Virtual Library

Abstract:
There are two clinical trial investigating the role of surgery in stage IIIA NSCLC.

Abstract not provided

Abstract:
Introduction: Standard treatment of stage IIIA non-small-cell lung cancer consists of definitive concurrent chemoradiotherapy (CTx/RTx) protocols. Based on the broad heterogeneity of stage IIIA alone, there are selected patients (single mediastinal lymph node involvement, IIIA3 Robinson) where induction chemotherapy (CTx) followed by definitive surgery may be an alternative and valid approach preferably to test within prospective clinical trials with a close documentation of the toxicity/efficacy ratio. Patients and Methods: The medical literature (PUBMED) was reviewed looking for the search terms “induction chemotherapy“ and “stage III“ and “non-small cell lung cancer“. Furthermore large clincal trials were added that had been presented at important clinical conferences such as ASCO, WCLC and ESMO. Prospective phase-III clinical trials and prospective phase-II clinical trials were examined and cathegorized for efficacy and outcome parameters. We looked specifically for general patterns in the reporting of clinical trials results. Results: General outcome parameters for efficacy that have been reported were: 1) objective response rates 2) overall survival (median) 3) progression-free survival rates 4) complete resection rates (R0-resection) 5) pathological complete response rates (pCR) in the primary tumor and 6) pathological complete response rates (pCR) in the mediastinum. On the other hand important benchmarks for toxicity were 1) grade 3 and grade 4 maximum toxicity rates during induction 2) perioperative toxicity rates grade 3 and 4 3) treatment related death rates. Very few investigations have looked at patient reported outcome parameters such as symptom improvement or quality of life evaluation during the complete treatment protocol. Several groups have tried to improve outcome data by the use of 1) three-drug regimen as induction treatment 2) second- and third-generation platinum-based combinations 3) introduction of new molecular targeted agents (VEGF, EGF-R etc) especially looking closely at the pathological complete response rates induced by induction therapy 4) inclusion of different radiation schemas within a concurrent or sequential preoperative application protocols. Several reported trials have also tried to alternatively give a definitive CTx/RTx protocol with increased radiation doses and have not included a definitive surgical approach. These studies could not report data on pathological responses and some have alternatively looked at FDG-PET response to induction therapy as a surrogate marker for pathological response. Currently the treatment protocols with the highest reported pathological response (pCR) rates were based on cisplatinum and taxane (paclitaxel and docetaxel) combinations and induction protocols including concurrent cCTx/RTx regimen were those with the highest pathological efficacy in the mediatinum as well as in the primary tumor. Conclusions and Outlook: With the existing broad heterogeneity in patient selection within the different clinical studies performed it is currently difficult to give an overall recommendation about the most optimal treatment approach in this setting of stage IIIA NSCLC. Induction CTx could potentially serve as a backbone for including new treatment principles (eg. molecular targeted agents, immunotherapy, CTx/RTx protocols) into these multimodality treatment protocols and closely monitoring outcome by translational investigations and pathological response evaluations.

Abstract not provided

Background:
Cisplatin-based chemotherapy and concurrent radiotherapy is the standard treatments for locally advanced non-small cell lung cancer ( LA-NSCLC). This trial evaluated two experimental regimens of chemotherapy with concurrent radiotherapy.

Methods:
Eligible patients (pts) with unresectable stage III NSCLC, 20 to 74 years of age, and ECOG PS of 0­–1 were randomized to either Arm SP, S-1 (40 mg/m[2]/dose per oral, b.i.d, on days 1-14) and cisplatin (60 mg/m[2] on day 1) repeated every 4 weeks or Arm VP, vinorelbine ( 20mg/m[2] on day 1, 8) and cisplatin (80 mg/m[2] on day) repeated every 4 weeks with early concurrent thoracic radiotherapy of 60Gy at 2 Gy per daily fraction. The primary endpoint was overall survival rate at 2-year (2yr-OS). A pick-the-winner design was used to identify the treatment regimen most likely to be superior. The planned sample size was 55 patients per arm, assuming in each arm that the null hypothesis for 2yr- OS was 50% versus an alternative hypothesis for 65% with one-sided alpha of 0.10 and power of 80%. All the radiation treatment plans were reviewed at quality assurance committee meetings. (Study ID: UMIN000002420)

Results:
One hundred eleven patients were registered between Sep 2009 and Sep 2012. Of 108 patients for efficacy analysis, the 2yr-OS was 76% (95% CI, 62-85%) for SP and 69% (95% CI, 54-79%) for VP. The hazard ratio (HR) of death between the two arms was 0.85 (0.48-1.49). The median progression-free survival (PFS) was 14.8 months for SP and 12.3 months for VP with a HR of 0.92 (0.58-1.44). 80% and 48% of pts completed the protocol treatment in SP and VP, respectively. Common grade 3-4 toxicities of both SP and VP were neutropenia 33%, 75%, platelets 9%, 4%, hemoglobin 26%, 28%, febrile neutropenia 9%, 17%, diarrhea 6%, 0% respectively. There were 4 and 5 treatment-related deaths in Arms SP and VP, respectively. The quality assurance committee judged that 74% of radiation treatment plans had no deviation and 24% had a minor deviation.

Conclusion:
Both arms rejected the null hypothesis for 2yr-OS. In this study Arm SP was declared the winner in terms of 2yr-OS, PFS, treatment completion, and toxicity.

Background:
Approximately 30% of non-small cell lung cancer (NSCLC) patients present with locally advanced (stage III) disease, and half are elderly (age ≥70). Young, fit patients with stage III NSCLC have improved survival with the use of combined chemotherapy and radiation therapy (CRT) over radiation therapy (RT) alone – HR 0.74 in a 2010 Cochrane systematic review. Elderly patients have more comorbid illnesses and suffer greater treatment toxicity, thus it is unclear whether they benefit more from CRT over RT. The objective of this systematic review is to explore the evidence base for using CRT in elderly patients with stage III NSCLC.

Methods:
We performed a systematic review including trials identified in MEDLINE, EMBASE and CENTRAL databases from inception to March 8, 2015, plus relevant conference proceedings since 2000. We included randomized controlled trials (RCTs) of elderly patients (≥70 years old) with stage III NSCLC or elderly subgroups from individual patient meta-analyses comparing CRT versus RT alone. We excluded studies that treated patients with palliative intent, included surgical patients, or in which both arms received chemotherapy. We did not restrict language. Two reviewers independently extracted summary outcome data. Risk of bias was assessed using the Cochrane Risk of Bias tool. We used a random effects model and inverse variance method to pool time-to-event outcomes. We calculated Peto Odds Ratios (POR) using RevMan 5.3 to pool dichotomous outcomes with a zero cell and otherwise calculated Risk Ratios (RR).

Results:
We screened 2951 citations identifying 68 articles for full text evaluation, 16 of which have not been accessible yet. Four reports of three studies met inclusion criteria (n = 407 elderly patients). All trials were evaluated as having a high risk of bias due primarily to lack of blinding. Overall survival in elderly patients was superior in those treated with CRT compared to RT (HR 0.66, 95%CI 0.53 to 0.82, I[2] 0%, p 0.0009). Progression-free survival was also improved with CRT (HR 0.67, 95%CI 0.53 to 0.85, I[2] 0%, p 0.001). Toxicity assessments were available in two studies with 119 patients receiving CRT and 121 RT. Treatment-related death occurred in 6 (5%) with CRT and 5 (4%) with RT (RR 1.22, 95%CI 0.38 to 3.88) and grade ≥3 pneumonitis was seen in 6 patients in each group, (RR 1.01, 95%CI 0.34 to 3.06) – neither was significantly different between treatments. Neutropenia – 57% v 2% (POR 14.38, 95%CI 8.26 to 25.04) and thrombocytopenia – 30% v 3% (RR 7.62, 95%CI 2.09 to 27.79) were more common with CRT. Febrile neutropenia occurred in 3 (2.5%) patients with CRT and zero patients with RT, but this did not meet significance (POR 7.54, 95%CI 0.78 to 72.82). No studies included patient-reported quality of life.

Conclusion:
CRT in elderly patients with stage III NSCLC results in improved survival as compared to RT alone, at the expense of increased treatment-related hematologic toxicity. Quality of life assessment should be included in any future trial design. CRT can be considered for fit patients ≥70 years of age with stage III NSCLC.

Background:
Locally advanced lung cancer lacks effective treatment options and requires aggressive radiotherapy (RT) with higher doses. In the light of RTOG 0617, multi-center dose escalation trials should avoid increasing organ at risk (OAR) toxicity and require strict quality assurance (QA). Exploiting the predictive value of FDG-PET, sub-volumes can be dose escalated, and by implementing image-guided adaptive RT, the total treatment volume (PTV) can be reduced. Incorporating these elements, the randomized multicenter trial NARLAL2 aims at increasing loco-regional control at 30 months without increasing major toxicity.

Methods:
Figure 1 In the standard arm, the PTV is treated with a homogenous dose of 66 Gy/33 fractions. In the experimental arm, the dose is heterogeneously escalated to the FDG-PET avid volumes, with mean doses up to 95 Gy/33 fractions and 74 Gy/33 fractions to the escalated volumes in the tumor and malignant lymph nodes, respectively. The escalation dose will be limited in favor of OAR constraints. A standard and an experimental treatment plan with similar mean lung doses of maximum 20 Gy are made for each patient prior to randomization. Quality Assurance: FDG-PET scans of a standard phantom (NEMA) and PET signal processing software from all centers were compared and acceptable agreement achieved. Multicenter delineation of OARs was performed and consensus achieved. Treatment planning and adaptive strategy consensus were based on a study including five patients with repeated CT-scans, requiring several steps before the achievable level of dose escalation and the number of patients needed in the trial could be defined. Daily online tumor set-up and adaptive strategies were mandatory. A QA committee for evaluation of RT plans and treatments and a central committee for evaluation of all non-biopsy-verified recurrences were established.



Results:
A mean dose of 91,9 Gy to the FDG-PET avid part of the tumor and 80 Gy to the clinical target volume was achieved in the planning study, corresponding to 16% estimated increase in locoregional control at 30 months. Assuming a loco-regional control of 56% at 30 months in the standard arm, a total of 330 patients were needed in order to resolve this effect with a power of 80% (95% significance level). Recalculation of escalated plans on CT-scans acquired at fraction 20 revealed an increase in OAR doses of 4-7Gy for two of five patients, endorsing the need for adaptive strategies.

Conclusion:
A dose escalation trial with strict QA has been set up. Patient enrollment started January 2015.

Background:
While the curative management of unresectable stage III non-small cell lung cancer (NSCLC) is definitive chemoradiotherapy, clinical outcomes remain poor. Cellular heterogeneity in tumors is correlated with therapeutic resistance and poor prognosis. We hypothesize that tumor-specific mutant allelic frequency in cell-free DNA from plasma quantifies tumor heterogeneity and that tracking allelic evolution via blood from patients during and after treatment can serve as a non-invasive means to monitor treatment response and recurrence.

Methods:
Between 2009-2013, 156 patients with unresectable NSCLC who received definitive radiotherapy or chemoradiotherapy were consented to have blood drawn at baseline before starting radiotherapy, once or twice during treatment, and once or twice during follow up visits. Cell-free plasma DNA was sequenced using a cell-free circulating tumor DNA (ctDNA) next generation sequencing (NGS) assay (Guardant360) that uses digital sequencing to report single nucleotide variants (SNVs) in 68 genes and amplifications in 16 genes. This ctDNA assay has high sensitivity (detects 85%+ of the SNVs detected in tissue in advanced cancer patients) and analytic specificity (>99.9999%). Over 670 serial samples were collected from these patients. Here we report the initial analysis of the first 26 patients of this ongoing study.

Results:
Among this initial cohort, 23 (88%) had a recurrence (PFS ranged from 1.2 – 27.9 months) and three (12%) had no evidence of recurrence as of last contact (32.8 – 42.8 months post-radiotherapy completion). Twenty-one patients (81%) had ctDNA alterations present pre-radiotherapy, of which six had a classic driver mutation: KRAS G12F x2; KRAS G12S; PIK3CA E545K x2; PIK3CA H1047R. These six patients had significantly shorter PFS compared to patients without a driver mutation present pre-radiotherapy: average PFS of 4.2 months (1.2 - 8.3) vs. 18.6 months (4.4 - 42.8) respectively (p=0.002). All six had the driver mutation disappear during radiotherapy, four had new alterations appear during and/or post-treatment. One patient had the driver mutation reappear in ctDNA post-radiotherapy and had the shortest PFS (1.2 months) of all patients. Ten patients (38%) had no ctDNA alterations present in the post-radiotherapy blood sample and a trend was observed of improved PFS among patients without ctDNA alterations post-treatment (average PFS 52.3 vs. 75.5 months respectively) however this was not statistically significant (p=0.1). Of note, the three patients without evidence of recurrence as of last contact had no ctDNA alterations identified in the post-treatment sample. This trend is anticipated to become significant with larger sample size.

Conclusion:
In this interim analysis, we found that the dynamic alterations of specific mutant alleles strongly correlated with clinical response and that persistence of ctDNA mutant allele concentrations post-definitive treatment is likely a marker of early metastatic recurrence. Undetectable ctDNA in post-treatment sample was seen in the three patients with approximately three years of PFS. These initial results suggest that serial ctDNA analysis may be useful to monitor treatment response and identify patients at high risk for early recurrence who may benefit from additional systemic therapy.

Abstract not provided

Background:
Concurrent chemo-radiotherapy (CRT) is the treatment of choice in loco-regional advanced non-small cell lung cancer (LA-NSCLC). Even though the patients are treated with curative intend the loco-regional control at 2 year is only about 30% in clinical trials. The aim of this study is to compare the loco-regional failure in patients treated with 66 Gy vs 60 Gy in the randomized phase II trial, NARLAL. Furthermore to analyze the localization of relapse compared to the original treatment plan.

Methods:
From 2009-2013 117 patients with LA-NSCLC were randomized in a national multicentre protocol between 60 Gy/ 30 F (arm A) and 66 Gy/ 33 F (Arm B), 5 FW. Navelbine[®] 50 mg 3 days a week was given as concomitant regimen. Patients were followed with CT scans every 3[rd] month in 2 years and hereafter every 6[th] month for another 3 years. As part of the protocol a PET-CT scan was performed 9 months after randomization. In case recurrent disease was suspected a biopsy was done from the lesion if possible. The recurrence gross tumor volume will be delineated and registered with the original radiation treatment plan to identify the site of failure.

Results:
Fifty-nine patients were treated in arm A and 58 patients in arm B. The median local recurrence free interval was 10 months in arm A and 10.9 months in arm B (p=0.57). At the end of this analysis 22 patients were alive with no evidence of loco-regional disease, 16 patients had died with no evidence of loco-regional failure. Loco-regional failure in high-dose area was diagnosed in 60 (51%) patients (33 patients in arm A and 27 patients in arm B). Loco-regional failure outside high-dose area was diagnosed in 19 patients. Fig 1. Treatment plan 60 Gy/ 30 F and PET-CT with relapse (verified by biopsy) Figure 1



Conclusion:
Although this treatment was with curative intend, the loco-regional control was disappointingly poor in both treatment arms. This is in line with other newly published clinical dose-escalations trials for NSCLC. In order to improve loco-regional control and hopefully survival homogeneous dose-escalation is not the choice. Inhomogenous dose-escalation may be an alternative. A phase III trial on this subject has just started enrolment in Denmark (NARLAL II, www.clinicaltrials.gov). Acknowledgements Supported by CIRRO- The Lundbeck Foundation Center for Interventional Research in Radiation Oncology.

Background:
Surgical resection after neoadjuvant chemoradiation therapy for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) carries high postoperative complications. Careful selection of candidate for surgery should be based on analysis of proven risk factors.

Methods:
We retrospectively reviewed all consecutive patients with clinical stage IIIA-N2 non-small cell lung cancer who underwent surgical resection after neoadjuvant chemoradiation therapy from 1997 to 2013. Preoperative, perioperative, and outcome variables which related to the morbidity and mortality were assessed. Univariate and multivariate analysis was done to identify predictors of postoperative morbidity and mortality.

Results:
During the study period, 574 patients underwent major pulmonary resection after induction therapy. The median time interval between the end of induction therapy and surgery was 33 days (range, 5-79 days). Thirty-day and ninety-day postoperative mortality were 1.4% (8 patients), and 7.1% (41 patients), respectively. The most common cause of In-hospital mortality was acute respiratory distress syndrome (n=6, 4.5%). Morbidity rate was 34.7 % (199 patients). Median hospital stay was 8 days (interquartile range, 7-11 days). Significant predictors of morbidity by multivariable analysis included patient age more than 70 years (odds ratio- 1.82;p=0.040), low body mass index <18.5 (odds ratio - 2.62;p=0.022), and pneumonectomy (odds ratio – 1.8;p=0.026). Significant predictors of mortality by multivariable analysis included patient age more than 70 years (odds ratio – 1.82; p=0.022), and pneumonectomy (odds ratio – 3.256; p=0.003). Ninety-day mortality was 15.8 % (9/57) in patient age more than 70 years, and 17.8 % (13/73) in patients who underwent pneumonectomy.

Conclusion:
Surgical outcomes after neoadjuvant CCRT for patients who are older than 70 year or undergo pneumonectomy are relatively poor. For those patients, there should be extra concern about the respiratory complications. And for the elderly patients with limited pulmonary reserves, other possible alternative treatment options, such as definitive CCRT rather than surgery should be considered.

Background:
Molecular profiling is a standard procedure in advanced non squamous NSCLC. Gene alteration in EGFR, BRAF or ALK gene can lead to prescription of targeted therapies and prolongs survival. The influence of molecular abnormalities on the survival of stage III NSCLC patients definitely treated by CRT is unknown.

Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intent for stage III NSCLC in a single institution. Paraffin embedded tissue block were collected. DNA was extracted for gene mutation analysis by next generation sequencing and ALK, ROS1 and RET rearrangements were detected by FISH analysis. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method.

Results:
Between January2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Platinum-based chemotherapy was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Seventy-eight patients were evaluable for mutation profile, 20 (26%) were female, 47 (60%) were current smoker, 40 (51%) had adenocarcinoma and there were 47/31 stage IIIA/IIIB. Mutations were positive as follow: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/66), PI3KCA 2% (1/58), HER2 0% (0/65), NRAS 3% (1/32), CTNNB1 3% (1/32). FISH was positive for ALK in 5% (3/56) of the NSCLC. In 32 NSCLC for which the test was performed, there was no alteration in ROS1, RET, HRAS and AKT1. Median Follow-up was 3.1 years (minimum 0.9 year). EGFR mutated or ALK+ (EGFR/ALK) group (n=11) and other mutation group (n=17) had a poorer progression free survival (median 0.8[95%CI: 0.6 ; 0.9] year and 0.5 [0.4 ; 0.8] year ; multivariate hazard ratio (HR)= 1.8 [0.8 ; 3.8] and 2.8 [1.5 ; 5.1] respectively, p=0.004) compared to the wild group (n=50) (median 1 year [0.9;1.3]). There was no significant difference (p=0.23, multivariate Cox) in overall survival: median 2.4 years [1.3 ; NR] for EGFR/ALK group, 1.1 [0.6 ; 2.5] for other mutation group and 1.9 [1.5 ; 2.5] for wild type. In multivariate analysis, only the dose of radiotherapy was significantly associated with overall survival (HR=0.5 [0.3 ; 1.0], p=0.04 in contrast with performance status or stage.

Conclusion:
This study suggests that selected gene alterations could be associated with a poorer survival in stage III NSCLC patients treated by combined modality treatment or radiotherapy alone. Their prognostic and/or predictive value should be further evaluated in a larger population.

Background:
Combined chemoradiotherapy (CCRT) improves long-term outcome of patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC). However, most pts die from distant failure due to preexisting occult metastases. Based on the premise that EGFR-TKI would improve the outcome of pts with stage III NSCLC that harbors sensitive EGFR mutations, as for the pts with stage IV NSCLC, we initiated a randomized phase II pilot trial that incorporated erlotinib (E) into CCRT treatment paradigms.

