaluate the influence of BMI on long term overall survival (OS) in surgical patients with non-small cell lung cancer (NSCLC).

Methods:
Study population consisted of 1935 patients who underwent surgical resection for lung cancer at MD Anderson Cancer Center between 2000-2014. Patients with perioperative mortality, 90-day mortality, intraoperative transfusion, postoperative ICU days, postoperative pneumonia, and postoperative transfusion were excluded. Study variables included both patient and treatment related characteristics. Univariable and multivariable Cox regression analyses were performed to identify variables associated with overall survival. Propensity matching was performed to compare patients with BMI <25 and BMI≥30 matching on type of surgery, age, gender, histology, and pathological stage.

Results:
On univariable analysis, significant predictors of improved survival were higher BMI, pathologic tumor stage (stage I vs II, III, or IV), type of surgery (lobectomy/pneumonectomy vs wedge resection/segmentectomy), younger age, female gender, and adenocarcinoma histology (vs squamous) (all p<0.05). Patients considered morbidly obese (BMI≥35) had a trend towards better outcomes than those classified as obese (BMI ≥30 and <35), overweight (BMI ≥25 and <30), or healthy weight (BMI<25) (HR 0.727, 0.848, 0.926, and 1, respectively, p=NS). On multivariate analysis, BMI remained an independent predictor of survival (p=0.02, see Table). Propensity matching analysis demonstrated significantly better OS (p=0.008) in patients with BMI≥30 compared to BMI <25 (Figure).

Multivariate Cox Regression Model

		N (%)	Overall Survival HR (95% CI)
BMI	<25 (Reference) ≥25	646 (33.4%) 1289 (66.7%)	1.000 0.833(0.713-0.975)
Age	Continuous variable	Median 66 (13-88)	1.024 (1.015-1.032)
Gender	Female (Reference) Male	984 (50.9%) 951 (49.1%)	1.000 1.236 (1.061-1.441)
Stage	I (Reference) II III IV	1149 (59.4%) 431 (22.3%) 299 (15.5%) 56 (2.9%)	1.000 1.839 (1.570-2.271) 2.653 (2.182-3.225) 2.737 (1.934-3.873)
Surgery	Wedge/Segmentectomy (Reference) Lobectomy/Pneumonectomy	198 (10.2%) 1737 (89.8%)	1.000 0.602 (0.479-0.755)
Pre-op therapy	No (Reference) Yes	1604 (82.9%) 331 (17.2%)	1.000 1.399 (1.160-1.686)
Histology	Adenocarcinoma (Reference) Squamous Other	1252 (64.7%) 472 (24.4%) 211 (10.9%)	1.000 1.225 (1.035-1.451) 0.959 (0.747-1.231)

Figure 1



Conclusion:
In a large, single center series, after controlling for disease stage and other variables, higher BMI was associated with improved OS following surgical resection of NSCLC. Further studies are necessary to define the complex relationship between BMI and treatment outcomes.

Background:
The extent of lymph nodes (LN) involvement and the adequacy of systematic LN sampling are significantly correlated with the prognosis of cancer patients. The index combing these two factors, cancer-involved LN ratio (LNR), has been proved a strong prognostic factor by extensive previous studies, including non-small cell lung cancer (NSCLC). However, intrapulmonary or mediastinal LNs associate with different examination strategy. It might not be appropriate to apply the LNR indistinguishably to all patients. Therefore, we sought to examine the performance of LNR separately.

Methods:
A consecutive cohort of patients who underwent radical resection with systematic lymph node sampling for NSCLC between Sep 2009 and Dec 2011 were collected. LNR for intrapulmonary and hilar LNs was recorded as LNR1, and LNR for mediastinal LNs was recorded as LNR2. LNR was incorporated in the Cox regression model as a continuous variable. Disease free survival (DFS) was the primary endpoint.

Results:
A total of 681 cases were included for analysis. Overall LNR was a significant prognostic factor in overall population (HR 11.75, 95% CI 6.99 to 19.75; P<0.001). For patients with ‘N2’ disease, overall LNR remained a prognostic factor (HR 3.07, 95% CI 1.22 to 7.74; P=0.02). However, further explorations revealed that LNR2 has prognostic impact (HR 3.59, 95% CI 1.68 to 7.67; P<0.01) but not LNR1 (HR 0.99, 95% CI 0.48 to 2.06; P= 0.99). For those with ‘N1’ disease, LNR1 was not a significant prognostic factor (HR 3.19, 95% CI 0.87 to 11.66; P=0.08) but the prognostic value of overall LNR is strong (HR 36.17, 95% CI 6.23 to 210.13; P<0.01).

Conclusion:
This study suggests that for pathological ‘N1’ NSCLC, overall LNR should be considered a prognostic value while for ‘N2’ disease, only medialstinal LNR should be included in prognostic stratification.

Background:
Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The prognosis of MLCs is not known. Herein, we evaluate the prognosis of patients with MLCs, one resected LC, and recurrent LC, to ascertain whether patients with MLCs have a distinct natural history compared to the other two groups.

Methods:
After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria and comprehensive pathologic assessment. Clinicopathologic data was collected. We used the Kaplan-Meier method and log-rank test to assess overall survival (OS) of patients with MLCs, one LC, or recurrent LC, from the time of surgery/pathologic confirmation of their MLC, one LC, or recurrent LC, respectively.

Results:
2352 patients were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113).Median OS and 2-year OS for patients in these subgroups stratified by stage, is depicted in Table 1. In patients with one LC, never smokers (p<0.001), adenocarcinoma histology (p<0.001), and surgery type (p<0.001) were associated with improved OS. In patients with recurrent LC, never smokers (p=0.015), and adenocarcinoma histology (p=0.009) were associated with favorable OS, compared to smokers and squamous histology respectively. In patients with MLCs, adenocarcinoma histology was associated with improved OS when compared to squamous histology (p=0.049).

	Pathologic Stage (n)	Median Overall Survival (months, 95% CI)	Two-Year Overall Survival	p value
One Lung Cancer (n=2238)	All	Not Reached (75.2-NA)		0<0.001
	IA		0.914
	IB		0.841
	IIA		0.789
	IIB		0.755
	IIIA		0.691
Multiple Lung Cancers(n=113)	All	55.5 (49.4-NA)		0.32
	IA		0.810
	IB		0.806
	II/III		0.830
Recurrent Lung Cancer (n=348)	All	10.4 (9.1-12.3)		0.077
	IA		0.263
	IB		0.180
	IIA		0.273
	IIB		0.351
	IIA		0.083

Conclusion:
Martini-Melamed criteria and comprehensive pathologic assessments successfully identify patients with MLCs. Prognostic data for patients with MLCs, one LC and recurrent LC, highlight that these patients have a long natural history. MLCs have a long survival stage for stage, which underscores a definitive therapeutic approach where possible, based on favorable prognosis of these patients.

Background:
Lung cancer is an important cause of cancer mortality. Mutations of the EGFR gene may cause deranged activation leading to cell proliferation and the inhibition of apoptosis and metastases. Screening for EGFR mutation plays a key role for managements of lung cancer cases. The aim of our study is to determine a possible relationship between EGFR gene mutations in exon 19,20,21, along with serum EGFR levels and non small cell lung cancer.

Methods:
A total of 35 patients; 29 (%82.9) male and 6 (%17.1) female with non small cell lung cancer who underwent surgical resection between February 2011 and July 2013 were analyzed.Mean age of the patients was 60.1(41-79) Mediastinoscopy was performed to all patients prior to the resection. Lobectomy, pneumonectomy and bilobectomy were performed to 30(%85.7), 4(%11.4) and 1 (%2.9) patients respectively. The most common tumour histopathology was adenocarcinoma(%55.6). EGFR gene mutations were analyzed for exon 19,20 and 21 by direct sequencing. In addition, serum EGFR levels were determined by ELISA in non small cell lung cancer patients and control group

Results:
Exon 19,20 and 21 aminoacid substitutions that could cause significant mutations were detected.At exon 19,20 and 21, totally 17 mutations were detected in 10 different regions.One of these mutations were (2237-MT) E746- T751>V, E746-T751VA, E746-S752>V on exon 19. In one sample 5 different regions of exon 20 mutations were detected. On exon 21 two mutations that cause aminoacid changes were detected which includes Leu 861 Gln ve Leu 861 Arg. In our study there was no significant difference in survival rates between the cases who have EGFR mutations or who have not(p=0.21). Serum EGFR average levels of non small cell lung cancer patients and healthy control groups were calculated respectively as, 341,49±125,41 pg/ml ve 574,9±125,96 pg/ml and the difference was found statistically significant (p<0,001). According to the EGFR levels survival rate at 3 years was %45 and mean survival time is 19 (%95 confidence interval :14-29 months)and 23 (%95 confidence interval 18-29 months)month in patients with serum EGFR levels higher and lower than 400 pg/ml respectively. The patients with high serum EGFR levels (>400 pg/ml) have better survival time than the ones who had low serum EGFR levels (p=0.04).

Conclusion:
EGFR mutation did not lead to survival difference in resected patients with lung adenocarcinoma.. However, survival of patients with higher serum EGFR levels seems better. The modus operandi of this effect and validation of the data need further studies.

Abstract not provided

Background:
Stage III NSCLC has large variations in primary and nodal metastatic tumor burden and its treatment is controversial.We determined the benefit to overall survival (OS) of these patients from surgery, and potentially complementary role of FDG-PET/CT-based metabolic tumor volume of primary tumor (MTV~T~), nodal metastasis (MTV~N~), and whole-body (MTV~WB~) in selecting patients for surgery.

Methods:
With IRB approval, we retrospectively reviewed 239 stage III NSCLC cases with pre-therapy FDG-PET/CT scans treated 2004 – 2013 (141 IIIA and 98 IIIB, 115 men and 124 women, median age 67.2 years), and measured MTV~T~,MTV~N~, and MTV~WB~. Kaplan-Meier curves and log-rank test were used for determining survival differences between surgically and non-surgically treated patients. Multivariate Cox regression analyses were conducted. Logistic regression analysis was used to evaluate whether each covariate was associated with receiving surgery(including surgery alone and surgery in combination with chemo or radiation). Wilcoxon rank-sum tests were performed for determining differences of primary, nodal, and whole-body MTV between the groups.

Results:
30% (42/141) of IIIA patients and 10% (10/98) of IIIB patients had surgical treatment (p<0.001, Chi-square test). OS was different between surgically and non-surgically treated patients (p<0.001) at 1 year(86% vs. 54%), 2 years(64% vs. 32%), 3 years(52% vs. 21%), and 5 years(39% vs. 14%), with median survival of 37.3 months vs.13.6 months, respectively. Covariates associated with OS were: surgery (0.43 ≤ HR ≤ 0.46, p≤0.001), log~10~MTV~T~ (HR=1.54, p<0.001), log~10~MTV~N~ (HR=1.63, p<0.001), and log~10~MTV~WB~ (HR=2.06, p<0.001) (Figure 1). Log~10~MTV~T~, Log~10~MTV~N~, and Log~10~MTV~WB ~were inversely associated with receiving surgery, with odds ratio of 0.53(p=0.01), 0.55(p=0.036), and 0.38 (p=0.002), respectively. MTV~T~, MTV~N~, and MTV~WB~ were smaller in surgically treated patients, with median of surgically vs. non-surgically treated patients of 17.8 vs. 55.0, 5.3 vs. 15.1, and 27.8 vs. 92.0 cc, respectively (p≤0.004). Additionally, those with stage IIIB disease were significantly less likely to receive surgery after controlling for age, gender, and MTV. No statistically significant interactions were found between surgery and stage or between surgery and log~10~MTV~T~, log~10~ MTV~N~, or log~10~MTV~WB~.Figure 1



Conclusion:
Surgery and smaller MTV are associated with better OS of stage-III NSCLC patients. Smaller MTV and stage IIIA (vs. IIIB) are associated with receiving surgery. FDG PET/CT-based metabolic tumor volume can potentially inform surgical treatment decisions to further improve survival outcome.

Background:
Recent developments of radiological examinations have been able to bring more accurate information about the biological malignancy of primary tumors in non-small cell lung cancer (NSCLC). The aim of this study is to elucidate the optimal candidate of lobe-specific selective lymph node dissection (LND) that reduces the extent of mediastinal LND according to clinical information including radiological evaluation of primary tumor on thin-section computed tomography (TSCT) and tumor location in clinical(c)-stage I NSCLC patients.

Methods:
Eight hundred and seventy-six patients with c-stage I NSCLC (adenocarcinoma and squamous cell carcinoma), who underwent complete surgical resection between January 2003 and December 2009 were included in this study. For all tumors, we obtained the maximum dimension of the tumor (tumor) and solid component (consolidation) using a lung window level setting from the TSCT scan images, and estimated the consolidation-to-tumor ratio (C/T ratio) for each tumor. We elucidated the lymph node metastatic incidence and distribution according to the primary tumor lobe location and extracted the associated clinicopathological factors with mediastinal lymph node involvement.

Results:
The patients included 490 men and 386 women, with a median age of 66 years old. The radiological findings were ground glass opacity (GGO)-predominant (C/T ratio ≤ 0.5) in 134 patients and solid-predominant (C/T ratio > 0.5) in 742 patients. There were 744 adenocarcinoma cases and 132 squamous cell carcinoma cases, and the incidences of mediastinal lymph node metastasis were 9.9% in adenocarcinoma cases and 4.5% in squamous cell carcinoma cases, respectively. There were no cases with hilar and mediastinal lymph node metastasis in GGO-predominant tumors. There was no significant association of clinical factors with subcarinal lymph node metastasis in right upper-lobe and left upper-division lung adenocarcinoma. In 257 bilateral lower-lobe lung adenocarcinomas, a total of 32 cases (12.5%) were positive for mediastinal lymph node metastasis, and seven cases (2.7%) were negative for subcarinal lymph node metastasis but positive for upper mediastinal lymph node metastasis (mediastinal skip metastasis). An elevated preoperative serum carcinoembryonic antigen (CEA) level (p < 0.001) showed only a significant association with upper mediastinal lymph node metastasis in the patients with bilateral lower-lobe primary lung adenocarcinoma.

Conclusion:
It would be acceptable to perform selective LND in patients with c-stage I NSCLC with GGO-predominant tumor. Elevated serum CEA was associated with upper mediastinal lymph node involvement in lower-lobe primary lung adenocarcinoma with radiologically solid-predominant tumor. We should be careful when applying selective LND to patients with solid-predominant tumor, especially located in the lower lobe.

Background:
Mediastinal lymph node evaluation in Non Small-Cell Lung Cancers (NSCLC) is of paramount importance for optimum planning of treatment. Recently, it was claimed that subcarinal lymph node dissection could be spared in upper lobe NSCLC resections because of the low incidence of metastatic disease. These data, however, were single institution reports. We used complete national data to investigate patterns of unsuspected mediastinal lymph node involvement in patients operated for NSCLC.

Methods:
A national registry was used to identify every single patient operated for NSCLC during an 11-year period (2003-2013). Unsuspected mediastinal lymph node involvement was investigated by comparison of clinical and final pathological nodal stage, and patients with clinical mediastinal lymph node metastases were excluded. For every patient we extracted information about tumor location, histopathology, clinical and pathological TNM-stage. All preoperative imaging and staging investigations were recorded.

Results:
An unsuspected mediastinal lymph node metastasis was found in 426 patients (9.8%) of 3953 patients and 167 (4.4%) had unsuspected subcarinal metastases, which were significantly more frequent in patients with lower lobe or middle lobe cancers compared with upper lobe cancers 7 % (101/1440) versus 1.8% (42/2258), (p<0.01). Preoperative invasive mediastinal staging was used in 57% (n=2253) of all patients and significantly more frequent in upper lobe cancers (62% (n=1400), p<0.01), in patients who had unsuspected mediastinal lymph node metastasis (75% (n=320), p< 0.01) and in patients with subcarinal metastases (74% (n=124), p< 0.01).

Location of the tumor	All patients	Patients with N2 disease	Metastasis in station 7
RUL	1254	121	28 (2.2 %)
LUL	1004	116	14 (1.4 %)
RLL	672	78	52 (7.7 %)
LLL	585	62	36 (6.2 %)
Middle lobe	183	16	13 (7.1 %)
Bilobectomy	255	33	24 (9.4 %)
Total	3953	426	167

Conclusion:
A substantial number of patients undergoing surgery for NSCLC have unsuspected subcarinal mediastinal lymph node involvement despite 74% had preoperative invasive mediastinal staging. Unsuspected subcarinal metastases were most common in lower and middle lobe cancers but were also frequent in upper lobe NSCLC. Subcarinal lymph node dissection should therefore be a routine part of surgery for NSCLC - regardless of tumor location to avoid undiagnosed subcarinal lymph node metastasis.

Background:
Intra-operative lymph node sampling during lung cancer resection is a key surgical performance measure. It informs prognosis, treatment selection for adjuvant chemotherapy and surveillance programs following treatment. This study aimed to analyse the relationship between adequacy of intra-operative lymph node sampling and survival at a large thoracic oncology centre in the United Kingdom.

Methods:
A retrospective review of pathological reports for all patients undergoing lung cancer resections at the University Hospital South Manchester from 01/01/2011 to 31/12/2013 was undertaken. Intra-operative lymph node sampling was assessed for adequacy against standards set out by the IASLC Staging Manual in Thoracic Oncology. Survival data was obtained through national death registry data and provided a minimum of twelve months follow-up for all patients at the time of analysis in January 2015.

Results:
A total of 987 patients underwent surgical resection for NSCLC in the study period. Overall, there was no significant difference in survival between patients with adequate intra-operative lymph nodal sampling and those with inadequate sampling (log rank p=0.66). Median survival times were not estimable for pN0 and pN1 patients as only a small proportion died. However there was a significant difference in the median survival time of pN2 patients according to whether the intra-operative lymph node sampling was adequate or inadequate (Figure 1). Figure 1Figure 2





Conclusion:
Few patients have died in the pN0 and pN1 categories limiting interpretation. As the data matures we expect to see a survival difference according to adequacy of intra-operative nodal sampling that is supported by the differential median survival data of pN2 patients according to nodal adequacy. The data supports that the survival difference is due to inaccurate staging, inadequate resection (R1) and inappropriate omission of adjuvant.

Abstract not provided

Background:
Currently adjuvant chemotherapy is not recommended for patients with completely resected stage I lung cancer. The ability to sub-stratify survival within stage I is an important consideration as it is assumed that survival is heterogeneous within this sub-group. Liang et al recently published a Chinese multi-institutional logistic regression derived model to predict post-operative survival in over 5000 patients undergoing lung cancer surgery for all stages. The aim of our study is external validation of their published nomogram in a British cohort focusing on stages IA and IB to determine applicability in selection of adjuvant chemotherapy within stage I.

Methods:
We retrospectively analysed data from a prospectively collected database from our institutions. Patient variables were extracted and the score individually calculated. Receiver operative characteristics curve (ROC) was calculated and compared with the original derivation cohort and the discriminatory ability was further quantified using survival plots by splitting our (external) validation cohort into three tertiles and Kaplan Meier plots were constructed and individual curves tested using Cox regression analysis on Stata 13 and R 3.1.2 respectively.

Results:
From April 2007 to February 2015 a total of 1442 patients underwent surgery for primary lung cancer at our institution. We excluded 118 patients with carcinoid tumours (not in the original Chinese development set) and 86 patients without complete lymph node assessment leaving 1238 patients for validation. For all patients from stage IA to IIB the mean (SD) score was 9.95 (4.2). The ROC score comparing patients who died versus those that remained alive was 0.62 (95% CI 0.58 to 0.67). This was lower than the 0.71 reported by the Chinese group when split into 1,3 and 5 year survival. When divided into prognostic score tertiles, survival discrimination remained evident for the entire cohort, as well as those for stage IA and IB alone. The P value comparing survival between the middle and highest score with baseline (low score) was P=0.031 and P=0.034 respectively. Figure 1. Survival discrimination within Stage I Figure 1



Conclusion:
Our results of external validation suggested lower survival discrimination than reported by the original group, however discrimination between survival remained evident for stage I.

Background:
Video-assisted thoracoscopic wedge resection of multiple small, non-visible, and nonpalpable pulmonary nodules is a clinical challenge. We propose an indocyanine green (ICG) injection and intraoperative fluorescence detection with a near-infrared (NIR) fluorescence for localization of small sized pulmonary nodules.

