Virtual Library

Background
Lung cancer computed tomography (CT) screening is a controversial topic. Results from the National Lung Screening Trial showed that low dose CT (LD-CT) can reduce lung cancer mortality by at least 20%. However a critical issue is the high rate of indeterminate lung nodules and false positive cases. The aim of the study was to evaluate the diagnostic accuracy of CT/PET for lung cancer diagnosis in the context of lung cancer screening.

Methods
Between 2004 and 2005, 5203 asymptomatic high-risk individuals (≥20 pack-years, age ≥50 years) were enrolled to undergo annual LD-CT for 10 years. Nodules ≤5 mm were scheduled for repeat LD-CT a year later. Nodules >5.0≤8.0mm received LD-CT 3-6 months later. Nodules >8.0mm or growing nodules underwent CT-PET. Results from all PET scans performed during the screening workup of COSMOS participants were reviewed. Those performed for suspected collateral disease (pleura, mediastinum, other cancers) were excluded. Outcome was based on the pathological findings for patients who underwent surgery or on findings at follow-up. Outcome was considered negative for those with negative CT findings for at least two years. PET results were visually evaluated by expert radiologists.

Results
383 nodules in 351 patients were studied by CT/PET. In 5 occasions, PET evaluation was dubious. 197 nodules turned out to be malignant. Overall sensitivity, specificity and accuracy of CT/PET to distinguish between benign and malignant nodules was 64%, 89% and 76% while it was 82%, 92%, 88% when considering only PET scans performed during baseline screening work-up. Diagnostic performance was high (sensitivity 87%, specificity 73%) for nodules larger than 15 mm in their maximum diameter, reaching 98% sensitivity for solid nodules larger than 15 mm. The diagnostic performance of the test was significantly lower for nodules investigated at annual repeat CT compared to baseline CT (p<0.0001, sensitivity ranging from 30 to 71%) and for non-solid compared to solid nodules (p=0.0001; sensitivity 22% for non-solid versus 79% for solid nodules).

Strata	PETs	VN	FN	FP	VP	Sensitivity	Specificity	Accuracy	p-value accuraccy
Overall	378	164	70	21	123	64%	89%	76%
Diam <10mm	145	75	40	4	26	39%	95%	70%
Diam 10-15mm	104	51	19	4	30	61%	93%	78%
Diam >15mm	117	30	10	11	66	87%	73%	82%	0.06
Solid	263	123	26	16	98	79%	88%	84%
Non solid	48	15	25	1	7	22%	94%	46%
Partially solid	65	25	19	3	18	49%	89%	66%
Non/Part solid	114	41	44	4	25	36%	91%	58%	<0.0001
Age <60	147	64	31	14	38	55%	82%	69%
Age >60	231	100	39	7	85	69%	93%	80%	0.02
Inferior lobe	139	69	29	8	33	53%	90%	73%
Superior lobe	208	85	33	9	81	71%	90%	80%
Other location	30	10	8	3	9	53%	77%	63%	0.09
Left lobe	148	64	27	8	49	64%	89%	76%
Right lobe	206	90	35	10	71	67%	90%	78%	0.70
Baseline	148	81	11	7	49	82%	92%	88%
2[nd] year	57	17	11	3	26	70%	85%	75%
3[rd] year	62	19	28	3	12	30%	86%	50%
4[th] year	44	10	10	4	20	67%	71%	68%
5[th] year	47	31	6	4	6	50%	89%	79%
6[th] year	20	6	4	0	10	71%	100%	80%	<0.0001
Male	264	113	44	12	95	68%	90%	79%
Female	114	51	26	9	28	52%	85%	69%	0.05
Non/part solid <15mm	72	27	34	2	9	21%	93%	50%
Non/part solid >15mm	37	10	9	2	16	64%	83%	70%
Solid <15mm	177	99	25	6	47	65%	94%	82%
Solid >15mm	80	20	1	9	50	98%	69%	88%	<0.0001

Conclusion
CT/PET is a highly sensitive test for the differential diagnosis of screening-detected cancer, in particular at baseline CT, for solid nodules and those with a diameter larger than 15mm. Sensitivity of CT/PET for sub-solid nodules is very low suggesting that other diagnostic tests, such as volume doubling time, should be used.

Background
Early diagnosis of lung cancer is associated with a better survival. The measurement of volatile organic compounds (VOCs) in exhaled breath using an electronic nose may prove to be a novel, effective and simple technique for screening and diagnosing lung cancer. The aim was to test the validity of the VOC profile in discriminating subjects with early stage lung cancer (I and II) (ESLC) from healthy ever smokers (HS).

Methods
243 subjects: 54 ESLC and 189 HS provided a breath sample after tidally breathing through an inspiratory port filter for 5 minutes. It was analysed using a 32 sensor Cyranose 320 (Smiths Detection). Subjects were divided into training (n=159) and independent test set (n=84) groups. Canonical discrimination analyses were performed to determine significance of difference between subject groups and calculate cross validated accuracy (CVV) of the groups using leave one out classification method. Area under the curve (AUC) of Receiver Operating Characteristic Curves were also determined (SPSS V17.0).

Results
Validation of the training VOC profile model using an independent test group showed 79% accuracy (p=0.001) in distinguishing ESLC (n=20) from HS (n=64). (AUC 0.933). There was no significant difference in age, lung function and smoking history between the training and test groups.

Conclusion
Exhaled breath VOC profile model to discriminate between ESLC subjects and HS was validated in an independent group with a high accuracy. A clinically high sensitivity of the VOC profile model to discriminate between ESLC and HS can be achieved by selecting an appropriate cut point. The cyranose has potential to be a clinically useful diagnostic and screening tool for early stage lung cancer.

Background
Implementing effective lung cancer screening programs requires extensive knowledge on the natural history of lung cancer and the sensitivity of the proposed screening modality. Data from the National Lung Cancer Screening Trial (NLST), the Prostate, Lung, Colon and Ovarian Cancer Study (PLCO) and Surveillance Epidemiology and End Result (SEER) data from 2004-2008 are used to investigate the screening sensitivity (by stage and histological type) of Computed Tomography (CT) and chest radiography (CXR) and the mean preclinical sojourn time (MPST) of lung cancer (by gender, stage and histological type).