Methods:
Eligible pts over 18 years old with unresectable stage IIIA or IIIB NSCLC, ECOG PS 0–1, and adequate organ function were screened for EGFR mutation in axons 18–21 in the tumor sample. Those with EGFR mutation (+) tumors were randomized upfront to receive 3 cycles of 3-weekly E 150 mg/day treatment, and then either E x2 cycles concurrently with CCRT and x6 more cycles after CCRT (Arm A) or CCRT with 2 cycles of irinotecan-cisplatin (IP) but no additional therapy after CCRT (Arm B). When disease progression (PD) is documented during follow-up, E was re-instituted. Pts with EGFR mutation (-) or unknown tumors were randomized to receive either 3 cycles of IP induction followed by CCRT concurrently with 2 cycles of IP (Arm C) or CCRT with IP x2 first then consolidation with IP x3 (Arm D). IP chemo dose-schedule was irinotecan 60 mg/m[2] and cisplatin 30mg/m[2] iv on days 1 and 8 when given concurrently with RT (2.4 Gy/fx, total 60 Gy); irinotecan 65 mg/m[2] and cisplatin 30 mg/m[2] iv on days 1 and 8 when given every 3 weeks as induction or consolidation. The primary endpoint was overall response rate (ORR), toxicity, and overall survival (OS).

Results:
From 02/2008 to 03/2015, 59 pts (44 men and 8 women) with median age of 62 years (range: 37-78) were enrolled. There were 13 never smokers, 28 had adenocarcinoma, and 44 had IIIB tumors. EGFR mutation was (+) in 12, (-) in 28, and unknown in 19. There was apparent imbalance in histology and smoking status between the pts assigned to Arms A&B and C&D. ORR after induction E therapy was 75.0% for the 12 pts with EGFR mutation(+) tumors (Arm A, n=7; B, n=5). ORR after IP induction therapy was 63.6% for pts with EGFR mutation(-) or unknown tumors in Arm C (n=22). After completion of upfront CCRT therapy with IP in Arm D (n=25), ORR was 68.0%. There were no noticeable unusual side-effects. Median PFS for Arm A, B, C, and D, was 11.84, 8.09, 8.36, and 11.81 months respectively, with a trend toward better OS for pts with EGFR mutation(+) tumors (Arm A: not reached, B: 31.18 mos) than those EGFR mutation(-) or unknown tumors (Arm C: 17.93 mos, Arm D: 25.33 mos).

Conclusion:
The combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC patients. Although the number is rather small, pts with EGFR mutation (+) tumors seem to be a distinct subset with better overall survival than the others, which warrants careful consideration in chemoradiation therapy trial design and outcome evaluation.

Abstract not provided

Background:
RTOG 0617 investigated standard dose radiotherapy (RT) versus higher dose in the context of concurrent chemoRT with no advantage to higher dose treatment. IDEAL CRT investigated an alternative RT dose-escalation strategy with concurrent chemoRT in locally advanced NSCLC. Dose-per-fraction-escalation was used to achieve intensification without treatment prolongation. The trial would determine the maximum tolerable dose (MTD) deliverable to esophagus, and assess toxicity and early clinical outcomes for the schedule.

Methods:
Patients were enrolled to 2 groups, depending on maximum esophageal dose. Tumor doses were determined by esophageal constraints in Group 1 and other normal tissue constraints in Group 2. Patients received 63-73Gy in 30 once-daily fractions / 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. Group 1 esophageal dose-escalation followed a 6+6 design, increasing maximum dose to 1cc esophagus from 65Gy, 68Gy then 71Gy in successive cohorts, defining MTD by early and late toxicity. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and tumor response.

Results:
8 centres recruited 84 patients, treating 13, 12 and 10 in 65Gy, 68Gy and 71Gy group 1 cohorts. Prescribed RT doses are shown in figure 1. Median follow-up 24 months. 57 patients (68%) were stage IIIa and 21 (25%) IIIb. 5 grade 3 esophagitis events observed across both groups and 3 grade 3 pneumonitis. Following 1 fatal esophageal perforation in the 71Gy cohort, 68Gy was declared as esophageal MTD. Overall Survival (OS) and Progression Free Survival (PFS) were 87.8% and 72.0% at 1 year, and 67.1% and 50.4% at 2 years, median OS 39.3 months. OS is shown in figure 2. Figure 1 Figure 2





Conclusion:
Acceptable toxicity rates and promising survival were achieved. The isotoxic design proved practical, allowing significant treatment intensification and definition of MTD with relatively few patients. Results from longer follow-up are required and will be presented at the meeting.

Background:
Although the mean age at diagnosis of stage III non-small cell lung cancer (NSCLC) is 70 years, trials mainly include younger patients. Therefore, a lack of knowledge remains regarding tolerance and survival of standard treatment (concurrent chemoradiation (cCHRT)) and other treatment options for the elderly. The aim of this study was to evaluate administered treatment, assess motivations to omit cCHRT, and determine predictors for treatment tolerance and survival among unselected elderly with stage III NSCLC.

Methods:
In this multicenter retrospective study, all stage III NSCLC patients aged ≥70 and diagnosed in 2009-2013 in three Dutch teaching hospitals were included. Data on patient and tumor characteristics were derived from the Netherlands Cancer Registry and medical records regarding treatment details, geriatric patient characteristics, tolerance (completing treatment and/or no unplanned hospitalizations) and survival. Treatment and motives for omitting cCHRT were described. Univariate and multivariable analyses were performed to gain insight into predictive factors.

Results:
In the 219 included patients, mean age was 76 years, 78% was male and 51% had squamous cell carcinoma. Sixty-eight percent had a WHO Performance Status (PS) of 0-1, 22% PS 2, and 11% PS 3. Serious co-morbidity (severe organ decompensation or ≥2 moderate decompensations) was present in 59%, average co-morbidity (moderate organ compensation or ≥2 mild decompensations) in 16%, mild co-morbidity (mild organ decompensation) in 11% and 15% had no co-morbidities. Chemoradiation (CHRT) was administered in 55% of patients (33% cCHRT and 22% sequential CHRT (sCHRT)), 16% received only radical radiotherapy (RT) and 29% Best Supportive Care (BSC). CHRT was less often administered to patients aged ≥75 and those with a PS 2-3 (p<0.001). Also, patients with serious co-morbidity were less likely to receive CHRT, although not significant (p=0.10). The most common motives for omitting cCHRT were co-morbidity and/or poor PS (57%) and patient refusal (15%). Multivariable analyses showed that treatment and co-morbidity were predictive for tolerance. In comparison to cCHRT, tolerance was significantly better for RT (Odds Ratio (OR) = 5.1(95% Confidence Interval (95%CI) 2.1-13)) and non-significantly better for sCHRT (OR=2.2 (0.97-4.9)). Patients with serious co-morbidity had significantly worse tolerance compared to no co-morbidity (OR=0.28 (0.11-0.68). Even when corrected for patient characteristics, survival was not significantly better after cCHRT compared to sCHRT (Hazard Ratio (HR) = 1.1 (95%CI 0.76-1.7)) or compared to RT (HR=1.3 (0.81-2.0)). The 1-and 3-year Overall Survival (OS) rates for cCHRT were respectively 56% and 17%, for sCHRT 54% and 16%, and for RT 48 % and 9%.

Conclusion:
Co-morbidity, poor PS and patient refusal were the most common motives for omitting cCHRT. Although relatively fit and younger elderly were assigned to cCHRT, treatment tolerance was worse. OS was not significantly different between cCHRT, sCHRT and even RT. Since limited information on geriatric characteristics was available in this retrospective study, prospective studies including geriatric assessments are urgently needed to gather evidence on treatment options, resulting in the most optimal balance between quality of life and survival.

Background:
Uncertainty exists regarding the optimal surveillance strategy following definitive chemoradiation (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) with regards to both frequency and modality. We sought to determine the efficacy of frequent (q2-4 month) post-treatment imaging in detecting asymptomatic recurrent disease and document the clinical impact of frequent surveillance imaging.

Methods:
The records of all patients treated with CRT for stage IIIA/IIIB NSCLC between August 1999 and April 2014 at our institution were reviewed. Patients were included if they underwent frequent (Q2-4 month) chest computed tomography (CT) or positron emission tomography (PET/CT) for routine surveillance following CRT for at least one year following CRT or until disease progression or death. Radiographic findings and clinical interventions from the first year following CRT were identified.

Results:
We identified 145 patients with LA-NSCLC treated with CRT, 65 of whom underwent Q2-4 month surveillance imaging for at least one year or until progression or death. Median age was 63.6 years (range, 41.0-86.9 years). Forty-nine (75.4%) also underwent an initial baseline CT within the first 6 weeks following CRT. An asymptomatic recurrence was detected by surveillance imaging within the first year in 40 (61.5%) patients, 31 (77.5%) by CT and 9 (22.5%) by PET/CT. Among these patients, 21 (52.5%) initiated palliative systemic therapy. Three (7.5%) underwent attempted definitive therapy for isolated disease, including one patient treated with definitive lobectomy for what was found to be a histologically distinct new primary early stage NSCLC, and two patients treated with stereotactic ablative radiotherapy for isolated recurrences, both of whom subsequently developed metastatic disease. Urgent palliative local therapies (radiotherapy and bronchoscopy) were performed in 2 patients for impending neurologic and airway compromise, respectively. Ten patients (25%) with recurrences detected on surveillance imaging were not candidates for or declined additional cancer-directed therapy. Seven patients (10.8%) developed a symptomatic recurrence detected between planned scans. Five patients (7.7%) underwent additional diagnostic procedures for false-positive surveillance imaging findings.

Conclusion:
Frequent surveillance imaging within the first year following CRT for LA-NSCLC detected asymptomatic recurrences in a high proportion of patients in our population. However, definitive interventions were attempted in less than 5%, and were successful in only one patient. The predominant potential benefit of frequent radiographic surveillance appears to be the expedient initiation of palliative systemic therapy. Evidence-based algorithms for follow-up imaging among this population are needed, and should account for patient-specific factors including expected tolerance of, benefit from, and willingness to undergo systemic therapies.

Background:
Endostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC).

Methods:
Nineteen patients with unresectable stage III NSCLC, ECOG performance status 0-l, and adequate organ function were treated with 60–66 Gy thoracic radiation therapy over 30–33 fractions concurrent with weekly 7.5 mg/m[2] endostatin for 14 days, 50 mg/m[2] paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m[2] endostatin for 14 days, 150 mg/m[2] paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment (Fig.1). The objective response rate was recorded according to the RECIST criteria, and the toxicity was evaluated using the NCI Common Toxicity Criteria. Figure 1



Results:
Six patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 13 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% [95% CI, 51%–97%]. The median progression-free survival was 10 months (95% CI, 7.6–12.3 months), and the median overall survival was 14 months (95% CI, 10.7–17.2 months) (Tab.1). The toxicity analysis of 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity. Figure 1



Conclusion:
The results demonstrated no evidence of the efficacy of endostatin concurrent with chemoradiotherapy of locally advanced unresectable NSCLC. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined.

Abstract not provided

Background:
The risk of recurrent lung cancer decreases markedly after 4 years. It is unknown whether frequent surveillance after this time period would be beneficial in order to diagnose and treat secondary lung cancers. The purpose of investigation is to assess whether there is an increasing frequency of second lung cancers and whether the first primary reduces Overall Survival(OS)/Lung Cancer Specific Survival(LCSS) as compared to similar patients presenting with their first lung cancer (new primary, NP).

Methods:
The SEER databases were used to investigate incidence (1973-2010) and OS/LCSS (1998-2010) of secondary lung cancer. Incidence was examined by frequency and trend analyses. A SP population was chosen who was originally treated for Stage I-III NSCLC and developed a new primary at least four years after diagnosis of their original primary lung cancer (N=1,699). The OS/LCSS of their SP NSCLC were compared to patients presenting with a new primary (NP) NSCLC. OS/LCSS in NP and SP were analyzed by Kaplan-Meier estimation, multivariate proportional hazards modeling and log-rank tests in the overall group and in a favorable sub-group (stage I, < 4cm).

Results:
The annual incidence rates per 100,000 persons for SP NSCLC has increased almost 5 fold in last three decades (2.5 in 1973; 12 in 2010; p<0.001), more so in male patients. OS and LCSS in SP were higher than NP in the log rank tests (p<0.001). In the subgroup of NP and SP who had favorable tumor characteristics, OS/LCSS was significantly different between NP and SP (P=0.0032; P=0.0015), but did not remain so after accounting for treatment, tumor factors, and patient characteristics (HR=0.983, p=0.8493; HR=1.154, p=0.1770). Rates of OS and LCSS improved significantly with increasingly aggressive treatment in the SP group. Patient and tumor characteristics of the first primary NSCLC were not signantly linked to mortality.

Conclusion:
Patients presenting with a second primary lung cancer had a similar or better OS/LCSS as compared to patients presenting with a new primary lung cancer. The SP population also benefitted from increasingly aggressive treatment. Continued surveillance for new primary lung cancers after 4 years may be beneficial to lung cancer survivors.

Background:
Surgical resection is the most important curative treatment modality for early-stage non-small-cell lung cancer (NSCLC). However, incomplete (margin-positive) resection is associated with inferior survival. We sought to develop a valid facility-based quality metric to measure surgical quality, adjusting related patient demographic and clinical characteristics.

Methods:
We identified facilities that performed cancer-directed surgery for patients diagnosed with AJCC stage I-IIIA NSCLC in the NCDB between 2004 and 2011. We used a multivariate logistic regression model, adjusting for patient risk-mix in each facility, to predict the expected number of risk-adjusted margin positivity (RAMP) cases for each facility. We divided the number of observed margin positivity (OMP) cases by the expected number of RAMP cases to obtain an observed: expected (O/E) ratio for each facility. We categorized facility performance as low outlier (O/E ratio<1 and p<.05), high outlier (O/E ratio>1 and p<.05), or non-outlier. Facility characteristics across performance categories were compared by chi-square test. Five-year unadjusted overall survival (OS) rates were estimated by Kaplan-Meier analyses and compared across categories with the log-rank test.

Results:
A total of 96,596 NSCLC stage I-IIIA patients underwent surgery in 941 facilities. The overall OMP rate was 4.6%. We identified 73 facilities as low outliers (mean O/E ratio=0.41), 755 as non-outliers (mean O/E ratio=1.28) and 113 as high outliers (mean O/E ratio=2.78). Compared to patients treated at high-outlier facilities, patients treated at low-outliers were more likely to be privately insured (34.7%[Low] vs. 32.9%[High]), reside in high-income neighborhoods, have no comorbidity (51.7% [Low] vs. 41.9 [High], p<.001), have adenocarcinoma (62.4%[Low] vs. 58.1%[High], p<.001), stage IA disease (41.6%[Low] vs. 39.6%[High], p<.001) and receive sub-lobectomy (11.7%[Low] vs. 9.9%[High], p<.001). Low-outlier facilities were more likely to be teaching/research or NCI-designated programs (54.8% [Low] vs. 18.5% [High], p<.001) and in the highest quartile of total cancer surgical volume (90.4% [Low] vs. 34.5% [High], p<.001) and lung cancer surgery volume (42.5% [Low] vs. 29.2% [High], p<.001) (Table 1). They also had smaller proportions of uninsured/Medicaid patients (45.2% [Low] vs. 36.2% [High], p=.006). The 5-year unadjusted OS estimates were: 0.62 (low-outliers), 0.58 (non-outliers), 0.57 (high-outliers); log-rank p<.001. Table 1. Facility characteristics across performance categories

	High-Outlier(N=113)	Non-Outlier(N=755)	Low-Outlier(N=73)	p-value
	N(%)
Census_region
Northeast	18(15.9)	154(20.4)	19(26.0)	0.03
Midwest	39(34.5)	223(29.5)	15(20.6)
South	37(32.7)	257(34.0)	35(48.0)
West	19(16.8)	121(16.0)	4(5.5)
Facility_type
Community_Cancer_Program	23(20.4)	164(21.7)	0(0.0)	<0.001
Comprehensive_Community_Cancer_Program	62(54.9)	419(55.5)	28(38.4)
Teaching/Research	17(15.0)	128(17.0)	28(38.4)
NCI_program	4(3.5)	17(2.3)	12(16.4)
Other	7(6.2)	27(3.6)	5(6.9)
Proportion_of_Medicaid/uninsure_patients
Q1(low)	25(22.1)	206(27.3)	13(17.8)	0.006
Q2	16(14.2)	204(27.0)	20(27.4)
Q3	41(36.3)	174(23.1)	21(28.8)
Q4(high)	31(27.4)	171(22.7)	19(26.0)
Lung_cancer_surgery_as_a_proportion of_all_surgery
Q1(low)	8(7.1)	73(9.7)	0(0.0)	<0.001
Q2	37(32.7)	224(29.7)	9(12.3)
Q3	35(31.0)	226(29.9)	33(45.2)
Q4(high)	33(29.2)	232(30.7)	31(42.5)
Total_cancer_surgery_volume
Q1(low)	12(10.6)	98(13.0)	0(0.0)	<0.001
Q2	32(28.3)	193(25.6)	0(0.0)
Q3	30(26.6)	253(33.5)	7(9.6)
Q4(high)	39(34.5)	211(28.0)	66(90.4)

Conclusion:
Facility performance in lung cancer surgery can be captured by using the RAMP rate. Low-outlier facilities delivered superior OS than high-outliers. RAMP metrics could allow facilities to understand their performance and serve as a quality improvement benchmark.

Background:
Lymph node (LN) metastasis is an important prognostic factor for patients with surgically resected NSCLC. We have previously described the extent of missed N1 LN metastasis in a cohort of patients treated at metropolitan institutions. With long-term follow up, we now quantify the survival impact of missed LN metastasis.

Methods:
We conducted a prospective cohort study to retrieve intrapulmonary LNs from discarded NSCLC resection specimens after completion of routine pathology examination. Retrieved materials were histologically examined and classified as LNs with and without metastasis. Survival information was retrieved from institutional tumor registries. Survival distributions were plotted using the Kaplan-Meier method and evaluated with proportional hazards models controlling for gender, race, pathologic N-category, tumor size, margin status, and Charlson score.

Results:
We evaluated 111 patients who were 47% male with a median age of 66 years. Clinical characteristics are summarized in Table 1. Discarded LNs with metastasis were found after re-dissection in 25 (23%) patients. Patients with discarded LN metastasis had an increased risk of death (Figure 1) with an unadjusted hazard ratio (HR) of 2.0 (p-value=0.06) and an adjusted HR of 1.8 (p-value=0.23) compared to those with no discarded LNs with metastasis. When >2 discarded LNs with metastasis were found, patients had 4.8 (p-value=0.0002) times the hazard of death compared to those with no discarded LNs with metastasis (adjusted HR=4.4, p-value=0.0032).

N(%)	No LN Metastasis	LN Metastasis	Total
Bi-lobectomy	8	2	10
	9%	8%
Lobectomy	75	16	91
	87%	64%
Pneumonectomy	3	7	10
	3%	28%
N0	71	6	77
	83%	24%
N1	6	12	18
	7%	48%
N2	9	7	16
	10%	28%
T1	45	3	48
	52%	12%
T2	29	11	40
	34%	44%
T3	10	8	18
	12%	32%
T4	2	2	4
	2%	8%
Margin Negative	83	22	105
	97%	88%
Margin Positive	3	3	6
	3%	12%
Mean(SD)
Charlson Score	1.8	1.8	1.8
	1.6	1.7	1.6
Tumor Size(cm)	3.2	5.0	3.6
	1.8	2.1	2.0

Figure 1



Conclusion:
The presence of metastasis in inadvertently discarded LNs in NSCLC resection specimens has significant implications for patients’ post-operative clinical course. Additional LN metastasis found on re-dissection was associated with reduced survival. A more rigorous protocol for gross dissection of lung resection specimens is needed, and should prove beneficial to patients’ long-term survival.