Methods:
Fluorescence properties of ICG topically injected into the lung parenchyma were determined using a resected porcine lung and previously reported by the authors. In clinical study, 15 cases of VATS pulmonary resection for small sized pulmonary nodules were enrolled in the study. The ICG mixed with iopamidol was injected into the pulmonary nodules by CT-guided percutaneous injection. ICG fluorescence was visualized by a near-infrared (NIR) thoracoscope, then the target nodule was excised by VATS procedure.

Results:
Topically injected ICG / iopamidol mixture spot remained at the injected point of the lung parenchyma for more than 6 hours in each case, and each ICG fluorescence was identified at the pulmonary nodule with the NIR thoracoscope. Each target nodule was successfully removed with negative surgical margin.

Conclusion:
CT guided ICG injection and intraoperative NIR thoracoscopic detection is a feasible method to localize small sized pulmonary nodules.

Background:
Current British Thoracic Society (BTS) guidelines advocate the use of a global risk prediction score such as Thoracoscore to estimate the risk of death prior to radical surgical management in those with non-small cell lung cancer (NSCLC). A recent publication by Powell et al(1) used the National Lung Cancer Audit (NLCA) linked to Hospital Episode Statistics (HES) to produce a score to predict 90 day mortality. The aim of this study is to validate this score, henceforth called the NLCA score, and compare its performance with Thoracoscore.

Methods:
We identified data on all patients in the NLCA who received curative surgery for NSCLC between 2010 and 2012. We calculated the proportion that died in hospital and within 90 days of surgery. Each person was given a score based on the coefficients and constants in the NLCA score and Thoracoscore. The discriminatory power of both scores was assessed by a receiver operating characteristic (ROC) and an area under the curve (AUC) calculation.

Results:
We identified 2858 patients for whom we had complete data to form our validation cohort. The 90 day mortality was 5%. We generated ROC curves to assess the discrimination of the NLCA score in predicting 90 day mortality and to test the ability of Thoracoscore to predict in-hospital mortality. Area under the ROC curve was 0.68 and 0.60 respectively. We performed a post hoc analysis using data from the NLCA on all 15554 patients who underwent curative surgery for NSCLC between 2004 and 2012 to derive summary tables for 90 day mortality, stratified by procedure type, age and performance status (table 1).

Conclusion:
These results suggest that although the NLCA score performs slightly better than Thoracoscore neither performs well enough to be advocated for routine use to risk stratify patients prior to lung cancer surgery. It may be that the addition of physiological parameters to demographic and procedural data or use of physiological measurements alone would better predict mortality; however this would form the basis of a further project. In the interim we advocate the use of our summary tables that serve to provide clinicians and patients the real-life range of mortality according to performance status and age for both lobectomy and pneumonectomy. 1. Powell HA, Tata LJ, Baldwin DR, Stanley RA, Khakwani A, Hubbard RB. Early mortality after surgical resection for lung cancer: an analysis of the English National Lung cancer audit. Thorax. 2013;68(9):826-34. Figure 1

Background:
ENB is limited by diagnostic accuracy of 60-80%[ [1]]. We hypothesize that using intraoperative CBCT with real time 3D overlay onto fluoroscopic images to confirm placement of biopsy tools in the lesion will increase the diagnostic accuracy of ENB biopsies. [1] Wang Memoli JS, Nietert PJ, Silvestri GA. Meta-Analysis of Guided Bronchoscopy for the Evaluation of the Pulmonary Nodule. Chest. 2012;142(2):385-393. doi:10.1378/chest.11-1764

Methods:
Patients with undiagnosed small pulmonary nodules (<20 mm) underwent biopsy where an initial CBCT of the chest under breath hold was performed, followed by a 3D model reconstruction of the lesions while the surgeon started the ENB. At the end of the bronchoscope navigation, the 3D model of the lesion was fused and automatically registered in real time over the 2D fluoroscopy, allowing an evaluation of the biopsy tool positioning in 3-dimensions. Multiple samples were collected after confirmation of the tool position using various oblique views. Figure 1



Results:
In our initial experience with 10 cases, CBCT acquisition, reconstruction and 3D-overlay was successful in all cases. This procedure enabled confirmation of biopsy tool position within the target lesion in all cases. In one case, the new information obtained successfully discriminated a diaphragm implant from what previously had been interpreted as a basilar parenchymal nodule. In a second case, CBCT reconstruction enabled biopsy of a 15mm lesion thought to be a solitary metastasis. The biopsy was interpreted as normal, albeit in clinical circumstances which were suspicious for malignancy. The patient elected non-surgical treatment of an esophageal primary, precluding definitive pathologic confirmation. A third case provided a biopsy interpreted as normal in a patient who ultimately proceeded to resection for growth of the nodule. While frozen section suggested a benign entity, final pathology demonstrated scattered elements of malignancy. In the remaining cases, CBCT and 3D overlay assisted in successful and accurate biopsy of nodules <20mm.

Conclusion:
Intraoperative CBCT and real time 3D overlay onto fluoroscopic images to confirm appropriate positioning of the biopsy tools in the lesion during ENB is technically feasible. It effectively combines the advantage of real time CT imaging with the advantages of ENB biopsy. This has the potential to increase the diagnostic accuracy of ENB aided tissue diagnosis of small pulmonary nodules. This novel technique will facilitate early accurate diagnosis of lung cancer in small nodules with a minimally invasive approach.

Abstract not provided

Background:
Sublobar resection of small pulmonary nodules by minimally invasive techniques can be a challenge, as this approach reduces the haptic feedback often required to reliably localize small lesions. Use of Electromagnetic Navigational Bronchoscopy (ENB) is a relatively new technique that has potential to assist in real time operative localization of such lesions, as ENB can deliver visual cues for their location in the form of either a dye marking or a radio-opaque clip, or both. There is limited data available on the feasibility of this approach. We want to describe our experience with this technique.

Methods:
A retrospective review of cases in which ENB was used to localize small pulmonary nodules was done from August 1, 2013 to February 1, 2015. We start by using ENB to navigate to the target lesion. In our initial experience, methylene blue was injected into the parenchyma around the mass, and dye migration to the pleural edge was used as a visual cue for location. We then amended our protocol to include placement of both methylene blue dye and a radio-opaque clip in the parenchyma immediately adjacent to the target lesion. Fluoroscopy was then used to triangulate the location of the clip, and by extension the mass, via markings on the chest wall with the lung deflated prior to incision. The visual cue of the dye marking as well as the fluoroscopic localization of the clip served to confirm each other. This was followed by minimally invasive resection of the lesion using these cues to assist in port placement. Figure 1



Results:
A total of 28 cases were identified. ENB was successful in navigating to the lesion in all cases. ENB dye localization alone was successful in 5 of 6 cases. After the first unsuccessful dye localization, our amended protocol of dye marking and clip placement led to successful localization in 22 consecutive cases.

Conclusion:
Use of electromagnetic navigational bronchoscopy to localize small pulmonary nodules is a feasible approach and is technically straightforward. As we see broader implementation of lung cancer screening protocols, thoracic surgeons can expect to encounter many more small pulmonary nodules requiring resection. There is accumulating data that sublobar resection is equivalent to lobar resection for small, peripherally located lung cancer. Use of the algorithm – ‘Navigate, Triangulate and Resect’ will enable thoracic surgeons to more successfully perform sublobar resections of small pulmonary nodules by minimally invasive techniques.

Background:
The rate of mediastinal lymph node metastasis is controversial for patients with clinical N0 non-small cell lung cancer. The primary advantage of video-assisted mediastinoscopic lymphadenectomy(VAMLA) over conventional mediastinoscopy or videomediastinoscopy is to reduce the false-negative rate. We aimed to analyze to evaluate the value of routine VAMLA for patients with clinical T1a-T2aN0 patients prospectively.

Methods:
From March 2010-January 2015, 41 patients with non-small cell lung cancer with clinical stage T1-T2aN0 by postireon emission tomography/computed tomography underwent routine VAMLA before planned resectional surgery.Routinely, stations #2L, 2R, #4R, #4L, 7 were nearly completely resected. In some patients, #10R and #8 lymph nodes were biopsied. The prevalence of mediastinal lymph node metastases at VAMLA and lung resection was recorded.

Results:
There were 5 females (12.2%) and 36 (87.8%) males. The mean age was 62.5 . years. A total of 5 patients were had cT1a-bN0, whereas 36 patients had T2aN0. Eleven patients (26.8%) had occult mediastinal lymph node metastasis. A total of 26 patients underwent lung resectional surgery; only one patient (3.8%) were upstaged to pN2, whereas 3 patients (11.5%) were upstaged to pN1.

Conclusion:
VAMLA seems to disclose considerable number of mediastinal lymph node metastasis in these patients with T1 and T2 clinically staged N0 by positron emission tomography/computed tomography. Routine use of VAMLA is recommended with limited use of mediastinal lymph node evaluation in patients during resectional surgery.

Background:
One measure of the quality of thoracic surgery for non-small cell lung cancer (NSCLC) is the adequacy of nodal evaluation; the rate of pathological nodal upstaging can introduce bias in patient selection for surgical therapy. Robotic-assisted thoracic surgery (RATS) offers the ability to sample nodal stations not easily assessed with conventional open surgical methods. We sought to determine the rate of nodal upstaging as a function of the frequency of various lymph node stations sampled in clinical stage I NSCLC patients undergoing RATS.

Methods:
We retrospectively reviewed the charts of patients with right-sided clinical stage I NSCLC who underwent robotic-assisted pulmonary resection with mediastinal lymph node dissection at our institution from 2013 to 2015. CT or PET scan was used to determine clinical stage. The DiPasquale Quality Index (DQI) defines a complete lymph node dissection (LND) as sampling LN 4R, 7, and 9 for right-sided tumors. Our institutional policy for the initial two years of our RATS program was to limit such to right-sided tumors.

Results:
Robotic anatomic lung resection was performed in 70 patients with right-sided clinical stage I NSCLC. The majority were of the upper lobe (41; 58.6%). The most frequent lymph node stations sampled robotically were LN 4R, 7, 9, 10, and 11 (60.6%, 90.1%, 66.2%, 49.3%, and 64.8%, respectively). According to the DQI, 31 (44.3%) tumors underwent complete LND. Pathologic nodal upstaging occurred in 5 patients (7.1% [pN1 4, 5.7%; pN2 1, 1.4%]). Hilar (pN1) upstaging occurred in 2.8%, 0%, and 20.0%, respectively, for cT1a, cT1b, and cT2a tumors. Comparatively, historic hilar upstage rates of video-assisted thoracoscopic surgery (VATS) versus thoracotomy versus recent robotic data for cT1a, cT1b, and cT2a were 5.2%, 7.1%, and 5.7%, versus 7.4%, 8.8%, and 11.5%, versus 3.5%, 8.6%, and 10.8%, respectively. The 1-year overall survival was 97% and the disease-free survival was 98% at 1 year.

Conclusion:
When patients are appropriately selected and proper lymph node sampling is performed, the rate of upstaging with RATS is comparable to VATS and lower than thoracotomy. The rate of hilar upstaging with robotic resection, however, increases with increasing clinical T stage and appears superior to both VATS and thoracotomy for cT2a tumors. This also has implications for patients who may be considered for therapies like stereotactic radiation therapy. Larger studies comparing matched open, VATS, and robotic approaches are necessary to quantify long term survival and local failure rates.

Background:
Surgery is the treatment of choice for early stage lung cancer (LC). While lobectomy (L) is the historic standard, whether long term outcomes of sub-lobar resection (SL) are comparable is still under debate. The only randomized trial was conducted 20 years ago; 5 subsequent meta-analyses showed inconclusive or conflicting results. We present a comprehensive review of the literature on 5 year-survival after SL compared to L for early stage LC.

Methods:
A priori inclusion criteria were: 1) observational studies, 2) L compared to SL for early stage LC, 3) at least CT staging, 4) 5-year survival reported. A Medline search through January 2015 resulted in 32 studies, representing 24 distinct datasets. The absolute difference in 5-year survival was calculated and plotted for each study.

Results:
There were 4,702 cases treated with L, 2,323 treated with SL. Of 20 studies reporting the reason for SL, 11 indicated that SL was performed because of comorbidities, or impaired cardiopulmonary function. Among all 24 studies, 4 showed no difference in 5-year survival, 13 favored L, and 7 favored SL (Figure 1). Of the two studies using propensity scores, one favored L and the other SL. No meta-estimate could be calculated due to high statistical heterogeneity. Of 21 studies reporting recurrence rate (Figure 2), 11 favored L and 10 favored SL. Figure 1



Conclusion:
Studies comparing 5-year survival rates of SL to L are heterogeneous, and traditional meta-analytic summary estimates of survival and recurrence could not be calculated. SL survival is often similar to L survival, despite the fact that SL is performed in patients with comorbidities or impaired cardiopulmonary function. New approaches to comparing L to SL survival are needed.

Abstract not provided

Background:
Small cell lung cancer (SCLC) is an aggressive malignancy with an average of 20,000 new cases per year and 16,000 deaths per year. SCLC accounts for about 10-15% of newly diagnosed lung cancers. Even in the face of extensive research, the standard of care- platinum-based combination chemotherapy- has not changed in decades. Yet even with modern chemotherapy formulations, the two year survival rate for advanced disease stages is less than 5%. Complicating treatment is that often at the time of diagnosis, SCLC as already metastasized to the patient’s surrounding lymph nodes. Therefore, a novel therapeutic strategy will have address three disease aspects: (1) reduce primary tumor growth and eliminate metastatic spread; (2) avoid resistance mechanisms used by SCLC to escape radio- and chemotherapies; (3) synergize with or supersede current therapeutic strategies. Chimeric antigen receptor T cells, little explored in SCLC, is well suited to address these aspects.

Methods:
Human SCLC cell lines were analyzed using a 90 gene signature to establish immunological targets. Western blot analysis confirmed the expression of CD56 and other targets on SCLC cell lines. For CAR T cell generation, PBMC were electroporated with the Sleeping Beauty transposase and a transposon containing a CD56R chimeric antigen receptor. CD56R-CAR transduced T cells were cultured for 4 weeks in the presence of K562 cells expressing CD56 and the cytokines IL-2/IL-21 to expand CD56R-CAR T cells. CAR T cells were tested in vitro for killing ability in the presence of three SCLC cell lines using a chromium release assay. CAR T cells were also analysed via FACS to assess CAR expression, T cell phenotype, and memory status.

Results:
An analysis of immune markers in SCLC cell lines revealed that, compared to NSCLC lines, there is a reduction in the expression of suppressive ligands and co-stimulatory ligands, antigen presentation, and natural killer ligands. SCLC cell lines, however, express high levels of CD56. When two CD56-positive and one CD56-negative cell line was tested, CD56-CAR T cells could kill efficiency CD56 expressing cell lines, however there was little killing of the CD56-negative cell line. An analysis of PBMCs cultured after electroporation revealed that a large percentage of CD3+ T cells expressed the CD56 CAR and even after 4 weeks in culture, the CAR T cells displayed a memory phenotype.

Conclusion:
An interrogation of SCLC cell lines versus NSCLC cell lines revealed that SCLC cell lines had reduced expression of checkpoint ligands, NK cell killing ligands, antigen presentation, but consistent with their origin, high expression of CD56. Our conclusion from this analysis is that expansion of SCLC-specific immune responses in vivo or elicitation of de novo responses in vivo will be hindered. Therefore, immunotherapies centered around adoptive transfer of T cell that can kill in an HLA-independent manner maybe better suited for SCLC. In that vein, CD56R-CAR T cells effectively targeted CD56-positive SCLC in vitro, but was unable to kill CD56-negative cells- which indicates a possible escape variant. Our lab is now moving toward testing CD56R-CAR T cell in vivo in both xenograph models and spontaneous ones.

Background:
Small cell lung cancer (SCLC) is an extremely aggressive and lethal disease for which there is a desperate need for novel and more effective treatments. A recently discovered oncolytic picornavirus, Seneca Valley Virus (SVV), infects tumors with neuroendocrine features, including SCLC with high selectivity. SVV is highly effective in the eradication of solid tumors in multiple in vivo models; however the mechanism of selective tropism for SVV is unknown. Because of the strong selectivity of the virus for SCLC, we hypothesize the host determinants of SVV permissivity could constitute future druggable targets for the treatment of SCLC.

Methods:
A retroviral gene trap mutagenesis screen was utilized in HAP1, a haploid human cell line permissive to SVV, HAP1. Once mutagenized, resistant cells, or cells with retroviral insertion in a gene essential to the viral life cycle, were selected for by incubation of the pool with SVV at a high multiplicity of infection (MOI). Hits from this screen were deconvoluted using an insertion mapping approach. Illumina sequencing provided quantitative counts of each insertion site in each gene. Hits from the screen were validated using various mechanistic approaches.

Results:
Our screen identified multiple unique insertion sites in the gene RPS25 on Chromosome 11. The RPS25 protein is a ribosomal protein that is a component of the 40S subunit of the ribosome. RPS25 has been previously shown to be important for IRES-dependent translation of multiple viral genomes as well as cellular mRNAs containing IRES elements. Using the CRISPR-Cas9 approach, we knocked out the RPS25 gene in the SVV-permissive SCLC cell line, NCI-H446. Upon total knock-down of RPS25, H446 cells become completely resistant to cell killing by SVV at high MOI. Surprisingly, these cells also show a severely marked decrease in doubling time and robustness in culture. In contrast, RPS25 CRISPR knock-down in HEK293T cells has been previously shown to have no distinguishable phenotype other than defects in IRES-dependent translation. Further studies to fully characterize the interaction of RPS25 with the SVV genome as well as the importance of RPS25 in other SCLC cell lines are ongoing.

Conclusion:
We have identified a host protein that is essential for SVV replication and infection using a genome wide mutagenesis screen. SCLC cells completely defective in RPS25 are resistant to SVV-dependent cell killing. RPS25 appears to not only be important for the life cycle of SVV but may be important in proliferative capacity in SCLC. As SVV is highly selective for SCLC, we hypothesize that the host determinants of SVV tropism may be very specific to SCLC cells. Proteins important in the SVV life cycle may be novel “druggable” targets for the treatment of SCLC.

Background:
Small cell lung carcinoma (SCLC) represents 15% of lung cancers and is treated using chemotherapy +/- radiation but despite initial responses most recur within a few months and become resistant to therapy. Novel immune checkpoint inhibition of programmed death-1 (PD1) targeted therapy has shown promise in other solid tumors including non-small-cell lung cancer (NSCLC) and malignant melanoma. In some tumor types correlation with response and significant expression of programmed death- ligand 1 (PD-L1), the lead candidate biomarker of anti-PD-1 therapy, has been described but no data is available regarding expression levels in SCLC. Here we report the rate of PD-L1 expression in SCLC and in associated tumor infiltrating immune cells lymphocytes and macrophages.

Methods:
Immunohistochemistry (IHC) for PD-L1 using two monoclonal antibodies (clone 5H1 and clone SP142) and for CD3 (clone PS1) was performed on standard formalin fixed paraffin embedded tissue sections of 21 resected SCLC specimens (median age: 67) and three additional tumors with pre- and post-therapy biopsies. Since there is no generally accepted scoring system for PD-L1 expression we chose to evaluate staining in tumor cells and immune cells infiltrating the tumor nests and in adjacent stroma using a 4 tier semi quantitative scoring system (score 0 -no or <1%, 1+ 1-<5%, 2+ 5-25% and 3+ >25% of cells staining). Both cytoplasmic and membranous staining was accepted as positive. The number of tumor infiltrating lymphocytes (TIL) were estimated utilizing a CD3 stain while macrophages were identified on corresponding H&E stains.

Results:
PD-L1 staining of tumor cells and Immune Cells (TIL & Macrophage) are shown in the table below. Membranous PD-L1 staining was only seen in two tumors and in variable number of immune cells with 2+ or 3+ PD-L1 scores. The majority of positive staining was cytoplasmic with both antibodies. The staining intensity was stroger with the 5H1 antibody. The paired pre- and post-therapy samples were all negative for PD-L1.