Methods
The MISCAN-Lung model was used to reproduce the lung cancer incidence by method of detection (clinical or screen-detected), gender, histology and stage in both trials, by calibrating screening sensitivity and natural history parameters.

Results
Major differences in sensitivity between CT and CXR are estimated for the less advanced stages, for example the sensitivity for stage IA adenocarcinoma is estimated to be 56.63% for CT compared to 16.91% for CXR. The model suggests that the MPST varies by histological type and gender. The largest difference between genders was estimated for adenocarcinoma for which the MPST in pre-clinical stages IA to IV was estimated to be 4.48 years for men compared to 6.01 years for women.

Conclusion
This study provides detailed insights in the natural history of lung cancer and the differences in the effectiveness of screening between the NLST and PLCO trials. This knowledge may help to determine effective lung cancer screening programs.

Background
Introduction: Based on a 20% reduction in lung cancer deaths in the CT screening arm of the National Lung Screening Trial (NLST), yearly CT screening for lung cancer is now widely recommended. Recently, a multivariate risk model for lung cancer (LC), be used to identify smokers at greatest risk, has been proposed to better select smokers for CT ([#]Tammemagi et al. JNCI 2011;103:1058).This risk model includes age smoking history, history of COPD, BMI, recent CXR and educational level. This model has been validated in the NLST where recent CXR and educational level was omitted due to the unavailability of this data. In this sub-study of the NLST, we examine the role of the known clinical risk factors for lung cancer and whether they mediate risk for lung cancer via risk for COPD. To test this we compared risk factors between LC cases and controls after stratifying cancer-free screening participants (controls) by spirometry-defined COPD.

Methods
Using a sub-group of the NLST (drawn for validation of a gene-based risk stratification tool), we compared known risk factors for LC (recently validated in the PLCO[#] study) in 345 screen-detected lung cancer cases and 1482 randomly selected cancer free screening controls stratified by COPD (pre-bronchodilator GOLD 1-4). These variables included age, pack years, family history of LC (FHx), self-reported COPD and BMI.

Results
When the LC risk variables were compared between LC cases (N=345) and the cancer-free screening controls, stratified from baseline data into controls with COPD (N=489) and without COPD (n=993) (see Table1), we found the following; age and pack years but not FHx were significantly higher in those with COPD and LC compared to cancer-free controls with no COPD, self reported COPD was 2 fold higher in COPD controls and LC cases compared to controls without COPD, and BMI was significantly lower in the LC cases and those with COPD compared to cancer-free controls with no COPD. Figure 1

Conclusion
These data from the NLST suggest the risk of LC is strongly mediated by variables underlying risk of COPD (age, pack years and BMI). [#]Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

Abstract not provided

Background
The existence of healthcare disparities by race and ethnicity is well documented, often attributed to a lack of economic and educational parity among groups, and manifested by unequal healthcare access and delivery. Inexplicably however, in many countries the wealthiest and most educated populations have the worst health outcomes. We hypothesize that minority status within a country rather than race, ethnicity, socioeconomics or educational level is more closely associated with poor health outcomes globally and functions independently of other variables.

Methods
Minority and majority populations in 34 countries/territories were evaluated for smoking prevalence and age-adjusted lung cancer incidence rates. A global, systematic review of over 1000 sources of epidemiological data was performed using rigorous screening criteria including only national data in original form (national cancer registry, census, or health surveys), from an official government agency, or from peer-reviewed publications. Relative risks (RR) of smoking and lung cancer were computed for all minority groups with the majority population as the referent null. Relative wealth based on median per capita income and relative schooling based on educational attainment were also calculated. Minority groups were only included if so defined by both the Minority Rights Group International and the CIA World Fact Book.

Results
Data were collected from approximately 60% of the global population including all six WHO world regions and every populated continent. The RR of smoking for at least one minority group was greater than that of the referent majority in every country or territory analyzed. The RR of lung cancer for at least one minority group was greater than that of the referent majority in all but three countries/territories. These results were remarkably consistent and durable with RR ≥ 1.0 for smoking prevalence and lung cancer incidence in nearly all countries despite minority status being defined differently in many nations whether by race, ethnicity, religion, language, indigenous affiliation, or immigrant status. These results were further corroborated by age-specific lung cancer incidence for selected countries/territories. Racial and socioeconomic status differentials were insufficient explanations for these observations. In the U.S., for example, blacks are generally less wealthy and educated than whites and have higher smoking prevalence and lung cancer incidence rates. However, in neighboring Bermuda and distant South Africa where blacks are the majority, whites have both higher smoking prevalence and lung cancer incidence rates despite being far wealthier and educated. This relationship of increased smoking and lung cancer rates in wealthier, more educated minorities is replicated in nine of the 34 countries in this study.

Conclusion
Our results show an empirical relationship between minority status and both increased smoking prevalence and lung cancer incidence rates in minority populations globally. This suggests that minority status may be a potent, behavioral driver leading to elevated health risks in minority populations around the world. Moreover, minority status seems to be independent of traditional socioeconomic variables, and alone may be a powerful predictor of disparate health outcomes in many diverse nations, distinctive societies, and unique cultures on a global scale.

Background
There are population-specific differences in the presence of lung cancer, these are related with: health outcomes, quality of health care and access to health care services that exist across racial and ethnic groups. Disparities represent a lack of efficiency within the health care system and therefore account for unnecessary costs. Few publications are available about disparities in African-American (AA) populations with lung cancer and very few about Hispanic (H) populations with this disease.