Background:
A right-sided pneumonectomy after induction therapy for non-small cell lung cancer (NSCLC) has been shown to be associated with significant perioperative risk. We examined the impact of laterality on long-term survival using the National Cancer Data Base (NCDB).

Methods:
Perioperative and long-term outcomes of patients who underwent pneumonectomy following induction chemotherapy ± radiation from 2003-2011 in the NCDB were evaluated using Kaplan-Meier method, multivariable logistic regression analysis and multivariable Cox proportional hazards modeling.

Results:
During the study period, 1,652 patients met inclusion criteria, of whom 740 (45%) underwent right-sided pneumonectomies. Right-sided patients were more likely to have adenocarcinomas, cN2 disease and lower co-morbidity scores (Table). The 30-day mortality rate was higher for right-sided procedures in univariable (11% [84/740] vs 4% [39/912], p<0.001) and multivariable (OR 9.1 [1.8-50.0], p<0.01) analysis. However, 5-year overall survival between right and left pneumonectomy were not significantly different (figure) after a median follow up of 30.2 months. Right-sided procedure also did not impact overall survival in multivariable analysis (hazard ratio (HR), 1.41 [95% CI: 0.87-2.27], p=0.16), while increasing age (HR, 1.02 [95% CI: 1.01-1.03]), Charlson co-morbidity Score of 2 (HR, 1.42 [95% CI: 1.04-1.93]), adenosquamous histology (HR, 1.72 [95% CI: 1.18-2.51]), cN1 status (HR, 1.27 [95% CI: 1.02-1.58]), cN2 status (HR, 1.38 [95% CI: 1.14-1.66]), cN3 status (HR, 1.84 [95% CI: 1.19-2.83]), cM1 status (HR, 2.04 [95% CI: 1.42-2.92]) and incomplete resection (HR, 1.45 [95% CI: 1.14-1.84]) all predicted worse survival. Figure 1

Table: Baseline characteristics.

Variable	Right-sided (n=740)	Left-sided (n=912)	p
Induction chemoradiation	461 (62%)	584 (64%)	0.47
Age (median, IQR)	59 (52-66)	60 (52-67)	0.07
Charlson/Deyo Comorbidity Score			0.02
0	518 (70%)	610 (66%)
1	190 (26%)	243 (27%)
2	32 (4%)	68 (7%)
Histology			0.02
Adenocarcinoma	227 (37%)	243 (32%)
Squamous	310 (50%)	450 (59%)
Large cell	28 (5%)	19 (2%)
Adenosquamous	20 (3%)	21 (3%)
Neuroendocrine/carcinoid	4 (1%)	7 (1%)
BAC	28 (5%)	23 (3%)
Clinical N			< 0.01
0	190 (27%)	269 (31%)
1	134 (19%)	187 (21%)
2	368 (52%)	381 (44%)
3	16 (2%)	34 (4%)

There were no significant differences between the groups with regards to sex, race, facility type, and clinical T and M status.



Conclusion:
In this population analysis, right-sided pneumonectomy after induction therapy was associated with a significantly higher perioperative but not worse long-term mortality compared to a left-sided procedure. These findings can be used in the risk/benefit analysis when considering patients for pneumonectomy following induction therapy.

Abstract not provided

Background:
Outcomes of pneumonectomy after neoadjuvant chemoradiastion therapy (CCRT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) have been well-known as grave. Whenever possible, we have tried sleeve resection in patients to avoid pneumonectomy(PN). We evaluated whether the sleeve resection (SL) could have avoided the postoperative mortality/morbidity and achieved comparable long-term outcomes with pneumonectomy.

Methods:
We retrospectively reviewed medical records of 574 consecutive patients with clinical stage IIIA-N2 non-small cell lung cancer who underwent surgery after neoadjuvant CCRT from 1997 to 2013. Clinical outcomes were analyzed and compared in 98 consecutive patients who had either SL (n = 25) or PN (n = 73) after neoadjuvant CCRT in a single institution.

Results:
Thirty-day postoperative mortality were 0% (0/25) in SL group, and 5.5% (4/73) in PN group (p=0.120). Ninety-day postoperative mortality were 12.0% (3/25) in SL group, and 17.8% (13/73) in PN group (p=0.498). The most common cause of ninety-day mortality was acute respiratory distress syndrome (n=11). Morbidity rate was 48.0 % (12/25) in SL, and 49.3% (36/73) in PN. The 5-year survival was lower in the PN group (PN, 24.7 % versus SL, 45.1%, p=0.086). The recurrence pattern (locoregional versus distant) did not differ between two groups (p=0.726). When recurrences occurred (n = 50), the site of first recurrence was local (stump site) in 0 % (0/25) of patients with SL and in 4.1% (3/73) of patients with PN.

Conclusion:
Following neoadjuvant CCRT for patients with stage IIIA-N2 NSCLC, SL showed a comparable or even better early and long term clinical outcomes with PN. Therefore, SL should be considered, whenever possible.

Background:
Biopsy of APW (levels 5/6) lymph nodes can be important for lung cancer staging, but the APW is not accessible by routine mediastinoscopy or EBUS. Although some consider ECM potentially dangerous, we reviewed our ECM experience to determine safety and accuracy and to define/validate parameters for patient selection.

Methods:
With IRB approval we reviewed two institutions' databases for patients undergoing ECM between 3/1/97 and 12/31/11. Physical parameters (PP) that were thought to impact on the difficulty and safety of ECM, ie., clavicular head (CH), thoracic inlet (TI), and anterior mediastinal (AM) dimensions, were measured using 55 CT scans available from the first 100 pts.

Results:
Of 190 patients, 128 (67.3%) were male and ages ranged 28-91 yrs. Indication for surgery was either cancer (>95% with lung cancer >80%) or adenopathy (<5%). All procedures were performed by a single surgeon during routine mediastinoscopy. There were no intraoperative complications and blood loss was <25 cc in all cases. Morbidity occurred in 15 (7.9%) with 1 (0.55%) major complication and no mortality. A pathologic diagnosis was obtained in 189 (99.5%). Postop pain was easily controlled with bupivicaine. PP were compared to those in an additional 12 control patients with failed procedures (Table). Although each PP alone was not useful, the APWI (TI X AM product) did predict degree of difficulty (p=0.015) and divided patients into 3 groups predictive of the degree of difficulty: Straightforward (APWI>17), Intermediate (APWI=6-17), and Prohibitive (APWI<6) (Figure). The APWI was then prospectively validated with excellent accuracy in the next 90 patients. The APWI can be helpful in the selection of patients for thoracic surgeons, particularly those learning ECM. A short video demonstrating the technique of ECM will be presented.

Table: Physical Parameter Measurements (values were obtained from CT scans available on 55/100 initial patients comparing with a separate group of 12 patients with unsuccessful ECM

Parameter	Successful ECM (cms)	UnSuccessful ECM (cms)
Clavicular Head (CH)	2.3+0.36	2.28+0.36
Thoracic Inlet (TI)	6.32+1.07	5.99+0.62
Anterior Mediastinum (AM)	2.53+0.82	1.89+0.82
APWI (TI X AM)	16.2+6.77	11.1+4.4*
*p=0.015

Figure 1



Conclusion:
ECM is straightforward, safe, and accurate in mediastinal staging. Our novel APWI helps to safely select patients for any thoracic surgeon's skill and comfort level.

Background:
In our cancer network, single station N2 NSCLC may be managed with surgical resection followed by adjuvant chemotherapy as meaningful survival has been shown in such circumstances. Multi-station N2 disease diagnosed pre-operatively is not considered a surgical entity. However, sometimes occult multi-station pN2 may only be identified during intra-operative nodal sampling. This study aimed to analyse the survival of such patients at a large thoracic surgical centre in the United Kingdom.

Methods:
A retrospective review of all pathological reports from NSCLC resections at the University Hospital South Manchester from 01/01/2011 to 31/12/2013. Based on the histological results from intra-operative nodal sampling, patients were stratified into nodal categories pN0, pN1, pN2 single station and pN2 multi-station. Survival data was obtained through national death registry data allowing a minimum of twelve months follow-up for all patients at the time of analysis in January 2015.

Results:
987 surgical resections for NSCLC were performed during the study period 2011 to 2013 at UHSM. A total of 132 patients had pN2 disease; 85 with single station pN2 and 47 with multi-station N2. The median survival time for those patients with multi-station pN2 was 798 days (95% CI 405-1191 days) and 762 days (95% CI 616-908 days) for those with single station pN2. Median survival times were not estimable for patients with pN0 and pN1 as only a small proportion of patients died. For pairwise comparisons between N categories, a Bonferroni adjustment for multiple comparisons used a critical value of 0.008 for significance. Patients with single station pN2 and multi station pN2 had significantly lower survival times than patients with N0, but there was no statistically significant difference in survival between patients with pN1, single station pN2 and multi-station pN2 (Figure 1).Figure 1



Conclusion:
Interestingly, patients with multi-station pN2 had a similar survival to those with single station pN2. This cohort of multistation pN2 patients is likely to represent those with microscopic nodal metastases and does not represent all multistation N2 disease. Although the numbers are small it does raise interesting questions about the exclusion of patients with radiologically-occult multi-station N2 disease, detected during the pre-operative systematic sampling of small mediastinal nodes through endoscopic or surgical techniques, being excluded from surgery as part of their multi-modality treatment in our network.

Abstract not provided

Background:
Current nodal staging for non-small cell lung cancer (NSCLC) only take into account the anatomic location of lymph node (LN). Although among patients with same pathologic N1 NSCLC, they are known to have heterogeneous prognosis and prognostic significance of extent of LN involvement is still uncertain. The objective of current study was to evaluate whether LN ratio (LNR) is a marker of prognostic factor for survival in patients with pathologic stage II/ N1 NSCLC after complete resection

Methods:
A total of 4,089 consecutive patients underwent curative surgical resection for NSCLC between 2004 and 2012. Of these, 413 patients who found to have pathologic stage II/N1 NSCLC after complete resection were retrospectively analyzed. For LNR, the optimal cutoff value was determined using chi square score, which were calculated using the Cox proportional hazards regression model. The prognostic value of the LNR was calculated by Cox regression hazard model analysis.

Results:
The study included 337 males and 76 females with a mean age of 62 years. The mean numbers of metastatic and dissected LN were 1.84 and 26 respectively and the mean LNR was 0.082. The number of the metastatic LN was significantly correlated to the LNR (r=721; p<0.0001). Based on the maximum chi square score and minimum p value approach, the optimal cutoff value of LNR was 0.1 and patients were classified into two groups according to LNR. Both 5-year overall survival rate and the lung cancer-specific survival rate in the high LNR group (LNR ≥0.1) were significantly lower than those in the low-LNR group (overall survival: 55.4.% vs 69.8%, p=0.003; lung cancer specific survival rate: 58.4% vs. 77.0%, p<0.0001) Also, disease free survival (DFS) rates according to LNR were 56.8% in low-LNR group (LNR<0.1) and 35.0% in high-LNR group (LNR≥0.1). DFS rate in the low-LNR group was significantly higher than that in the high-LNR group (p<0.001). LNR is an independently related prognostic factor with overall survival (OR=2.288; 95% CI=1.513~3.459; p<0.0001), lung cancer-specific survival (OR=2.740; 95% CI=1.709~4.395; p<0.0001) and DFS (OR=2.191; 95% CI=1.543~3.110; p<0.0001) after adjustments of clinical variables including sex, age, stage, surgical extent, histology and adjuvant treatment.

Conclusion:
LNR is an independent prognostic factor of survival in patients with pathologic N1 NSLC after complete surgical resection.

Background:
Conversion to open thoracotomy occurs when thoracoscopic manipulation becomes difficult as a result of particular situations during complete thoracoscopic lobectomy after the surgeon starts to dissect blood vessels Based on special intra-operative situations, conversion to open thoracotomy can be divided into active and passive conversion. Active conversion to open thoracotomy implies that the surgeon gives up the thoracoscopic manipulation voluntarily and performs open surgery under direct vision as a result of the difficulty of thoracoscopic manipulation when encountering problems, such as adhesions of lymph nodes and difficulty of exposing huge tumors, which may result in massive bleeding, tumor rupture, and undue extension of the operative time. Passive conversion to open thoracotomy implies that the surgeon has to discontinue thoracoscopic manipulation and perform open surgery under direct vision because of urgent or serious intra-operative complications, including blood vessel breakage and bronchial membrane rupture, which are difficult to treat thoracoscopically. Lymph nodes are an important etiology affecting the conversion of complete thoracoscopic lobectomy to open thoracotomy.Five hundred consecutive patients with non-small cell lung cancer underwent complete thoracoscopic lobectomy at the Department of Thoracic Surgery of Peking University People’s Hospital, and the conversion to open thoracotomy was performed in 47 cases (9.4%). Lymph node interference means that a lymph node cannot be separated easily, and was the reason for conversion to open surgery in 31 cases (65.9% of 47 cases).The effect of lymph node interference on surgery has not been thoroughly addressed to date. We studied the data of patients who underwent complete thoracoscopic lobectomy in our hospital, and analyzed the effect of lymph nodes on the conversion to open thoracotomy and corresponding factors.

Methods:
Between September 2006 to April 2013, 1006 patients （545 men, 461women, median age 60 years, range from 13 to 86 years)received completly thoracoscopic lobectomy, including segmectomy(n=13), simple lobectomy(n=846), compound lobectomy(n=131), pneumonectomy (n=8), sleeve lobectomy(n=8). The main procedure was completely video-assisted anatomical lobectomy with mediastinal lymphadenectomy as we have reported.

Results:
All procedures were carried out smoothly without serious complication. 83 cases converted to thoracotomy(8.2%), including 70 cases of initiative conversion and 13 cases of passive conversion in which 59 cases was interference by doornail lymph nodes. Pathological result show 821 cases of malignant disease and 185 cases of benign disease. All patients recovered well.the average operative time in the conversion thoracotomy group was significantly longer (272.7 ± 67.2min versus186.9 ± 58.1min, P = 0.001)compared with completely endoscopic surgery group, the average blood loss was significantly increased(564.2 ± 507.7ml versus 158.0 ± 121.0ml, P = 0.001), the drainage time was significantly longer(8.9 ± 5.0d versus 6.6 ± 3.5d, P = 0.001) and the postoperative hospital stay was significantly longer(12.5 ± 7.7d versus 9.2 ± 5.8d, P = 0.001).

Conclusion:
Interference of lymph doeds was the main reason for conversion to thoracotomy on VATs lobectomy. It may prolonged the operative time, increase the blood loss in operation and delay the postoperative recovery of the patients. Select the proper indication of conversion thoracotomy may reduce the negative effects of conversion thoracotomy.

Background:
Bronchoplasty has become widely accepted as a reliable and safe lung-saving procedure for lung cancer. The purpose of this study was to evaluate the factors contributing to the outcomes of bronchoplasty for lung cancer by analyzing a single institution’s data for a 30-year period.

Methods:
In the 2416 patients who underwent lung resections for lung cancer at Nagasaki University Hospital from 1980 to 2010, there were 222 bronchoplastic procedures. After excluding patients who underwent carinoplasty, 213 patients (161 bronchoplasty and 52 broncho-angioplasty) were included. The patients were divided into two groups by the date of surgery: the 1[st] period was 1980 to 1995, and the 2[nd] period was 1996 to 2010.

Results:
Bronchoplasty and broncho-angioplasty were performed in 100 (75.8%) and 32 (24.2%) patients, respectively, in the first period and 61 (75.3%) and 20 (24.7%) patients, respectively, in the second period. Overall 90-day operative morbidity and mortality rates were 25.8 and 9.8%, respectively, in the first period and 45.7 and 2.5%, respectively, in the second period. Thirty-day mortality rates were 6.8% in the first period and 0% in the second period. Five-year survival was 41.1% (n = 132) in the first period and 61.5% (n = 81) in the second period (P = 0.0003). Comparing bronchoplasty and broncho-angioplasty, the 5-year survival was 45.6 and 26.5%, respectively, in the first period (P = 0.0048) and 60.9 and 62.1%, respectively, in the second period (P = 0. 8131). Using multivariate analysis to identify potential prognostic factors, the type of operation (broncho-angioplasty), postoperative complications and histology (non-squamous cell carcinoma) were significant factors affecting survival in the first period, but none of the factors significantly affected survival in the second period. When the rates of pN2 or N3 histological type disease were compared in each period, the rate of pN2 or N3 disease in non-squamous cell carcinoma was 51.4% in the first period and 45.5% in the second period; both were significantly higher than in squamous cell carcinoma (31.6 and 16.9%, respectively; P = 0. 0365 and 0.0073). Figure 1



Conclusion:
The present study suggests that progress in the preoperative staging system and perioperative medical management, as well as surgery, has contributed to current improvements in patients undergoing bronchoplasty and broncho-angioplasty. However, since nodal status in non-squamous cell carcinoma is not precisely evaluated before the operation, the indication for bronchoplasty should be considered carefully.

Background:
Non-small cell lung cancer (NSCLC) may be treated with curative intent using radiotherapy, either as single modality or in combination with systemic chemotherapy. Most commonly, radiation treatment is planned based on findings at 18-Fluorodeoxyglucose Positron Emission Tomography (PET), following pathologic confirmation of involvement at a single mediastinal site. We hypothesized that systematic mediastinal evaluation with EBUS-TBNA in NSCLC patients considered for radical radiation therapy may identify disease extent discrepant with that indicated by PET-CT.

Methods:
This prospective ethics board-approved multi-centre cohort study in three Austrailan tertiary centres consented patients prior to mediastinal evaluation with Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) for NSCLC,where non-invasive imaging indicated the likely treatment modality would include radical radiotherapy. EBUS evaluation was performed systematically with sampling of any lymph node (LN) exceeding 6mm diameter.

Results:
Thirty eligible patients with NSCLC form the basis of this report. No procedural complications occurred during performance of EBUS-TBNA. LN sampling was performed from a mean 2.5 lymph node stations per patient (median 3,range 1–5). Adequate samples were obtained from all sites examined by EBUS-TBNA. Mean long-axis size of sampled LN was 16+7.8mm (median 13mm,range 5–36mm). 24% of sampled LN were 10mm or less. Discordant findings were observed in 10 of 30 patients (33%) (Figure 1) EBUS-TBNA identified a greater extent of mediastinal involvement than PET in four patients, with invasive sampling resulting in upstaging in three patients. In one further patient, extent of disease was greater than noted on PET due to more proximal involvement of LN disease not resulting in stage advancement. Median size of LN upstaged by EBUS was 7.5mm (range 7–9). In eleven mediastinal LN in six patients, EBUS identified a lesser extent of mediastinal disease than PET, including two patients down-staged from N3 à N2. Median size of LN down-staged by EBUS was 12mm (range 6–21). FIGURE 1. Flowchart of patients Figure 1



Conclusion:
Our findings demonstrate clinically significant discrepancy between two modalities frequently used to stage mediastinal disease extent in NSCLC patients being considered for radiotherapy. PET-based radiotherapy planning alone may not be appropriate given the risk of excessively large, or insufficiently large, radiation fields where planning is not based on invasive LN sampling. These results suggest minimally invasive comprehensive/systematic mediastinal staging should be considered for all patients prior to radiotherapy to accurately assess pathologic stage and extent of disease, and to ensure treatment fields most accurately encompass all sites of disease.

Abstract not provided

Background:
Sentinel node (SN) is defined as the first node draining a tumor, and should be the first site affected in lymphatic dissemination. Recently, with the increased incidence of small sized non-small cell lung cancer (NSCLC), segmentectomy is again under evaluation for clinical T1a N0 NSCLC patients. In the ongoing trial regarding segmentectomy (JCOG0802), the eligibility criteria for segmentectomy include a prerequisite of no lymph node metastasis by intraoperative findings because node-positive cases have a chance to be locoregionaly controlled and to be correctly staged by converting to lobectomy. Therefore, intraoperative sampling and frozen sectioning of true SNs is important in ensuring the radicality of segmentectomy. The objective of this study was to assess the safety and the feasibility of computed tomography (CT) lymphography by transbronchial injection of a water-soluble extracellular CT contrast agent which was developed as a new method for identifying SNs in patient with NSCLC.