Clone/score	PD-L1 staining in
5H1	Tumor	IC in tumor	IC in stroma
0 (<1%)	19/21 (90%)	7/21 (33%)	5/21 (24%)
1+ (1-<5%)	1/21 (5%)*	11/21 (53%)	6/21 (29%)
2+ (5-25%)	1/21 (5%)*	3/21 (14%)	7/21 (33%)
3+ (>25%)			3/21 (14%)
SP142	Tumor	IC in tumor	IC in stroma
0 (<1%)	20/21 (95%)	8/21 (38%)	10/21 (48%)
1+ (1-<5%)	1/21 (5%)*	11/21 (52%)	7/21 (33%)
2+ (5-25%)		2/21 (10%)	4/21 (19%)
3+ (>25%)

* Tumors with membranous staining; IC: immune cells

Conclusion:
Most SCLC are tumor membrane PD-L1 negative by IHC. A subset of SCLC contain PD-L1 positive TILs and/or macrophages in the tumor and the stroma. No up regulation of PD-L1 expression was seen in a small pilot sample of matched pre- and post-therapy biopsies. It is unclear whether PD-L1 expression assessed by IHC will be a predictive marker for PD-1 targeted therapy in SCLC. Preliminary data indicates single agent and combined checkpoint inhibitors (PD1 plus CTLA-4 inhibitors) are active in previously treated SCLC indicating additional research is required to understand their mechanism of action in a tumor type that has seen no therapeutic advances in the last two decades.

Background:
Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. PD-L1 interaction is a major pathway often hijacked by tumors to suppress immune control. Studies on the roles of PD-L1 in non-small cell lung cancer (NSCLC) are controversial, but its roles in small cell lung cancer (SCLC) are rare and unclear. Moreover, MET/HGF axis seems to be the other one of the most aberrant signaling pathways in SCLC. The aim of our study was to investigate the expression and prognostic roles of PD-L1 and cellular-mesenchymal to epithelial transition factor(c-MET) in SCLC.

Methods:
The expression of PD-L1 and c-MET were evaluated by immunohistochemical analysis in 83 specimens of SCLC, including 47 limited disease (LD) and 36 extensive disease(ED). Tumors with PD-L1 staining in over 5% of tumor cells were scored as positive for PD-L1 expression. Tumors with c-MET strong staining in at least 10% or weak to moderate staining in at least 40% of tumor cells were scored as positive for c-MET expression. Survival analysis was performed using the Kaplan-Meier method.

Results:
The positive rate of PD-L1 and c-MET in SCLC specimens were 51.8% and 25.3% respectively. The higher expression level of PD-L1 in tumor specimens was significantly correlated with a limited disease (LD) stage (p=0.004), a normal serum LDH level (p=0.031), and a normal NSE level (p=0.005). No association was found between the expression level of c-MET and PD-L1 , or c-MET expression with the other clinical characteristics of SCLC patients. SCLC patients with PD-L1-positive tumors showed significantly longer overall survival (OS) than those with PD-L1-negative (median OS, 17.0 vs 9.0, p=0.018). SCLC patients with positive c-MET expression showed a trend of shorter overall survival (12.0 vs 15.0, p=0.186). But sub-analysis of Limited disease (LD)-stage patients showed that the c-MET negative group had a longer OS (25.0 vs 14.0; p=0.011). Multivariate analyses revealed that LD stage, good performance status but except for PD-L1 or c-MET immunoreactivity were independently predictive of better OS.

Conclusion:
In patients with SCLC, expression of PD-L1 was positively correlated with a LD stage and better OS, but was not an independently predictive factor of outcome. High expression level of c-MET revealed a trend of worse outcome. It was associated with poor prognosis especially in LD-Stage patients.

Abstract not provided

Background:
As a subtype of lung cancer, small cell lung cancer (SCLC) remains a severe threat to human health. Although it is initially a chemosensitive disease, development of acquired resistance is a major problem. Studies in recent years revealed that cancer stem cell (CSC) could play a role in this process. However, the CSC specific marker and the detailed signal pathway associated with acquired resistance in SCLC is unknown yet. It was recently reported that the voltage-dependent calcium channel α2δ1 subunit positive cells is a CSC marker in hepatic cell cancer and that 1B50-1 is the specific monoclonal antibody of the α2δ1 subunit. In present study, we attempted to disclose that α2δ1 could play a role in acquired resistance of SCLC. Also we investigated possible molecular mechanism of α2δ1 mediated resistance in SCLC and finally provided the potential strategies overcoming the resistance.

Methods:
We screened for positive expression of 1B50-1and CD133 in SCLC cell lines and in patient-derived xenograft (PDX) models, and we used flow cytometry to verify the properties of CSCs. We recorded the expression of 1B50-1 before and after chemotherapy in PDXs in chemosensitive and resistant models to determine if α2δ1 subunit-positive cells were related to acquired resistance. We used exome and transcriptome sequencing to explore the expression of genes related to stem cell properties and drug resistance. We used Western blotting to verify the key molecules and pathways in the process of drug resistance. On the basis of these results, we explored the mechanisms of acquired drug resistance that are mediated by the α2δ1 subunit.

Results:
We observed a difference in the positive expression levels of 1B50-1 and CD133 in SCLC cell lines (H1048, H69, and H209) and PDX models. Both 1B50-1-positive and CD133-positive cells exhibited stem cell-like properties such as the capacity to self-renew in vitro, tumorigenesis in vivo, the potential for differentiation, and high expression levels of genes related to CSCs and drug resistance. Chemotherapy could induce the enrichment of 1B50-1-positive cells but not CD133-positive cells in PDXs. Also, high rates of 1B50-1-positive cells corresponded to high levels of resistance. Together, these findings indicated that the expression of 1B50-1 is related to chemoresistance. Exome and transcriptome sequencing revealed that the expressions of multiple pathway related genes in pathways, including MAPK, CAMs, TGFβ, and Notch, were increased in 1B50-1-positive H1048 cells. Western blotting revealed the activation of the Erk protein in the MAPK pathway and the over-expression of the Erk protein in 1B50-1-positive H1048 cells. The specific α2δ1 antibody 1B50-1 improved response to chemotherapy and delayed relapse when combined with chemotherapy or used y as maintenance therapy.

Conclusion:
The α2δ1 subunit positive SCLC cells (1B50-1+) displayed CSC properties, and were associated with acquired resistance. The Erk protein in the MAPK pathway was highly expressed in the 1B50-1-positive H1048 cell line, and might be the key molecule involved in resistance mediated by the α2δ1 subunit. The α2δ1 subunit-specific antibody 1B50-1 could improve response to chemotherapy and delay relapse when combined with chemotherapy or when used as sequential therapy.

Background:
Small cell lung cancer (SCLC) is an extremely aggressive cancer with limited treatment options and poor outcome. The majority of SCLC patients respond to frontline chemotherapy, but experience rapid recurrence with metastasis, that may be attributed to the prevalence of cancer stem cells (CSCs). We previously demonstrated that PI3K/mTOR signaling is key for CSCs in cell culture and solid tumor models. As shown with a dual PI3K/mTOR inhibitor, VS-5584, inhibition of multiple PI3K isoforms and mTOR is necessary to achieve preferential targeting of CSCs.

Methods:
Antitumor activity of VS-5584 was assessed by in vitro proliferation assay as well as in multiple xenograft models in vivo, including patient-derived xenograft models. Anti-CSC activity was measured by the side-population CSC assay in vitro and in limiting dilution tumor initiation assay in vivo.

Results:
VS-5584 inhibited SCLC growth in vitro at sub-µM IC50, and was synergistic with cisplatin and etoposide in reducing the viability of SCLC cells. In vivo, single agent VS-5584 (20 mg/kg, 3 days per week dosing, MWF) demonstrated robust anti-CSC activity in the NCI-H841 SCLC model by reducing tumor initiating potential 70-fold (p=5x10[-6]). In tandem, VS-5584 partially reduced tumor growth of the NCI-H841 xenograft tumors. Furthermore, a VS-5584 dose dependency was evident, both for tumor initiating potential and tumor growth reduction. When VS-5584 was combined with cisplatin and etoposide, the standard of care agents for SCLC, an increased tumor growth inhibition was observed whether VS-5584 was concurrently administered or added sequentially following the dual chemotherapy. In the SCLC PDX model, combination treatment also suppressed the regrowth of the tumor following cessation of chemotherapy for extended duration. VS-5584 was found to preferentially induce apoptosis in CSCs in multiple cell lines, indicating that these cells are eliminated through cell death-related mechanism. Importantly, we demonstrated that for eradication of CSCs it is necessary to inhibit simultaneously multiple PI3K isoforms and mTOR pathways.

Conclusion:
The VS-5584 pre-clinical findings support the preferential targeting of CSCs in SCLC models and provide an important rationale for advancing clinical development of the compound. A phase 1 dose finding clinical trial is on-going to establish a Phase 2 dose of VS-5584 and explore target inhibition. VS-5584 alone or in combination with standard of care chemotherapy may lengthen the time to relapse and improve outcome for patients with small cell lung cancer.

Background:
NOTCH expression is associated with cancer cell survival via effects on cancer stem/progenitor cells. Targeting NOTCH2 and 3 decreases growth and survival of SCLC patient-derived human tumor xenografts (PDX). Phase1b/2 trials testing Tarextumab (TRXT) anti-NOTCH2/3 therapy are underway (NCT01647828 and NCT01859741) and show promising anti-tumor activity. Here, we studied NOTCH3 protein expression using immunohistochemistry (IHC) in SCLC human tissues and correlated with survival. Also, we studied NOTCH3 gene expression in phase 1b patients (pts) treated with TRXT.

Methods:
For NOTCH IHC staining, murine monoclonal antibodies were generated by immunizing mice with a NOTCH3 extracellular domain (ECD) protein, then creating hybridomas. Clones were screened by FACS and western blots for specificity to NOTCH3.ECD. A lead clone was selected for NOTCH3 protein measurement in 47 SCLC samples represented in a tissue microarray from Yale Pathology Tissue Services (YPTS). NOTCH3 signal was determined in tumors using H-scores generated by Leica Aperio Scanscope IHC membrane image analysis. For survival analysis, NOTCH3 signal was binarized with cutoffs defined by X-tile software. For the phase 1b clinical trial, a standard 3+3 dose escalation design was employed with cohorts of 3 to 6 pts treated at each dose level. TRXT was given IV on Day 1 of each 21 day cycle with etoposide 100 mg/m[2] (Days 1-3) and cisplatin 80 mg/m[2 ]or carboplatin at AUC 5 (Day 1) for 6 cycles, followed by TRXT alone every 21 days until progression of disease or unacceptable toxicities. Then, the MTD TRXT plus etoposide and carboplatin was confirmed in a cohort of 6 subjects. All pts are required to submit tissues for Notch 3 gene expression and IHC staining.

Results:
A single hybridoma clone demonstrating specific reproducible membranous staining with a dynamic range for NOTCH3.ECD in control and PDX tissues was chosen for IHC analysis in SCLC human FFPE tissues (n=47). Forty cases (85.1%) demonstrated NOTCH3 signal, with eighteen (38.3%) having none to very low signal. Of the 31 cases with adequate follow-up, there was a strong trend with worse outcome and high NOTCH3 expression in the extensive stage (p=0.063), but not in limited stage (p=0.857). The level of significance was a function of the experimental cut-point and can only be considered exploratory. Finally, 27 pts were treated with TRXT in the phase 1b trial, with an overall response rate of 84%. The median duration of treatment was 128 days (6 cycles) with mPFS and mOS of 124 and 228 days, respectively. The median follow-up for PFS and OS was 86 and 107 days, respectively. Twenty-five pts have tissues evaluable for NOTCH3 gene expression and the analysis is underway.

Conclusion:
NOTCH3 IHC staining showed expression in most SCLC cases, with high NOTCH3 trending towards worse survival in extensive stage. This supports the rationale of targeting NOTCH3 by TXRT in SCLC pts. Further evaluation of the prognostic and predictive value of TRXT for anti-Notch therapies in SCLC is underway in an ongoing Phase 2 clinical trial.

Background:
Pulmonary neuroendocrine tumors such as small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC) remain among the most deadly malignancies and are increasing in incidence. Patient-derived xenograft (PDX) tumors provide excellent models to study tumor biology and discover tumor-initiating cell (TIC) populations. Novel therapies that target and eradicate TIC represent a promising strategy to improve survival. An effectively targeted antibody-drug conjugate (ADC) carrying a cell-cycle independent toxin should result in significant anti-tumor activity and eliminate TIC.

Methods:
Whole transcriptome sequencing was performed using TIC isolated by fluorescence-activated cell sorting from SCLC and LCNEC PDX tumors. Quantitative RT-PCR, microarray analysis of PDX tumors and cell lines, and mining of publically available transcriptome and proteome datasets were executed to validate that prospective targets, such as Delta-like protein 3 (DLL3), were highly expressed in neuroendocrine tumors, but limited in their expression in normal tissues. DLL3-specific monoclonal antibodies were generated and used to determine protein expression by immunohistochemistry, flow cytometry and ELISA. Select DLL3-specific antibodies were conjugated to a cell-cycle independent pyrrolobenzodiazepine (PBD) dimer toxin and evaluated for their ability to internalize and mediate cell killing. Finally, established SCLC and LCNEC PDX tumors were treated in vivo with a lead anti-DLL3 ADC (i.e. SC16LD6.5). Limiting dilution assay (LDA) serial transplantation experiments were executed to assess the impact of SC16LD6.5 on TIC.

Results:
Elevated expression of DLL3 mRNA was discovered in TIC of SCLC and LCNEC PDX tumors and confirmed in additional distinct primary SCLC and LCNEC tumor samples and PDX tumors. In contrast, little to no mRNA expression was detected in vital organs and other normal tissues outside of the brain. DLL3-specific antibodies confirmed protein expression on the cell surface in both primary SCLC and LCNEC tumors and in PDX tumors initiated from patients with these diseases, whereas protein was scarce in normal tissues. SC16LD6.5 rapidly internalizes and localizes to late endosomes, and treatment of 10 SCLC and 2 LCNEC PDX tumor models resulted in significant and durable tumor regression with a median time to progression benefit of 75 days versus 16 days with standard-of-care (SOC: SCLC, cisplatin/etoposide; LCNEC, cisplatin). During the course of these in vivo studies, many mice were cured as tumors often did not recur despite being followed for 120+ days post-randomization and treatment. LDA experiments executed using tumors actively responding to SC16LD6.5 provided further functional evidence that the common lack of tumor recurrence following treatment resulted from effective targeting of DLL3-expressing TIC. In vivo efficacy strongly correlated with DLL3 protein expression, and responses were observed in PDX tumor models initiated from patients with both limited and extensive stage disease and independent of their sensitivity to SOC.

Conclusion:
The DLL3-targeted ADC, SC16LD6.5, effectively targets and eradicates TIC in SCLC and LCNEC PDX tumors. SC16LD6.5 (i.e. rovalpituzumab teserine) is currently concluding Phase 1b trials and is a promising first-in-class therapeutic for the treatment of high grade pulmonary neuroendocrine tumors.

Abstract not provided

Background:
Although most patients with SCLC are current or former smokers, this disease has been reported in never-smokers. In our prospective genomic profiling of SCLC patients, we have identified four never-smokers. Here, we report next generation sequencing (NGS) results for these four SCLC patients and describe how they differ from those of smokers.

Methods:
We are evaluating pathologically confirmed SCLC tumors in patients undergoing treatment. Formalin-fixed, paraffin-embedded surgical resections, core biopsies, and fine needle aspirates are being evaluated using a targeted, hybrid capture-based, NGS assay, MSK-IMPACT, which identifies single nucleotide variants, indels, and copy number alterations in 341 cancer-associated genes. We determined never-smoking status prospectively: all smoked <100 cigarettes in their lifetime. Clinical data on stage [extensive (ES), limited (LS)], treatment, and response were collected.

Results:
Four never-smokers have been identified within the 50 patient samples that have undergone NGS evaluation thus far. The median age at diagnosis of the four never-smokers is 58 (range, 47-75); 50% are male; and one presented with LS-SCLC. None of these four patients developed SCLC as acquired resistance to EGFR tyrosine kinase inhibitors after treatment for EGFR-mutant lung cancers. The tumors from the four never-smokers displayed a median of 3 non-synonymous somatic mutations, while those from moderate (<20 pack years) and heavy (20+ pack years) smokers contained 4.5 and 8 mutations, respectively (P<0.05). None of the four never-smoker samples contained smoking associated G-to-T transversions (see Table). Inactivation of RB1 and TP53 occurred in 75% and 50% of the samples, respectively. Only patient 4 had platinum-refractory disease. The median survival of these patients was 20.7 months (range, 17 to 25).

Sample	Gene altered	Alteration Present	Protein Alteration	Base Pair Alteration
Patient 1	PHOX2B	Missense Mutation	P82L	G-to-A
	NOTCH1	Frame-Shift Insertion	P2485fs
	RB1	Splice Site	R500_splice	G-to-A
	TP53	Frame-Shift Deletion	V218fs
	TP53	Frame-Shift Deletion	V73fs
	TERT	Amplification
Patient 2	CBL	Missense Mutation	C401S	G-to-C
	GNAS	Missense Mutation	M102V	A-to-G
	MYCL	Amplification
Patient 3	TP53	Nonsense Mutation	R342	G-to-A
	RB1	Frame-Shift Insertion	T197fs
	CDKN2C	Amplification
	MYCL	Amplification
Patient 4	RB1	Nonsense Mutation	C666
	ETV1	Amplification

Conclusion:
Using a targeted NGS assay, we have shown that the molecular characteristics differ between never-smokers and smokers, while the majority of the tumors demonstrate RB loss. Whole exome sequencing of the tumors from these never-smokers is underway. Ongoing comprehensive, multiplexed genotyping is needed to fully characterize the molecular diversity of SCLC in this unique population.

Background:
SCLC is an aggressive malignancy that shows dramatic clinical responses in 70% of cases to platinum-based chemotherapy in the first line setting, while the remainder have de novo treatment resistance. Of initial treatment responders, almost all will relapse with drug-resistant disease within months of initial therapy. From a clinical perspective, the emergence of drug resistance remains one of the most important barriers to improving SCLC patient outcomes. Better models of in vitro and in vivo drug resistance are therefore required. Cell surface markers are proteins expressed on the outer surface of cells that can identify specific cell types and biologic states. Surface markers represent an attractive class of biomarkers in SCLC: 1) they are independent of cellular transport mechanisms that are known to play a role in SCLC drug resistance; and 2) they can be readily accessed for diagnostic and therapeutic purposes using commercial antibodies.

Methods:
NCI-H69 is a classic SCLC cell line derived from a patient prior to systemic treatment, and is chemotherapy sensitive. H69AR is an anthracycline-resistant derivative cell line generated through serial culture of NCI-H69 in increasing concentrations of Adriamycin. H69AR is also cross-resistant to other cytotoxic drugs commonly used to treat SCLC. We performed a pilot screen in both cell lines in duplicate using a human cell surface marker panel containing Alexa Fluor 647-conjugated antibodies against 242 unique cell surface proteins. High-throughput multiplexed flow-cytometry was performed to generate cell surface expression profiles for each antibody in each cell line.

Results:
A total of 53 markers were expressed in at least 20% of cells in either cell line, with 22 positive markers shared by both cell lines including CD44. NCI-H69 was uniquely positive for 24 markers including CD56, a neural progenitor marker used commonly to diagnose SCLC. Seven markers were uniquely positive in H69AR including CD9 and some of its known interactors. The percentage H69AR cells positive for each of the 7 markers ranged from 25% to 88%. CD9 is a member of the transmembrane 4 superfamily involved in many cellular processes including differentiation, adhesion, and signal transduction. Eighty-eight percent of H69AR cells were positive for CD9 compared to only 5.4% of H69 cells. CD9 has previously been implicated in a cell adhesion-mediated drug resistance mechanism in unrelated SCLC chemotherapy-resistant cell lines (S. Kohmo et al. Cancer Research 2010).

Conclusion:
Our pilot data provides a proof-of-concept for our surface biomarker screen-based approach to further understand mechanisms of chemotherapy-resistance in SCLC. We have expanded this screen to additional drug-sensitive and drug-resistant SCLC cell line pairs. Results of the expanded screen will be presented at the meeting.

Background:
Most cases of small-cell lung cancer (SCLC) are detected at extensive stage, where current guidelines recommend 4-6 cycles of chemotherapy. Although upfront progression to doublet platinum based chemotherapy in SCLC is <20%, current clinical practice often includes treatment monitoring with imaging, mainly with computed tomography, every two cycles. Since the purpose of imaging during treatment is identification of progression (to avoid further exposure to an ineffective but still potentially toxic regimen), we sought to evaluate whether monitoring SCLC patients during treatment with a blood-based biomarker (ProGRP) would correlate with response.

Methods:
Patients with SCLC treated with mainly standard chemotherapy at six centers worldwide (Europe and China) were included. ProGRP levels from serum or plasma were measured with a fully automated ProGRP assay in a prospective fashion prior to treatment start and repeatedly during treatment. Imaging was done and interpreted according to local guidelines at each institution. Percent change of ProGRP from baseline to the time of maximum response (‘best response’) was correlated with imaging findings, and patients were divided into two groups: Responders (= stable disease [SD] or better) vs. Non-Responders (= progression on scan). The ability of ProGRP to discriminate between Responders and Non-Responders was assessed by sensitivity and specificity.