Methods
We reviewed registry data on 2,255 pts with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated during last 10 years (2002-2011) at Memorial Health Care System. The main objective of the study was to evaluate differences in lung cancer survival according to ethnicity. Chi-square was used to compare distribution of tumor stage. Survival curves were compared using log-rank test for each of the tumor stages. Adjusted hazard ratios (AHR) and 95% confidence intervals (95% CI) were reported based on the results of a multivariate Cox regression model for overall survival (OS) with adjustment for gender, age at diagnosis, race, stage and health insurance

Results
A total of 1940 pts (86%) had the diagnosis of NSCLC, the rest were SCLC. There were 1170 (52%) females. Non-Hispanic whites (NHW) were 1,791 pts (79%), Hispanics (H) 266 (12%) and African-American (AA) 149 (7%). Fifty eight percent of patients had stage III/IV at diagnosis. 2054 of the pts were insured (91%). There was a significant difference in age at diagnosis among H (66.5 y), AA (64.4y) and WNH (69.5y). The probability of being diagnosed at a late stage (IIIB/IV) was two times higher among AA compared to NHW (OR= 1.77, p<0.05) or H (OR) = 1.67, p <0.05). There was no survival difference between NSCLC and SCLC (19m vs. 16m). Females with NSCLC lived significantly longer than males (Adjusted Hazard ratio (AHR= 1.14 p<0.01). The same was true for SCLC (AHR = 1.43 p < 0.01). Significant predictors for worse survival for patients with NSCLC were: older age at diagnosis (AHR = 1.01, p<0.001), male gender (AHR=1.12, p<0.05) and late stage at diagnosis (AHR=2.27, p<0.001). Insurance and ethnicity were not significant predictors of survival.

Conclusion
There are significant disparities in presentation and outcomes among minority patients (AA and H) with lung cancer. We will further evaluate if other social or genetic factors can explain these disparities.

Background
Writing on behalf of the I-ELCAP Investigators. The goal of CT screening is to maximize lung cancer cure rates by early diagnosis and treatment of lung cancer. To achieve this, a regimen of screening is important, particularly for small nodules. To better understand the importance of a regimen, we compared two large databases of screen-diagnosed lung cancers, the International Early Lung Cancer Action Program (I-ELCAP) and the National Lung Screening Trial (NLST) CT arm as the former had a specified diagnostic workup algorithm while the latter did not mandate any specific approach.

Methods
We compared all lung cancers including small-cell and carcinoids, that were diagnosed under screening, that is, either screen-diagnosed because of a positive result of the CT screening or symptom-prompted after a negative CT screening. We compared the stage and size distribution of the screen-diagnosed cancers in the International Early Lung Cancer Action Program (I-ELCAP) from 1993 to 2011 and those in the NLST-CT arm from 2002 to 2006. In I-ELCAP, the screenings were performed according to a common protocol in which the diagnostic workup for a participant was defined by a specified protocol which has been continually updated whereas in the NLST, “… no specific diagnostic evaluation approach was mandated.”

Results
In I-ELCAP, a total of 799 patients were diagnosed under screening of which 11 (1.4%) were interim-diagnoses; 8 prior to the first annual repeat screening and 3 between annual rounds, leaving 788 screen-diagnosed patients. In the NLST CT arm, 1060 patients were diagnosed with lung cancer, but only 692 were diagnosed under screening. There were 18 interim-diagnosed cases before the first annual repeat screening and 26 between the 2 annual repeat screenings, a total of 44 (6.4%) interim-diagnosed cases for this cohort. This left 649 screen-diagnosed patients. The frequency of clinical Stage I was 82% (95% CI: 79%-84%) vs. 69% (95% CI: 65%-72%) in I-ELCAP and NLST, respectively. Average tumor size (95% confidence interval) was 17.3 mm (16.6-18.1) vs. 23.1 mm (21.7 -24.4), respectively. Surgical resection was performed in 86% (676/788) and 77% (497/649) of the screen-diagnosed patients, respectively. The frequency of pathologic Stage I (clinical, if not resected) was 73% (95% CI: 70%-76%) vs. 63% (95% CI: 59%-67%).

Conclusion
Stage I disease, both clinical and pathologic, was significantly higher in I-ELCAP than NLST. The tumor size was significantly lower in I-ELCAP than NLST, all strongly suggestive of the importance of a specified regimen of screening. This is further substantiated by the reported 71% for pathologic Stage I (clinical, if not resected) by the NELSON study which is close to that reported by I-ELCAP as the NELSON also followed a well-defined regimen of screening.

Background
Low-dose CT screening for lung cancer can reduce mortality among high-risk people but to reduce unnecessary evaluations with attendant risks, alternative thresholds for defining positive result and cancer diagnoses needs to be further understood. The purpose of the study is to assess the frequency of positive results and potential delays in diagnosis in the baseline round of screening using more restrictive thresholds.

Methods
Among the participants who were randomly assigned to the CT arm of the National Lung Screening Trial (NLST) cohort, we identified the frequency of solid and part-solid pulmonary nodules and the rate of lung cancer diagnoses using a 5.0, 6.0, 7.0. 8.0 and 9.0 mm threshold for the largest noncalcified nodule identified in the baseline CT scan. we compared these results with those previously published for the I-ELCAP cohort.

Results
The frequency of positive results in the baseline round, using the definition of positive result (any parenchymal, solid or part-solid, noncalcified nodule > 5.0 mm), was 15.9% (4,104/25,814). Using alternative threshold values of 6.0, 7.0, 8.0 and 9.0 mm, the frequencies (95% CI) of positive results were 10.5% (10.2, 10.9), 7.2% (6.9, 7.5), 5.3% (5.0, 5.6) , and 4.2% (3.9, 4.4), respectively. Use of these alternative definitions would have reduced the workup by 33.8%, 54.7%, 66.6%, and 73.8%, respectively. Concomitantly, proportion of lung cancer diagnoses made within first 12 months would be delayed for 0.9%, 2.6%, 6.1%, and 10.0% of the patients, respectively. These results are similar to those found in I-ELCAP.