Methods:
Between April, 2010 and January, 2015, clinical stage I NSCLC patients who were candidates for lobectomy or segmentectomy were enrolled in this study. An ultrathin bronchoscope was inserted to the target bronchus under the guidance of virtual bronchoscopic navigation images. CT images of the chest were obtained 30 seconds after 2 or 3ml of iopamidol was injected through a microcatheter. SNs were identified when the maximum CT attenuation value of the lymph nodes in postcontrast CT images increased by 30 Hounsfield units or more compared to precontrast images. Patients underwent video-assisted thoracic surgery lobectomy with standard lymph node dissection. SNs were harvested according to findings of CTLG and to intraoperative findings of near-infrared fluorescence imaging with indocyanine green. All lymph nodes, including SNs, were histopathologically examined by standard hematoxylin and eosin staining.

Results:
The ultrathin bronchoscope could access targeted bronchus, and iopamidol was delivered into the peritumoral area in all 41 patients without any complications. SNs were identified in 38 of 41 patients (92.7%), and the average number of SNs was 1.4 (range: 1-4). Lymph node metastases were found in 6 cases, including one false-negative case. Enlargement of lymphatic vessel was seen in 3 out of 6 (50%) cases with lymph node metastases, whereas it was seen in 6 out of 35 cases (17%) without lymph node metastases.

Conclusion:
CT lymphography by transbronchial injection of iopamidol was a safe and feasible method to identify SNs in clinical stage I NSCLC patients. Lymphatic remodeling including peritumoral lymphangiogenesis and enlargement of lymphatic vessel has been reported to one of the crucial step of lymph node metastasis of cancer. Enlargement of lymphatic vessel seen in CT lymphography may be a risk factor for lymph node metastasis of NSCLC.

Background:
Lung cancer has been the leading cause of cancer related mortality for the past decades worldwide and in China. Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases. For patients with early stage NSCLC, surgical resection is the mainstay of the treatment. This study aimed to better understand characteristics of NSCLC patients who underwent curative-intent lung surgical resections in China.

Methods:
Data were obtained from the NSCLC surgical outcome registry, which included 3,464 NSCLC patients who underwent curative-intent surgical resections from 13 tertiary hospitals in 11 provinces in 2013 and 2014. The registry documented detailed information on demographics as well as perioperative parameters.

Results:
The median age at the time of surgery was 60 (range 14 to 92) years, and 64.0% of the patients were male. Approximately 49.1% had a smoking history and 12.6% had a family history of cancer. About 45.7% patients had at least one comorbidity. The most prevalent comorbidities were cardiovascular disease, metabolic disease, respiratory disease, and other tumor, which affected 45.2%, 15.5%, 13.3% and 9.7% of the patients, respectively. The pulmonary function test showed a mean FEV1 of 2.33 (SD=0.63, range 0.32 to 4.81) L and FEV1/FVC of 79.3% (SD=12.6%, range 0.5% to 100.0%). The types of resection were lobectomies (lobectomies, bi-lobectomies and sleeve lobectomies) 79.3%, sublobar resections (segmentectomies and wedge resection) 8.5%, pneumonectomies 7.0%, and others 4.3%. 44.5% resections were performed by video-assisted thoracoscopic surgery (VATS). Adenocarcinoma and squamous cell carcinoma were the most common types of NSCLC, accounting for 60.2% and 31.4% of the patients, respectively. The most common tumor locations were right upper lobe (26.9%), left upper lobe (22.8%), right lower lobe (19.4%), left lower lobe (16.5%), and right middle lobe (6.5%). Pathologic staging showed 48.5% patients had stage I tumor; stage II, III, and IV accounted for 23.0%, 25.3% and 3.3%.

Conclusion:
The NSCLC patients who underwent curative-intent lung resection surgeries in China were relatively young and had good lung function. Adenocarcinoma and squamous cell carcinoma were the most common types. Nearly half of the procedures were performed by VATS and almost one out of two patients had pathologic stage I disease.

Background:
Video-assisted thoracic surgery (VATS) plays an important role in thoracic surgery especially for early stage lung cancer because it is less invasive. However, the existence of severe pleural adhesions may make VATS difficult and complicated. So, preoperative detection of pleural adhesions can be very useful for the assessment of surgical approach. The aim of this study was to assess the accuracy of inspiration and expiration computed tomography (respiratory dynamic CT: RD-CT) in evaluation of pleural adhesions prior to thoracic surgery. Video-assisted thoracic surgery (VATS) plays an important role in thoracic surgery especially for early stage lung cancer because it is less invasive. However, the existence of severe pleural adhesions may make VATS difficult and complicated. So, preoperative detection of pleural adhesions can be very useful for the assessment of surgical approach. The aim of this study was to assess the accuracy of inspiration and expiration computed tomography (respiratory dynamic CT: RD-CT) in evaluation of pleural adhesions prior to thoracic surgery.

Methods:
From January to December 2014, RD-CT was performed on 107 patients undergoing thoracotomies (both VATS and open surgery, except for pneumothorax). We assessed synchronous motion during respiration on RD-CT using a three-dimensional CT image software, as Sliding Score. Regarding intraoperative findings, we categorized the severity of pleural adhesions into 4 groups as Adhesion Grade. Then, comparing Sliding Score and Adhesion Grade, we assessed the utility of preoperative evaluation. In addition, to confirm these patients could expire enough in expiration phase, we assumed lung volume in expiration phase/ inspiration phase as CT- Respiratory Ratio in each case.

Results:
Operations were performed mainly for lung cancer (78 cases; 72.9%), others are metastatic lung tumor, mediastinal tumor, lung abcess and so on. A negative correlation between Sliding Score and Adhesion Grade was revealed. Sliding Score in adhesion positive patients was significantly higher than that in adhesion negative patients (P < 0.0001). The sensitivity of RD-CT was 63.6%, specificity was 74.1%, and accuracy was 72%. Among 62 patients with a CT-Respiration Ratio of less than 0.65, the sensitivity of RD-CT was 77.8%, specificity was 86.8%, and accuracy was 85.5%. Regarding severe adhesions, RD-CT demonstrated a sensitivity of 100% in all 107 patients. No significant correlation was revealed between CT- Respiratory Ratio and respiratory function or Adhesion Grade.

Conclusion:
RD-CT may be useful for detecting the presence of pleural adhesions, especially to rule out the severest adhesions. It can be adopted as one of the criteria for deciding the surgical approach, VATS or open surgery. And it may enable an operation to be performed more safely and systematically.

Background:
In our model of Combined Clinical Staging (CCS) for lung cancer, patients with a Computerized Tomography (CT) scan of the chest that does not show distant metastases will then routinely undergo whole body Positron Emission Tomography (PET/CT) and Magnetic Resonance Imaging (MRI) of the brain prior to any therapeutic decision. We aim to determine the accuracy of CCS and the value of brain MRI in this population.

Methods:
A prospective database was queried for all patients who underwent resection of lung cancer from 01/2012 to 06/2014. Demographics, wait times, clinical and pathological stage (7[th] edition AJCC/UICC), and costs of staging were collected. Krippendorff’s alpha was used to determine correlation between clinical and pathological stage.

Results:
Of 315 patients with primary lung cancer, 55.6% were female and the median age was 70 (27-87, Table 1). The mean time from initial CT scan to surgical treatment was 9.12 +/- 6.0 weeks. Krippendorff’s alpha between CCS and pathological stage was 0.193 (0.125 to 0.260, Table 2). When correlation was analyzed without consideration for sub-stages A and B, 49.8% (157/315) of patients were staged accurately, 39.7% (125/315) were over-staged, and 10.5% (33/315) were under-staged. Only 4.7% (15/315) of patients underwent surgery without appropriate neo-adjuvant systemic treatment. Preoperative brain MRI detected asymptomatic metastases in 4/315 patients (1.3%). At a median postoperative follow-up of 16 months (1-40), 7 additional patients developed symptomatic brain metastases, all of which had normal brain MRI preoperatively. The total cost of CCS was $416,924 over the study period, with $131,824 (31.6%) going towards brain MRI.

Table 1: Baseline descriptive data, N=315

Age Mean (SD)	69.80 (9.62) (Min: 27.34, Max: 86.61)
Gender
Female (%)	175 (55.6%)
Male (%)	140 (44.4%)
Weeks First Visit to Consent Mean (SD)	5.49 (8.15) (Min: 0, Max: 63)
Weeks Consent to Surgery Mean (SD)	2.24 (2.07) (Min: 0, Max: 11)
Weeks Initial CT to Surgery Mean (SD)	9.12 (6.01) (Min: 0, Max: 53)
Weeks First Visit to Surgery Mean (SD)	8.00 (8.25) (Min: 0, Max: 64)
Brain Metastases at Baseline (%)	4 (1.3%)
Brain Metastases at Follow Up (%)	11 (3.5%)

Table 2: Frequency and agreement of CCS and pathological stage

Stage (N=315)	Clinical Stage N (%)	Pathological Stage N (%)	Same Staging by Both (True Positives)
0	1 (0.3%)	-	-
Stage IA	89 (28.3%)	103 (32.7%)	55
Stage IB	39 (12.4%)	82 (26.0)	19
Stage IIA	42 (13.3%)	47 (14.9%)	7
Stage IIB	32 (10.2%)	42 (13.3%)	12
Stage IIIA	78 (24.8%)	39 (12.4%)	16
Stage IIIB	21 (6.7%)	0 (0.0%)	0
Stage IV	13 (4.1%)	2 (0.6%)	2
Krippendorff's Alpha for level of agreement = 0.193 (0.125 to .260)

Conclusion:
CCS is effective for patients with resectable lung cancer, with less than 5% of patients being under-staged in a way that denied them appropriate systemic treatment before surgery. Brain MRI is a low yield and high cost intervention in this population, and its routine use should be questioned.

Background:
The noninvasive dynamic characterization of hypoxia using molecular imaging approaches is supportive for evaluation of malignant tumor. In this study, we evaluated the clinicopathological impact of newly developed tumor hypoxia PET tests for localized non-small cell lung cancer (NSCLC).

Methods:
Forty-nine patients with localized NSCLC were enrolled[F1] [木下智成2] . They underwent chest hypoxia PET tests, namely [18]F-fluoroazomycin arabinoside (FAZA) and/or [62]Cu-diacetyl-bis (N4)-methylsemithiocarbazone (ATSM) PET in addition to routine whole-body [18]F-fluorodeoxyglucose (FDG) PET before treatment. Uptake of hypoxic tracers was quantified by calculating maximum standard uptake values (SUVmax) and tumor muscle ratios (TMR).

Results:
The uptake of [18]F-FAZA were in positive proportion to that of [62]Cu-ATSM (P < 0.05). Neutrophil lymphocyte ratio and tumor size were significantly correlated with uptake both in [18]F-FAZA (P < 0.01) and [62]Cu-ATSM (P < 0.05 in [18]F-FAZA and [62]Cu-ATSM). Pathologically, the case with vascular or pleural invasion, which indicate tumor malignancy, had higher uptake of [18]F-FAZA (P < 0.05). Those accumulations increased according to advanced TNM staging (P < 0.05). The patient with higher uptake of these tracers significantly had a poorer overall survival (P < 0.01 in [18]F-FAZA and P < 0.05 in [62]Cu-ATSM), and progression-free survival (P < 0.01 in [18]F-FAZA and P < 0.05 in [62]Cu-ATSM).

Conclusion:
[18]F-FAZA and [62]Cu-ATSM can provide useful information on tumor malignancy and prognosis, and might contribute toward guiding individualization of treatment of localized NSCLC. Figure 1Figure 2

Background:
New technologies in radiotherapy of lung tumours aim to reduce toxicity and increase tumour control by increasing the dose delivered, and reducing the size of radiotherapy margins. Kilovoltage intrafraction monitoring (KIM) is a novel image guidance technology, which permits visualisation of fiducials implanted into the tumour whilst the radiotherapy beam is on. KIM has been used in both prostate[1] and liver tumours[2], and has been shown to increase the accuracy of radiotherapy delivery. In this Phase I study we aim to establish whether it is feasible to use KIM to monitor the motion of lung tumours during radiotherapy delivery. 1. Ng J et al. IJROBP 2012:84(5):e656 2.Poulsen P et al. Radiotherapy and Oncology 2014:111(3):424

Methods:
Patients receiving curative radiotherapy for lung cancer will have between 3-5 fiducials inserted into their tumour during endobronchial ultrasound (EBUS). Radiotherapy will be planned and delivered as per standard departmental protocols for lung cancer patients. 4D-cone beam CT (CBCT) will be performed , in conjunction with acquisition of KIM images and respiratory motion signal acquisition on the 1[st], 6[th], 11[th], 16[th], 21[st], 26[th], and 30[th] fractions before treatment to assess the accuracy of patient and tumour position.

Results:
Initial studies in a respiratory motion phantom have indicated that 0.4mm diameter Gold Anchor fiducials are visible during radiotherapy treatment. Ethical approval has been obtained with patient recruitment to the study to commence shortly. The primary endpoint of this study is the successful visualisation by the KIM technique of fiducials inserted into the tumour. Each patient will have a minimum of 3 fiducials (markers) inserted. As the implanted fiducials may be migrated or lost, the definition of technical success will vary according to the number of fiducials present. In the case of 1 to 3 markers being present, segmentation of at least 1 marker will be required for the image acquisition to be deemed successful. In the case of 4 or more fiducials being present, segmentation by the KIM technique of at least 2 markers for each image will be required for the image acquisition to be deemed successful. Secondary endpoints include assessment of the stability of implanted markers, and the rate of marker migration, quantitative assessment of tumour motion, assessing the impact of tumour motion on dosimetry and an assessment of toxicity associated with marker insertion.

Conclusion:
Lung tumours move during radiotherapy treatment, both between radiotherapy fractions and whilst the radiotherapy dose is being delivered[3]. Establishing the feasibility of KIM will enable the visualization of tumour motion whilst the radiotherapy treatment is being delivered. This is currently impossible on a standard linac, limiting the ability of the clinician to implement changes in margin size, which could potentially reduce the severity of side-effects for patients. Assessing intra-fraction motion of lung tumours is a key step in this process – by identifying the uncertainty in treatment, we will in the future be able to implement gating and tracking of tumours, thus resulting in safer and more effective treatment. 3. Sonke J. et al. IJROBP 2008:70(2):590

Background:
We recently reported an association between progression-free survival and metformin exposure in patients with early stage non-small cell lung cancer (NSCLC). Local recurrence in stage I disease is estimated to be as high as 50% in US populations. Therefore, a method to identify NSCLC patients who are most likely to benefit from metformin treatment has potential clinical relevance.

Methods:
Three previously published, publically available gene expression array data sets documenting the effects of metformin treatment on transcriptional activity in human cell lines were used for the initial stages of the present study. These data sets were evaluated individually for enrichment of differentially expressed genes with a gene set analysis related to biological processes also performed. Differentially expressed genes common to all three studies were then used to form a metformin meta-gene. This combined meta-gene was evaluated topologically using a protein-protein interaction database to determine if any gene products had previously observed direct interactions. The metformin meta-gene network was then examined in expression array data sets from stage I NSCLC patients (n=293) assembled from multiple published studies.

Results:
We identified several biological themes resulting from metformin treatment, including: immune cell differentiation, response to hypoxia, steroid receptor signaling, alternate splicing, and changes in cellular metabolism. Intersecting the differentially expressed genes from each data set, we identified 105 genes consistently up-regulated and 30 genes consistently down-regulated by metformin treatment, forming a tissue-independent meta-gene for metformin effects. Two networks of interacting genes were identified in this analysis; the first network consisting of 27 genes (22 up-regulated and 5 down-regulated) and the second consisting of three up-regulated genes.This meta-gene was then examined in two independent cohorts of stage I adenocarcinoma. In the first cohort (n=125), patients clustered into two groups when k-means analysis was performed with respect to the 30 genes in the metformin meta-gene network. These patients had a significantly (p=0.014) different incidence of recurrence between the two clusters. This result was independently validated in the second data set (n=168) where patients clustered into two groups and also demonstrated significant stratification of recurrence (HR=1.21; p=0.001).

Conclusion:
We have identified a meta-gene of interacting proteins associated with both metformin therapy and recurrence-free survival in early stage lung cancer patients. This suggests a potential method for identifying NSCLC patients most likely to benefit from metformin therapy, and furthermore, identifies mechanistic avenues by which metformin treatment may benefit early stage lung cancer patients.

Background:
Serum based biomarkers are routinely used for prognosis and monitoring of some solid tumors (e.g. colorectal, pancreatic, and ovarian carcinomas) but have not yet been widely adopted in NSCLC management. We prospectively evaluated the prognostic role of serum biomarkers in the management of early stage NSCLC treated at a single specialized center.

Methods:
Prospective collection of blood samples from patients (pts) with resectable NSCLC was done before surgery and thereafter during routine follow up visits. A panel of serum biomarkers was measured, including CYFRA 21-1 (Cytokeratin fragment 19) and CEA (carcinoembryonic antigen). Several risk models were established and prediction accuracy was assessed by C-Index (generalized AUC), Hazard Ratio (HR) at median split and Net Reclassification Index (NRI).

Results:
275 pts were enrolled (n= 180 men). Histology was adenocarcinoma (AC) in 133 pts (48.4%), squamous cell carcinoma in 103 pts (37.5%), and other in 39 (14.1%). Stages were based on IASLC 6[th] edition and included IA (n= 39), IB (n= 120), IIA (n= 7), IIB (n= 66), and IIIA (n= 43). 92 pts (33.5%) recurred after a median of 11.9 months follow-up. Occurrence of first relapse showed two main peaks, at 6-12 months and 21-27 months, respectively, indicating a high-risk group for early relapse. In multivariate analyses, clinical prognostic factors included: TNM stage, age, gender, histology, and smoking history. Addition of the baseline CYFRA 21-1 and CEA biomarkers significantly increased the number of pts allocated to the correct prognostic group in the model by 13.2% compared to clinical variables only (HR for first relapse from 2.14 to 3.02; NRI 0.132).

Conclusion:
In this largest cohort of NSCLC pts with prospective serum biomarker sample collection to date, time to first relapse in localized NSCLC showed subgroups of early and late relapse pts. Baseline levels of the CYFRA 21-1 and CEA biomarkers identified a higher number of pts who were likely to recur within the first year and might benefit from closer surveillance. The CYFRA 21-1 assay is currently not cleared or approved for use in the USA.

Background:
The UK National Lung Cancer Audit has been collecting, analysing and reporting data on the management of lung cancer patients for 10 years. This abstract summarises the progress made in this period.

Methods:
Hospitals working within the UK National Health Service are invited to submit data to a web portal on all incident cases of lung cancer (and mesothelioma). The dataset covers demographics, referral, investigation, diagnosis, treatment and outcome.

Results:
Clinical and organisational engagement in the audit increased rapidly over the first 5 years such that currently all hospitals submit data on 100% of the expected incident cases, with 93% of cases having stage and performance status recorded. Measures of good practice have shown incremental improvements (e.g. histological confimation rate 68% to 75%, proportion with subtyped NSCLC 64% to 87%, proportion of patients seen by a specilaist nurse 51% to 84%, proportion receiving anti-cancer treatment 45% to 60%. The surgical resection rate in histologically-confirmed NSCLC has risen from 14% to 23% in keeping with other data sources, reinforcing the suggestion that these improvements reflect real changes in practice rather than just better data. Survival has improved in patients with early stage disease and good PS as previously published utilising the audit data (Khakwani et al 2013). Moreover, overall survival in the whole cohort appears to be improving when clinical features (age, sex, stage PS) are taken into acocunt as shown in Table 1.

*Adjusted for age, sex, stage and PS

Year	HR*	CI
2008	1.0	-
2009	0.97	0.96-0.99
2010	0.96	0.94-0.98
2011	0.90	0.90-0.93
2012	0.88	0.87-0.90
2013	0.87	0.85-0.89

Despite these overall improvements in process and outcome, there remains a variatin in ractice across organisations that perists after adjustment for case-mix (example Figure 1). Figure 1



Conclusion:
The NLCA has been instrumental in driving improvements in lung cancer care in the UK. Future comparative audit projects spanning national and international boundaries hold the promise of further insights into variations in care and improvement in outcomes for our patients.