Results:
215 patients with available CT result were included, of whom 145 had received first-line treatment (131 received platinum+VP-16 doublet). Clinical characteristics were as follows: 60.5% male, median age was 62 years, 72.1% were (ex)smokers, 93.5% with Stage IIIB or IV SCLC, and the majority of patients were either Caucasian (59.6%) or Asian (32.6%). Across all lines of treatment, 186/215 (86.5%) had SD or better as best response to treatment. There was a positive trend for higher ProGRP levels with clinical stage at presentation, and in general higher pre-treatment levels in 1[st] line compared to later lines of treatment. A decline in ProGRP levels was strongly correlated with response, whereby higher baseline levels were associated with subsequent higher relative declines of ProGRP during treatment. Using different cut-off levels for ProGRP decline during treatment (-50%, -70%, or -90%), we detected patients with no response to treatment based on ProGRP levels alone, with a sensitivity of 82.8%, 89.7% and 96.6%, and a specificity of 65.6%, 55.4%, and 39.8%, respectively. Specificity was increased by approximately 10% when only patients with baseline ProGRP levels exceeding 100 pg/ml were included.

Conclusion:
To our knowledge, this is the largest SCLC cohort to date with available ProGRP data for therapy monitoring. The data showed that ProGRP levels at baseline were positively correlated with advanced disease stage, and decline in ProGRP levels during treatment was associated with tumor control in SCLC. The ProGRP assay used in this study is currently not cleared or approved for use in the USA.

Background:
Aurora kinase expression has been associated with a poor prognosis in non-small cell lung cancer (NSCLC) and aurora kinase inhibitors have activity in preclinical lung models. Aurora kinases are required for mitosis and cell division. Small cell lung cancer cells have rapid proliferation and higher rates of MYC family amplification, which makes aurora kinase inhibition a natural target.

Methods:
23-SCLC lines with known MYC family amplification and MYC family gene expression were exposed to varying concentrations of the specific aurora kinase B inhibitor AZD1152-HQPA. The percentage growth inhibition compared to control was determined in MTS assays at 120 hours. Cell lines were classified as “sensitive” if the GI50 concentration was < 50 nM and with ≥ 80% growth inhibition at 100 nM. Fisher’s exact test was used to determine the correlation between amplification of MYC family members and sensitivity of the cell lines to growth inhibition by AZD1152-HQPA. A two-group t-test (gene expression as a continuous variable) and an odds ratio estimate (dichotomized gene expression level) were used to determine a correlation between MYC family gene expression and growth inhibition by AZD1152-HQPA. To determine whether growth inhibition correlated with the published MYC-signature gene expression, we used Fisher’s exact test. In vivo growth inhibition by AZD1152 (prodrug) was evaluated on SCLC xenografts in nude mice.

Results:
Nine (39%) of the 23 cell lines were sensitive to AZD1152-HQPA with IC50 values < 50 nM. There was a significant association between sensitivity to growth inhibition by AZD1152-HQPA and cMYC amplification (p = 0.018). The odds of being sensitive is 16 (95% CI, 1.4, 183) times higher for cMYC amplified compared to non-cMYC amplified cell lines. By a two-group t-test, the mean cMYC gene expression of 10.9 (std 4) in sensitive lines compared to 7.2 (std 3.3) in resistant lines was also significant (p = 0.026). Cell lines were separated into two groups based on cMYC gene expression > 12.9 vs < 12.9. The odds of being sensitive is 11 (95% CI, 1.2, 103) time higher for cell lines with cMYC gene expression > 12.9 compared to cell lines with cMYC gene expression < 12.9. Sensitive cell lines were enriched in a published MYC-signature of gene expression (p = 0.042). AZD1152 (prodrug) caused significant growth delay in vivo in two of these lines. The doses of AZD1152-HQPA used in this study are within the range reported to be clinically achievable.

Conclusion:
Aurora kinase inhibitors have promise in SCLC therapy. Questions that currently need answering in translating aurora kinase inhibitors in the clinical setting are: (1) the dosing schedule to avoid myelosupression, (2) should aurora kinase inhibitors be used in maintenance therapy and (3) should the aurora kinase inhibitors be evaluating in combination with chemotherapy.

Abstract not provided

Background:
Small cell lung cancer (SCLC) has a poor prognosis and harbors complex genetic alterations including frequent loss-of-function mutations of p53 and Rb, which impair the G1/S checkpoint control. Checkpoint Kinase 1 (Chk1) is a vital serine/threonine specific protein kinase responsible for halting the cell cycle in check after DNA damage. With abrogation of Chk1-mediated cell cycle checkpoint control, cancer cells may enter mitosis with extensive DNA damage leading to mitotic catastrophe and apoptotic cell death. Previous in vitro studies showed that p53 deficient cancer cells benefit from Chk1 inhibition. Here we demonstrate that a combination of Chk1 inhibition and cisplatin causes more growth inhibition and caspase activation in SCLC cell lines compared to cisplatin alone, regardless of p53 status.

Methods:
Chk1 inhibition was achieved by siRNA knockdown (Qiagen) and AZD7762 (Selleckchem) in p53 mutant SCLC cell lines (GLC4, NCI-H82) and p53 intact SCLC cell lines (NCI-H128, NCI-H209). Cell viability was measured by Cell-Titer Glo assay (Promega) after 72hrs of drug treatment. Synergism was defined by combination index (CI)>1 using the Chou-Talalay method. Cell cycle analysis was performed by PI staining and detected by FACS. Western blotting and immunofluorescent staining were used to evaluate caspase activation and other signaling proteins.

Results:
SCLC cell lines were treated with cisplatin 24hrs at each IC50 dosage after Chk1 siRNA transfection. In GLC4 after 2.5uM cisplatin treatment, cell viabilities of control siRNA-treated and Chk1 siRNA-treated cells were 28% and 10.6% (p=0.006, by paired t-test), respectively. Similar significant reduction of cell viability was observed in 1uM cisplatin-treated NCI-H82 cells (44.6% vs. 29.7%; p=0.0632) and in 3uM cisplatin-treated NCI-H128 cells (62.5% vs. 45.3%; p=0.0155), respectively. More cleaved caspase-2 and caspase-3 were noted in Chk1 knockdown plus cisplatin-treated GLC4 cells than in cisplatin alone. The IC50 (72hrs) of single agent AZD7762 (Chk1 inhibitor) treatment was 240nM, 211nM, 266nM and 215nM in GLC4, NCI-H82, NCI-H128 and NCI-H209 respectively. The combination indexes of AZD7762 and cisplatin (both given at around IC50s) calculated by Chou-Talalay method indicated synergism in all these 4 cell lines. Cell cycle analysis revealed that AZD7762 abrogated cisplatin-induced G2/M arrest in GLC4 and G1 arrest in NCI-H128. Inhibition Chk1 by AZD7762 was associated with reduction of CDC25C and CDC2 phosphorylation. Phospho-Histone H3 (mitotic marker) was increased in AZD7762 and cisplatin combined treatment compared to cisplatin alone in a p53 independent fashion. Intriguingly, inhibition of Chk1 by AZD7762 alone in GLC4 cells activated caspase-2.

Conclusion:
Chk1 inhibition both by siRNA knockdown and AZD7762 enhances cisplatin cytotoxicity. The synergism was primarily due to increased apoptosis and abolished cell cycle arrest. Although p53 is frequently mutated in SCLC, growth inhibition was seen in a p53 independent manner. In GLC4, single agent AZD7762 treatment can cause caspase-2 activation through an as yet unidentified mechanism. Our findings suggest that Chk1 is a potential therapeutic target in small cell lung cancer and is synergistic with chemotherapy. The effects of Chk1 inhibitor and its combination with chemotherapy agents in SCLC animal models are currently underway.

Background:
Small cell lung cancer (SCLC) is a highly aggressive disease representing 12-13% of all lung cancers, with 5 year survival rate of only 6%. While most patients respond initially to cytotoxic chemotherapies such as irinotecan, etoposide, or carboplatin, resistance rapidly emerges and response to second line agents such as topotecan is limited. In contrast to non-small cell lung cancer, few targetable oncogenes have been identified in SCLC. STA-12-8666 is a small molecule drug, which binds the tumor-concentrated active form of heat shock protein 90 (HSP90), with a cleavable linker attached to SN-38, the active metabolite of irinotecan. Cleavage of the linker within the tumor provides time-release of SN-38 at high local concentration, while significantly limiting drug exposure and toxicity in non-transformed tissue. The goal for this work was to evaluate STA-12-8666 for potential use as a new second line monotherapy, or as adjuvant in the frontline setting for SCLC.

Methods:
Three dose levels of STA-12-8666 were evaluated in comparison to irinotecan, ganetespib, carboplatin, etoposide, cisplatin and chemotherapy combinations in 4 independent SCLC xenograft models, including parental and cisplatin-resistant derivative cell lines (SCLC1, SR2), and a patient-derived xenograft (PDX). STA-12-8666 was also evaluated in drug combinations. Intratumoral responses were profiled using a mass spectrometry based approach to evaluate kinase pathway activation, and results confirmed by immunohistochemistry and western blot analysis. Pharmacokinetic analysis was performed to benchmark retention of STA-12-8666 to irinotecan in lung tumors.

Results:
In all four models, high dose (150 mg/kg) STA-12-8666 was tolerated without side effects. In most cases, three doses administered at weekly intervals caused complete regression of established tumors, with response durable for > 2 months. Those tumors that regrew were responsive to re-dosing with STA-12-8666, and were subsequently eliminated. Further, STA-12-8666 induced complete or partial regression of tumors that progressed following first or second line treatment with standard of care agents for SCLC. Low dose (50 mg/kg) STA-12-8666 inhibited tumor growth and enhanced the anti-tumor activity of 30 mg/kg carboplatin, resulting in complete tumor regression. Pharmacokinetic and proteomic analysis confirmed STA-12-8666 concentration in tumors, and identified a signature of DNA damage response biomarkers in STA-12-8666-treated tumors that is different from that induced by irinotecan.

Conclusion:
The findings that HSP90i-drug conjugate STA-12-8666 is highly active in preclinical models of SCLC (in both frontline and second line settings) support the evaluation of this novel compound in clinical trials.

Background:
With the advent of modern chemotherapy and radiotherapy, we hypothesize that patients who undergo surgery followed by adjuvant therapy for locally advanced small cell lung cancer (SCLC) may have significantly better long-term survival compared to historical data suggesting 2-year overall survival of 4-20% for patients undergoing surgery for SCLC.

Methods:
Prospectively-collected perioperative outcomes and survival data of patients with pathologic T1-3, N1 and (limited) N2 SCLC and non-small cell lung cancer (NSCLC) who underwent complete resection with adjuvant chemotherapy ± radiation and no induction therapy were reviewed from the US National Cancer Data Base from 2003-2011 using Kaplan-Meier method and propensity-score matching. Groups were matched for common prognostic co-variates including year of diagnosis, age, sex, race, education, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, T and N status, tumor size, and tumor location. These prospective data were acquired by certified tumor registrars and include over 70% of cancer diagnoses annually in the U.S.

Results:
During the study period, 369 and 12,152 patients underwent complete resection for pathologic T1-3 N1-2 M0 SCLC and pT1-3 N1-2 M0 NSCLC, respectively. Median follow-up time was 43 months. Five-year overall survival was 37% for SCLC pN1 patients and 26% for SCLC pN2 patients (Table). Matched patients with pN1/N2 NSCLC had better 5-year survival compared to patients with pN1/N2 SCLC (Table and Figure). Figure 1 Figure 2





Conclusion:
SCLC T1-3 N1-2 patients who undergo complete resection followed by adjuvant chemotherapy ± radiation have 5-year survival greater than 26%. Compared to NSCLC, SCLC patients with N1/N2 disease have worse survival; however, the differences in survival between NSCLC and SCLC patients with N1/N2 disease are much smaller than previously reported. These results support a re-evaluation of the role of surgery in multimodality therapy for locally advanced small cell lung cancer.

Abstract not provided

Background:
Proteasome inhibitors synergize with topoisomerase inhibitors (eg, etoposide), which are frequently used to treat extensive-stage small cell lung cancer (ES-SCLC; Takigawa et al. Anticancer Res 2006;26:1869–76). Results from study PX‑171-007 (NCT00531284) suggest that carfilzomib has activity in relapsed SCLC (Papadopoulos et al. Cancer Chemother Pharmacol 2013;72:861–8), and clinical experience in myeloma suggests that carfilzomib may be added to other agents with limited additive toxicity. Preliminary results are presented from the phase 1b portion of the CFZ004 trial (NCT01987232) intended to determine the maximum tolerated dose (MTD) and safety of carfilzomib with carboplatin and etoposide in patients with previously untreated ES-SCLC.

Methods:
Patients received carfilzomib (30-minute intravenous infusion) on days 2, 3, 9, and 10 (20 mg/m[2] [days 2 and 3 of cycle 1]; 20–56 mg/m[2] thereafter) and fixed doses of carboplatin (target area under the concentration-time curve: 5 mg/mL/min) on day 1 and etoposide (100 mg/m[2]) on days 1, 2, and 3 of a 21‑day cycle for up to 6 cycles. Assessment of dose‑limiting toxicities (DLTs) in cycle 1 was used to determine dose escalation up to the MTD or recommended phase 2 dose. Disease response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Patients achieving ≥stable disease (SD) after 6 cycles could receive single-agent carfilzomib until disease progression or unacceptable toxicity.

Results:
As of March 31, 2015, 17 patients (median age: 59.0 years) had been treated in the phase 1b portion in 5 dosing cohorts; enrollment in the 56-mg/m[2] cohort is ongoing. Patients initiated a median of 6 cycles of carfilzomib; the median treatment duration was 16.3 weeks. One patient (56-mg/m[2] cohort) experienced a DLT. There were no on-study deaths. Two patients discontinued carfilzomib due to an adverse event (AE; metastatic pain: n=1; decreased neutrophil count: n=1). All-grade AEs were generally consistent with the profiles of the agents under study. Thirteen patients (76.5%) had a grade ≥3 AE; the most common (≥3 patients) were anemia (n=4), neutropenia (n=4), decreased neutrophil count (n=4), and leukopenia (n=3). The preliminary overall response rate (≥partial response) in 14 response-evaluable patients was 57.1%, with 1 complete response (Table 1). All response-evaluable patients achieved ≥SD.

Conclusion:
The MTD of carfilzomib with carboplatin and etoposide has not been reached. Patients are showing encouraging responses to treatment, with AEs generally consistent with the profiles of the agents under study. Response data, currently immature, will be updated at the meeting. Table 1. Phase 1b Best Overall Responses per Investigators

	Cohort
	1	2	3	4	5	Total
	CFZ, mg/m[2]
	20/20 (n=5)	20/27 (n=3)	20/36 (n=3)	20/45 (n=3)	20/56 (n=3)	(N=17)
Best overall response, n (%)[a]
CR	0	1 (33.3)	0	0	0	1 (5.9)
PR	2 (40.0)	2 (66.7)	3 (100.0)	0	0	7 (41.2)
SD	3 (60.0)	0	0	2 (66.7)	1 (33.3)	6 (35.3)
Not evaluable	0	0	0	1 (33.3)	2 (66.7)	3 (17.6)
Overall response rate (CR+PR), n (%)
All patients	2 (40.0)	3 (100.0)	3 (100.0)	0	0	8 (47.1)
Response-evaluable patients	2 (40.0)	3 (100.0)	3 (100.0)	0	0	8 (57.1)

[a]Per RECIST, v1.1.

Background:
Four cycles of etoposide plus cisplatin (EP) concurrently with accelerated hyperfractionation thoracic radiotherapy (AHTRT) is the standard treatment for limited-disease small cell lung cancer (LD-SCLC). The objectives of this study were to evaluate efficacy and toxicities of CODE or amrubicin plus cisplatin (AP) chemotherapy following one cycle of EP and AHTRT in patients with LD-SCLC, and to select the promising arm for subsequent phase III trials.

Methods:
Eligibility criteria included patients with previously untreated LD-SCLC with measurable lesion, ECOG PS of 0-1, and 20-70 years of age. Eligible patients received one cycle of EP (etoposide 100 mg/m[2] on days 1-3 and cisplatin 80mg/m[2] on day 1) plus AHTRT (45Gy/ 30 fractions in 3 weeks). Patients who achieved CR, PR or SD were secondarily registered and randomized to receive either 3 cycles of CODE (cisplatin 25 mg/m[2] on days 1 and 8, doxorubicin 40 mg/m[2] on day 1, etoposide 80 mg/m[2] on days 1-3, and vincristine 1 mg/m[2] on 8 every 2 weeks) or 3 cycles of AP (amrubicin 40 mg/m[2] on days 1-3 and cisplatin 60 mg/m[2] on day 1 every 3 weeks). G-CSF was administered on the days when chemotherapy was not administered in CODE, or on day 5 to the day when a neutrophil count exceeded 5,000/µL in AP. Patients with CR after CODE or AP received prophylactic cranial irradiation. The primary endpoint was the one-year progression-free survival (PFS) after the second registration. Tumor responses were assessed with RECIST version 1.1 by the central review committee. A better regimen for phase III trial is determined with a randomized phase II selection design. The sample size was 72 randomized patients to detect >= 10% difference in one-year PFS with a probability of 80%.

Results:
From May 2011 to Jan 2014, 85 patients from 28 institutions were registered. After the induction EP plus AHTRT, 75 patients were randomized to CODE (n=39) or AP (n=36). Patient demographics were well balanced between the arms. One patient did not receive CODE and 34 (89%) of the 38 patients received 3 cycles of CODE, whereas 33 (92%) of the 36 patients received 3 cycles of AP. Grade 4 neutropenia, anemia and thrombocytopenia were observed in 47%, 21% and 16% of patients in CODE, and in 78%, 6% and 17% of patients in AP, respectively. Grade 3 non-hematological toxicities with the incidence of 5% or higher included febrile neutropenia (16%), hyponatremia (8%), hypokalemia (5%), fatigue (5%), and anorexia (5%) in CODE, and febrile neutropenia (42%), nausea (11%), anorexia (11%), fatigue (8%), esophagitis (6%) in AP. CR and PR were noted in 13 and 25 patients in CODE, and in 10 and 24 patients in AP, respectively. The median overall survival in the 74 patients was 42.8 months. The one-year PFS (95% CI) was 41.0 (25.7 - 55.8) % in CODE and 54.3 (36.6 - 69.0) % in AP.

Conclusion:
The one-year PFS seemed better in AP than in CODE. AP arm is considered to be the test regimen for the subsequent phase III trial.

Background:
PCI has become standard of care for extensive stage small cell lung cancer (ES-SCLC) patients. However, one recent randomized study establishing this standard did not require brain imaging prior to enrollment, and another, which did, failed to show a benefit for PCI. CALGB 30504 (Alliance) was a randomized phase II study of sunitinib vs placebo in ES-SCLC patients responding to at least 4 cycles of platinum based therapy requiring baseline brain imaging at enrollment. As this study spanned the introduction of PCI for ES-SCLC, PCI was left to the discretion of the treating team. Therefore, we performed a secondary analysis of CALGB 30504 to determine the impact of PCI on ES-SCLC patients.

Methods:
CALGB 30504 was a phase II randomized study in ES-SCLC comparing maintenance sunitinib versus placebo following SD or CR/PR to 4-6 cycles of etopside 100 mg/m[2] d1-3 and either carboplatin AUC=5 or cisplatin 80 mg/m[2] d1 q 21 days. Sunitinib was 150 mg PO d 1 then 37.5 mg PO qd until progression. The primary objective was to determine if maintenance sunitinib would improve PFS, as was recently reported. PCI was recommended at 25 Gy in 2.5 Gy fractions, within 4-6 weeks of chemotherapy, but not required. Sunitinib was to be held 2 days prior, during, and 2 days after the completion of PCI. All statistical analyses were performed by the statisticians at Alliance/CALGB Statistical and Data Center on the platform of SAS (version 9.3; SAS Institution Inc., Cary, North Carolina).