Conclusion
These results are similar to those found in I-ELCAP and suggest that even in the higher-risk participants enrolled in the NLST, higher threshold values can be used. This reduction in the positive result rate compared to the 28% positive result rate reported in the NLST, which used a 4mm threshold, is considerable.

Abstract not provided

Background
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are smoking related diseases and the presence of COPD increases itself the risk of developing lung cancer, probably due to underlying inflammation. LC is typically detected at late stages of the disease and carries a dismal prognosis. There is an unmet need for useful early detection methods of lung cancer in high risk subjects, such as smokers.

Methods
The expression of inflammatory proteins was studied in bronchoalveolar lavage samples (BAL) by antibody arrays in a prospective discovery cohort of 60 patients with the following inclusion criteria: age > 40 years, diagnostic broncoscopy due to hemoptysis or pulmonary nodule, smokers or ex-smokers pack of more than 30 pack-years, divided into four groups (control, LC, COPD, LC & COPD). Relevant biomarkers were validated by western blot. Additional validation was carried out by ELISA in two independent controlled cohorts of 139 (control, LC, COPD, LC & COPD) and 160 patients (control, all LC histological subtypes).

Results
CCL-1 and IL-11 were selectively expressed in samples of adenocarcinoma patients, with or without COPD (p<0•001) in the discovery cohort. These proteins exhibited a remarkable diagnostic performance for lung adenocarcinoma in an independent cohort of 139 patients. ROC curves showed that the optimum diagnostic cutoff value for IL-11 was 42 pg/mL (area under curve [AUC] 0•93 [95% CI 0•896-0•975], sensitivity 90%, specificity 86%), and for CCL-1 was 39•5 pg/ml (0•83 [95% CI 0•749-0•902], sensitivity 83%, specificity 74%). Further validation of the ELISA biomarkers at the mentioned cutoffs was performed in an additional cohort of 160 patients (20 controls, 66 LC, 74 LC & COPD). There was a significant correlation between BAL levels of IL-11 and CCL-1 (r2= 0•76, p<0•001), and the use of both biomarkers increased the diagnostic accuracy to 96,1% in the two validation cohorts. Appropriate diagnostic performance was observed for all subgroups regardless of stage at diagnosis, involvement of bronchial tract, pack-years smoked, and number of cells in BAL.

Diagnostic performance of IL-11 and CCL-1 in the first validation cohort (N=139)
Adenocarcinoma vs all patients	AUC (95%IC)	Sensivity (95%IC)	Specificity (95%IC)	PPV (95%IC)	NPV (95%IC)	Positive LR	Negative LR
IL-11	0.93 (0.896-0.975)	90.2% (79%-95.7%)	88.7% (80.6%-93.5%)	80.7% (68.7%-88.9%)	94.5% (87.8%-97.6%)	7.95 (4.53-13.98)	0.11 (0.05-0.26)
CCL-1	0.83 (0.749-0.902)	80% (66.4%-87.7%)	74.1% (63.9%-82.2%)	72.1% (59.2%-73.4%)	86.3% (76.6%-92.4%)	3.02 (2.05-4.47)	0.29 (0.17-0.52)
IL11 and CCL-1		71.2% (57.7%-81.7%)	94.4% (88.4%-97.4%)	86% (72.7%-93.4%)	87.2% (79.9%-92.1%)	12.8 (5.77-28.41)	0.31 (0.20-0.47)
IL-11 and/or CCL-1		94.3% (84.6%-98.1%)	74.1% (65.1%-81.4%)	64.1% (53%-73.9%)	96.4% (89.9%-98.8%)	3.64 (2.63-5.04)	0.08 (0.03-0.23)
Diagnostic performance of IL-11 and CCL-1 in the second validation cohort (N=160)
Adenocarcinoma vs all patients	AUC (95%IC)	Sensivity (95%IC)	Specificity (95%IC)	PPV (95%IC)	NPV (95%IC)	Positive LR	Negative LR
IL-11	0.95 (0.92-0.98)	90.6% (79.7%-95.9%9	83% (86.8%-87.7%)	60.8% (49.7%-70.8%)	96.8% (92.7%-98.6%)	5.32 (3.81-7.41)	0.11 (0.05-0.26)
CCL-1	0.91 (0.87-0.96)	91.7% (80.4%-96.7%)	77.5% (71.0%-82.9%)	51.2% (40.8%-61.4%)	97.3% (93.3%-99%)	4.08 (3.09-5.04)	0.11 (0.04-0.28)
IL11 and CCL-1		71.2% (57.7%-81.7%)	96.3% (92.5%-98.2%)	84.1% (70.6%-92.1%)	92.3% (87.7%-95.3%)	19.1 (9-41.13)	0.3 (0.19-0.46)
IL-11 and/or CCL-1		92.3% 82.6%-98.1%)	84% (78%-88.5%)	62.5% (51.5%-72.3%)	98.1% (94.6%-99.4%)	5.88 (4.21-8.22)	0.07 (0.02-0.20)

Conclusion
IL-11 and CCL-1 are highly specific biomarkers with great accuracy for the diagnosis of lung adenocarcinoma in BAL specimens. Further study of these proteins as markers for early diagnosis and screening in plasma and other biological materials is warranted.

Background
Selenium is known as a chemoprotective anti-cancer agent. The impact of low selenium serum level on the frequency of early lung cancer (LC) detection rate in patients participating in a low dose chest CT (LDCT) screening program is assessed.

Methods
A program of early LC detection was conducted in a single city of 400000 inhabitants from 2008 till 2011 (Protocol I). Enrollment criteria included both sexes aged 55-65 years with a history of 20 pack-years of tobacco smoking. All detected lesions were followed up in accordance with IELCAP protocols. A new pilot study (Protocol II) launched in 2012 was based on preselection of the participants by measure of their selenium serum level. Only individuals with a low selenium level (< 75 microgramms/ml) were invited for CT scans. Other enrollment criteria were the same as in Protocol I. All cases requiring surgery were referred to a single local thoracic surgery department. The following data were analyzed: number of all detected lesions as well as LC detected in both protocols.