Background:
Epidermal growth factor receptor (EGFR) mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC). Treatment of advanced NSCLC patients with EGFR-tyrosine kinase inhibitors (EGFR-TKI) confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to IIIA EGFR-mutated NSCLC.

Methods:
Patients with surgically resected stage IB (with high risk factors) to IIIA EGFR-mutated NSCLC were randomly assigned (1:1) to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other received platinum-based chemotherapy supplemented by a consolidation therapy of orally administered icotinib (125 mg thrice daily) two weeks after chemotherapy for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease free survival (DFS).

Results:
39 patients were enrolled between February 2011 and December 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 18 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122). At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225), respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066). In the Cox proportional hazards model, the treatment groups and pTNM stage showed a statistically significant, the HR was 0.136 (95%CI: 0.022-0.829, p = 0.030) and 5.498 (95%CI: 1.333-22.673, p = 0.018) respectively. Adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib.Figure 1



Conclusion:
The results suggest that, firstly, chemotherapy plus orally icotinib displayed a longer DFS compared with chemotherapy only, and secondly, patients receiving extra orally icotinib showed favorable tolerance without severe side effects. Nonetheless, our results are promising and future trials with larger sample sizes could confirm our current data.

Background:
In the U.S., racial/ethnic and gender differences in treatment and survival of early stage non-small cell lung cancer (NSCLC) have been reported. These findings come largely from analyses of SEER-Medicare data, which inherently exclude younger and managed care patients, up through 2005. Whether such differences exist in an integrated health care system, other than the U.S. Military Health System and Veterans Health Administration, has not been comprehensively examined.

Methods:
Using electronic health record and cancer registry data from Kaiser Permanente Northern California, a fully integrated health care system, we identified a cohort of 1,566 patients of non-Hispanic White, Asian/Pacific Islander, Black, or Hispanic race/ethnicity diagnosed with incident stage I/II NSCLC at ages 21 to 80 years from 2004 to 2011. Patients were followed from NSCLC diagnosis to health plan termination, death, or study end (through 2013), whichever occurred earliest. We examined whether the following prognostic factors (at NSCLC diagnosis, unless otherwise specified), in addition to 3-year overall survival, differed statistically (p<0.05) by race/ethnicity or gender: age; marital status; smoking history; comorbidity score; tumor stage, size, and histology; and receipt, modality, and timing of initial treatment. Using multivariable Cox regression, we further examined the extent to which race/ethnicity and gender were associated with overall survival after accounting for other prognostic factors.

Results:
Our cohort included 1137 non-Hispanic Whites (482 men, 655 women); 232 Asian/Pacific Islanders (95 men, 127 women); 126 Blacks (52 men, 74 women); and 71 Hispanics (36 men, 35 women). The median age at diagnosis was 68 years. Overall, 92% were treated (89% of those treated by surgery), within 1.8 months post-diagnosis on average, and 41% died during 69,894 person-years of follow-up (median=3.3 years). Comparing across the race/ethnicity groups, non-Hispanic Whites were generally older at diagnosis, while Asian/Pacific Islanders were more likely to be married, never or former smokers, have a lower comorbidity score, and diagnosed with adenocarcinoma. The group most commonly treated with surgery was Asians/Pacific Islanders (87.5%), followed by Hispanics (81.7%), non-Hispanic Whites (79.9%), and Blacks (65.1%), with 3-year overall survival probabilities of 77%, 73%, 69%, and 63%, respectively. Compared to women, men were more likely to be married, former or current smokers, have a higher comorbidity score, and have a tumor of higher stage, greater size, and squamous cell histology, although both their receipt of surgery (women: 82%, men: 78%) and 3-year overall survival probabilities (women: 71%, men: 69%) were similar. After accounting for age, marital status, smoking history, comorbidity score, tumor characteristics, and receipt, modality, and timing of initial treatment, overall survival was similar for Asian/Pacific Islanders (hazard ratio (HR): 0.90; 95% confidence interval (CI): 0.69-1.17), Hispanics (HR: 0.96; 95% CI: 0.66-1.42), and Blacks (HR: 0.99; 95% CI: 0.75-1.31) compared to non-Hispanic Whites, and for men (HR: 0.95; 95% CI: 0.80-1.13) compared to women.

Conclusion:
Among early stage NSCLC patients in our integrated health care system, we found racial/ethnic differences in treatment, but no racial/ethnic or gender differences in overall survival after accounting for treatment and other prognostic factors.

Background:
Second primary lung cancer (SPLC) is an important cause of death in survivors of head and neck squamous cell cancer (HNSCC). The goal of this Dutch population study was to compare treatment patterns and outcomes in early-stage SPLC after HNSCC.

Methods:
Details on all patients in a population of 16 million diagnosed with lung cancer between 1997 and 2011 were obtained from the Netherlands Cancer Registry. After excluding patients with a history of other malignancies, patients were dichotomized with a primary lung cancer or a SPLC after HNSCC. The latter included oral cavity, oropharynx, larynx, and hypopharynx sub-sites. Baseline characteristics of early-stage primary and SPLC were compared using the chi-square, fisher’s exact, or t-test, where appropriate. After stratifying patients into five consecutive 3-year time periods, the Chi-Square Trend test was used to determine trends in treatment patterns over time. Overall survival was calculated using the Kaplan-Meier method, and the log-rank test used to assess differences in survival. 30- and 90-day treatment related mortality were calculated. To assess for stage migration due to routine availability of PET-staging, as well as the availability of stereotactic ablative radiotherapy (SABR), outcomes were analyzed before and after 2005. All statistical tests were two-sided and considered significant when p<0.05.

Results:
Of the 153,330 lung cancer patients, 19,501 with a history of a non-HNSCC primary cancer were excluded from the analysis. Of the 133,829 remaining patients, 2,556 (2%) represented a SPLC following HNSCC. SPLC patients were more likely to present in stage I (27% versus 16%, p<0.01) rather than stage IV (34% versus 44%, p<0.01). For early-stage SPLC, initial HNSCC anatomical subsites were most commonly larynx (53%) and oral cavity (24%). Treatment for early-stage SPLC included surgery (53%), radiotherapy (RT, 33%), or best supportive care (14%). The proportion of RT patients undergoing SABR was unknown. When compared to surgery, early-stage SPLC patients receiving any-form of RT tended to be older, with more advanced T-stage disease, poorly differentiated histology, and lower rates of pathologic diagnosis (all p<0.01). The proportion of all early-stage lung cancer patients receiving surgery over time remained stable in the primary setting (range: 59-63%, p=0.69), but decreased for early-stage SPLC patients (range: 68-42%, p<0.01). The use of RT increased over time for both primary (range: 21-30%, p<0.01) and early-stage SPLC patients (range: 23-43%, p<0.01). 30- and 90-day treatment related mortality rates were higher in surgical versus RT patients in both pre-2005 (3.8%, 8.6% versus 4.0%, 8.0%) and post-2005 (2.3%, 4.0% versus and 0%, 3.2%) eras. Overall, early-stage SPLC surgical patients had improved survival when compared to RT patients (p<0.01). In the post 2005 era, however, survival was similar for these two modalities (p=0.13).

Conclusion:
In survivors of HNSCC who develop early-stage SPLC, RT deserves attention as an alternative gold standard to surgery. Previous studies indicated that a majority of RT delivered for early-stage NSCLC after 2006 was SABR [Palma D, 2010]. Despite negative selection of poorer baseline characteristics, use of RT resulted in comparable survival and lower post-treatment mortality when compared to surgery in the modern era.

Abstract:
Evidence from countries of all income levels shows that price increases on cigarettes are highly effective in reducing demand. Higher prices induce cessation and prevent initiation of tobacco use. Article 6 of the WHO Framework Convention on Tobacco Control, "Price and Tax Measures to Reduce the Demand for Tobacco", recognizes the importance of this policy and calls on governments to implement tax and price policies to contribute to their national health objectives. Guidelines on Price and Tax Measures to reduce the demand for Tobacco, adopted by the 180 parties to the FCTC at the Sixth Conference of the Parties in October 2014, stipulate: “Any policy to increase tobacco taxes that effectively increases real prices reduces tobacco use. According to the studies referenced in the WHO technical manual on tobacco tax administration and IARC Handbooks of Cancer Prevention: Tobacco Control. Volume 14, the relationship between real prices and tobacco consumption is generally inelastic, meaning that the decline in consumption is less than proportional to the increase in real price. Most estimates of the price elasticity of demand lie between -0.2 and -0.8. In all settings, studies have shown that the price elasticity of demand is higher (in absolute terms) in the long term, meaning that consumption will fall even more in the long term. People with lower socioeconomic status are more responsive to tax and price changes because such changes have a greater impact on their disposable income. As regards the effect of higher taxes and prices on tobacco use by young people, it is estimated that young people are two to three times more responsive to tax and price changes than older people. Therefore, tobacco tax increases are likely to have a significant effect on reducing tobacco consumption, prevalence and initiation among young people, as well as on reducing the chances of young people moving from experimentation to addiction.”[1] [1] Conference of the Parties to the WHO Framework Convention on Tobacco Control, Sixth session, Guidelines for implementation of Article 6 of the WHO FCTC (Price and tax measures to reduce the demand for tobacco), Moscow, Russian Federation,13–18 October 2014.

Abstract not provided

Abstract:
Learning Objectives: • Describe FDA’s authority under the Family Smoking Prevention and Tobacco Control Act and the steps FDA has taken to regulate tobacco products in the 6 years since enactment of the law. • Understand FDA’s Center for Tobacco Products’ (CTP) strategic priorities and CTP’s vision for the regulation of tobacco products to help reduce the death and disease toll caused by tobacco use. • Describe how the CTP Office of Science supports and evaluates research to ensure that CTP has the science base to make regulatory decisions. • Discuss the ways the public health community can engage with FDA to participate in tobacco product regulation. • Identify opportunities to inform FDA action on tobacco to promote public health. Abstract: The landmark Family Smoking Prevention and Tobacco Control Act (TCA) gave the U.S. Food and Drug Administration (FDA) sweeping new authorities to create a healthier future for America’s families by regulating the manufacture, marketing, and distribution of tobacco products. The law, passed by Congress and signed by the President in 2009, gave FDA the authority to establish the Center for Tobacco Products (CTP), which drives powerful change to protect children and families from the dangers of tobacco products. The TCA takes a comprehensive approach—grounded in rigorous, timely science and the law—to improve public health, especially for the next generation. FDA uses its regulatory authority to take action to protect American families, charting a new course for comprehensive change. These actions include: • Developing science-based regulations to safeguard the nation’s health. • Publishing guidance to help the industry comply with regulations for tobacco products. • Conducting retailer inspections to ensure compliance with laws restricting sales of tobacco products to youth, and issuing warning letters and monetary penalties for violations. • Requiring tobacco manufacturers to report the ingredients in their products so FDA can evaluate the harm caused by the ingredients, take steps to reduce the harm, and educate the public about the toxic substances in tobacco products so public health can be improved. • Reviewing proposed modified risk tobacco products before they can be sold. • Restricting the access and attractiveness of cigarettes and smokeless tobacco to young people. • Enforcing the ban on the manufacture and sale of fruit- or candy-flavored cigarettes. • Prohibiting the use of misleading claims such as “low,” “light,” and “mild” that falsely imply that some tobacco products are safer. • Reviewing new tobacco products to determine whether they can be legally marketed. • Launching public information and education campaigns, particularly targeted to youth, about the dangers of regulated tobacco products. • Partnering with other public health agencies to conduct cutting-edge research on a range of topics such as smoking initiation and nicotine addiction. Currently, FDA regulates cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco. FDA has also published a proposed rule to bring other products that meet the definition of tobacco product under FDA’s regulatory authority, such e-cigarettes, waterpipes, some or all cigars, and pipe tobacco. Despite major progress over the past half-century tobacco use kills more than 480,000 Americans each year, making it the leading cause of preventable death and disease in the United States.[1] Every day in the United States, nearly 2,900 youth under the age of 18 smoke their first cigarette, and more than 700 youth under age 18 become daily smokers.[2] Nationwide, 5.5 percent of high school students currently use smokeless tobacco.[3] Nearly 9 out of 10 daily adult smokers used their first cigarette before the age of 18.1 On a global level, tobacco use causes nearly six million deaths a year and at current rates could kill up to one billion people this century.[4] Tobacco use is the most important risk factor for cancer causing around 20% of global cancer deaths and around 70% of global lung cancer deaths.[5] Tobacco regulators around the globe seek to protect present and future generations from the devastating health, social, environmental and economic consequences of tobacco consumption and exposure to tobacco smoke. We share common priorities and face common challenges in the fight to improve global public health. It is imperative that all global stakeholders, including the medical and scientific community, learn from one another’s successes and failures. In the United States, FDA's unique position as a regulatory agency allows for a framework of decisionmaking based on – and within the limits of – both the science and the law. CTP uses a comprehensive approach as the best way to end the negative health effects of tobacco use. This includes defining policy, issuing regulations, conducting research, educating Americans on regulated tobacco products, and making decisions on whether new products and claims can be marketed—including reviewing and evaluating applications and claims before the products are allowed on the market. CTP educates the public about the harms of tobacco products, working to reduce their appeal and keep them out of the hands of America’s youth. CTP is committed to protecting and improving public health by focusing on three top priorities: • Reduce initiation rates and prevent youth from starting to use tobacco • Encourage tobacco users to quit • Decrease the harms of tobacco product use This session will help the global medical, research, and public health communities understand the authority granted to the FDA to regulate tobacco and how science is used to make the most effective regulatory decisions. FDA staff will describe actions taken by the FDA in the first six years of regulating tobacco products and preview future regulatory priorities. Attendees will learn about specific ways in which they can collaborate with and inform FDA’s work. At the conclusion of this session, attendees will be able to describe the FDA's role, its activities to date and priorities for the future. References: 1. US Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress. A Report of the Surgeon General. Atlanta, GA: US Dept of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014. 2. Substance Abuse and Mental Health Services Administration (SAMHSA). Results from the 2012 National Survey on Drug Use and Health, NSDUH: Table 4.10A Past Year Initiation of Substance Use Among Persons Aged 12 or Older Who Initiated Use Prior to the Age of 18, by Gender: Numbers in Thousands, 2012 and 2013. Rockville (MD): US Dept of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, 2014. 3. Centers for Disease Control and Prevention. Tobacco Product Use Among Middle and High School Students - United States, 2011-2014. Morbidity and Mortality Weekly Report 2015; 64: 381-385. 4. http://www.who.int/mediacentre/factsheets/fs339/en/ 5. http://www.who.int/mediacentre/factsheets/fs297/en/ The U.S. Food and Drug Administration (FDA) Center for Tobacco Products (CTP) oversees the implementation of the Family Smoking Prevention and Tobacco Control Act (TCA). This session will help the medical, research, and public health communities understand the authority granted to FDA to regulate tobacco and how science is used to make the most effective regulatory decisions. Mr. Zeller will describe actions taken by the FDA in the first six years of regulating tobacco products and provide an overview of CTP’s strategic priorities. Attendees will learn about specific ways in which they can collaborate with and inform FDA’s work. At the conclusion of this session, attendees will be able to describe the FDA's role, its activities to date and priorities for the future and understand CTP's strategic priorities and vision for the regulation of tobacco products to help reduce the death and disease toll caused by tobacco use.

Abstract:
Product liability litigation has played a critical, if supporting, role in tobacco control. Most prominently, lawsuits brought by US state attorneys general in the mid-1990s seeking reimbursement for expenses incurred in treating residents for smoking-related diseases forced the industry to begin disgorging incriminating internal documents, with over 14 million now available on the internet, detailing industry misbehavior around the world (http://legacy.library.ucsf.edu). Public exposure of these misdeeds made the tobacco industry politically toxic, easing the way for subsequent regulatory legislation. Under the Master Settlement Agreement resolving these cases, the industry agreed to eliminate various marketing techniques and promotional stratagems and pay the states about $10 billion/year, resulting in dramatic cigarette price increases that greatly reduced teenage smoking. Some of that money went into effective tobacco control programs. Every stage of tobacco litigation (initial filings, motions, hearings, decisions, appeals) provides ‘teachable moments’ for public education about the underlying issues: the health consequences of smoking, addictiveness, and tobacco industry misbehavior. The cases dramatize the impact of smoking on real people, not just statistics. Even the industry's counter-spin, that smokers who contract lung cancer ‘assumed the risk’, implicitly acknowledges the reality of the causal link. Product liability litigation can take many forms. Most legal systems allow individuals, including smokers or their survivors, to seek compensation for their financial and emotional losses from product manufacturers that sell unreasonably dangerous products, fail to warn about the dangers of these products, and/or actually lie about these dangers. In the USA, multimillion-dollar punitive damages, designed to deter others from misbehaving like tobacco companies, are sometimes also available. Similar cases can be brought by victims of secondhand smoke, though establishing causation in cases against tobacco manufacturers has proven extremely difficult; obtaining workers compensation from employers, however, has become fairly routine. Injuries from cigarette-caused fires are compensable, since cigarettes with low ignition propensity can easily be manufactured. Injured smokers and non-smokers are not the only possible plaintiffs: as mentioned, many US states were permitted to sue tobacco companies in the 1990s for medical costs incurred in caring for smokers whose diseases could be attributed to tobacco industry misconduct. Similar cases are pending in Israel, and most Canadian provinces now have legislation facilitating such lawsuits. Finally, legal systems sometimes permit consumers with similar claims to proceed in a single class action, greatly reducing litigation costs. In May 2015 a judge in Quebec, Canada awarded more than US$100,000/smoker to a class of about 100,000 smokers with lung or throat cancer or emphysema, as well as about $100 million to another class of addicted smokers. U.S. courts have allowed class actions to go forward to fund medical monitoring programs for long-term smokers, and to compensate smokers who were fooled into thinking that “light” cigarettes were safer than regular cigarettes. Cases can be brought to stop tobacco industry misconduct brought by parties who were not themselves injured by that behavior. Thus, the US Department of Justice brought a successful case against the major tobacco companies to prevent their continued violations of the Racketeer Influenced and Corrupt Organizations Act. And cases can even be brought in some jurisdictions to force the government to protect the lives and health of their citizens. Thus, the Indian Supreme Court insisted upon legislation to protect nonsmokers from secondhand smoke. The efficacy of product liability litigation depends as much on procedural rules as on substantive legal doctrines (legal ‘rights’). In most countries other than the USA, the absence of contingency fees (where plaintiff's lawyers are compensated with a portion of the plaintiff's judgment or settlement, if any) means the lawyers must either provide their services for free or bill their ill, dying, or bereaved clients on an ongoing basis: hence, few such cases are brought. Worse, many legal systems require plaintiffs who lose their cases to pay the defendant's legal costs, thus putting the plaintiff's remaining assets at risk. These unfortunate procedural rules can, of course, be changed by court rule or statute. Going forward Article 4.5 of the WHO Framework Convention on Tobacco Control (FCTC) recognizes that ‘issues relating to liability… are an important part of comprehensive tobacco control’. Article 19, ‘Liability’, provides that ‘Parties shall consider taking legislative action… to deal with… civil liability, including compensation where appropriate’. Legislation correcting the procedural rules that prohibit contingency fees and shift litigation costs to the losing party, permitting consumer class actions, and facilitating healthcare cost recovery lawsuits, are examples of such highly desirable legislative action. Article 19 also encourages parties to assist each other in carrying out legal proceedings and to share relevant information with each other, and invites the Conference of the Parties (COP) to develop ‘appropriate international approaches to these issues’ as well as to support parties in their activities relating to liability. The COP has currently charged an expert group to design a mechanism for collecting, archiving and sharing litigation documents and for providing advice and assistance—electronically or in person—to attorneys bringing liability cases against the tobacco industry. For at least a decade tobacco company defendants in the US have admitted on their websites and ceased to deny in court that smoking is the major cause of lung cancer and chronic obstructive pulmonary disease (COPD), though they often contest the diagnosis or aetiology in particular cases. By contrast, and despite universal availability of the internet, tobacco defendants in Europe and Asia have been remarkably successful in confusing courts on the epidemiology of smoking and disease. The recent acceleration in the globalization of tobacco control efforts, inspired by the FCTC and supported by the Bloomberg and Gates Foundations, and the commitment of parties under Article 12 of the FCTC to conduct public education on tobacco control issues, can be expected to equalize around the world knowledge of basic tobacco epidemiology. Similarly, the presence of millions of easily accessible internal tobacco industry documents on the internet should simplify the process of establishing the liability of the major transnational tobacco companies and their affiliates.