Results:
85 patients received maintenance therapy(41placebo, 44 sunitinib). 41 (48%) received PCI, 44 didn’t. All patients and tumor characteristics were balanced between PCI and no-PCI patients. PCI dose was 25 Gy for 31 patients (range: 25-37.5 Gy). Median time to PCI was 21 wks (range: 12-27 wks) from enrollment. For all patients, PCI was associated with an improvement in PFS (median 7.8 vs 6.5 mo HR=0.63 (95% CI: 0.41-0.98), p=0.037), but not OS (median 12.9 vs 13.2 mo, HR=1.01 (95% CI: 0.64-1.62), p=0.955). In placebo patients, there was no PFS or OS difference between patients receiving PCI or not. In patients randomized to sunitinib, PCI conferred a PFS benefit (9.7 vs 6.8 mo, HR=0.49 (95% CI: 0.26-0.92), p=0.024), but not an OS benefit (14.1 vs 13.5 mo, HR=0.85 (95% CI: 0.44-1.66), p=0.636). When restricted to patients who did not receive PCI, there was no difference in survival between sunitinib or placebo patients. In PCI patients, those receiving sunitinib had non-significant improvement in PFS (9.7 vs 6.7 months, HR=0.63 (95% CI: 0.34-1.20), p=0.158) and trended towards an improvement in OS (14.1 vs 10.6 months, HR=0.56 (95% CI: 0.29-1.10), p=0.087), which was magnified and approached significance when crossover patients were excluded (14.1 vs 10.0 mo, HR=0.49 (95% CI: 0.22-1.06), p=0.064).

Conclusion:
PFS, and trends for OS improvement were limited to patients receiving the combination of PCI and maintenance sunitinib. Placebo patients did not benefit from PCI. Improved outcomes for ES-SCLC patients with PCI are likely limited to patients who achieve both intracranial and extracranial disease control.

Background:
Pazopanib is a small anti-angiogenic molecule inhibiting the tyrosine kinase of VEGFR‑1, VEGFR‑2, VEGFR‑3, PDGF, and c‑kit. An increased angiogenesis and VEGF expression has been reported in SCLC which is correlated with disease dissemination and poor prognosis. A multicenter phase II study of second line pazopanib in patients with SCLC was conducted.

Methods:
Patients with histologically confirmed SCLC who relapsed at least 3 months after the completion of front line VP-16/CDDP chemotherapy (platinum sensitive disease) were enrolled. Eligible patients should have measurable disease and ECOG performance status (PS) 0-2. Treatment consisted of daily p.o. pazopanib 800 mg in cycles of 28 days until disease progression. The primary endpoint was progression-free rate (PFR) at 8 weeks since anti-angiogenic factors are not associated with objective tumor shrinkage.

Results:
Thirty seven out of 39 enrolled patients (2 pts are still ongoing) were evaluable for response and toxicity. The median age was 65 years (range 39-82); male=33 pts; PS 0=22 pts; PS 1=15 pts. Eleven (28.2%) patients had only local relapse. The median interval from previous treatment was 5.4 months (3.0-38.2). One (3%) CR, 10 (26%) PR and 10 (26%) SD were documented, for an overall progression free rate (PFR) of 55% (95% CI: 39.4- 71.2%). The median PFS and OS was 3.7 and 10.6 mo, respectively, while the estimated 1-year survival was 58% (median follow up= 18.9 mo). Grade 4 adverse events (AEs) included neutropenia (n=2 pts) and diarrhea (n=2 pts) whereas grade 3 AEs were fatigue (n=4pts), nausea (n=1 pt), diarrhea (n=2 pts), hand-foot syndrome (n=1 pt) and transaminasaemia (n=1 pt). Epistaxis (gr 2) was reported in 3 pts, proteinuria (gr 2) and hypertension (gr 2) in 2 pts each. There were no treatment-related deaths.

Conclusion:
Second line treatment with pazopanib of patients with sensitive SCLC, was well-tolerated and resulted in a promising overall survival and disease control rate, including objective responses.

Abstract not provided

Background:
Pneumonitis is a major side effect for the treatment of limited stage small cell lung cancer with concurrent chemotherapy and radiotherapy (CChRT). Prevention is more important than treatment when patients develop grade 3-5 severe pneumonitis (SP). We investigated factors causing SP among patients with limited stage small cell lung cancer (SCLC) treated by CChRT.

Methods:
This is a retrospective analysis of 559 patients with limited-stage SCLC treated at a single institution from 1986-2009 with definitive CChRT to a total dose of 45-70 Gray (Gy). Candidate variables included tumor size, year of diagnosis & treatment period (1986-1999 vs. 2000-2009), gender, age, Karnofsky’s Performance Status (KPS), ethnicity, radiation dose, cycles of induction chemotherapy, use of intensity-modulated-radiation-therapy (IMRT) and fractionation. CTCAE v2 before 2003 and CTAE v3 in 2003-2009 were used to evaluate SP Grade 3-5 which were similar. Chi-square test was used for between group comparisons for categorical variables and the median test was used for between group comparisons for continuous variables. Kaplan-Meier estimates were constructed for overall survival (OS), disease-free survival (DFS), local-recurrence-free survival (LRFS), distant metastasis-free survival (DMFS). Analysis was performed using Logistic regression analysis with SP as the primary endpoint.

Results:
Of the 559 patients included in this analysis, tumor size was available for 520 patients. Median follow-up was 21.2 months (range 1.2-240.8). Thirty-five (6.2%) patients developed SP (26 Grade-3, 8 Grade-4 & 1 Grade-5). 2D or 3DCRT was used before 2000 and IMRT was usually used for small cell lung cancer in 2000-2009. Univariate analysis (UVA)showed that SP was associated with treatment given in 2000-2009 ( OR 3.93, P<001) ,age ≥ 60 (OR 7.72, P=0.001) ,KPS < 90 (OR 2.22, P=0.02), IMRT (OR 2.3, P= 0.026) and twice daily fractionation( OR 2.38, P=0.03).Induction Chemotherapy reduced SP (OR 0.39, P= 0.023) compared to immediate CChRT. Tumor size (at cut points 3 cm & 5 cm) did not make significant difference regarding SP. Multivariate analysis (MVA) has shown that significantly higher SP was associated with treatment given in 2000-2009 (OR 3.42, P=0.006), age ≥ 60 (OR 7.77, P= 0.001), male (OR 2.12, P=0.047)and twice daily RT (OR 2.45, P=0.026) . OS was significantly reduced among SP group vs. Pneumonitis ≤ Grade 2 (MST 17.9 vs.25 months, P= 0.038) (5-year OS 16 % vs. 27%), respectively. SP were not significantly correlated with DFS, LRFS and DMFS.

Conclusion:
Significantly higher SP was seen among patients with limited stage small treated in 2000-2009, age ≥ 60, male and twice daily RT. OS was significantly reduced SP. UVA showed IMRT causing significantly higher SP. MVA did not show IMRT was a significant factor for SP. Tumor size did not show significant difference regarding SP.

Background:
Prophylactic cranial irradiation (PCI) is the standard treatment in patients with small-cell lung cancer (SCLC) without progression after chemo-radiotherapy in stage I-III disease and after having a remission after chemotherapy in stage IV. In an international phase III trial (NCT01780675), patients with SCLC are randomised to receive PCI with or without Hippocampal Avoidance (HA). Accurate delineation of the hippocampus is crucial for this trial. In this study we evaluate the hippocampus delineation variability among radiation oncologists in multi-institutions for SCLC patients.

Methods:
The left and right hippocampus from 5 randomly selected patients (10 structures) were delineated by 5 radiation oncologists and 2 neuroradiologist in 7 institutions according to the RTOG atlas (http://www.rtog.org/CoreLab/ContouringAtlases/HippocampalSparing.aspx), together with a questionnaire. For each patient, a high resolution 3D inversion recovery T1 weighted MRI-scan was first registered to the planning CT-scan (1mm slicing). The observer then delineated the hippocampus according to the atlas on axial slices of the MRI. The mapped delineations on the CT were then used in dose planning with a 5mm margin. The mean and standard deviation (SD) of 1) volume and 2) range in medio-lateral, superior-inferior and anterior-posterior directions were computed for each structure. The corresponding inter-observer reliability was estimated by the intra-class correlation coefficient (ICC absolute agreement) using a linear mixed model. A median surface was computed and the overall delineation variability per structure was calculated by the root-mean-square (rms) of the local SD per sampled points on the median surface, while the local SD corresponds to the perpendicular distance between each observer and a sampled point.

Results:
The standard deviation of the delineated volume per structure varied from 0.14 to 0.48cm3. The corresponding inter-observer reliability (ICC) was 0.19, implying a high variability among the observers. The overall delineation variability per structure varied from 0.6 to 1.0mm. Areas with good agreements were the superior and inferior part of the hippocampus. The difficult area (Fig.1) was in the anterior medial area, close to the amygdala and uncus. The ICC in medio-lateral, superior-inferior and anterior-posterior directions were 0.55, 0.64 and 0.80, respectively. A large spread of the SD of range in medio-lateral direction and the relative low ICC imply that a better instruction, or training is desirable to improve the delineations. Figure 1



Conclusion:
There was a substantial variability in hippocampus delineation among the observers. Stricter adherence to the RTOG guidelines and (web-based) training are needed. The implication of the variations on the dose distribution is currently verified.

Background:
Small cell lung cancer (SCLC) has poor outcomes. The past thirty years have seen some advances in the management options for SCLC. However the impact of these advances on outcomes in the general population with SCLC is unclear.

Methods:
The Surveillance, Epidemiology, and End Result (SEER) registry 18 was used to identify SCLC cases from 1988 to 2011. Patients were classified either limited stage (LS) or extensive stage (ES) disease at diagnosis. Cox regression model was used to compare overall survival after adjustment for confounding covariates.

Results:
A cohort of 83,396 SCLC patients was analyzed. A higher proportion of males had ES-SCLC compared to females (72.7% vs. 67.4%; p<0.0001) Males had worse median overall survival (OS) compared to females (LS-SCLC: 10 vs. 12 months, HR: 1.11; 95% CI, 1.08-1.14; ES-SCLC: 6 vs. 7 months; HR: 1.16, 95% CI, 1.14-1.18). A higher proportion of younger patients (≤70 years) compared to older patients (>70 years) had ES-SCLC at diagnosis (70.76 vs. 68.02%; p<0.0001). However, median OS was worse in older patients for both stages (LS-SCLC: 10 vs. 13 months; HR 1.31, 95% CI 1.27-1.34; ES-SCLC: 6 vs. 8 months, HR: 1.19, 95% CI 1.16-1.21). A higher proportion of whites presented with ES-SCLC as compared to blacks or others (70.1% vs. 66.5% and 65.9%; p<0.0001). Blacks had worse median OS compared to whites (LS-SCLC: 10 vs. 11 months; HR: 1.07, 95% CI, 1.02-1.12; ES-SCLC: 6 vs. 7 months, HR: 1.07, 95% CI 1.02-1.12). Compared to the reference period 1993-1997, patients diagnosed with ES-SCLC during the latter time periods had worse OS: 1998-2002 (HR: 1.12; 95% CI, 1.08-1.15), 2003-2007 (HR: 1.23, 95% CI 1.20-1.27) and 2008+ (HR: 1.53, 95% CI, 1.49-1.58). A similar difference was not seen in patients with LS-SCLC, where only the most recent time period 2008+, had a worse survival compared to 1993-1997 period (HR: 1.37, 95% CI, 1.30-1.43).

Conclusion:
Females, whites, and younger patients with SCLC had better OS compared to males, blacks and older patients, respectively. Unfortunately, survival from SCLC has not improved significantly and may actually have worsened, during the past 20 years. The reason for this discord between clinical trial evidence and real-world evidence need to be investigated further. Newer treatment approaches are urgently needed for this disease.

Abstract not provided

Abstract not provided

Abstract:
Neo-angiogenesis, critical for sustenance and growth of cancers, is regulated by a number of pro- and anti-angiogenic factors. The vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis and has therefore been pursued as a target for cancer therapy. Bevacizumab, a monoclonal antibody against VEGF, was the first anti-angiogenic agent to be approved for the treatment of non-small cell lung cancer (NSCLC). It provides modest improvements in overall survival when given in combination with carboplatin and paclitaxel for patients with advanced non-squamous NSCLC (12.3 m vs. 10.3 m).[1] A second phase 3 study of bevacizumab in combination with cisplatin and gemcitabine improved progression-free survival (PFS), but survival was not prolonged.[2] Bevacizumab can also be safely combined with the combination of carboplatin and pemetrexed, though there was no survival benefit for this combination when compared to carboplatin-paclitaxel-bevacizumab. [3] In all of these studies, bevacizumab was also given as maintenance therapy following 4-6 cycles of combination therapy for patients that achieved stable disease or an objective response. An ongoing phase III study (E5508) compares the role of bevacizumab, pemetrexed or both as maintenance therapy following initial therapy with carboplatin-paclitaxel-bevacizumab for 4 cycles. Based on its therapeutic utility in advanced stage NSCLC, bevacizumab was studied in earlier stages of the disease. However, administration of bevacizumab with concurrent chemoradiotherapy in the treatment of stage III NSCLC was deemed unsafe by a study conducted by SWOG. The results of a phase III study that evaluated bevacizumab in combination with chemotherapy in the adjuvant setting for early stage NSCLC (E1505) will be reported at the 16[th] World Conference on Lung Cancer. In another encouraging development, the combination of bevacizumab and erlotinib was associated with improved progression-free survival (PFS) in patients with epidermal growth factor receptor (EGFR) mutations compared to erlotinib alone in a phase II study conducted in Japan.[4] The median PFS was approximately 16 months for the combination compared to 9.7 months with erlotinib. This is the first study to show incremental efficacy over that of an EGFR tyrosine kinase inhibitor in this patient population. An ongoing study in the Western population will verify the results of the Japanese trial. Taken together, bevacizumab has proven to be a valuable addition to the therapeutic armamentarium against NSCLC. The use of bevacizumab is not recommended for patients with squamous cell histology due to the higher risk of hemoptysis. A number of small molecule VEGFR tyrosine kinase inhibitors were studied in patients with advanced NSCLC. Though many of these agents including sunitinib, sorafenib and axitinib were active as monotherapy, combination studies with chemotherapy or other targeted therapy failed to demonstrate survival benefit. Consequently, the development of nearly all of these agents has been discontinued in NSCLC. Recently, nintedanib, a small molecule tyrosine kinase inhibitor of VEGFR, fibroblast growth factor and platelet-derived growth factor, has been approved in Europe for the treatment of advanced lung adenocarcinoma in combination with docetaxel. Nintedanib has demonstrated single agent activity in advanced NSCLC and was subsequently studied in combination with docetaxel as salvage therapy in a large phase III study.[5] There was a statistically significant improvement in overall survival for patients with adenocarcinoma histology that received the combination of docetaxel and nintedanib compared to docetaxel alone (12.6 m vs. 10.3 m, HR 0.83). A second confirmatory study is presently ongoing in patients with lung adenocarcinoma. Ramucirumab is a monoclonal antibody against the VEGF-R2 receptor. It has recently been approved for the treatment of advanced NSCLC in the salvage therapy setting in combination with docetaxel. This was prompted by the REVEL study that compared docetaxel given with ramucirumab or placebo in patients with advanced NSCLC following progression with a prior platinum-based regimen.[6] There was an improvement in overall survival with the addition of ramucirumab to docetaxel (10.5 m vs. 9.1 m, HR 0.86). The median PFS was also improved for the combination (4.5 m vs. 3.0 m, HR 0.76). The incidence of grades 3/4 febrile neutropenia (16% vs. 10%), fatigue (14% vs. 10%) and hypertension (6% vs. 2%) were higher in the ramucirumab group. The overall results are noteworthy since this is the first study to demonstrate improvement in overall survival for a combination regimen in salvage therapy of advanced NSCLC. In summary, though the role of novel anti-angiogenic agents in NSCLC has been well established, their impact has been relatively modest in improving patient outcomes. The lack of predictive biomarkers has proven to be a major hurdle to identify patients that are likely to gain robust benefits. Efforts to identify combination strategies to improve the efficacy of anti-angiogenic agents have also been unsuccessful to date. Activation of alternate pathways that regulate angiogenesis could be an important reason for the limited success of anti-angiogenic therapy. The recent data on the combination of VEGF inhibition and EGFR inhibition in patients with an activating EGFR mutation warrant further evaluation, particularly to understand the mechanistic basis for the interaction. If confirmed, this approach is likely to be studied in patients with other ‘driver’ oncogenic events.References 1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. The New England journal of medicine 2006; 355(24): 2542-50. 2. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2010; 21(9): 1804-9. 3. Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013; 31(34): 4349-57. 4. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. The lancet oncology 2014; 15(11): 1236-44. 5. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The lancet oncology 2014; 15(2): 143-55. 6. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384(9944): 665-73.

Abstract:
Angiogenesis-targeting drugs have been evaluated in a multitude of lung cancer settings, with variable results. Unlike other pathways, these drugs target host related pathways and host responses to lung tumors. Thus there is the potential for both host and tumor mechanisms to lead to variable responses to therapy. In the advent of precision medicine, there has been a concerted effort to evaluate whether there are known genetic and genomic, epigenomic, serologic, and tissue biomarkers of response or toxicity to both anti-angiogenesis monoclonal antibodies and small molecule inhibitors of the angiogenesis pathways. Such studies will be reviewed in detail. Nonetheless, the evaluation of such biomarkers has been challenging, as the relevant anti angiogenesis pathways are large, mechanisms of drug function are often incompletely understood, and tumor-stromal interactionsare particularly difficult to measure. There are currently no clear examples of biomarkers that can define the anti-angiogenesis drug responsive patient. However, this review will focus on both the key opportunities and challenges associated with defining potential biomarkers related to anti-angiogenesis drug therapy in lung cancer, and the current state of ths research. Biomarker development has mostly focused on the discovery of novel marekrs of the VEGF pathway. The roles of assessing magnitudes and directions of association must still be supplemented by the evaluation of test performance, namely biomarker discriminatory performance and calibration. The need to move biomaker association studies towards these other specific evaluations will help move the field of VEGF-related biomarker research forward.