Results
Protocol I: 15020 patients were screened by LDCT. 6240 pulmonary lesions were detected with the majority (59%) smaller than 5mm. 182 patients (2.9% of all detected lesions) were referred for thoracic surgery. 119 primary LC were diagnosed and treated. Protocol II: 2440 patients have had selenium serum level measured. 720 of them were screened by LDCT. 210 lesions were detected with 49% smaller than 5mm. 14 patients (6.8%) were referred for thoracic surgery. 9 primary LC were diagnosed and treated surgically. Protocol II was more specific because number of all detected lesions was significantly smaller than in Protocol I (p < 0.0001, OR: 0.55; CI: 0.46 – 0.64) but the LC detection rate in Protocol II was more than twice as high as in Protocol I (p = 0.0226, OR: 2.38; CI: 1.19 – 4.76).

Conclusion
The detection rate of LC in the program of early detection based on LDCT is higher if the protocol is supported by preselection of high risk tobacco - smoking patients based on a low level of selenium in serum.

Abstract not provided

Background
Disease control rate (DCR) – the sum of partial (PR) and complete response (CR) plus stable disease (SD) – is a significant predictor of subsequent survival following platinum-based chemotherapy in patients with advanced non-small cell lung cancer (Lara, et al. JCO 2008). We evaluated whether this observation is also relevant in patients with platinum-treated ES-SCLC on investigational systemic therapy.

Methods
Updated patient-level data from recent SWOG trials in 2[nd] and/or 3[rd] line ES-SCLC (S0802: topotecan + aflibercept; S0435: sorafenib; and S0327: PS-341) were pooled. Landmark analysis was performed among patients still alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors (including age, sex, platinum sensitivity status, number of prior chemo, weight loss, and LDH, among others) with DCR was assessed using logistic regression. A Cox proportional hazards model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors.

Results
319 patients were included: median age = 63 years; male sex = 51%; PS 1 = 68%; weight loss > 5% = 29%; > 2 prior chemo = 16%; and elevated LDH = 43%. Only 8 patients had PR by RECIST for an overall response rate of 2.5%. Disease control at 8 weeks was observed in 74 patients (8 PR + 64 SD), for a DCR of 23.2%. Bivariate analysis of OS from the 8-week landmark revealed that only DCR (Hazard Ratio [HR] 0.53, p<0.0001) and elevated LDH (HR 1.69, p=0.001) were significantly associated with OS. Multivariable analysis showed that only DCR remained as an independent predictor of subsequent survival from the 8-week landmark (HR=0.58, p=0.002).

Conclusion
In this large 2[nd]- and 3[rd]-line ES-SCLC database, DCR at 8 weeks was found to be the strongest predictor of subsequent survival in patients receiving investigational therapy. Thus, DCR at 8 weeks should be considered for use as a surrogate clinical trial endpoint to screen for drug activity against ES-SCLC. These results have critical implications in the design of future prospective trials in ES-SCLC.

Background
About 40% of all cases of small cell lung cancer (SCLC) occur in the over 70 year age group (70+), and 10% in patients aged over 80 years. A SEER database reports decreasing SCLC 5-year survival with age (7.1%, 3.9% and 2.2% in the <70, 70-79 and 80+ age groups, respectively). However age has been inconsistently reported as a prognostic factor in SCLC trials. Recently a series of randomized trials of chemotherapy (CT) in SCLC were pooled to analyze the prognostic impact of patient sex (Wheatley-Price et al, Annals of Oncology 2009). We used the same dataset to investigate the impact of age.

Methods
Five randomized phase II and III CT trials, performed by the MLCG and MRC CTU between 1993 and 2005, were pooled for analysis (one study from the previous analysis was excluded as it did not contain elderly patients). One trial investigated a dose-dense approach and 4 trials compared CT regimens. The primary endpoints were overall survival (OS) in limited stage (LS) and extensive stage (ES) and the rates of haematological and non-haematological toxicity.

Results
In total 1439 patients were included, of whom 45% were female and 36% had ES disease. The median age was 63 years (range 30-88), and 343 (24%) were 70+, and only 33 (2%) were 80+. Anthracycline-based CT was given in 61%, versus platinum-based CT in 38% of patients. More patients in the younger group had a good performance status (ECOG 0-1, Karnofsky 80-100); 65% versus 39% (p=0.0007). Baseline hyponatremia was present in 35% and did not differ by age group. Overall, median OS was significantly longer in younger patients in univariate analysis (9.3 months versus 7.4 months; HR 0.79, 95% CI 0.66-0.95, p=0.01). By disease stage, median OS in LS patients was significantly longer in younger patients (HR 0.88, 95% CI 0.79-0.99, p=0.04), and a similar effect was observed in ES (HR 0.75, 95% CI 0.55-1.01, p=0.06). However in multivariate analysis (age, stage, sex, hyponatremia, anemia), factors significantly associated with longer survival were LS, female sex, good PS and absence of hyponatremia, but younger age was no longer prognostic (HR 0.96, 95% CI 0.86-1.08, p=0.52). The elderly were more likely to experience grade 3 or 4 leucopenia (52% versus 40%, p=0.0035), neutropenia (36% versus 31%, p=0.045) and thrombocytopenia (34% versus 22%, p=0.0003), but less likely to experience grade 3 or 4 emesis (8% versus 14%, p=0.022) or mucositis (5% versus 11%, p=0.021). There were no differences in infection rates or blood transfusion rates, although the elderly required more platelet transfusions (p<0.0001). The dose intensity (total number of CT cycles delivered divided by the planned number of cycles) was higher in the younger group (p<0.0001).

Conclusion
In a large pooled analysis of CT trials in SCLC, age was not a prognostic factor for survival. However the elderly experienced higher rates of grade 3 and 4 hematological toxicity. Further analysis is ongoing.