Abstract:
Immunotherapy has recently confirmed its place as an important treatment strategy for a number of solid tumors, including melanoma and non-small cell lung cancer. Checkpoint blockade, in particular, has emerged as an ‘off-the-shelf’ immunotherapy which does not rely on known tumor antigens, costly and time-consuming individualised preparation of autologous tumor, or viral vectors. This overview will cover the history of immunotherapy in mesothelioma, recent reported clinical trials, trials in progress, and current cutting edge research with the potential for translation. Although mesothelioma is not classically considered immunogenic, there is abundant evidence that it is recognised by the immune system. Earlier studies described the relationship between tumour infiltrating lymphocytes and prognosis, occasional spontaneous remissions are seen, and there have been reports of low rates of responsiveness to a range of immunotherapies over the past 30 years. There is also a body of work demonstrating impaired immune responsiveness in people with mesothelioma and an immunosuppressive intratumoral milieu. Specifically, NK cell activity is reduced, CD4+ lymphocyte numbers are reduced, and dendritic cell function is impaired (Cornwall S, unpublished data), amongst other changes. Regulatory T cells and inhibitory cytokines within the tumour may contribute to an immunosuppressive milieu [1]. The presence of CD8+ infiltration within the tumour is a predictor of more favourable outcomes [2]. More recently, mesothelioma, in particular sarcomatoid subtype, was shown to overexpress PD-L1 and to predict poor prognosis [3] Historically, response rates below 20% have been seen in clinical trials of systemic and intrapleural interferons, generally accompanied by high toxicity [4]. Similarly, other cytokines such as Interleukin-2 or GM-CSF have shown either poor response rates, low feasibility, or excessive toxicity [5]. Gene therapy approaches have similarly shown very low response rates and are technically demanding [6]. More recent trials have focussed on antigen-specific approaches using the known tumor antigens mesothelin and WT-1, and the use of checkpoint blockade. Immunological checkpoints are inbuilt mechanisms that negatively regulate the size and duration of an immune response, both during induction of the T cell response and during the effector phase of the response, in tumor tissue. Their normal function is to prevent excessive and ongoing T cell activation which may lead to overwhelming autoimmunity. Many tumors, including mesothelioma, express ligands for these checkpoint molecules, allowing tumors to negatively regulate the anti-tumor immune response and thus evade elimination [3]. The expression of checkpoint molecules including Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and PD-1 on T cells, and the expression of ligands such as PD-L1 and PD-L2 on tumors, has allowed the development of antibody blockade which can prevent downregulation of the anti-tumor response by inhibitory signals, hence ‘taking off the brakes’ and facilitating a more effective host response to tumor. CTLA4 is expressed on T cells after activation, and counter-regulates the T cell activation which normally occurs when the co-stimulatory receptor CD28 is engaged. Whilst ligation of CTLA4 normally restricts ongoing T cell co-stimulation and activation, abrogating anti-tumour immunity[7], CTLA4 blockade using monoclonal antibody inhibitors can allow the endogenous anti-tumour response to proceed unopposed. The first report of a clinical trial of this drug class in mesothelioma was published by Calabro and colleagues in 2013 [8], with results showing some similarities to the first trials of CTLA4 blocking antibodies in melanoma. Durable partial responses were seen in two patients, with a further seven of 29 patients experiencing prolonged stable disease. The disease control rate was 31%, median progression free survival was 6·1 months, and almost 40% of participants were alive at two years. The phenomenon of early progression followed by a lengthy partial response was seen in one patient. The authors noted that the progression free survival and two year survival results were better than expected for this population, and although partial responses were uncommon they were long lasting. This study provided the rationale for the subsequent testing of tremelimumab in a large randomised phase II study in mesothelioma which has recently completed recruitment (NCT01843374). A recent presentation at the American Association for Cancer Research (AACR) reported on results from the mesothelioma cohort enrolled in the KEYNOTE-028 study. This trial used PD1 axis blockade with pembrolizumab in patients with mesothelioma selected to express the PD-L1 ligand. Of 25 patients treated, partial response was observed in 7 (28%) and stable disease in 12 (48%), giving a disease control rate of 76% with a tolerable toxicity profile. Many of the responses seen were profound and durable[9], highlighting the enormous potential of this approach in mesothelioma. Finally, mesothelin is highly expressed on mesothelioma cells, predominantly of the epithelioid subtype. A number of methods of targeting mesothelin are under development and clinical testing. The anti-mesothelin immunotoxin SS1P has been administered together with lymphodepletion using cyclophosphamide and pentostatin. Major responses were observed in a subset of patients in a small clinical trial (n=10), notably with some reports of immune pseudoprogression before eventual treatment response. Other treatments using mesothelin as a target include CRS-207, a live attenuated listeria monocytogenes strain which expresses mesothelin, and MORAb-009, a monoclonal antibody that targets mesothelin. Immunotherapy in mesothelioma remains very immature. Results of PD1 and/or PD-L1 blockade in larger numbers of treated patients are needed, and phase III studies will be important to define any benefits. Combinations of checkpoint blockade have shown outstanding efficacy in other cancer types and must be tested in mesothelioma. Underpinning these trials must be the search for biomarkers of treatment efficacy. Technologies such as tumor sequencing also have the potential to identify neoantigens with immunological reactivity in individual patients, an approach that could lead to the development of personalised vaccines, potentially in combination with other immunotherapies. References 1. Hegmans, J.P.J.J., et al., Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. European Respiratory Journal, 2006. 27(6): p. 1086-95. 2. Yamada, N., et al., CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother, 2010. 59(10): p. 1543-9. 3. Mansfield, A.S., et al., B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol, 2014. 9(7): p. 1036-40. 4. Boutin, C., et al., Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer, 1994. 74(9): p. 2460-7. 5. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 6. Schwarzenberger, P., et al., Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Am J Respir Cell Mol Biol, 1998. 19(2): p. 333-7. 7. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 2012. 12(4): p. 252-64. 8. Calabro, L., et al., Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol, 2013. 14(11): p. 1104-11. 9. Alley, E.W., et al., Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028, in Proc Am Assoc Cancer Res. 2015.

Abstract:
Mesothelin is a tumor differentiation antigen that is highly expressed in several cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissue and its high expression in many solid tumors make it an attractive candidate for cancer therapy. Several drugs targeting mesothelin, including immunotoxins (SS1P, RO6927005), a chimeric monoclonal antibody (Amatuximab), an antibody drug conjugate (Anetumab Ravtansine), and a tumor vaccine (CRS-207), are in various stages of development to treat patients with mesothelin-expressing tumors. The first anti-mesothelin therapeutic agent to enter the clinic was the immunotoxin SS1P and it demonstrated that mesothelin could be successfully exploited as a target for cancer therapy and has led to a broad interest in developing different approaches for mesothelin immunotherapy treatment of solid tumors including malignant mesothelioma. Immunotoxins are targeted anti-cancer therapeutics that kill cancer cells by inhibition of protein synthesis using a cytotoxic bacterial toxin payload. In a phase I clinical trial SS1P had limited anti-tumor activity because it was immunogenic and patients develop antibodies to the drug limiting treatment efficacy. However, we have recently shown that co-administration of SS1P with a lymphocyte depleting regimen of pentostatin and cyclophosphamide can delay anti-drug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pre-treated mesothelioma patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and non-specific toxicity have been developed through protein engineering techniques. RO6927005 is a next generation anti-mesothelin PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity so that patients can receive multiple cycles of the drug. In pre-clinical studies RO6927005 has increased activity compared to SS1P against mesothelioma tumor cells directly obtained from patients as well as activity in mesothelioma tumor models either alone or in combination with chemotherapy. A phase I clinical trial of RO6927005 has just been initiated for patients with mesothelin expressing cancers including malignant mesothelioma. There are other antibody based therapeutics in advanced clinical development for treatment of malignant mesothelioma including amatuximab and anetumab ravtansine. In a phase II single arm trial of unresectable, chemotherapy naïve patients with pleural mesothelioma, amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Based on these results a registration front-line study of amatuximab with pemetrexed and cisplatin versus pemetrexed and cisplatin alone has been initiated for treatment of newly diagnosed patients with pleural mesothelioma. Anetumab Ravtansine (BAY 94-9343) is an antibody-drug conjugate in which a human anti-mesothelin monoclonal antibody is conjugated to the maytansinoid tublin inhibitor DM4. In preclinical studies it showed significant anti-tumor activity against mesothelioma cell lines as well as mesothelioma patient derived xenografts. Anetumab Ravtansine is currently being evaluated in patients with mesothelin expressing cancers who have failed standard therapies and represents a potential therapeutic option for treatment of patients with mesothelioma given the high and uniform expression of mesothelin in this tumor. Hopefully, these different approaches to exploit mesothelin for immunotherapy of malignant mesothelioma will result in new treatment options for these patients.

Abstract:
In recent years immunotherapy has become a new standard in the treatment of malignant diseases. Most clinical evaluated treatments like anti-PD1 aim to reactivate the cytotoxic T-cell response directed against the tumor (CTL-t ). A requirement for this treatment to be effective is the presence of CTL-t within the tumor as reviewed by us recently [Aerts, 2013]. CTL-t formation is dependent on a number of factors which are inhibited by tumor-derived factors and tumor-induced immune suppressive cells, precluding patients to respond to the PD-1 checkpoint blockade pathway. Knowing and bypassing these inhibition pathways of the tumor increases the number of responding patients. For instance, in melanoma it has been shown that combination treatment of anti-PD-1 and anti-CTLA-4 almost doubles the patients benefitting from checkpoint blockade inhibitors. However the number of inhibition pathways is diverse and also changeable according to the act – react principle. The blockade of one inhibitory pathway of the tumor may ultimately lead to the upregulation of another inhibitory pathway. This complex interplay inhibits the formation of new CTL-t and an exhaustion of the CTL-t present in the tumor. That is why cell based therapy, either with ex-vivo generated T-cells or stimulated dendritic cells (DC), precluding a number of inhibitory mechanisms in the patient is an alternative to increase the number of responding patients and thus the efficacy of immunotherapy. Mesothelioma is an aggressive neoplasm, with highly specific growth features making it a distinctive malignant tumor from other cancer types. One of the key immunological features in mesothelioma is the abundant immunosuppressive environment it is creating. There is a large infiltration of regulatory T-cells, immunosuppressive macrophages and myeloid derived suppressor cells (MDSC). Furthermore, the tumor milieu negatively influences immune activation for instance by the presence of hypoxic areas. , tumor metabolites (e.g. arachidonic acid), and suppressive cytokines and chemokines negatively influence the immune activation. Some early phase studies showed a possible clinical effect of immunotherapy in mesothelioma. For instance, checkpoint inhibition with anti-CTLA-4 and anti PD-1 in a subgroup of patients showed some benefit which is now further evaluated in larger studies in second and further line treatment [Calabro 2013, NCT01843374 results pending, NCT02399371 amongst others] . Although it can be questioned whether that is the right setting to determine clinical benefit in placebo controlled trials. Anti mesothelin antibodies also did show clinical efficacy which is now investigated further [Hassan 2010]. Cell based therapy may increase efficacy of immunotherapy also in mesothelioma. The choice of the tumor associated antigens (TAA) to induce a CTL-t is critical, considering the diverse and changing repertoire of TAA. Genetically altered T-cells, directed against mesothelin or Wilms tumour-1 (WT-1) have been developed and are tested in the clinic [NCT02414269 amongst others]. Also DC therapy, being the most powerful initiator of an immune response, is also tested. An advantage of DC, apart from the induction of a natural CTL-t activation, is the ability to load the DC with a pluripotent antigen mixture. DC therapy with an autologous tumor cell lysate demonstrated promosing results [Hegmans 2010] and an allogeneic tumor cell lysate is now tested as tumor associated antigen source in the clinic [NCT2395679]. In the patient stimulation of DC seems an attractive option and has been investigated but may be hampered by the immunosuppressive environment created by the tumor [Powell, 2006]. A new concept with in vivo activation of DC with mesothelin loaded listeria bacteria is now investigated in mesothelioma [NCT01675765]. DC treatment can also be optimized with the addition of different checkpoint activators or inhibitors [Lievense WCLC 2015] Apart from the immune activation strategies, investigations should focus on how to diminish the highly immunosuppressive effect of mesothelioma. Results of our trial on combination treatment with ex vivo matured DC loaded with autologous tumor cell lysate and regulatory T cell (Treg) depletion showed a reduction in circulation Treg [data submitted for publication]. We are in the field of a whole new changing treatment paradigm for mesothelioma. Immunotherapy will be one of the new treatment options. Much effort has to be invested to determine the optimal combination treatment for particular patients. Dendritic cell-based therapy seems an attractive option to generate a more robust immune response that can serve as a backbone for combination treatment.

Abstract not provided

Abstract:
Mediastinal germ cell tumors represent 2% of all germ cell tumors. The anterior mediastinum is the site of origin. There is never a clinical situation where a patient has a primary tumor in the testis with spread to the anterior mediastinum, as typical nodal spread goes to the ipsilateral retroperitoneal lymph nodes and subsequently to the posterior mediastinal. The most common mediastinal germ cell tumor is mature teratoma. These patients will have a normal hCG and AFP and routinely be cured with surgical resection alone. Mediastinal seminomas are all good-risk disease unless there is spread to liver, bone, or brain. Patients with mediastinal seminomas might have a slight elevation of hCG, but would never have an elevation of serum alphafetoprotein. In the past, they were treated with radiation therapy, but now they are treated with standard chemotherapy, usually BEP x 3 unless the patient is over age 50. Despite the size of the tumor, the expected cure rate is 90-100%. Primary mediastinal non-seminomatous germ cell tumor reflects a much worse prognosis and regardless of the size of the tumor or amplitude of tumor marker, they are all categorized as advanced disease. These tumors represent a real challenge for the multi-disciplinary team consisting of medical oncology and thoracic surgery. The cure rate is only 40-50% and if cure is not possible with first-line therapy, subsequent cures with any form of non-surgical salvage chemotherapy, including high dose chemotherapy, is very low. We prefer etoposide (VP-16) + ifosfamide + cisplatin (VIP) for 4 cycles in preference to BEP x 4. A prior phase III study in advanced germ cell tumors of any category revealed similarity in cure rates with these 2 regimens. Because these patients will usually require extensive thoracic resections, we prefer to avoid the 12 weeks of bleomycin. The ability to cure these complicated patients is dependent upon the diagnostic skill of pathologists, the clinical acumen of medical oncologists, but especially the skill and experience of thoracic surgical oncologists. It is strongly advised that such patients be seen at tertiary centers for optimal management, especially surgery.

Abstract:
While rare tumors overall, thymic tumors are one of the most common malignancies of the anterior mediastinum. The histology of these tumors is typically described using the WHO classification, which includes type A, AB, B, and type C tumors. This histologic classification system can help to determine prognosis when combined with stage. While there are multiple categories within this classification system, perhaps the most clinically relevant differentiation is between thymoma and thymic carcinoma (type C). Although there is great heterogeneity in prognosis for patients with thymic tumors in general, typically, patients with thymic carcinoma have a somewhat more rapid course of disease them those with thymoma. There are two dominant staging systems in use for description of patients with thymic tumors: the Masaoka staging system and the TNM staging system. The Masaoka staging system is probably the most widely used and centers around the primary tumor’s degree of invasion into the capsule (completely encapsulated tumors are stage I, while tumors with trans-capsular invasion or invasion into surrounding fatty tissue are stage II) or surrounding tissues (tumors with macroscopic invasion into neighboring organs are stage III). Notably, the Masaoka staging system differentiates stage IV thymic tumors into stage IV A, which is metastatic disease involving the pleura only and stage IV B, where patients have hematologic or lymphatic dissemination (including regional and local lymph nodes). One of the hallmarks of thymic tumors, is paraneoplastic syndromes. The most common paraneoplastic syndrome in patients with thymoma is myasthenia gravis. In patients newly diagnosed with myasthenia gravis, approximately 10-15% will have a thymoma. Conversely, approximately half of patients with thymoma develop myasthenia gravis. It is important to be aware of the diagnosis of myasthenia gravis prior to surgical resection. Multiple other paraneoplastic syndromes have been described in patients with thymoma including pure red cell aplasia, hypogammaglobulinemia, Good’s syndrome, and neuromyotonia. Notably, paraneoplastic syndrome such as these are distinctly uncommon in patients with thymic carcinoma. The treatment of patients with early stage thymoma is primarily surgical. For patients with a clinical diagnosis of an anterior mediastinal mass that is suggestive of thymoma or thymic carcinoma, if the tumor is small, it may be reasonable to resect the tumor rather than perform a biopsy prior to surgery. In patients with more locally advanced disease or where the diagnosis is uncertain, it is appropriate to perform a needle biopsy prior to surgery or other therapy. In general, patients with stage I and II disease are best managed with surgery alone. Given the critical nature of complete surgical resection for long-term outcomes, those patients with more locally advanced disease may benefit from induction chemotherapy prior to surgical resection. The most common chemotherapy regimens used for preoperative chemotherapy include platinum/taxane combinations, cisplatin and etoposide, and the 3 drug combination of cisplatin, doxorubicin, and cyclophosphamide. None of these regimens has been prospectively compared. For patients in whom surgical resection is not feasible, radiation therapy may be appropriate. For patients with recurrent or metastatic disease that is not amenable to surgical resection, systemic therapy is appropriate. Chemotherapy regimens similar to what is described for preoperative therapy are widely used. For those patients with thymoma, anthracycline-based combinations seem to have the highest response rates as initial therapy. For those patients with thymic carcinoma, there is supportive data for the use of platinum/taxane combinations as preferred initial therapy. At the time of progressive disease after first line therapy, multiple drugs have been explored, however as in first-line therapy, there are no randomized prospective trials to determine the optimal regimen. For those patients with octreotide-avid disease, administration of octreotide in combination with prednisone has been found to be useful. Data supporting the efficacy of a number of drugs has been reported. More recent data support the use of pemetrexed, everolimus, sunitinib (for thymic carcinoma), as well as cixutumumab, an anti-IGF 1R antibody. Given the rarity of this tumor and the multidisciplinary nature of care required for patients with thymic carcinomas or thymoma, referral to a multidisciplinary team with experience in management of patients with thymic tumors is appropriate.