Abstract:
When the results of E4599 were presented over a decade ago the era of anti-angiogenesis in the treatment of advanced stage NSCLC began. Though the overall survival benefit with the addition of the vascular endothelial growth factor (VEGF) antibody, bevacizumab, to carboplatin/ paclitaxel was only 2 months, it was not only the first randomized phase III trial to show a survival benefit with the addition of any agent to a first line platinum doublet, but also the first to break the 12 months overall survival barrier in a first-line advanced stage NSCLC trial.(Sandler 2006) The enthusiasm lessened with the results of AVAiL, which failed to show an overall survival benefit when bevacizumab was added to cisplatin/gemcitabine.(Reck 2010) However, significant response improvement has been seen in all trials with bevacizumab and many patients benefit from this anti-angiogenesis approach. Recent data from China confirmed the overall survival data from E4599 with a carboplatin/ paclitaxel chemotherapy backbone.(Zhou 2015) The use of bevacizumab with multiple different chemotherapeutics has been explored, and many agents have been added to the E4599 backbone regimen, unfortunately with limited success to date. Ongoing trials continue to utilize this strategy including with everolimus, vorinostat, cixutumumab, GDC-0941, TG4010, and innumerable others. Of particular note, S0819 is a large randomized phase III study in the United States exploring the addition of cetuximab to carboplatin/paclitaxel +/- bevacizumab.(ClinicalTrials.gov Identifier: NCT00946712) A biosimilar bevacizumab (Pf 06439535) is under investigation in a randomized phase III trial of 798 patients in combination with carboplatin/paclitaxel, compared to the E4599 regimen.(ClinicalTrials.gov Identifier: NCT02364999) Key research questions about bevacizumab at this time focus on duration of therapy. E5508 (ClinicalTrials.gov Identifier: NCT01107626), which recently completed accrual, addresses the question of maintenance with bevacizumab. This trial builds on E4599 such that all patients receive carboplatin/ paclitaxel/ bevacizumab for 4 cycles. Those without progression at that time then continue on bevacizumab alone until progression (as per E4599) or stop bevacizumab and start pemetrexed, or receive both agents. The results of this randomized phase III trial of over 1200 patients are eagerly awaited to determine an optimal maintenance approach. The results will also determine the benefit of prolonged bevacizumab use. Earlier work with bevacizumab in a maintenance setting included the AVAPERL trial which showed promising results with the combination of pemetrexed/bevacizumab maintenance compared to bevacziumab maintenance alone after a cisplatin/ pemetrexed/ bevacizumab first line regimen in advanced nonsquamous NSCLC.(Barlesi 2013) Based on positive data in colorectal and ovarian cancer, and retrospective data in lung cancer, demonstrating a survival benefit with continuation of bevacizumab beyond progression, the phase IIIb study AvaALL (MO22097) (ClinicalTrials.gov Identifier:NCT01351415) randomizes patients to continuation of bevacizumab, or not, at the initiation of second line chemotherapy after progression on a bevacizumab containing first-line regimen.(Gridelli 2011) Overall survival is the primary endpoint and a clear survival benefit in this trial will significantly alter the treatment landscape for those patients with adenocarcinoma, without a driver mutation, who are treated with first line bevacizumab. Similar smaller studies are also ongoing. The use of bevacizmab with EGFR targeted therapy in patients with tumors harboring EGFR mutations is an area of particular interest after positive phase II trial results with the combination were published in 2014.(Seto 2014) This Japanese study showed a significant progression free survival advantage with the combination compared to single agent erlotinib as first line therapy in this patient population. Several ongoing trials seek to confirmation these results including a randomized phase II study in the United States (ClinicalTrials.gov Identifier: NCT01532089) and a non-randomized trial in Europe (BELIEF ClinicalTrials.gov Identifier: NCT01562028). Trials looking at bevacizumab in combination with newer immune targeted drugs such as the checkpoint inhibitors targeting PD-1 and PD-L1 are ongoing. The largest is a 3-arm phase III study looking at carboplatin/ paclitaxel with or without bevacizumab PLUS the PD-L1 targeted atezolizumab (MPDL3280A) compared to a control arm of carboplatin/ paclitaxel/ bevacziumab.(ClinicalTrials.gov Identifier: NCT02366143) The study will enroll 1200 patients. Smaller phase I trials of other PD-1 agents in combination with multiple different regimens include carboplatin/ paclitaxel/ bevacizumab arms. Examples include a multi-arm pembrolizumab study (ClinicalTrials.gov Identifier: NCT02039674) and a trial with nivolumab which includes a bevacizumab maintenance with nivolumab arm.(ClinicalTrials.gov Identifier:NCT01454102) Bevacizumab is not the only anti-angiogenesis agent. The VEGFR-2 antibody ramucirumab had recent approval by the US FDA when given in combination with docetaxel in the 2[nd] line setting.(Garon 2014) In contrast to bevacizumab, which is restricted to non-squamous NSCLC, ramucirumab is approved for any histology of NSCLC. Ongoing trials with ramucirumab include a large (N=462) randomized double-blind study of erlotinib with ramucirumab or placebo in EGFR mutation positive NSCLC (ClinicalTrials.gov Identifier: NCT02411448) and a phase 1 study of the agent in combination with pembrolizumab.(ClinicalTrials.gov Identifier: NCT02443324) The VEGFR TKIs continue to have unrealized potential in NSCLC. Combination studies with first-line chemotherapy have been universally negative for an overall survival benefit, though response rates and progression free survival were positive in many studies. Second line trials with docetaxel have also shown response and PFS benefit and subset overall survival benefits, particularly with nintedanib.(Reck 2014) Single agent activity of many is seen, but in a small percentage of patients. However, enthusiasm for these agents in NSCLC has waned and current trials with these drugs are limited. Bevacizumab remains an important component of first-line platinum combination therapy for many patients with advanced stage NSCLC. Ongoing trials are exploring duration of therapy questions with this drug and best ways to incorporate its use with newer immunotherapeutics. Combinations with molecularly targeted agents hold promise. Ramucirumab use may also be expanded to combinations with targeted agents pending results of ongoing trials. Resurrection of the VEGFR-TKIs in NSCLC will require further understanding of best combination therapies and better understanding of how to target them to the proper patients. The biggest challenge with anti-angiogenesis therapy remains a lack of reliable biomarkers. REFERENCES: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al.; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, et al. BEYOND: A randomized, double-bline, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer.J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. Gridelli C, Bennouna J, de Castro J, Dingemans AM, Griesinger F, Grossi F, Rossi A, Thatcher N, Wong EK, Langer C. Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. Clin Lung Cancer. 2011 Nov;12(6):407-11. Epub 2011 Jun 25. Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): An open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. Epub 2014 Aug 27. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. Lancet. 2014 Aug 23;384(9944):665-73.. Epub 2014 Jun 2. Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55.

Abstract not provided

Abstract:
The optimal management of locally advanced NSCLC is discussed controversially and depends from various aspects including the extend of N2 disease and/or T-stage as well as the patients risk profile and preference and the institutional experience. Therefore existing guidelines need a balanced modification during the tumorboard taking into account the different aspects relevant for the patient’s outcome and hence to define the best individualized treatment. Due to the lack of fully convincing randomized trials and the diversity of phase II studies and especially the heterogeneity of the study population, it is not surprising that the available evidence is interpreted differently and discussed controversially. Survival data may differ widely between studies and an explanation is often elusive. Patient selection is among other factors the key for differences in outcome. Unfortunately N2 disease is often imprecisely described. Several authors have proposed that N2 disease should be divided into subgroups. The question, whether N2 disease is resectable, cannot be answered easily in borderline situations since several co-founding factors play a role. The question includes at least four different aspects. The first aspect is resectability. The surgeon has to answer if the affected lymph nodes are completely removable. This question is a prerequisite and is typically answered by analysing images especially the CT or PET/CT by an experienced surgeon. The second and even more critical aspect relates to the question if local resection is useful for the patient since N2 disease may be the tip of an iceberg and indicate more than just locally advanced disease and rather a disease with systemic spread of tumor cells to other organs. The third aspect is the response rate of the tumor and mediastinal lymph nodes to neoadjuvant chemo- or chemo-radiotherapy. Finally the fourth consideration has to take into account the risk benefit ratio for the patient regarding the treatment. It is relevant for the decision making to evaluate to what risk the patient is exposed when a lobectomy or pneumonectomy is performed after neoadjuvant therapy. There are subgroups in stage IIIA (N2) which can be defined in which treatment recommendations are agreed among most oncologists, surgeons and radiotherapists. Microscopic N2 found unexpectedly during surgery and a radical resection of the tumor as well of the lymph nodes is possible and tolerated by the patient, surgery should be completed and adjuvant therapy is recommended. On the other hand in cases of bulky multilevel N2 at initial diagnosis and especially persistent after neoadjuvant therapy, surgery is not generally indicated since the patient will not experience a profit. The main controversy occurs in cases with initially diagnosed N2 disease at either a single or in some adjacent stations but surgically resectable. These patients are recommended to undergo neoadjuvant chemo- or chemo-radiotherapy followed by surgery most cases but direct surgery followed by adjuvant treatment is justified in single station N2 without extranodal disease. Definitive chemo-radiotherapy is reserved for those who are not completely resectable or with a high perioperative mortality. In general, these patients require a lobectomy with a complete mediastinal lymphadenectomy. In locally advanced stages, many surgeons still prefer to do these operations though a thoracotomy and in only a smaller percentage of patients can be operated minimal invasively by VATS. The invasiveness of the approach (VATS or open) is in any case of less importance than the completeness of the resection. Pneumonectomy should be avoided whenever possible and reconstructive techniques with bronchial-and or vascular reconstructions (sleeve resections) should be considered. These techniques can be done safely, even after induction chemo-or chemoradiotherapy. However, there are clear situation, when a pneumonectomy is necessary to achieve a complete resection and this should be considered, when the patient tolerates it functionally. Treatment of patients with locally advanced lung cancer is a challenge and requires the expertise of specialists from each discipline who respect the benefit and limitations of each individual technique in order to define the best individual treatment.

Abstract:

Abstract:
Overview Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with regard to tumor extent, prognosis and treatment options. Surgery is indicated in some patients, but the majority of patients receive radiotherapy and chemotherapy alone. The standard of care for unresectable stage III NSCLC patients with a good performance status consists of concurrent chemoradiation. The chemotherapy regimen usually consists of a platinum doublet and radiation doses of at least 60 Gy is standard. The prognosis for these patients remains dismal with a median survival time of 15-22 months and the need for improved treatment approaches is urgent. The optimal choice of chemotherapy and radiation dose and the schedules for these have been under investigation but is still not clearly defined. Radiation dose escalation studies have not resulted in better outcomes and with potentially harmful effects. Clinical studies of targeted agents in unselected patient groups, including therapies against epidermal growth factor receptor (EGFR) and angiogenic factors, have not been successful. The recent advances in molecularly targeted therapies together with technological advances in radiotherapy opens up for novel treatment strategies with potentially improved outcomes and less toxicity. This presentation will give an overview of randomized studies incorporating new approaches to combined modality therapy in stage III disease, including immune therapy with PD-1/PD-L1 inhibitors, inhibitors of EGFR and ALK as well as proton radiotherapy.

Abstract:
Radon exposure is recognized as the second cause of lung cancer, after active cigarette smoking (1,2). Each year, 15 000 to 21 000 lung cancer deaths are estimated for the consequence of radon exposure in USA. In Europe, 18 000 deaths are attributable to radon, around 9 % of deaths from lung cancer. Atmospheric concentrations of natural radon gas vary importantly due to concentration of [226]Ra and [232]Th, present in soil of some geographic areas. Most of the radon in indoor spaces of houses and other dwellings is derived from the inert gas transfer from the soil or rock. Short-lived radioactive progeny from inhaled radon, polonium-214 and polonium-218 induce emission of alpha particles (2 protons and 2 neutrons) that directly damage DNA and can induce lung cancer. Radon progenies are inhaled either as free particles, or attached to airborne particles, as dust. The adverse effect of radon has been described since the fifteenth century in the Ore Mountains of Eastern Europe. As early as the 20[th] century, radon was identified a cause of lung cancer in miners in Eastern Europe. Large epidemiological studies on miners showed a link between lung cancer risk and radon exposure at high concentration. In 1988, International Agency for Research on Cancer (IARC) recognized radon, as a group 1 carcinogen, based on the results of epidemiological studies in uranium miners. The risk was correlated to radon exposure in eleven cohort studies in non-smoker and smoker miners, with a sub-multiplicative interaction between smoking and radon (3). In 1970s, it was recognized that the population could be exposed to radon in indoor environments, including home and dwellings. An association between the risk of lung cancer and residential radon concentration during the previous 30 years was outlined. Epidemiological case-control studies have reported clear evidence of a relation between lung cancer incidences in the general population and radon indoor exposure, at an average annual concentration above 200 Bq/m[3] (4,5,6). A dose-response model is used without a threshold value, but this concept is matter of controversy for low dose To improve the statistical power, pooled case-control studies have been made in the USA, Europe and China, after variable adjustment for sex, smoking habits (Table 1). The combined estimation from the pooling studies showed an increase of 10% per 100 Bq/m[3 ](7). In the European pooled case-control studies, the estimated lung cancer risk, at 0, 100, and 400 Bq/m[3], was 25.8, 29.9, 42.3 for current smokers (15-24 cigarettes per day) versus 1.0, 1.2, 1.6 for lifelong non-smokers (6). The relationship between active smoking and radon exposure seems to be synergic. The same relation is observed in patients with lung cancer exposed both to radon and environmental tobacco smoke (ETS). In Spain, a case control-study demonstrates that ETS exposure at home upgrades significantly the risk in individuals with radon exposure than 200 Bq/m[3 ](7). Concerning histological types of lung cancers observed, an excessive relative risk for small-cell lung cancer was first reported among the underground miners. In fact, all the histological types are present, most common being adenocarcinoma and squamous cell carcinomas. A recent study in Spain, in never-smoker cases exposed to radon, finds that the most frequent histology is adenocarcinoma, as now observed in non-smoker patients (8). The exact mechanism of lung cancer induced by alpha particles is not known. Alpha particles can cause DNA damage, chromosome aberrations, and generate reactive oxygen species. The results are a cell cycle modification, an up- and down-regulation of cytokines, and an increased potential for carcinogenesis. Despite these promising investigations on a mutation hotspot in one codon of the TP53 gene and in other regions, any molecular fingerprint of alpha particles has been identified in specific genes involved in lung cancer carcinogenesis. Reducing and controlling this natural radiation, the second cause of lung cancer, is paramount in the general population, especially in radon prone area. The WHO guideline has proposed a reference level of 100 Bq/m[3] (2.7 pCi/L) to reduce the risk of lung cancer in the population (9). In the USA, the Environmental Protection Agency action level is 148 Bq/m[3] (4 pCi/L) for the home. In Sweden, 35-40 % of lung cancer attributable to radon could be prevented if in all homes or dwellings radon concentrations over 100 Bq/m[3] were lowered to 100 Bq/m[3] (10). Buildings or houses with high radon concentration must be identified. New constructions should be “radon-proof”. Many strategies have been proposed to reduce indoor radon levels in the home. In conclusion, radon is the second leading cause of lung cancer among smokers and a major cause in non-smokers. Radon exposure must be identified in the population to reduce the level of exposure to individuals. Preventive measures are necessary for new homes in a high radon area. Smoking cessation is also important to reduce the risk of lung cancer from radon exposure. Bibliography 1. Samet JM, Avila-Tang E, Boffetta P, et al. Lung cancer in never smokers: clinical epidemiology and environmental risk factors. Clin Cancer Res 2009;15(18):5626-45. 2. Tirmarche M, Harrison JD, Laurier D et al. ICPR, 2010. Lung cancer risk from radon and progeny and statement on radon. ICPR publications 115, Ann. ICPR 40(1). 3. Lubin JH, Boice JD, Edling JC et al. 1994. Radon and lung cancer risk: A joint analysis of 11 underground miner studies. Publication No. 96-3644. US National Institutes of Health, Bethesda, MD, USA. 4. Krewski D, Lubin JH, Zielenski JM at al. Radon and risk of lung cancer: a combined analysis of 7 North-American case-control studies. Epidemiology 2005;16:137-45. 5. Lubin JH, Wang ZY, Boice JD Jr et al. Risk of lung cancer and residential radon in China: pooled results of two studies. Int J Cancer 2004;109:132-7. 6. Darby S, Hill D, Deo H et al. Residential radon and lung cancer-detailed results of a collaborative analysis of individual data on 7,148 persons with lung cancer and 14,208 persons without lung cancer from 13 epidemiological studies in Europe. Scand J Work Environ Health 2006;32(suppl 1):1-83. 7. Torres-Duràn M, Ruano-Ravina A, Parente-Lamelas I et al. Lung cancer in never smokers. A case-control study in a radon prone area (Galicia, Spain). Eur Respir J 2014;44(4):994-1001. 8. Torres-Duràn M, Ruano-Ravina A, Parente-Lamelas I et al. Residential radon and lung cancer characteristics in never smokers. Int J Radiat Biol. 2015 May 13:1-24. 9.World Health Organization. Handbook on indoor radon. A public health perspective. WHO Geneva, Switzerland, 2009. 10. Axelsson G, Anderssson EM, Barregard L. Lung cancer risk from radon exposure in dwellings in Sweden: how many cases can be prevented if radon levels are lowered? Cancer Causes Control 2015; 26 (4): 541-7.

Geographic area	Population Controls Cases	Relative risk per 100 Bq/m[3 ](95% CI)
USA, Canada 7 studies	4 966 3 662	1.10 (0.99-1.26)
China 2 studies	1 995 1 050	1.13 (1.01-1.26)
Europe 13 studies	14 208 7 148	1.08 (1.03-1.16)

Table 1: Pooled analysis of case-control studies of indoor radon exposure, based on measured concentration radon (4-6).

Abstract:
Indoor air pollution. Indoor air pollution is thought to be the main determinant of the elevated risk of lung cancer experienced by nonsmoking women living in several regions of China and other Asian countries. The evidence is stronger for coal burning in poorly ventilated houses, but also burning of wood and other solid fuels, as well as fumes from high-temperature cooking using unrefined vegetable oils such as rapeseed oil. A positive association between various indicators of indoor air pollution and lung cancer risk has also been reported in populations exposed to less extreme conditions than those encountered by some Chinese women, for example populations in Central and Eastern Europe and other regions. Overall, the evidence is stronger for studies of indoor pollution in population which used coal as main fuel. IARC has classified indoor emissions from household combustion of coal as established human carcinogen, and indoor emissions from household combustion of biomass fuel (primarily wood) as probable human carcinogen. Outdoor air pollution. There is abundant evidence that lung cancer rates are higher in cities than in rural settings.This pattern, however, might result from confounding by other factors, notably tobacco smoking, and occupational exposures, rather than from air pollution. Cohort and case-control studies are limited by difficulties in assessing past exposure to the relevant air pollutants. The exposure to air pollution has been assessed either on the basis of proxy indicators—for example, the number of inhabitants in the community of residence, residence near a major pollution source—or on the basis of actual data on pollutant levels. These data, however, reflect mainly present levels or levels in the recent past and refer to total suspended particulates, sulfur oxides, and nitrogen oxides, which are not likely to be the agents responsible for the carcinogenic effect, if any, of air pollution. Furthermore, the sources of data might cover quite a wide area, masking small-scale differences in exposure levels. The combined evidence suggests that urban air pollution might entail a small excess risk of lung cancer on the order of 50%, but residual confounding cannot be excluded. In four cohort studies, assessment of exposure to fine particles was based on environmental measurements. The results of these studies are suggestive of a small increase in risk among people classified as most highly exposed to air pollution. IARC recently classified outdoor air pollution as an established lung carcinogen in humans.

Abstract:
Marijuana is a mixture of dried, shredded leaves, flowers, stems, and seeds from the hemp plant, Cannabis Sativa. Cannabis is a genus of flowering plants that has psychoactive properties. The main active chemical is THC (delta-9-tetrahydrocannabinol). The psychoactive effects are primarily a state of relaxation and euphoria to some degree. Record of cannabis use dates back to the Chinese Emperor Shen Nung in 2727 BC. In the 1500s, Spaniards imported it into the Americas. The amount of THC in marijuana has been steadily increasing and is much stronger now than 30 years ago. The average THC levels have risen from less than 1% in the 1970s to 12% in 2012. (1,2) Uruguay is the first and only country to fully legalize marijuana, but a number of other countries are considering doing so. The Netherlands, especially Amsterdam, is well-known for its tolerance of marijuana use. Medical marijuana use is legal in 23 of the 50 states in the USA. The states of Colorado, Washington, Oregon, Alaska, and District of Columbia have legalized recreational marijuana use. A number of other states have decriminalized the use of marijuana and others are considering approval for recreational use. Most users smoke marijuana in hand-rolled cigarettes called joints, but it can also be smoked in blunts (cigars), bowls, pipes, bongs, or vaporizers. It is also available in oral forms for ingestion. This lecture will be limited to the health effects on the lungs of smoking marijuana. (2,3) Lung Effects: Marijuana smoke contains many of the same toxins and carcinogens as tobacco smoke. (4) In a systematic comparison of smoke from marijuana and tobacco cigarettes consumed under two sets of smoking conditions, there were qualitative similarities and some quantitative differences. Ammonia was 20-fold greater in marijuana. Nitric oxide, hydrogen cyanide, and some aromatic amines were three to five times more than those in tobacco smoke. Selected polycyclic aromatic hydrocarbons were in lower concentration in marijuana. (4) Accurate studies on the health effects of marijuana use are difficult due to the illegal status of its use, variation in its use, and concomitant use of tobacco. (3,5) Bronchoscopic biopsies from subjects who smoke marijuana alone or marijuana and tobacco have been evaluated for histopathologic changes and molecular alterations. Smokers of marijuana alone reported symptoms of cough, sputum, wheeze, and acute episodes of bronchitis. (6) Histologic abnormalities were most frequent in smokers of both marijuana and tobacco. However, smokers of marijuana along did show changes of basal cell hyperplasia, inflammation, and squamous cell metaplasia in a large percentage of the 40 subjects examined. (6) Immunohistochemical analysis of bronchial biopsies from smokers of marijuana only demonstrated increased Ki-67 expression (cell proliferation marker) in 92% and increased EGFR expression in 57%. (7) Marijuana smoking does not appear to cause airflow obstruction. A study with 20 years of follow-up did not observe any significant change in pulmonary function. In a large cross section of US adults, cumulative life-time marijuana use up to 20 joint-years was not associated with airway obstruction. (8) There have been conflicting reports on the association of marijuana smoking and lung cancer. A 40-year cohort study from Sweden evaluated the baseline use of cannabis and cigarette smoking and the risk of lung cancer. They observed a strong dose-response relationship between tobacco use and lung cancer. They also reported a two-fold risk of lung cancer [HR 2.12 (95% CI 1.08-4.14)] in heavy cannabis smokers, even after adjustment for baseline tobacco use. (9) A major weakness of the study was reliance on only baseline self reporting of tobacco and cannabis use. No other data on use of these two agents was obtained throughout the 40 years of the study. A pooled analysis of six case-control studies from the US, Canada, United Kingdom, and New Zealand was performed to study the specific association between cannabis smoking and lung cancer. This included data on 2,159 lung cancers and 2,985 controls. (10) The odds ratio was 0.88 (95% CI 0.63-1.24) for individuals who smoked one or more joint-equivalents of cannabis per day and odds ratio of 0.94 for those who consumed at least 10 joint-years. The results from the pooled analysis provide little evidence for an increased risk of lung cancer among habitual long-term cannabis smokers. In summary, smoking marijuana causes airway inflammation and bronchitis, but to date there is no convincing data that it causes COPD or lung cancer. The level of the evidence is limited by the suboptimal quality of past studies. The current use and dose of inhaled marijuana is changing and therefore measurement of the pulmonary health effects are a moving target. References: http://www.deamuseum.org/ccp/cannabis/history/html (last accessed June 30, 2015) Volkow ND, et al. NEJM 2014; 370:2219-27 Tashkin DP. Annals ATS 2013; 10:239-47 Moir D, et al. Chem Res Toxicol 2008; 21:494-502 Howden ML, et al. Expert Rev Resp Med 2011; 5:87-92 Fligiel SH, et al. Chest 1997; 112:319-26 Barsky SH, et al. J Natl Cancer Inst 1998; 90:1198-1205 Kempker JA, et al. Annals ATS 2015; 12:135-41 Callaghan RC, et al. Cancer Causes Control 2013; 24:1811-1820 Zhang LR, et al. Int J Cancer 2015; 136:894-903