Background
A previous Intergroup study of L-SCLC showed that accelerated hyperfractionated thoracic radiotherapy (TRT) given over 3 weeks with concurrent etoposide and cisplatin (EP) led to improved 5-year survival rates compared with daily TRT given over 5 weeks, albeit with higher rates of grade 3 acute esophagitis. We retrospectively compared the efficacy and toxicity of TRT with concurrent EP for L-SCLC given in <6 weeks (Group A) versus >6 weeks (Group B).

Methods
A total of 577 patients with cytotogically or histologically biopsy proven L-SCLC (staged by chest/upper abdominal CT and brain MRI) received TRT+EP at a single institution in 1985‒2009. Group A received 45 Gy in 30 fractions over 3 weeks (BED=52) or 28 fractions over 5 weeks (BED=43) or 61.2 Gy in 34 fractions over 5 weeks (BED=72). Group B received a median 60 Gy in 6 weeks (BED=72). Cone-down fields were used routinely. Complete responders received prophylactic cranial irradiation (PCI). Kaplan-Meier analysis was used to estimate survival, with log-rank tests used to compare survival curves; p values ≤0.05 were taken to indicate signifiance. Cox regression analysis was used for univariate and multivariate analyses and toxicity was graded according to CTCAE v2.0.

Results
The median follow-up time for patients alive at the time of analysis was 32 months (range 1.2‒222 months); median age was 62 years (range 27–95); and 87% had Karnofsky Performance Status (KPS) scores of ≥80. Group A contained 503 patients and group B had 74. The groups did not differ in KPS, age, smoking history, or receipt of PCI. Group A was more likely to have received concurrent chemoTRT than sequential chemoTRT (p<0.001). At 5 years, the overall survival (OS) rates were 26.1% for group A vs. 14.1% for group B (p=0.077); disease free-survival (DFS) rates were 31.6% (group A) vs. 13.5% (group B) (p=0.008); local-regional control (LRC) rates were 55.1% (A) vs. 36.2% (B) (p=0.077); and distant metastasis-free survival (DMFS) rates were 40.8% (A) vs. 20.0% (B) (p=0.008). No differences were found in rates of grade ≥3 acute esophagitis (17% group A vs.18% group B) or pneumonitis (4% group A vs. 3% group B). Group B had a higher rate of grade ≥3 lung fibrosis (10% group A vs. 22% group B, p=0.01). Multivariate analysis showed that factors influencing worse DFS were receiving TRT in more than 6 weeks (HR=1.46, p=0.008) and receipt of sequential rather than concurrent chemoTRT (HR=1.51, p=0.001); age <62 years (HR=0.99, p< 0.039) and receipt of PCI (HR=0.77, p=0.015) were associated with better DFS.

Conclusion
TRT given with concurrent EP over periods longer than 6 weeks led to lower rates of DFS, worse local and distant disease control, and higher rates of severe lung fibrosis. Factors associated with better DFS were younger age, concurrent chemoTRT, and use of PCI. Rates of acute grade ≥3 esophagitis and pneumonitis were low in both groups. Final recommendations await the results of an ongoing prospective randomized trial.

Background
Pazopanib, a small molecule competitive inhibitor of the tyrosine kinase of VEGFR‑1, VEGFR‑2, VEGFR‑3, PDGF, and c‑kit has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Microvessel density and VEGF expression in SCLC tumor samples correlate with development of metastases and poor prognosis. A phase II trial of pazopanib in SCLC patients who have relapsed after, or have refractory disease to front-line chemotherapy was conducted.

Methods
This is a two-cohort, non-randomized, two-stage phase II study. Patients with sensitive (cohort A) and resistant/refractory (cohort B) histologically confirmed SCLC are enrolled onto the study. An interim analysis has been planned after enrolment of 19 patients in each cohort. Eligible patients have to have measurable disease (RESIST) and ECOG performance status (PS) 0-2. Up to 1 prior regimen (cisplatin/etoposide) for extended disease is allowed. Treatment consists of daily pazopanib 800 mg given p.o.q28 days, until disease progression. The primary endpoint is progression-free rate with a planned sample size of 39 eligible patients per cohort.

Results
We present the first interim analysis in cohort A. 19 eligible patients have been enrolled with a median age of 67 years (range 46-77); male 16; PS 0, 10 pts; PS 1, 9 pts. Four patients had only local relapse. Four (21%) partial responses and 8 (42%) stable disease were documented which is translated in a disease control rate (DCR) of 63% (95% CI: 41.5- 85%). The median PFS was 4.3 months and the estimated 1-year survival 58%. Grade 4 neutropenia and diarrhea occurted in 1 patient each; other grade 3 adverse events were fatigue (n=2), nausea (n=1); grade 2 hypertransaminasemia occurred in 2 patients, grade 1 hemorrhage (epistaxis) in 3 and hypertension in 2. No deaths related to the study drug were observed.

Conclusion
These preliminary results show that pazopanib is an active and well tolerated drug in patients with sensitive SCLC. Recruitment in both cohorts is ongoing. A biomarker analysis is planned.

Abstract not provided

Background
Prophylactic cranial irradiation (PCI) plays crucial role to prevent brain metastasis for small cell lung cancer (SCLC) patients – both limited stage (LS) or extensive (ES) – who respond to initial therapy. For better quality-adjusted life expectancy and to avoid neurointellectual impairment (NIP), optimum dose and fractionation for PCI needs to be explored, with due consideration to coexisting medical comorbidities that might enhance the adverse events, specially neurocognitive functions. Aim of the study was to find the safety and efficacy of PCI with the dose of 30 Gy/ 10 fractions and to analyze its impact on NIP with special focus on any possible influence of these medical comorbidities.