Abstract:
The mediastinum is customarily divided into an anterior, middle (visceral) and posterior (bilateral paravertebral) compartment. Studies encompassing large series of patients indicate that more than half of the mediastinal masses arise in the anterior compartment (54-59%), up to 20% in the middle compartment, and 25% in the paravertebral (posterior) compartment. The general approach to a patient with a mediastinal mass include a thorough history and clinical examination. The type of a mediastinal tumor largely depends on the age of the patient and the presence of associated symptoms and/or paraneoplastic conditions. The most common symptoms are nonspecific and include cough, dyspnea, chest pain, arrhythmias, dysphagia, pleural effusion or, in more aggressive forms, superior vena cava (SVC) syndrome. Some tumor markers may be helpful in some forms (germ cell tumors). Chest radiography and CT scan can image the mass and can allocate it to one of the mediastinal compartments. The CT characteristics may somehow guide the clinician to a differential diagnosis and to the nature (benign or malignant) of the mass. In selected cases MRI may be useful to assess the relationship with the vascular structures and the heart. PET or integrated PET-CT have a role to define the activity of the tumor and the correct stage. Biopsy of the mass, either through a fine-needle aspiration (FNA) or core biopsy is indicated in case the imaging is not diagnostic. Very often, a surgical biopsy through an anterior mediastinotomy (Chamberlain procedure), mediastinoscopy or VATS is needed to provide sufficient tissue to the pathologist for a correct diagnosis. A brief description of the histologic types and the diagnostic workup for the most common mediastinal tumors in the three compartments will be presented. In conclusion, diagnostic workup of mediastinal masses include a careful medical history (age, duration and type of symptoms); imaging definition with CT scan is essential to precisely determine the mediastinal compartment, and cyto-histological confirmation is required in case of undetermined lesions. Differential diagnosis is crucial to provide optimal treatment. Anterior mediastinal tumors. They represent more than half of the mediastinal masses at any age. The most common types are thymic tumors (35%), lymphomas (25%), intrathoracic thyroid tumors (15%), germ cell tumors (20%, malignant 10% - teratomas 10%), other tumors (5%). According to age groups, in adults (> 40 years) thymic tumors are the most common type in men and women. Thyroid tumors are the second most common type in elderly patients. In adolescent/young adults (<40 years) lymphomas are the most common type (either Hodgkin or non-Hodgkin), while thymic tumors are the second most common in young adults, and germ cell (teratoma) in adolescents. Finally, in children (<10 years) a similar prevalence of thymic tumors, teratomas, and lymphomas is observed. The diagnosis of an anterior mediastinal mass is based on the duration and type of symptoms. Thymomas, thyroid goitres and teratomas are usually asymptomatic or indolent, Hodgkin lymphoma and seminomas are associated with an intermediate duration of symptoms, while non-seminomatous germ cell tumors (NSGCT) and lymphoblastic lymphomas have a rapid onset of severe symptoms (SVC syndrome is frequent in these patients). High alpha-feto protein (AFP) or beta-HCG levels are diagnostic of NSGCT, and high lactate dehydrogenase (LDH) suggest a diagnosis of lymphoma; the association of Myasthenia Gravis secures the diagnosis of thymoma. Cyto-histological diagnosis is indicated in undetermined forms, usually to differentiate lymphoma from thymic tumors for optimal subsequent treatment. The average sensitivity of needle biopsy (either FNA or core biopsy) in the diagnosis of lymphoma is around 50%, and in most cases a surgical biopsy is needed in suspected cases. Mediastinotomy is preferred to mediastinoscopy (which reaches the middle-visceral mediastinal compartment). Video-assisted thoracic surgery (VATS) is also a reliable technique, particularly in case of associated pleural effusion. Middle mediastinal tumors. The vast majority of middle (visceral) mediastinal masses are benign. Half of these are cysts (bronchogenic, esophageal duplication cysts). The remaining masses are most often from lymphnodes and can be either malignant (lymphadenopathy from lung cancer, lymphomas), or inflammatory/granulomatous (tuberculosis, sarcoidosis). A small percentage of these lesion (<10%) are miscellaneous (Castleman disease, paraganglioma, intrathoracic thyroid mass). Diagnosis is usually easily accomplished with CT scan, which reveals the liquid component of the cyst. MRI is required in undetermined solid lesions. Cyto-histologic diagnosis (FNA/core biopsy or mediastinoscopy/VATS) is sometimes required for undetermined adenopathy for the differential diagnosis between lymphoma and solid tumors. Almost all the benign lesions are asymptomatic or associated with mild nonspecific symptoms (cough, arrhythmias). In the malignant lesions most symptoms result from the underlying disease (lymphoma, lung cancer). Paravertebral mediastinal tumors. Almost all the tumors in the paravertebral compartment arise from the nervous structures (nerves and ganglia). The prevalence of the different types is different in adults and children/adolescents. In adults almost 90% of the masses are benign, including schwannoma (50%), ganglioneuroma (20%) and neurofibroma (15-20%). The little percentage of malignant neurofibrosarcomas are part of a familial neurofibromatosis. In these patients the clinical presentation includes severe symptoms (pleural effusion, chest pain, dyspnea) and a large tumor (> 10 cm.). Benign paravertebral masses without symptoms can be observed over time if there is no spinal extension. Diagnosis is quite easy using CT scan. Intraspinal extension can be documented with MRI. Resection is indicated in symptomatic forms or in case of intraspinal extension. Patients with familial neurofibromatosis and paravertebral mediastinal mass should receive surgery due to the demonstrated high rate of malignant shift. In children less than 4 years of age paravertebral masses are in high percentages malignant neuroblastomas or ganglioneuroblastomas (virtually 100%l in children < 1 year). The percentage of malignant forms decreases with increasing age. In neuroblastomas, serum levels of vanillylmandelic acid (VMA) and metanephrine are almost always elevated and therefore diagnostic.

Abstract not provided

Abstract:
Prognosis for mesothelioma is bleak; median survival for the cohort is generally less than 12 months. However individual patients have been known to survive for many years. From the CARET study 5 year survival rates of 9% have been reported. Our own data shows 5 year survival at less than 5%. The most frequent question of newly diagnosed mesothelioma patients relates to their prognosis. Clinical and laboratory prognostic variables proposed nearly two decades ago from consortium data from the European Organisation for Research and Treatment of Cancer (EORTC) (Curran et al, 1998) and the Cancer and Leukaemia Group B (CALGB) (Herndon et al, 1998) have been validated. Prognostic variables including performance status (PS), age, gender, tumour histology, white blood cell count (WCC), haemoglobin (Hb) level, and the presence or absence of chest pain and weight loss are taken into account when giving the patient their prognosis. Clearly, besides tumour histology and possibly the laboratory variables, most relate to the overall health and fitness of the individual. Non-subjectively determined biomarkers have been proposed as an independent means of providing prognostic information. And indeed several markers have been shown in a research setting to reflect prognosis however few of these studies have taken into account the known clinical prognostic factors. The prognostic value of serum concentrations of soluble mesothelin, the most well studied mesothelioma biomarker, have been inconsistent between studies. Data is compromised by study cohort characteristics, as tumours of sarcomatoid histology tend to have low mesothelin levels and poor survival. Our own data suggests that mesothelin levels in patients with epithelioid tumours are reflective of tumour burden as assessed by chest x-ray, CT or PET scans, which itself is an indicator of survival. Several other serological biomarkers have been reported to have prognostic value, including aquaporin 1 and osteopontin. In addition there has been extensive work on inflammation-based prognostic indices, including the neutrophil to lymphocyte ratio as well as serum albumin levels. Another useful source of prognostic biomarkers is tumour associated antigens. We have shown that serum immunoreactivity to the ATP synthase protein ATP5B is positively correlated with prognosis, and have unpublished data showing a similar significant positive association of immunoreactivity to RAB38, a previously described melanoma associated tumour antigen. In addition to blood based biomarkers, in mesothelioma it is also possible to examine soluble biomarkers in the pleural effusion. There is evidence that pleural effusion concentrations of hyaluronic acid and of fibulin-3 may provide independent prognostic data. In the case of hyaluronic acid, higher concentration of this biomarker is associated with a better prognosis. Fibulin-3 has the potential to be a useful prognostic marker because its interpretation is not confounded by lower concentrations associated with a sarcomatoid histopathology; rather sarcomatoid effusions have higher concentrations of this marker and it has been shown to be markedly superior to effusion mesothelin as a prognostic marker. Other prognostic effusion biomarkers that have been identified are syndecan-1 and osteopontin. Recently, several novel pleural effusion based biomarkers have been reported from discovery studies; these include galectin-1, aldo-keto reductase and apoliproptein C-1. Of these high effusion levels of galectin-1 and aldo-keto reductase were associated with a relatively poor prognosis whereas high effusion levels apoliproptein C-1 were associated with improved prognosis. It is important to realize that these findings remain un-validated in other patient cohorts. These biomarkers that have been identified as having prognostic value were generally not initially investigated as prognostic markers, rather they have been studied for this purpose after their identification as potential diagnostic markers. Typically their initial identification has not been thoroughly investigated in independent cohorts of patients, nor have they been systematically investigated together to determine the degree to which they are independent of each other as prognostic markers. It is possible that more suitable markers could be identified that were initially investigated as prognostic markers. An example of this would be the identification of proteins that were under or over expressed in pleural effusions from patients with longer survival compared to those with a shorter survival time using proteomics discovery methods. This underscores the importance of prospective collection of biological samples with scrupulous recording of clinical details for future evaluation of markers as they are discovered.

Background:
Identifying surgical non-small cell lung cancer (NSCLC) patients with poor prognosis remains a priority in clinical oncology given their high 5-year mortality. [18]F-FDG PET/CT can add important biological information of glucose metabolism to conventional imaging modality. Pretreatment maximal standard uptake value (SUV~max~), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) may predict prognosis in NSCLC patients. Thus, we performed this meta-analysis to explore the prognostic value of SUV~max~, MTV and TLG on disease-free survival (DFS) and overall survival (OS) in surgical NSCLC patients.

Methods:
A systematic search of MEDLINE, EMBASE and Cochrane Library was performed. Inclusion criteria were: pathologically confirmed NSCLC; [18]F-FDG PET used as an initial imaging tool before treatments; patients underwent curative surgery without neoadjuvant therapy; prospective or retrospective studies reported; complete survival data. Three investigators reviewed and scored each article independently on four dimensions: the scientific design, the generalizability of the results, the analysis of the study data and the PET reports. DFS and OS were considered as the outcome. The correlation of SUV~max~, MTV or TLG with survival was measured by hazard ratio (HR). Sub-group analyses were performed according to the histological subtype and pathological stage. The inter-study heterogeneity was evaluated with the Cochrane’s Q test as well as I[2]. The possibility of publication bias was assessed by visual inspection of a funnel plot and Begg’s test. “Trim and fill” procedure that considers the possibility of hypothetical “missing” studies that might exist was performed to further assess the possible effect of publication bias.

Results:
Thirty studies with 5011 patients were included for the meta-analysis. The mean quality score was 77.5%, ranging from 70.0% to 87.5%. Only one study was prospectively designed. SUV~max~ was measured in 28 studies, all of which were normalized by body weight. MTV was measured in 6 studies and TLG was measured in 5 studies. Adjusted HRs could be determined for 20 studies. For DFS, the combined HRs were 2.61 (95%CI 2.20-3.11, unadjusted) and 3.04 (95%CI 2.24-4.11, adjusted) for SUV~max~, 2.27 (95%CI 1.77-2.90, unadjusted) and 2.49 (95%CI 1.23-5.04, adjusted) for MTV, 2.46 (95%CI 1.91-3.17, unadjusted) and 2.97 (95%CI 1.68-5.28, adjusted) for TLG, respectively. For OS, the pooled HRs were 2.22 (95%CI 1.90–2.61, unadjusted) and 1.61 (95%CI 1.32-1.96, adjusted) for SUV~max~, 3.40 (95%CI 2.27-5.09, unadjusted) and 1.91 (95%CI 1.13-3.22, adjusted) for MTV, and 3.85 (95%CI 2.52-5.86, unadjusted) and 1.76 (95%CI 0.96-3.21, adjusted) for TLG, respectively. When the publication bias was detected by Begg’s test, “trim and fill” procedure was performed and similar HRs were obtained. The predictive role of SUV~max~, MTV and TLG remained similar in the sub-group analysis.

Conclusion:
High values of SUV~max~, MTV and TLG predicted a higher risk of disease recurrence or death in patients with surgical NSCLC. It is suggested that FDG PET/CT be used to select patients at high risk of disease recurrence or death and may benefit from more aggressive treatments. Further individual patient data should be analyzed to determine the optimal threshold value.

Background:
The main objective of the ongoing phase III Lung Adjuvant Radiotherapy Trial (Lung ART) is to study the impact of post-operative conformal radiotherapy (PORT) on disease-free survival (DFS) in a population of patients with completely resected pathologically proven N2 non-small cell lung cancer (NSCLC), with or without induction or adjuvant chemotherapy. Quality of surgical resection and extent of lymph node dissection are critically important in the interpretation of results.

Methods:
A surgical advisory committee composed of 4 international expert thoracic surgeons meets regularly in order to establish the quality of resection, taking into consideration the International Association for the Study of Lung Cancer and European Society of Thoracic Surgeons published guidelines. The committee reviews anonymized surgical and pathological reports, and establishes whether tumor resection can be considered complete (no residual tumor and adequate lymph node assessment), uncertain (highest mediastinal nodal station involved, incomplete nodal exploration, involved N2 removed in fragments) or incomplete (presence of residual tumor). Nodal exploration is evaluated according to recommendations and classified as sampling, selective dissection or extensive dissection.

Results:
As of April 15th 2015, 298 patients have been included in the Lung ART trial and 116 patients’ reports have been analyzed by the surgical advisory committee. The basic characteristics are specified in the following table:

	Total n=116
	Frequency	Percent
Induction chemotherapy
no	89	77%
yes	27	23%
Type of surgery
for right-side tumors	70	60%
lobectomy	49	70%
bilobectomy	9	13%
pneumonectomy	5	7%
other	7	10%
for left-side tumors	46	40%
lobectomy	34	74%
pneumonectomy	10	22%
other	2	4%
Tumor Size (mm)
Median size (range)	35 [0*-105]
Number of mediastinal lymph nodes examined
Median number (range)	10 [1-37]
Number of mediastinal lymph nodes involved
Median number (range)	1[0*-15]
Number of mediastinal nodal stations involved
0*	5	4%
1	79	68%
2	20	17%
>2	12	11%
* patients with downstaging after induction chemotherapy

Nodal dissection was performed according to lobar location specific recommendations in most patients: for instance, station 7 was explored in 91% patients and right inferior paratracheal station 4R in 93% of right side tumours. Nodal dissection was performed according to recommendations in 71% pts; 16% patients had sampling, 22% a selective dissection and 62% a systematic dissection. Resection was considered complete (R0) in 43%, uncertain in 42%, microscopically incomplete (R1) in 14% and macroscopically incomplete (R2) in 1 patient. The most frequent reason for “uncertain resection” was involvement of the highest mediastinal lymph node.

Conclusion:
Most adjuvant trials have included completely resected patients, without monitoring of the quality of nodal exploration and resection. This analysis outlines the importance of an external committee evaluating the quality of resection in stage IIIA-N2 NSCLC, and the findings of this audit will be useful in the interpretation of the results of the trial.

Background:
We sought to show that TransCervical Mediastinal and hilar Lymphadenectomy (TCML), using standard mediastinoscopy equipment, reliably accesses both mediastinal and hilar lymph node stations, provides accurate pre-treatment cancer staging, and facilitates Minimally-Invasive Cancer Resection (MICR) via removal of nodes traditionally dissected during definitive cancer resection.

Methods:
We reviewed our prospective databases for patients who had TCML - complete removal of lymph node tissue (not sampling) using a standard mediastinoscope +/- video-assistance. Pathological findings from TCML and definitive cancer resections were correlated. TCML's impact on cancer resection was assessed.

Results:
From 2004-2011, 372 patients, mean age 68.4 (28-93) years, 239 (64%) males and 133 (36%) females, had TCML. Cancer diagnoses included lung 306 (82.3%) and other 37 (17.8%). Median surgical time was 93 mins (supervised residents). There were no intra-operative complications or deaths and only 9 (2.4%) postoperative complications. The mean number of individual lymph nodes removed was 31.2/patient (range 7-78). The total and mean numbers of nodal stations removed/patient are shown the Figure (mean = 7), and specific lymph node stations removed are shown in the Table. Although hilar nodes were removed in <43%, in specific circumstances, such as RUL tumors with neg. mediastinal nodes, hilar nodes were removed in 20/29 (69%) of cases. MICR immediately after TCML usually was technically easier and faster because of the hilar dissection When resections were delayed 3-7 days, TCML was less technically beneficial because of inflammation and scarring, and delays >1 week resulted in significant detrimental effects on resection. Complete removal of all nodal tissue was confirmed during definitive cancer resection in >98% thereby providing accurate pre-resection cancer staging. Figure 1

Data represents the percentage of the 372 TCML cases with the specified lymph node stations surgically addressed

	Right (%)	Left (%)	Midline (%)
Level 1	4.3	0.54
Level 2	78.23	38.17
Level 4	97.58	94.62
Level 10	43.01	24.19
Level 11	28.49	9.41
Level 12 (upper lobe)	10.75	3.23
Level 12 (lower lobe)	0.27	0.54
Level 12 (middle lobe)	1.35	N/A
Level 8	2.69	3.49
Level 9	0.00	0.27
Level 5		2.51
Level 6		4.03
Level 3 (anterior)			5.38
Level 3 (posterior)			1.62
Level 7			95.43

Conclusion:
TCML is safe, accurate and feasible without elaborate instrumentation. TCML is capable of reliably accessing not only mediastinal but also hilar nodal stations and facilitates MICR if performed within 7 days of TCML.

Abstract not provided

Background:
Significant controversy remains regarding the care of patients (pts) with clinical stage IIIA NSCLC. While multi-modality therapy is an acceptable strategy in selected pts, the optimal approach is not firmly established. We analyzed outcomes and predictors associated with trimodality therapy (TT) in the National Cancer Database (NCDB), an oncology outcomes database administered by the American College of Surgeons and the American Cancer Society.

Methods:
The NCDB was queried from 2003-2011 for NSCLC pts diagnosed with stage IIIA-N2 disease and treated with chemotherapy and radiation (CRT). Data was extracted on patient demographics, tumor pathology, treatments and outcomes. Three cohorts of pts were studied - CRT only/no surgery (NS), CRT + lobectomy (L) and CRT + pneumonectomy(P). The univariate and multivariable analyses (MV) were conducted using Cox proportional hazards model and log rank tests. All analyses were performed using SAS Version 9.3.

Results:
A total of 29,584 pts were included in this analysis: NS-91.7%, L-7%, and P-1.5%. Pt characteristics: median age 66 years (yrs); males 56%; whites 86%; academic centers 27%; metro locations 78%; government insured 63%; Charlson/Deyo comorbidity score 0 in 66%. Pts < 60 yrs were more likely to receive TT- L (47%), P (60%) vs. NS (29%); p<0.001. Pts in academic centers were more likely to get TT than NS (42% vs. 25%). On MV analysis, L and P had significantly better survival vs. NS: HR 0.43 (0.38-0.48) and HR 0.57 (0.46-0.71) respectively; p <0.001. The median survival of L, P and NS were 44.5 m vs. 25.6 m vs. 15.7 m (p<0.001) and 5- year survival rates (SR) were 44% vs. 33% vs. 14% respectively. 30-day mortality was higher in P vs. L [7% vs. 2.6%; OR 0.26(0.16-0.45); p<0.001]. Pts with <2 lymph nodes (LN) had better survival than pts with >2 LNs in L (50% vs. 37%; 60m vs. 38.8m) but worse in NS (13.8% vs.16.4%; 15.3m vs.18.5m). On MV analysis of LNs, L had better survival than NS: HR 0.4 (0.35-0.46) in <2 LN pts and HR 0.56 (0.46-0.69) in ≥2 LN pts; p<0.001. In pts with <2 LN, L had better survival than P (60m vs. 25.5m; p<0.0001). L and P had better SR than NS in all ages: 48% vs.37% vs. 19% in ≤60 yrs; 42% vs. 30% vs.14% in 61-70 yrs, 36% vs.19% vs. 10% in >70 yrs.

Conclusion:
TT was utilized in less than 10% of pts with stage IIIA-N2 disease, suggesting high degree of pt selection. In this selected group, TT was associated with favorable outcomes relative to CRT alone.

Background:
Video-assisted thoracoscopic lobectomy(VATS) is preferred over thoracotomy for the treatment of early stage non-small cell lung cancer (NSCLC). However, little evidenceindicated its perioperative and oncologic outcomes for advanced-stage NSCLC and the result of VATS surgery may be overestimated since the majority of patients were stage I patients in previous studies. Therefore, we evaluate whether VATS lobectomy for locally advanced NSCLC could be performed safely and with acceptable short- and long-term outcomes when compared with standard thoracotomy on a well-balanced population from a multi-institutional database.