Abstract:
The landscape of tobacco product use in the US is changing. Although cigarette smoking rates have declined in recent years, use of other tobacco products such as little cigars, waterpipe and electronic nicotine delivery systems (ENDS) is increasing. Background information about these “alternative” tobacco products, use trends, smoke or aerosol constituents and potential toxicities, especially those that may increase risk for lung cancer in users or bystanders, will be presented. Cigar consumption in the US increased from 6.2 billion cigars in 2000 to 13.3 billion in 2010 and is most common among young adults aged 18-24 years. This increased use has been attributed to use of little cigars and cigarillos, products that are less expensive alternatives to cigarettes in the US. “Small cigars” may be more likely to be smoked in similar fashion to cigarettes, especially by former cigarette smokers and dual users of cigarettes and cigars. Given that cigar smoke compared to cigarette smoke has higher concentrations of toxic and carcinogenic constituents (e.g., tobacco specific N-nitrosamines (TSNAs), carbon monoxide (CO), benzene), cigar users that inhale the smoke into the lungs may have greater risks for adverse health effects compared to cigarette smokers. Analysis of 25,000 participants from the US National Health and Nutrition Examination Survey (NHANES, 1999–2012) identified that current cigar/former cigarette smokers had significantly higher cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentrations compared to cigar smokers with limited cigarette use, and NNAL concentrations were comparable between daily cigar and daily cigarettes smokers. Waterpipe (WP), also known as hookah, shisha and narghile, heat a mixture of tobacco, honey or molasses, and flavorings using charcoal. A centuries old style of smoking tobacco popular in Middle Eastern countries, waterpipe use has markedly increased in Europe and the US, and is especially popular among young people who frequently misperceive that the water filters out the harmful chemicals in the smoke. WP smoke contains many of the known toxicants and carcinogens found in cigarette smoke, including polycyclic aromatic hydrocarbons (PAHs), nicotine, TSNAs, volatile aldehydes and CO. Due to the burning charcoal, WP users are exposed to higher levels of CO, benzene and PAHs compared to cigarettes smokers. E-cigarettes, the most popular types of electronic nicotine delivery systems (ENDS), were developed in China in approximately 2003 and are increasingly popular in the US and Europe. ENDS heat an “e-liquid”, typically composed of nicotine, propylene glycol or glycerin, and flavorings into an aerosol that is inhaled by the user. The chemical constituents in ENDS aerosols are impacted by the device design, the e-liquid composition and user behaviors, and have not been adequately characterized. Carcinogenic and toxic compounds that have been detected in e-cigarette liquids and aerosols include TSNAs, formaldehyde, acetaldehyde, acrolein, PAHs and metals. However, in general, the amounts identified have been less than in cigarette smoke. The potential cytotoxicity and carcinogenicity of e-cigarette flavorings are being investigated.

Abstract:
The global burden of lung cancer is significant and growing. In 2015, WHO reported that there were almost 1.7 million deaths from lung cancer and this number could increase 1.5 times by 2030 (1).The cost associated with the management of lung cancer is significant and can be expected to increase dramatically. It has been estimated that the costs to manage lung cancer will increase in Canada by 80% from 2010 to 2030 but this may prove to be a gross underestimate because of new targeted and immuno-therapies (2). As smoking is the main cause of lung cancer, smoking cessation programs could improve not only the health of nations but also help to contain rising health care costs. In the face of the increasing global burden of lung cancer, it is instructive to consider the cost-effectiveness of lung cancer treatment in relation to smoking cessation programs. Cost effectiveness of lung cancer treatment options Treatment options for lung cancer depend on the stage and type of cancer. Recent advances in the treatment of metastatic non-small-cell lung cancer (NSCLC) have markedly increased the cost to health care systems and to patients themselves. When considering the implementation of new health care technologies, decision-makers consider the incremental cost of the new therapy (∆C) compared to the current standard in relation to the incremental benefit (∆E), usually expressed in life-years gained, to determine the incremental cost-effectiveness ratio or ICER. The life-years gained may be adjusted for the quality of the life lived with the disease and its treatment producing an estimate of cost per quality-adjusted life year or QALY. The ICER is influenced by many factors including the choice of comparator (best supportive care vs a chemotherapy regimen), the time horizon of the analysis, the inclusion of the cost of managing early and late adverse events, amongst other factors. Not surprisingly, the major determinant of the ICER for most new drugs is the price of the drug and the magnitude of the clinical benefit. A review of economic evaluations of drugs used for advanced non-squamous NSCLC suggests that ICERs are progressively rising: the ICER for erlotinib as a 3[rd] line therapy was only $39,000/LY when compared to BSC (3). However, the ICER for pemetrexed used as a 1[st ]line treatment in tumours with no known mutations was $142,500 US dollars (2013) per QALY when compare to best supportive care (BSC) and $164,000 per life year (LY) gained when compared to erlotinib (4).Estimates of the ICER for afatinib based on the pan-Canadian Oncology Drug Review (pCODR) ranged from $39,000 to 211,000/QALY when compared to gefitinb reflecting the uncertainty in the clinical benefit in the absence of a head-to-head comparative trial (5). The ICER for crizotinib as first-line therapy in ALK +ve patients ranged from $173,570 (CDN) to $285,299, reflecting uncertainty in economic model assumptions related to the incremental benefit and the time horizon selected (5). ICERs above $100,000 per QALY are generally not considered “cost-effective” in Canada. The trend to higher ICERs could reverse with immune check point inhibitors given the potential for long term survival (much greater ∆E) in some patients, although the incremental cost may be unacceptably high (6). However, it must be remembered that dollars spent on lung cancer treatments cannot be spent on something else and represent a lost opportunity cost no matter how cost-effective the treatment appears. Value of smoking cessation programs Although some countries and American states have invested in public health programs to reduce smoking, globally there has been a low level of investment suggesting that there is resistance to investing in smoking cessation. This may be due to the perception that cessation interventions are ineffective, that smokers do not want to quit or that smoking cessation interventions are not cost effective (7). These commonly held perceptions are wrong. Smoking cessation (e.g., telephone counseling and pharmacological interventions) has been shown to improve health outcomes and survival. Most smokers in the general population, at least in North America, have made multiple quit attempts and express the desire to quit and cost-effectiveness estimates range from about $330 to $1500 US per life-year gained (7). A review of economic evaluations of smoking cessations programs shows that these programs are economically attractive and can even be cost-saving. For example, the American Cancer Society’s telephone counseling service nearly doubled a smoker’s odds of quitting and staying stopped for one year at a cost of approximately $1,500 per smoker (8).Nicotine Replacement Therapies (NRT) compared to self-help have an ICER of $1,500/QALY while varenicline was a dominant option compared to NRT. Also generally unrecognized are the health benefits to cancer patients, although these benefits have been well outlined in the 2014 U.S. Surgeon General’s Report on Smoking (9). Nonetheless, smoking cessation programs are rare in the oncology setting and information on the cost-effectiveness of smoking cessation in the oncology setting is limited. One study examined the cost-effectiveness of a pre-operative smoking cessation program for patients with early-stage NSCLC in the United States (10), and reported an ICER of $2,609/QALY and $2,703/LY at 5-years post-surgery. The cost-effectiveness of smoking cessation programs could be more dramatic over longer time horizons. Even though the benefits of smoking cessation programs on clinical outcomes have been reported, including the value for money of these programs, more evidence on the impact of smoking on outcomes for lung cancer patients receiving radiotherapy and systemic therapy is clearly needed. Discussion Faced with a global epidemic of lung cancer and a growing number of new but expensive drugs, recognition that smoking cessation programs are both effective and cost-effective should drive public policy. References 1. World Health Organization. Projections of mortality and burden of disease, 2002-2030. World Health Organization,; 2002 [cited 2015]; Available at:http:www.who.int/healthinfo/global_burden_disease/projections2002/en/. 2. Hermus G, Stonebridge C, Goldfarb D, et al. Cost risk analysis for chronic lung disease in Canada: The Conference Board of Canada 3. Cromwell I, van der Hoek K, Taylor SCM, et al. Erlotinib or best supportive care for third-line treatment of advanced non-small-cell lung cancer: a real-world cost-effectiveness analysis. Lung Cancer 2012;76(3):472-7 4. Matter-Walstra K, Joerger M, Kuhnel U, et al. Cost-effectiveness of maintenance pemetrexed in patients with advanced nonsquamous-cell lung cancer from the perspective of the Swiss health care system. Value in health. 2012;15165-71 5. Available at pcodr website . 6. Available at am.asco.org/aso-plenary-nivolumab-ipilimumab-combination-effective-advanced-melanoma. 7. Parrott S, Godfrey C, Raw M, et al. Guidance for Commissioners on the cost-effectiveness of smoking cessation interventions. Thorax 1998; 53 (Suppl 5, Part 2): S2-S3 8. McAlister A, Rabius V, Geiger A, et al. Telephone assistance for smoking cessation: one year cost effectiveness estimations. Tobacco control. 2004;13(1):85-6. 9. The Health Consequences of Smoking - 50 Years of Progress. A report of the Surgeon General, 2014. U.S Department of Health and Human Services, Office of the Surgeon General, Rockville, MD 10. Slatore CG, Au DH, Hollingworth W. Cost-effectiveness of a smoking cessation program implemented at the time of surgery for lung cancer. Journal of Thoracic Oncology. 2009;4(4):499-504.

Background:
Rovalpituzumab tesirine (i.e. SC16LD6.5) is a Delta-like protein 3 (DLL3) targeted antibody-drug conjugate (ADC) comprised of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio of 2. DLL3 is highly expressed in human neuroendocrine tumors and their tumor-initiating cells, including approximately two-thirds of small cell lung cancer (SCLC). DLL3 is not expressed at detectable levels in normal tissues. Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin/etoposide in DLL3-expressing SCLC patient-derived xenograft tumor models. Based on this promising activity, a first-in-human phase I trial in patients (pts) with recurrent SCLC was initiated and preliminary results are reported below.

Methods:
SCLC pts with progressive disease after 1 or 2 previous lines of therapy received escalating doses of rovalpituzumab tesirine as a single agent once every 3 weeks (Q3W) in 1-3 pt cohorts until dose limiting toxicities (DLTs) were observed. The doses were 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg Q3W. Midway through accrual, pharmacokinetic data revealed a longer than expected ADC half-life of ~11 days, prompting evaluation of a Q6W schedule. A DLL3 antibody was developed and utilized to assess antigen expression in archived tumor specimens. Biomarker positive (BM+) tumors were defined by IHC membrane-associated H-Scores ≥ 120.

Results:
52 pts were treated: 34 Q3W and 18 Q6W; 24F/28M; median age, 61 years (44-82). Acute and chronic DLTs of thrombocytopenia and capillary leak syndrome (CLS) were observed at 0.8 and 0.4 mg/kg Q3W, respectively. Maximum tolerated doses (MTD) of 0.2 mg/kg Q3Wx3 cycles and 0.3 mg/kg Q6Wx2 cycles were further evaluated in expansion cohorts. The most common treatment emergent adverse events of any grade among all pts were fatigue (40%), rash (39%), nausea (29%), dyspnea (23%), decreased appetite (21%) and vomiting (21%). Grade 3+ CLS and thrombocytopenia were seen in 7 (14%) and 3 (6%) pts, respectively, with no reported Grade 5 toxicity. Of 38 archived tumor specimens received from enrolled pts, 23 (61%) were DLL3 BM+. Among the 16 confirmed DLL3 BM+ pts treated at the MTDs, 7 pts (44%) had partial response (PR) and 8 pts (50%) achieved stable disease (SD) for a combined clinical benefit rate (CBR) of 94%. In all evaluable pts treated at the MTD without regard for DLL3 biomarker status (n=32), the ORR was 22% (n=7 PR) and SD 53% (n=17), for a CBR of 75%. Notably, all pts with PRs that were treated at the MTD, and those having the most durable clinical benefit (up to 569 days OS), were BM+. Similar response rates were observed among pts sensitive and refractory to first-line therapy, and in the third-line setting where no standard-of-care currently exists.

Conclusion:
Rovalpituzumab tesirine, a first-in-class DLL3-targeted ADC, has manageable toxicity and demonstrated significant anti-tumor activity (44% ORR and 95% CBR) as a single agent in second- and third-line pts with recurrent DLL3 BM+ SCLC. A pivotal study is being planned.

Background:
Selected patients with good responses to platinum based chemotherapy and good performance status were candidates for continuum platinum based chemotherapy versus chemo-radiotherapy in Extensive-stage small cell lung cancer (ES-SCLC). To evaluate the efficacy and toxicity of continuum platinum based chemotherapy versus chemo-radiotherapy in ES-SCLC in Asian Indian patient population.

Methods:
Between July 2008 and December 2009, 358 patients with ES-SCLC treated with induction Cisplatin (60-80mg/m2 d1) + Etoposide (80-120 mg/m2 d1-3) × 3 cycles for every 3 weeks. Patients with CR at both local as well as distant sites or PR at the local site, but CR at distant sites were randomized 1:1 to two treatment groups (n=287). A total of 287 patients with response were randomized to accelerated hyperfraction thoracic RT (45Gy/1.5 Gy twice daily) plus PE × 4 (144) versus PE × 4 alone without radiation (n=143). The PE doses were similar as in induction. All patients received prophylactic cranial irradiation (25Gy/10 fraction/5/week). The primary endpoint was the comparison of progression free survival (PFS) between the two arms and the secondary endpoints included overall survival (OS). All statistical analyses were performed by using SPSS version 20.0.

Results:
Baseline characteristics were well balanced. Mean age was 58 years (range 32-69), 78% had ECOG 0-1; 22% ECOG 2. In the CRT arm 66.67% and in CT only arm 57.34% patients were smoker. Median PFS 15 months (CRT arm) versus 10 months (CT only) (HR, 0.78; 95% CI, 0.56-1.18; p=0.06) and 5-year OS 10.3% (CRT arm) versus 6.2% (CT only) (HR, 0.83; 95% CI, 0.49 to 1.29; p=0.47) respectively. The survival difference at 1 year was not statistically significant (39% vs 31%; HR=0.89, CI 0.69-1.13; p=0.091). The survival difference at 3 years was just significant (18% vs 11%; HR=0.83, CI 0.72-1.08; p=0.047). Local control trended better in CRT arm, but no difference in distant metastasis control in both arms.

Conclusion:
CRT arm showed better PFS and OS than CT only arm within Asian Indian patient population. Thus, the CRT may be used as a continuum treatment in Asian Indian patients of ES-SCLC after induction chemotherapy.

Background:
Although TRT in patients with ES-SCLC did not lead to a statistically significant difference in overall survival (p=0.066), it did improve 2-year survival rates (p=0.004) in the CREST trial (Slotman et al., Lancet 385:36-42:2015). The failure to meet the primary study endpoint has evoked some controversy in the lung cancer community as to which patients should be offered TRT routinely. To define which patients benefit most from radiotherapy, analysis for overall survival (OS), progression free survival (PFS) and recurrence pattern was performed in patients with and without RITD, which was one of the stratification factors in the randomized study.

Methods:
Patients with confirmed ES-SCLC who responded to 4-6 cycles of platinum-etoposide were randomized to TRT (30 Gy/10fx) or control. All received prophylactic cranial irradiation (PCI). The primary study endpoint was OS. Secondary endpoints were PFS, intrathoracic control. relapse pattern and toxicity.

Results:
Out of 495 patients in the intent-to-treat analysis, 434 had RITD (215 allocated to TRT and 219 to the control arm) and 61 had not (32 allocated to TRT and 29 to the control arm). No significant differences in patient characteristics were observed between the groups. In patients with RITD, OS was significantly longer in the TRT-arm (HR 0.81,95% CI 0.66-1.00;p=0.044). Survival rates in the TRT and control arm were 33% (95%CI 27-40) vs 26% (95%CI 21-33) at 1 year, and 12% (95%CI 8-19) vs. 3% (95%CI 1-8) at 2 years, respectively. PFS was also significantly longer in the TRT-arm (HR=0.70, 95%CI 0.57-0.85; p<0.001). Intrathoracic progression was reported in 43.7% of the TRT arm vs. 81.3% in the control arm (p<0.001). There was no significant difference in the risk of brain metastases (10.2% vs. 5.5%). Exclusive progression outside thorax and brain occurred in 37.2% in the TRT arm, compared to 5.9% in the control arm (P<0.001). In patients without RITD, there was no significant difference in OS (HR 1.02, 95%CI 0.59-1.77, p=0.937) and PFS (HR=1,00, 95%CI 0.59-1.70, NS) between the TRT and control arms.

Conclusion:
This additional analysis of the CREST data shows that ES-SCLC patients with RITD after chemotherapy have a statistically significant improvement in OS, PFS and risk of intrathoracic progression if they undergo TRT. No such benefit for TRT is seen in patients without RITD. These findings support the routine use of TRT in patients who respond to chemotherapy but still have residual intrathoracic disease.

Background:
Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized IgG4 monoclonal antibody against PD-1 designed to block the interaction between PD-1 and its ligands PD-L1 and PD-L2, has demonstrated robust antitumor activity and a manageable toxicity profile in several advanced cancers, including NSCLC. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1–positive SCLC in the ongoing, multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov, NCT02054806).

Methods:
Key eligibility criteria for the SCLC cohort include failure of or inability to receive standard therapy, ≥1 measurable lesion per RECIST v1.1, ECOG performance status 0 or 1, PD-L1 expression in ≥1% of cells in tumor nests or PD-L1–positive bands in stroma as assessed by IHC using the 22C3 antibody at a central laboratory, no autoimmune disease, no interstitial lung disease, and no prior anti–PD-1 or anti–PD-L1 therapy. Pembrolizumab is given at 10 mg/kg every 2 weeks for 24 months or disease progression, intolerable toxicity, or investigator decision. Patients with progressive disease who are clinically stable may continue treatment until confirmation of progression 4 weeks later. Response will be assessed per RECIST v1.1 by investigator review every 8 weeks for the first 6 months, then every 12 weeks thereafter. Adverse events (AEs), including potentially immune-related adverse events, will be collected throughout the study and for 30 days (90 days for serious AEs) thereafter. Primary end points are safety and tolerability and the overall response rate. The relationship between pembrolizumab antitumor activity and potential biomarkers, including the level of PD-L1 expression, is an exploratory end point.

Results:
Of the 147 patients with SCLC who had evaluable tumor samples and were screened for PD-L1 expression, 42 (29%) had PD-L1–positive tumors. Overall, 24 patients with SCLC were enrolled and received ≥1 pembrolizumab dose. Among the 20 patients treated as of March 13, 2015, median age was 59.5 years, 55% were men, and 75% had an ECOG performance status of 1. All patients had received prior chemotherapy with a platinum + etoposide.

Conclusion:
Analyses of safety and tolerability and response are ongoing, as are analyses on the relationship between the level of PD-L1 expression and pembrolizumab response. These data will be available for presentation.

Abstract not provided

Background:
With the advent of modern chemotherapy, patients previously thought to have unresectable small cell lung cancer (SCLC) may have tumors amenable to surgery. This study was undertaken to test the hypothesis of whether surgery, in the setting of modern adjuvant therapies, offers a survival advantage among patients with node-positive SCLC.