Methods
This is an on-going single arm multicentric trial initiated in November 2010 where both LS- as well as ES-SCLC patients who responded to initial therapy and were not having any visceral metastasis are offered PCI for a dose of 30 Gy in 10 fractions with CT-based planning. All patients received Platinum + Etoposide for 6 cycles. LS-SCLC patients received, in addition, concomitant thoracic radiation after 2 cycles of chemotherapy. To minimize neuro-psychological impairment, at least 2 weeks gap is given before PCI and after completion of all chemotherapy to avoid entry of more chemotherapeutic agent into brain parenchyma by way of radiation induced permeability alterations. All relevant medical comorbidities (Diabetes, Hyperlipidimia, previous history of CVA) are recorded. Neuropsychological screening measure of immediate and delayed verbal memory by using Hopkins Verbal Learning Test - Revised (HVLT - R), assessment of cognitive function using Mini-Mental Status Examination (MMSE) and Instrumental Activities of Daily Living (IADL) questionnaires are applied before initiation of PCI and on follow up .

Results
Result of first 38 patients receiving PCI (LS- SCLC = 28, ES-SCLC = 10) with minimum duration of follow up of 18 months is being presented. Brain metastasis, in spite of PCI was faced by 0/28 of LS and 1/10 of ES-SCLC. Median duration of survival was 8.5 months for ES and 14 months for LS-SCLC. 1/10 ES-SCLC and 16/28 LS-SCLC lived one year. Corresponding data for 18 months is 0/10 and 4/28 respectively. MMSE deterioration was noted in 12/38 patients. Subset analysis of these 12 patients revealed 8/12 are having long standing diabetes and another 2/12 had both diabetes and hyperlipidimia. HVLT decline in immediate recall (13/38) was in 10/12 patients having MMSE deterioration and 9 out of these 12 had delayed recall deterioration also. So NIP (as evidenced by HVLT) was found in 10/14 diabetic patients receiving PCI, contrary to 3/24 non-diabetics (P = 0.0004).

Conclusion
30Gy/ 10 fractions is an effective PCI protocol for both LS and ES – SCLC. But patients with medical comorbidities, specially long standing Diabetes (and may be hyperlipidaemia) are more prone to develop impairment of neurocognitive functions (possibly due to presence of cerebral microinfarcts and lacunar infarcts) and deserve special attention and should be treated possibly with lower dose / fraction size less than 3 Gy. Further study with more patient accrual is required to arrive at a definite conclusion.

Background
Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC) except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected small cell lung cancer is limited but this is widely offered.

Methods
Data on 359,873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC; non-SCLC [NSCLC]) and whether they underwent a surgical resection. We explored their survival using Kaplan-Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socio-economic status.

Results
The survival of 465 resected SCLC patients was lower than resected NSCLC patients (five-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 “elective” SCLC where the diagnosis was most likely known before resection than for the subgroup of 267 “incidental” cases, where the SCLC diagnosis was likely to have been made after resection.

Conclusion
These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. SCLC patients treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected SCLC patients.

Background
Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.

Methods
Patients with completely resected stage I- IIIA HGNEC received 4 cycles of irinotecan (60 mg/m[2], day 1, 8, 15) plus cisplatin (60 mg/m[2], day 1). This regimen was repeated every 4 weeks. Other eligibility criteria included ECOG PS 0–1, age 20, and <75 years old, adequate organ function, and no prior chemotherapy or radiotherapy. Patients with UGT1A1 polymorphisms (homozygous for *6 or *28, or simultaneously heterozygous *6 and *28), associated with irinotecan-related severe toxicity, were excluded. The primary endpoint was the rate of completion of chemotherapy (defined as underwent 3 or 4 cycles), and secondary endpoints were 3-year relapse free survival (RFS), rate of 3-year survival and toxicities.

Results
Forty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were as follows: median age (range) 65 (45-73) years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90% C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86% and 74% among 23 LCNEC patients, and 74%, 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutrophils, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and 4 patients (10%) had grade 3 nausea. No treatment related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC at pathological central review among 7 pathologists. There were two specimens that showed the difference in between institutional diagnosis and central pathological diagnosis.

Conclusion
The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.In Japan, a randomized phase III trial is ongoing to evaluate adjuvant chemotherapy of irinotecan and cisplatin, compared with etoposide and cisplatin, for completely resected HGNEC.

Background
The SCOT registry is an international, multicenter, observational registry of newly diagnosed patients with SCLC. The treatment plan remained the responsibility of the patient’s physician and data collected in this registry reflect a "real world" approach for the diagnosis and treatment of patients with SCLC.

Methods
56 centers included 507 evaluable patients between 10[th] of November 2009 to 18[th] of August 2010. Participating countries are from Western Europe, Eastern Europe and Korea. Data has been entered into an electronic CRF via the internet.

Results
Mean age was 65.4 years, 73% of the patients were male, mean BMI was 25.5 Kg/m2. Smoking status showed 50% were current and 46% former smokers. The most common symptoms at presentation (>25%) were cough, dyspnea, weight loss and fatigue. Patients presented with an ECOG status of 0 (24%; 33% for limited disease (LD) and 19% for extensive disease (ED)), ECOG 1 (52%), ECOG 2 (19%) and ECOG 3 (5%). Histology was small cell carcinoma in 98% of patients and 66% presented with extensive disease. Chemotherapy alone was given to 59% of patients in the first 6 months of treatment. 58% of patients had one line of therapy, 26% had 2 lines, 11% had 3 lines of therapy and 4% had 4 lines or more. The agents most commonly used in each line of therapy are below: Table 1: Chemotherapy agents by line of therapy in SCOT (% within the treatments of the line)

AGENT/LINE	FIRST	SECOND	THIRD	> 3
Platinum/Etoposide	90.7	26.8	14.5	10.5
Topotecan	0.2	25.7	20.2	2.3
Taxanes	2.1	9.3	21.7	26.3
Cyclophosphamide	3.9	10.9	11.6	15.8
Cyclo/Vincristine	3.9	12.0	11.6	15.8
Vinorelbine	0.2	1.1	2.9	2.3
Gemcitabine	0.0	2.2	0.0	6.8

67 % of patients with LD received chemo + thoracic radiotherapy. PCI in the first 6 months was given in 26% of patients (LD 34% ED 22%). Best overall response at 6 months in patients with combined chemoradiotherapy was PR=51%, CR=22%, SD=16%, PD=11%. Median overall survival (OS) was 10.6 months [95%CI 9.6, 12.1] with 17.8mo for limited disease and 8.7mo for extended disease. Western Europe and Korea showed OS of 11.5mo and 11.3mo respectively whereas in Eastern European median OS was 9.1 months.