Methods:
Tumors that are greater than 5 cm in diameter, T3 or T4 tumors, tumors after neo-adjuvant treatment, and/or tumors with lymph node metastasis are defined to be locally advanced. By using a multi-institutional prospective database of high level comprehensive cancer hospitals, we analyzed locally advanced NSCLC patients who underwent lobectomy. VATS lobectomies were all performed by an improved technique, which had achieved proficiency that has been published previously. Using propensity-matched analysis based on preoperative variables, perioperative outcomes, oncologic efficacy and long-term survival were compared between VATS lobectomy and thoracotomy.

Results:
Matching based on propensity scores produced 125 patients in each group. Patient and tumor characteristics were similar. Conversion rate from VATS to thoracotomy is 9.6%. There were no intraoperative deaths and 1 perioperative death in each group. Postoperative outcomes like median operative time, blood loss and tube duration were similar between VATS and thoracotomy, Hospital length of stay was shorter after VATS than thoracotomy(10.4d vs 11.4d, p<0.01). VATS group had significant lower level of postoperative pain than thoracotomy group (p<0.01). The overall incidence of postoperative complications was 28.8% (36/125) and 36.0% (45/125)in the VATS group and in the thoracotomy group, respectively(p = 0.14).Similar number of lymph nodes (16.2vs 14.8, p= 0.148)and nodal stations (5.72 vs 5.66, p= 0.781) were removed by VATS and thoracotomy. Similar proportion of patients accepted postoperative chemotherapy (73.6% vs 72.0%, p= 0.776) , and completed similar cycles of postoperative chemotherapy (2.47 vs.2.35, p = 0.602) in the two groups. Median follow-up was 36.6 months. There were no significant differences in locoregional and distant recurrence patterns between the two groups. Disease-free survival(DFS) at 3-years were 50.1% and 47.3%, 5- years were 40.0% and 37.0% in the VATS and thoracotomy groups, respectively (p=0.878). Overall survival(OS) at 3-years were 75.0% and 68.9%, 5-years were 42.2% and 43.1% in the VATS and thoracotomy groups, respectively (p =0.551). Multivariate Cox regression analyses of DFS and OS confirmed the noninferiority of VATS, and showed that significant predictors of worse DFS and OS were advanced pathologic stage (HR,2.235; 95% CI,1.564 to 3.193; p<0.001), and without postoperative chemotherapy (HR,1.594; 95% CI,1.095 to 2.321; p=0.015).

Conclusion:
VATS lobectomy for locally advanced stage NSCLC can be performed safely, with shorter length of hospital stay, lower level of pain and showed similar long-term survivals compared to thoracotomy. With continued experience and optimized technique, VATS lobectomy can be performed in majority of cases without compromising the perioperative outcomes and oncologic efficacy. This work was supported by a funding named‘Beijing Municipal Science and Technology Project (D141100000214004)

Background:
Individual academic societies have published different recommendations about definitions and requirement of nodal assessment. It's generally agreed that radical mediastinal lymphadenectomy will provide accurate information for pathological staging and guiding adjuvant therapy. However it is not clearly established whether mediastinal lymphadenectomy compliant with international criteria will improve the oncological outcomes of clinical early-stage lung cancer. This retrospective study was aimed to compare the long-term survival between the cases treated with lymphadenectomy fulfilling the NCCN criteria and other cases not met the criteria in clinical early-stage lung cancer patients.

Methods:
During the investigation period, 712 consecutive cases of clinical N0/1 entered the analysis, confirming as 152 cases of pN2 (pathological N2) and 560 of pN0-1 (pathological N0-1) disease after surgery. Group A was defined as the cases fulfilling the National Comprehensive Cancer Network (NCCN) lymphadenectomy criteria (≥three stations of N2 nodes dissection) and Group B was those who did not meet the criteria. Two groups were stratified by pN status and the outcomes were analyzed and multivariate Cox regression was performed to determine prognostic factors.

Results:
5-year Overall survival (OS) and 5-year disease-free survival (DFS) were significantly different between two groups at cN0/1-pN2 status (5-year OS rates, 50±5% vs. 25±9%, p=0.006; 5-year DFS rates, 31.0±4% vs. 13±7%, p=0.014), but not at pN0-1 status (Figure 1). T staging and lymphadenectomy fulfilling NCCN criteria were prognostic factors in cN0/1-pN2 group by multivariate regression analysis. Furthermore, the cases treated with ≥ 4 stations of mediastinal lymph nodes dissection could not achieve better survival benefit compared to those harvesting 3 stations of N2 node in cN0/1-pN2 group (the 5-year OS rates, 46±6% vs. 59±9%, p=0.152).The spreading pattern of mediastinal nodes among pN2 cases was featured by tumor location. The most frequent involved station for right upper lobe-located lung cancer was 4R (83.7%), followed by 7 (37%) and 2R (14.0%). The top 3 involved stations for other cancer locations were 7 (75%), 4R (25%) and 2R (6.3%) for right middle lobe; 7 (81.6%), 4R (34.2%) and 2R (10.5%) for right lower lobe; 5+6 (90.9%), 4L (22.7%) and 7 (4.5%) for left upper lobe; 7 (66.7%), 5+6 (42.4%) and 8 (9.1%) for left lower lobe. Figure 1



Conclusion:
Mediastinal lymphadenectomy fulfilling with NCCN criteria may only improve the survival of pathological upstaging subgroup (cN0/1-pN2) among patients with clinical early-stage lung cancer. More extended dissection of mediastinal lymph node (≥ 4 stations) may not further improve the outcome in this group.

Abstract not provided

Background:
The two most commonly used chemotherapy regimens deployed concurrently with thoracic radiation (RT) for patients with unresectable IIIA and IIIB non-small cell lung cancer (NSCLC) are carboplatin/paclitaxel (CP) and cisplatin/etoposide (CE). Because there are no prospective comparisons of these two regimens in this setting, we conducted a systematic review of published trials to compare outcomes and toxicities between CE and CP.

Methods:
Studies which enrolled stage III patients receiving RT with CP or CE were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library) and meeting abstracts. Trials were excluded if they were phase I, enrolled less than 10 pts, or included surgical resection. A systematic analysis of extracted data was performed using Comprehensive Meta Analysis (Version 2.2) software using random and fixed effect models. Clinical outcomes were compared using point estimates for weighted values of median overall survival (OS), progression free survival (PFS), response rate (RR) and toxicities. Two-tailed T-test with a significance level of 0.05 was used for all comparisons.

Results:
3194 patients were included from 32 studies in the CE arm, and 3789 patients from 51 studies in CP. Baseline characteristics of patients on the CE arm versus CP arm were: median age 61 vs. 63 years, male 67.6% vs. 78%, squamous histology 39% vs. 40%, and median radiation dose 62 Gy vs. 63 Gy. There was no significant difference in response rates between CE and CP (65% vs. 56%, p =0.6), respectively. There was no significant difference in median progression free survival (11.5m vs. 9.3m p =0.2), overall survival (19.8m vs. 18.4m, p=0.48), 1-year survival rate (66% vs. 65%, p=0.8), or 3-year survival rate (31% vs. 25%, p=0.4) for CE vs. CP. CE was associated with higher grade 3/4 hematological toxicities than CP, such as neutropenia (53% vs. 23% p<0.0001), thrombocytopenia (14% vs. 6% p=0.001), anemia (16% vs. 8% p=0.06), as well as grade 3/4 nausea/vomiting (20% vs. 9% p=0.018), while rates of grade 3/4 pneumonitis and esophagitis were similar.

Conclusion:
CE and CP regimens were associated with comparable efficacy when used with concurrent radiotherapy for stage III unresectable NSCLC pts. The toxicity profile favored the CP regimen.

Background:
Standard treatment for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy. However, many patients die from recurrent disease, indicating that new treatment strategies are needed.

Methods:
PROCLAIM is a phase III trial comparing overall survival in patients with unresectable stage III nonsquamous NSCLC receiving pemetrexed+cisplatin (PemCis) and concurrent radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation (Arm A) versus etoposide+cisplatin (EtoCis) and concurrent radiotherapy for 2 cycles followed by consolidation with a platinum-based doublet of choice for up to 2 cycles (Arm B). Possible consolidation therapies in Arm B were EtoCis, vinorelbine+cisplatin (VinCis), and paclitaxel+carboplatin (PacCarb). Overall efficacy and safety results for the intent-to-treat population will be presented in a separate disclosure. Safety was a secondary objective. Interim safety results for the concurrent phase were previously presented. Here we present safety results for the consolidation phase. Treatment-emergent adverse events (TEAEs) were assessed according to the Common Terminology Criteria for Adverse Events (v3.0, CTCAE). TEAE incidences were compared using Fisher’s exact test (two-sided α=0.05).

Results:
Of 598 randomized patients, 555 were treated in the concurrent phase (Arm A: N=283; Arm B: N=272), most of whom (Arm A: n=229 [80.9%]; Arm B: n=202 [74.3%]) continued on to the consolidation phase (Arm B patients: EtoCis [33.5%], PacCarb [26.8%], VinCis [14.0%]). Baseline characteristics, including age, gender, performance status, smoking status, stage, and origin, were well-balanced across arms. Percentages of patients in Arm A completing ≥2, ≥3, and 4 consolidation cycles were 95.2%, 84.3%, and 73.4%, respectively. Percentages of patients in Arm B completing 2 consolidation cycles (maximum) were EtoCis (89.0%), PacCarb (93.2%), and VinCis (86.8%). Mean dose intensities for pemetrexed, etoposide, vinorelbine, cisplatin, paclitaxel, and carboplatin were 95.4%, 94.0%, 84.2%, 91.2%, 88.7%, and 92.7%, respectively. More patients in Arm B, compared to Arm A, experienced dose reductions, dose omissions, and cycle delays. Patients in Arm B reported more grade 3/4/5 drug-related TEAEs than Arm A (51.0% versus 31.0%, p<0.001; Table). Rates of drug-related serious AEs were similar between groups (Arm A: 14.4%; Arm B: 13.4%).

Drug-related Grade 3/4/5 TEAEs Occurring in ≥2% of Patients (or of Clinical Relevance) in the Consolidation Phase

CTCAE	Arm A (N=229) n (%)	Arm B (N=202) n (%)
Neutrophils	27 (11.8)	76 (37.6)*
Leukocytes	19 (8.3)	29 (14.4)
Hemoglobin	6 (2.6)	9 (4.5)
Platelets	5 (2.2)	10 (5.0)
Febrile neutropenia	7 (3.1)	7 (3.5)
Lymphopenia	8 (3.5)	5 (2.5)
Pneumonitis/pulmonary infiltrates	5 (2.2)	2 (1.0)
Fatigue	2 (0.9)	4 (2.0)
Pneumonia	5 (2.2)	0
Esophagitis	0	3 (1.5)
*p<0.001, Fisher’s exact test. Note: Of the TEAEs listed here, only one case (0.4%, Arm A, pneumonia) was grade 5.

Conclusion:
During the PROCLAIM consolidation phase, most patients were able to complete the planned number of cycles in either arm, with the highest dose intensity corresponding to pemetrexed. Pemetrexed consolidation had a significantly lower incidence of drug-related grade 3/4/5 TEAEs than the platinum doublets in Arm B. A more detailed analysis of Arm B (by treatment regimen) is underway.

Background:
Concurrent chemoradiotherapy imposes beneficial effects on overall survival (OS) in patients with locally advanced non-small cell lung cancer (NSCLC). Nonetheless, the optimal radiation scheme still needs to be identified. The RTOG 0617 trial showed that patients receiving a high dose radiation scheme (37 x 2 Gy) had a significant shorter median OS (22.9 months) as compared to patients receiving a conventional 30 x 2 Gy radiation scheme (28.7 months). Dose escalation using hypo-fractionation however seems promising and might contribute to a better OS. We investigated long term OS in locally advanced NSCLC patients treated with concurrent chemoradiotherapy, using a hypo-fractionation scheme of 24 x 2.75 Gy +/- Cetuximab.

Methods:
A 2-armed phase II, multi-center study (NTR2230) was performed with the initial aim to assess the effect of the addition of Cetuximab to concurrent chemoradiotherapy in locally advanced NSCLC patients. Arm A received high dose radiotherapy (24 x 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m[2]). Arm B received an identical treatment regimen with the addition of weekly Cetuximab (400 mg/m[2] loading dose one week prior to radiotherapy followed by weekly 250 mg/m[2]). Mortality follow-up information was completed until January 2015. Overall survival (OS) rates were calculated as time from randomization until death from any cause. Kaplan-Meier survival curves were plotted and 1-, 2- and 5-year OS proportions were calculated.

Results:
Between February 2009 and May 2011, 102 patients were randomly allocated in two arms; 51 patients (50%) in arm A and 51 patients (50%) in arm B. Follow-up information was available for 101 patients (99%). Median OS was 33.0 months (interquartile (IQ) range 20.0 to 46.0) and did not significantly differ between the two arms; 33.0 months (IQ-range 13.8 to 52.2) in Arm A and 30.0 months (IQ-range 15.3 to 44.7) in Arm B (Figure 1). 1-,2- and 5-year OS was 75.5%, 59.8% and 36.6%, respectively. Figure 1



Conclusion:
In this 2-armed phase II trial in NSCLC patients receiving concurrent chemoradiotherapy, the addition of Cetuximab to concurrent chemoradiotherapy did not improve 60-month OS in unselected patients with locally advanced NSCLC, in line with the RTOG 0617. However, the median OS was remarkably high when compared to the RTOG 0617: 30 and 33 months versus 23 and 29 months, respectively. Furthermore, 5-year OS was still 36.6%. Dose escalation using hypo-fractionation of 2.75 Gy per fraction might be one of the factors contributing to extended OS in patients with locally advanced NSCLC.

Abstract not provided

Background:
Intensity modulated radiation therapy (IMRT) has the potential to improve target coverage and spare toxicity in locally-advanced non-small cell lung cancer (NSCLC). However, the effect of IMRT on outcomes for NSCLC has not previously been assessed in a large prospective cooperative group clinical trial.

Methods:
A secondary analysis was performed in patients with stage III NSCLC in NRG/RTOG 0617, a randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) chemoradiotherapy +/- cetuximab. Radiotherapy (RT) technique was stratified by IMRT and 3D-conformal radiotherapy (3D-CRT). Baseline prognostic and RT dosimetric parameters were compared between IMRT and 3D-CRT after adjusting for RT dose levels and cetuximab use. The prognostic value of RT technique with respect to toxicity and efficacy was assessed through multivariate logistic regression (MVA) and Cox proportional hazards model after controlling for RT dose level, cetuximab use and other factors.

Results:
Of the 482 eligible patients treated with RT, 53% and 47% were treated with 3D-CRT and IMRT, respectively. The IMRT group had more stage IIIB (38.6 vs. 30.3%, P = 0.056), larger PTVs (mean 486 vs. 427 mL, P = 0.005), and larger PTV:lung ratio (mean 0.15 vs. 0.13, P = 0.013). In spite of larger PTV volumes, IMRT was associated with lower lung V20 (P = 0.08), and lower heart doses (V5, V20, V40) than 3D-CRT. In turn, IMRT was associated with a lower rate (3.5 versus 7.9%) of Grade 3+ pneumonitis (P = 0.0653). On MVA, the lung V20 significantly predicted grade 3+ pneumonitis, while the lung V5 and mean lung doses did not. Larger heart V40 was associated with worse OS (HR=1.013, P < 0.001), and the heart V40 was significantly lower in patients treated with IMRT. Patients treated with IMRT were also more likely (37 versus 29%) to receive full doses of consolidative chemotherapy (P = 0.05).

Conclusion:
Although IMRT was used to treat larger and less favorable tumors in RTOG 0617, it was associated with reduced risk of Grade 3+ pneumonitis and higher likelihood of receiving full doses of consolidative chemotherapy. The heart V40, shown to be highly prognostic for survival, can be substantially reduced with IMRT compared to 3D-CRT.

Background:
Incomplete resection of potentially curable Non-Small Cell Lung Cancer (NSCLC) is a significantly negative clinical event for which adjuvant radiotherapy, chemotherapy, or combined chemo-radiotherapy is often used to reduce mortality risk. After complete (R0) resection, randomized controlled trials and the PORT meta-analysis show radiotherapy to be harmful to patients with stage I-II disease, and of marginal benefit in patients with N2-positive stage IIIA. After incomplete resection (R1/R2), current National Comprehensive Cancer Network (NCCN) guidelines recommend radiotherapy for stage IA/IB and chemo-radiotherapy for patients with stage IIA-IIIA. Adjuvant therapy recommendations after R1/R2 resection have never been verified.

Methods:
With the objective of validating NCCN post-operative therapy guidelines, we evaluated patients with surgically resected pathologic stage I-IIIA NSCLC in the National Cancer Data Base from 2004-2011. Recipients of pre-operative adjuvant therapy and those with no lymph nodes examined were excluded. Post-operative therapy modalities were classified as chemotherapy, radiotherapy, chemo-radiotherapy, or no treatment. Analyses were adjusted for patient demographic, clinical, and surgical characteristics, as well as institutional characteristics. Analyses were conducted by margin status and stage groups based on NCCN classifications (Table I). Unadjusted stage-specific 5-year overall survival (OS) estimates were calculated based on the Kaplan-Meier method and compared across post-treatment modalities with the log-rank test. Survival was modeled with Extended Cox Regression to adjust for all covariates and allow for non-proportional hazards.

Results:
Among 98,176 NSCLC patients who underwent curative-intent surgery during 2004-2011, 48% were male, 79% white, 34% privately insured, and 58% Medicare insured, with a median age of 68 years. The 5-year OS estimates by treatment modality are shown in Table I (NCCN recommendations highlighted). Margin negative patients with stage IA or IB/IIA who received post-operative radiotherapy had significantly lower OS compared to those with no treatment (both p-values<0.0001). We also observed lower OS with post-operative radiotherapy in margin positive patients with stage IA (p-value=0.0006) and IB/IIA (p-value=0.0302). Survival was significantly higher in persons with stages IB-IIIA who received post-operative chemotherapy compared to no treatment (all p-values<0.0001). Fully adjusted modeling analyses (not shown) yielded similar results.

		5 Year Survival (P-Value)
NCCN Categorized Group		Margin Positive	Margin Negative
Stage IA (T1ab,N0)	No Treatment	60%(Ref)	71%(Ref)
	Chemo-Only	64%(0.86)	74%(0.33)
	Radiotherapy-Only	24%(0.0006)	47%(<0.0001)
	Chemo+Rad	44%(0.17)	43%(<0.0001)
		(N=458)	(N=41279)
Stage IB (T2a,N0) & Stage IIA (T2b,N0)	No Treatment	48%(Ref)	57%(Ref)
	Chemo-Only	66%(0.0002)	69%(<0.0001)
	Radiotherapy-Only	30%(0.0302)	41%(<0.0001)
	Chemo+Rad	39%(0.28)	48%(<0.0001)
		(N=1016)	(N=29111)
Stage IIA (T1ab-T2a,N1) & Stage IIB (T3,N0;T2b,N1)	No Treatment	27%(Ref)	39%(Ref)
	Chemo-Only	35%(<0.0001)	55%(<0.0001)
	Radiotherapy-Only	26%(0.84)	29%(<0.0001)
	Chemo+Rad	36%(<0.0001)	43%(0.0194)
		(N=1549)	(N=15543)
Stage IIIA (T1-3,N2;T3,N1)	No Treatment	15%(Ref)	26%(Ref)
	Chemo-Only	25%(0.0013)	41%(<0.0001)
	Radiotherapy-Only	11%(0.76)	19%(0.0551)
	Chemo+Rad	26%(<0.0001)	39%(<0.0001)
		(N=1109)	(N=8111)

Conclusion:
In patients with negative margins, results from the NCDB are consistent with randomized clinical trials and stage-specific NCCN post-operative adjuvant therapy recommendations. However, the NCCN recommendation of post-operative adjuvant radiotherapy for patients with early stage NSCLC with a positive resection margin is not supported by our results and should be further investigated in a randomized clinical trial.

Abstract not provided