Methods:
Overall survival (OS) of patients with pT1-2 pN1-2 M0 SCLC who underwent non-operative management (chemotherapy ± radiation) vs surgery (with adjuvant chemotherapy ± radiation) in the National Cancer Data Base (NCDB) from 2003-2011 was assessed using propensity-score-matched analysis. Groups were matched for common prognostic co-variates (year of diagnosis, age, sex, race, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, pathologic T and N status, and tumor location). NCDB data is prospectively collected by certified tumor registrars and include over 70% of cancer cases diagnosed annually in the U.S.

Results:
Of 1,071 patients who met inclusion criteria, 359 (33.5%) patients underwent surgery with adjuvant chemotherapy ± radiation and 712 (66.5%) underwent non-operative management. After propensity-score matching, 11 covariates were balanced between the surgery (n=231) and non-operative (n=231) groups. Surgery was associated with a significantly higher OS than non-operative management (5-year OS 28.1% vs 18.3, log-rank p<0.01) (Figure 1). To minimize treatment selection bias due to comorbidities, we limited the propensity-matched analysis to patients with no comorbidities; surgery remained significantly associated with a higher OS than non-operative management (5-year OS 32.1% vs 21.8%, log-rank p<0.01) (Figure 2). Figure 1 Figure 2





Conclusion:
In a propensity-matched analysis of a national population-based cancer database, surgery followed by adjuvant chemotherapy ± radiation for SCLC pT1-3 pN1-2 patients had improved outcomes when compared to non-operative medical treatment. These results support an increased role of surgery in multimodality therapy for more advanced limited-stage small cell lung cancer.

Background:
NCCN, ACCP and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC), while ESMO guidelines recommend surgery for patients with c-stage II (T1,2 N0,1). In addition, the clinical impact of surgery with other variables on patients with early-stage SCLC has yet to be determined. Therefore, clarification of the clinical profile of surgically resected SCLC is required. Suppression of MED12, a subunit of the transcriptional MEDIATOR complex in conjunction with cell surface expression of TGF-βRII was reported to be correlated with the resistance mechanism of EGFR-TKIs, crizotinib, and chemotherapy. Few investigators examined the expression profile of MED12 as well as receptor tyrosine kinases in SCLC. A next-generation sequencing (NGS) system is a novel technology for sequencing genomes at high-throughput and with great accuracy using deep sequencing. It has been instrumental for translational study integrating the detection of genetic alteration analysis into the better understanding of tumor biology, as well as treatment of various types of cancers. Recently, SOX-2 amplification, histone modification, and genetic alterations in the PI3K/AKT/mTOR pathway were reported to be potential targets of SCLC using NGS through whole exon analysis. However, further investigation is needed for the personalized treatment of SCLC. We updated the molecular data using NGS, which had been presented at ESMO 2014 (abstract ID: 5724).

Methods:
We reviewed the clinical courses of 156 patients with SCLC who had undergone surgery at 17 institutes from January 2003 through January 2013. One hundred twenty-five formalin-fixed paraffin-embedded tissue samples were subjected to immunohistochemistry using seven antibodies (MED12 and TGF-βRII, ALK, c-Met, EGFR, c-kit, and VEGFRII) and to NGS systems using MiSeq and TruSight Tumor Sequencing Panel (Illumina) loading 26 cancer-specific genes. (UMIN registration No. 000010116 /10117).

Results:
Median relapse-free survival and overall survival (OS) were 15.6 (95%CI=6.8-24.5) and 33.3 (20.9-45.8) months, respectively. Multivariate analysis revealed that OS was longer in patients without a history or presence of other types of cancer (HR: 0.545, 95%CI=0.335-0.887, p=0.014), with preoperative diagnosis (HR: 0.510, 95%CI=0.299-0.871, p=0.014), with c-stage II and under (HR: 0.288, 95%CI=0.154-0.541, p<0.001) and with prophylactic cranial irradiation (HR: 0.300, 95%CI=0.092-0.976, p=0.045). Of the 125 patients whose samples were available, MED12 and TGF-βRII were highly expressed in nucleus and cytoplasm, respectively in 92% and 55% of the samples. None of the tumors expressed ALK. There was no relationship between the expression of c-Met, EGFR, and VEGFRII and either of RFS or OS. Multivariate analysis demonstrated that high expression of c-kit in tumor is an independent factor for longer OS (HR=0.543, 95%CI: 0.310-0.953, p=0.033). Seventy-nine samples have been subjected to NGS. Three actionable gene mutations, EGFR (E746_A750del), KRAS (G12D), and AKT1 (E17K) were found.

Conclusion:
These results supported the ESMO guidelines for the management of early-stage SCLC, and indicated that presence or history of other types of cancer might be a major decisive factor for surgery. The results of immunohistochemistry using antibodies of selective molecules and NGS assist us in gaining a better understanding of the biology and treatment strategy of SCLC.

Abstract not provided

Background:
Given its widely metastatic nature at the time of diagnosis and the lack of effective therapies, early detection could theoretically have a beneficial impact on small cell lung cancer (SCLC) patient survival. However in the National Lung Screening Trial (NLST), there was no survival advantage for SCLC in the low dose computed tomography (LDCT) arm versus the chest radiography (CXR) arm. We investigated whether LDCT could detect SCLC and whether such screen detection offered a stage and/or survival benefit.

Methods:
Subjects randomized to the LDCT arm in NLST received three annual LDCT screens. Incident cancers were tracked with annual surveys and confirmed with medical records, with abstractors coding lung cancer stage and histology. “Best” stage was defined as pathologic stage if available, otherwise clinical stage. Deaths were tracked with the annual surveys and supplemented by the National Death Index. Cancer was denoted as screen-detected if it was diagnosed within one year of a positive screen or if it was diagnosed after a longer period but with no time gap between diagnostic procedures of more than one year. An interval cancer was defined as a cancer diagnosed within one year of a negative screen. Non-screen detected or interval cancers were denoted as non-screened if the subject did not receive any NLST screens or otherwise as post-screening.

Results:
26,722 subjects were randomized to the LDCT arm (median follow up 6.5 years; 59% men; median age at enrollment 62). 143 SCLCs were diagnosed [49 (34.2%) screen-detected, 15 (10.5%) interval, 79 (55.2%) non-screened/ post-screening]. The ratio of interval to screen detected cases was significantly higher for SCLC (15/49=0.31) than for NSCLC (29/591=0.05); p < 0.0001. 123 of 143 (86%) SCLCs were detected at late-stages (best stage III/IV); the unfavorable stage-distribution persisted among screen-detected, interval and non-screened/ post-screening cases with only 15 (10.5%) detected in early-stages. Three-year lung cancer-specific survival was 72% for early-stage versus 11% for late-stage disease. There was no significant difference in five-year survival between screen-detected, interval and non-screened/post-screening SCLCs (15.3%, 20.0% and 13.8%, respectively). Unlike NSCLC, even at small nodule sizes the proportion of screen-detected SCLCs that were late stage was very high.

Conclusion:
Analysis of SCLC detected in the NLST LDCT arm show that yearly LDCT screens do not detect a significant number of early stage SCLCs. Compared with NSCLC, a higher proportion of SCLCs are interval-detected than screen-detected. Further, there is no stage-shift or survival benefit for screen- detected SCLCs compared with interval or post-screen detected cases. To our knowledge this is the largest analysis to date of SCLC detected in a screening study. Our results indicate that in order for a screening modality to be successful for SCLC, it is necessary (but not sufficient) to be able to detect it earlier than does LDCT.

Background:
Small cell lung cancer (SCLC) accounts for 15-20% of lung cancer cases worldwide and is characterised by early dissemination. Despite initial responses to chemotherapy, most patients relapse with drug resistant disease and long term survival is rare. Targeting tumour vasculature in SCLC with anti-angiogenic drugs produced disappointing results. However, angiogenesis-independent tumour vascularisation including vasculogenic mimicry (VM), warrant further investigation. VM describes the ability of aggressive tumour cells with ‘stem-like’ plasticity to adopt endothelial characteristics and form fluid conducting channel-like structures independent of host vasculature. We sought to determine the prevalence of VM in SCLC and explore associations of VM with chemotherapy sensitivity and patient outcomes. We investigated the role of a VM-associated protein, VE-Cadherin in vitro and in vivo and in SCLC CTCs. We are testing the hypothesis that VM may contribute to the high prevalence of CTCs in SCLC and components of the VM pathway may be targets for SCLC therapeutics.

Methods:
VM was evaluated using CD31/periodic acid-Schiff (PAS) staining in a tissue micro-array (TMA) from 41 limited stage SCLC chemo-naive patients and in tumours from 11 Circulating Tumour Cell (CTC) Derived Explant (CDX) models (Hodgkinson et al Nature Medicine, 2014). The relative abundance of VM channels (CD31-ve/PAS+ve) compared to host derived blood vessels (CD31+ve/PAS+ve), (VM/total vessels) in the TMA was compared to patient overall survival (OS). VM was evaluated in vitro by network formation in Matrigel (Hendrix et al., PNAS 2001) in a panel of SCLC cells lines and in H446 cells where VE-Cadherin was knocked down with shRNA. H446 cells +/- VE-Cadherin were grown in vivo as xenografts and evaluated for VM. ISET filtered, DAPI stained CTCs were immune-stained for CD45, cytokeratin and VE-cadherin and a VM score was generated.

Results:
In the TMA, a VM/Total Vessels score >10% was a poor prognostic factor for OS by univariate (p=0.011) and multivariate (p=0.014) analyses. VM was present in all CDX models provide surrogate tissues in which to study VM. Of 12 SCLC cell lines studied, H446 showed significant VE-Cadherin expression and formed networks in Matrigel; VE-Cadherin shRNA abrogated this network formation. Similarly, a pilot in vivo study demonstrated that there were fewer VM vessels when VE-Cadherin was reduced. In CTC samples 37/38 chemonaive SCLC patients contained a sub-population of VE-Cadherin expressing CTCs where the VM score ranged from 0 – 100% (median 11%, mean 21%).

Conclusion:
We present the first evidence of VM in SCLC which correlates with poor OS consistent with findings in other cancer types. VE-Cadherin is required in SCLC for VM network formation in vitro and preliminary data indicate that VE-Cadherin influences VM in vivo. Furthermore, VE-Cadherin and pan-cytokeratin co-expression was found in SCLC CTC sub-populations. We are investigating the role of VE-Cadherin in VM in SCLC and are exploring the hypotheses that VE-cadherin and VM may play a role in drug delivery and/or sensitivity and may represent an aggressive, ‘stem-like’ population that may contribute to dissemination and relapse in this highly aggressive disease.

Background:
There were mainly two kinds of lung cancer xenograft models, xenograft models derived from stable cell lines and patient derived xenograft (PDX) models which adopted tissues resected by surgeries. However, these animal models may not reflect biological and genetic characteristics of advanced lung cancer, especially small cell lung cancer (SCLC). We utilized bronchoscopy-guided biopsy tumor tissues of advanced lung cancer to establish xenograft models and analyzed fidelity of histopathology, genetic profile and chemotherapeutic efficacy with their parental tumors. At last the molecular mechanism of drug resistance in refractory SCLC was studied.

Methods:
Primary pulmonary tumor tissues taken from bronchoscopy were implanted to NOD-SCID (nonobese diabetic-severe combined immunodeficiency disease) mice subcutaneously for model establishment and consecutive passage. The histopathology and genetic profile in samples of bronchoscopy-guided biopsy tumor tissues-derived xenograft (BDX) models and their parental tumors were detected. Parental fidelity of BDXs’ chemotherapeutic response was detected by chemosensitivity in vivo. Next generation sequencing (NGS) of target gene was taken in SCLC BDXs to analyze high-fidelity with their parental samples. Based on bioinformatic analysis, molecular mechanism of sensitive and refractory SCLC was discussed.

Results:
66 BDXs from 188 patients (35%) were successfully established. Successful rate of BDXs in SCLC was significantly higher than that in squamous cell cancer (SCC) (50.72% vs. 32.00%, p=0.005) and in adenocarcinoma (ADC) (50.72% vs. 16.22%, p=0.025). The growth rate of passage 1 BDXs in SCLC was slower than it in SCC or ADC (P<0.0001). Almost all BDXs kept similar histology, pathological marker and driver-gene mutations with their corresponding patients’ tissues. The gene mutations of which frequency was more than 10% in patient’s SCLC were kept consistent in BDXs with same genotype and frequency. Gene mutations which regulated mitogen activated protein kinase (MAPK) pathway as KRAS, KIT, MET were only detected in refractory SCLC and corresponding BDXs rather than sensitive disease. In further functional verification, the percentage of positive pERK was 100% (5/5) in refractory BDXs, but 20% (1/5) in sensitive BDXs (p=0.0476).

Conclusion:
BDXs which were successfully established with high-fidelity of histopathology, genetic profile and chemotherapeutic response could be utilized as animal models in research of unresectable lung cancer. MAPK pathway related gene mutations found in both BDXs and primary tumor tissues may be associated with resistance in refractory SCLC. PERK was promising to be used as molecular markers in genotype and prediction of chemotherapy-resistance for SCLC.

Abstract not provided

Background:
Myeloid-derived suppressor cells (MDSCs) play a key role in microenvironment for tumor progression and have been emerged as a promising target in immunotherapy for tumor. We reported the existence and characteristics of monocytoid MDSCs in peripheral blood of patients with small-cell lung cancer (SCLC). In this study, we further identify the predictive and prognostic of MDSCs in a larger cohort of SCLC patients.

Methods:
60 healthy and 228 chemotherapy-naïve patients with SCLC participated. Peripheral venous blood samples prior to chemotherapy (baseline) and after the second cycle of chemotherapy (2[nd] cycle) were collected and detected for MDSCs (CD11b[+]HLA-DR[-]CD33[+]) by flow cytometry.

Results:
Median age of the patients was 58 years (range 18-79). MDSCs in limited-stage (n=147) and extensive-stage patients (n=81) were (16.41±8.54)% and (17.20±10.43)% respectively, higher than those in healthy control (11.04±3.76)%, P<0.001。The level of MDSCs were lower after 2[nd] cycle than those pre-treatment, (8.47±5.51)% versus (17.61±6.69)%, P<0.001. Patients with response to chemotherapy (CR+PR+SD) showed lower MDSCs level than those with progression disease at both time points, (15.85±9.07)% versus (18.42±8.89)%, P=0.026 at baseline and (8.20±5.31)% vs (10.65±6.73)%, P=0.045 after 2[nd] cycle. Patients with MDSCs level ≥22% (2 fold of healthy control) showed favorable overall survival than those with MDSCs level <22% (13.9 months versus 7.9 months respectively, log rank P=0.003). No difference regarding to median progression–free survival was observed between the two groups.

Conclusion:
MDSCs level at both baseline and after the second cycle of chemotherapy was associated with response of SCLC patients to chemotherapy and overall survival, implying it is likely a new predictive and prognostic biomarker for SCLC patients.

Background:
Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been under-studied relative to novel therapies. Therapeutic antibodies to immune checkpoints are showing promising clinical results. Programmed death-ligand 1 (PD-L1), which can be expressed on many cancer and immune cells, plays an important role in blocking the cancer immunity cycle by binding programmed death-ligand 1 receptor (PD-1), which is a negative regulator of T-lymphocyte activation. Since knowledge about PD-L1 expression in SCLC is limited, we aimed to characterize PD-L1 expression in a cohort of 98 SCLC patients.

Methods:
PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC, SP142, Spring Bioscience) and mRNA in situ hybridization (ISH) in primary tumor tissue microarrays obtained from 98 SCLC patients. Membranous staining of PD-L1 protein and mRNA expression on tumor cells and protein expression on tumor-infiltrating immune cells (TIICs) were scored separately using semi-quantitative scores (H-score 0-300 and RNA score 0-4). An H-score ≥ 5 and an RNA score > 2 were defined as the cutoffs for PD-L1 protein and RNA expression positivity. The degree of TIICs was semi-quantitatively scored on hematoxylin and eosin-stained TMA slides as having “0” (no), “1” (mild), “2” (moderate), or “3” (marked) infiltration. The data was analyzed using the Fisher’s exact test, Spearman correlation, two-sample t-test, log-rank test and Kaplan- Meier survival analysis with significance level assumed to be 0.05.

Results:
3.16% of cases (3/95) were positive for PD-L1 protein expression in tumor cells, and 30.21% were positive for PD-L1 in TIICs (29/96, p<0.0001). PD-L1 mRNA expression was positive in 15.46% of the tumor cells (15/97). PD-L1 protein and mRNA expression on tumor cells demonstrated a positive correlation (p<0.0001, r=0.431). PD-L1 mRNA expression on tumor cells positively correlated with PD-L1 protein expression on TIICs (p<0.0001, r=0.354). The degree of TIICs positively correlated with both PD-L1 protein expression in tumor cells (p=0.011, r=0.264) and PD-L1 mRNA expression in tumor cells (p<0.0001, r=0.405). The degree of TIICs positively correlated with PD-L1 protein expression in TIICs (p<0.0001, r=0.625). The only significant association observed between PD-L1 expression with clinical characteristics or prognosis of the 78 SCLC patients with clinical data, was between age of patients and PD-L1 protein (p<0.0001) and mRNA expression (p=0.0006) on tumor cells.

Conclusion:
A subset of SCLCs is characterized by positive PD-L1 protein and/or mRNA expression in tumor cells and TIICs. PD-L1 mRNA expression was more frequently positive than PD-L1 protein expression in the tumor cells. PD-L1 protein expression was expressed more in TIICs than tumor cells. Higher PD-L1 protein and mRNA expression correlated with more infiltration of TIICs. PD-L1 expression represents the immune response in SCLC. The microenvironment may play a major role on the PD-1/PD-L1 pathway of SCLC. SCLC Patients with PD-L1 expression may respond to anti-PD-L1 treatment.

Background:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor characterized by extreme plasticity, high metastatic potential, and capacity for acquired resistance to chemotherapy. Despite significant advances in our understanding of SCLC genetics and etiology, the epigenetics of this deadly disease remain under studied. This study profiles DNA methylation in primary SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution.

Methods:
This study profiled DNA methylation at single-nucleotide resolution in 47 extensively characterized SCLC samples, including 34 fresh frozen primary SCLC tumors as well as 6 distinct primary patient-derived xenografts and 7 cell lines using the Illumina Human Methylation 450k Bead Chip array. Importantly, 24 primary SCLC in this study have previously been analyzed by whole exome sequencing and RNAseq, allowing integrated analysis of these data types with measurements of DNA methylation. We applied unsupervised clustering, discrete and locally clustered differential methylation analysis, correlation with gene expression, spacial correlation with genomic features, and interrogated the role of the EZH2 methyltransferase in SCLC using bioinformatic and pharmacologic approaches.

Results:
Unsupervised clustering of all samples revealed that PDX clustered with primary SCLC, while cell lines were easily discriminated. We explored this phenomenon further and found that while the top differentially methylated CpGs in both PDX and cell lines were >80% concordant with primary SCLC, only PDX maintained high concordance across larger probe lists. Unsupervised clustering of primary SCLC revealed three distinct subgroups at both the DNA methylation and gene expression levels that correlated with expression of the neurogenic transcription factors ASCL1 and NEUROD1. The chromatin modifier EZH2 was expressed >12-fold higher in SCLC than in normal lung. In addition to the high expression observed in SCLC compared to normal lung, we observed a significant correlation between median EZH2 gene expression and promoter methylation using data from The Cancer Genome Atlas (TCGA). Overall, EZH2 expression in SCLC is greater than or comparable to that of any other tumor type represented in TCGA. EZH2 protein expression was detected by Western blot in 15/17 SCLC PDXs (88%). We assessed the efficacy of the potent EZH2 inhibitor EPZ-5687 in the LX92 SCLC PDX in vivo. EPZ-5687 was well-tolerated and demonstrated remarkable efficacy at 100 mg/kg either QD or BID.

Conclusion:
DNA methylation patterns in primary SCLC are more closely mirrored by those found in PDX, compared to cell lines, including PDX lines of very high passage. Distinct epigenetic subtypes could be observed in SCLC, even among histologically indistinguishable samples with similar mutation profiles. SCLC is notable for consistent high level DNA methylation clustered in promoters containing CpG islands. Promoter methylation in SCLC is distinct from other lung cancers and correlates strongly with high-level expression of the histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth. These findings point to a critical role of EZH2 in SCLC tumor biology and support further preclinical efficacy studies in models of SCLC.

Abstract not provided