Conclusion
This observational study captured real world data of the current treatment paradigm of SCLC. Patients are commonly treated with etoposide/platinum or chemoradiotherapy as first line. The combination of platinum and etoposide remains by far the first choice of chemotherapy in 1[st] line and often at relapse, followed by topotecan starting from second line and beyond. Details on patterns of disease, treatment and efficacy by region and smoking status plus medical resource utilisation will be available at the meeting.

Background
Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.

Methods
Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.

Results
For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).

Conclusion
As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.

Abstract not provided

Background
Immunotherapy is now accepted as the fourth most important modality for malignant tumours, and is currently being applied in the treatment of non-small cell lung cancer (NSCLC). CD1d, a MHC class-like molecule, presents glycolipids to natural killer T (NKT) cells. In doing so, CD1D contributes to their anti-tumour activity. CD1d is expressed in certain tumour types, and there is increasing evidence that CD1d acts as a target for NKT-mediated cell killing, however most human and mouse solid tumours are CD1d-negative. Recently evidence has indicated that CD1d expression is epigenetically regulated through HDAC1/2 and Spl.

Methods
CD1d levels were examined at the mRNA level by RT-PCR. To determine whether CD1d expression is subject to epigenetic regulation, non-small cell lung cancer (NSCLC) cell lines were treated with various epigenetic modifying agents. The A549 (adenocarcinoma) and SK-MES-1 (Squamous cell carcinoma) cell lines were treated with HDACi, (a) SAHA at a dose of 5 µM for 24 h. Treatments with other epigenetic modifyng agents such as trichostatin A (TSA) and DNA methyltransferase inhibitors are currenly ongoing. iNKT cells were co-cultured wiht NSCLC cells to examine their antitumourigenic activity using a CD107a externalised assay.

Results
Using RT-PCR it was possible to confirm that SAHA significantly induced CD1d expression in both A549 and SKMES cell lines (p ≤ <0.005). RT-PCR was also performed on A549 and SKMES cell lines that had been allowed to recover, following treatment with SAHA. A549 cells showed a statistically significant induction in recovered SAHA-treated cells (p < 0.05). Using flow cytometry the cytotoxic T-lymphocytes (CTL) activity of iNKTs was measured. While there was a slight induction of CD107a-bearing iNKT cells, it is believed that treatment with HDACi will increase the anti-tumour activity of these cells. This work is ongoing at present.

Conclusion
CD1d expression is significantly induced using the HDACi, SAHA. This induction is present in A549 cells treated with SAHA and allowed to recover; indicating that SAHA may possibly be used to increase the anti-tumourigenic activity of iNKT cells. These results may have important consequences for treating patients with combined epigenetic targeting agents and immunotherapy.

Background
The elderly have less-robust immune responses to infections, immunizations, and tumors, compared with younger people. Furthermore, preclinical studies have indicated that immunotherapeutic interventions are less effective in older animals. Considering the effects of age-associated changes in immune function, most clinical trials of cancer-related immunotherapy have been conducted in relatively young patients. With the increasing focus on immunotherapy for non-small cell lung cancer (NSCLC), we investigated the relationship between patient age and tumor immune parameters in stage I NSCLC.

Methods
Tissue microarrays from patients with stage I NSCLC (n=1371; 1995-2009; median follow-up, 3.5 years) were constructed, and immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) were performed. Patients were categorized into 3 groups: (1) ≤65 years old, (2) 66-79 years old, and (3) ≥80 years old. Stains were analyzed for immune cell infiltration (low vs high) in the tumor nest. The Chi-Square test was used to analyze the association between immune parameters and age group. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS).

Results
In total, 1116 patients with stage I lung adenocarcinoma and 255 patients with stage I squamous cell carcinoma were enrolled. Patients aged ≥80 years did not have a significantly poorer prognosis (n=155; 5-year RFS, 76.0%) than the patients in the two younger groups (p=0.65; Figure 1A). There were no statistically significant differences in numbers of tumor-infiltrating lymphocytes in the tumor nest between the three groups (Figure 1B), nor was there a statistically significant difference between the elderly group and the younger patients when effector regulatory immune response ratios were compared (FoxP3/CD3 ratio; high vs low, p=0.85). Figure 1

Conclusion
In this large cohort of stage I NSCLC patients selected for surgical resection, the tumor microenvironment among elderly patients resembles other age groups. Our study provides important information while considering immunotherapy in elderly patients with lung cancer.

Background
EGFR tyrosine kinase inhibitors (TKIs) have an important role in the treatment of NSCLC, particularly in the context of activating mutations, but resistance invariably develops. Recently, the immune checkpoint blockers anti-PD1 and anti-PDL1 were the first immunotherapies to demonstrate activity in advanced lung cancer. As immunotherapies such as anti-CTLA4, anti-PD1 and anti-PD-L1 antibodies enter clinical practice, there is potential to combine immunotherapies with TKIs to improve patient outcomes. The immune effects of EGFR-TKIs have not been elucidated, and the aim of this study is to examine the effect of TKIs on the immune response in patients with NSCLC, to provide a rationale and pilot data to underpin future clinical development of combinations of TKIs and immunotherapy.

Methods
Patients with advanced NSCLC who were commencing an EGFR-TKI were included in this prospective study. Eligible patients had a confirmed diagnosis of NSCLC, were treated with a single-agent EGFR-TKI , had no concurrent autoimmune disease and received no chemotherapy within 21 days, or corticosteroid therapy within 3 days of study entry. Peripheral blood samples were collected before commencing a TKI and 7 days, 21 days and 8 weeks after start of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and immediately frozen for subsequent analysis by 8-colour flow cytometry for relevant surface and intracellular marker expression. 4 panels were developed to examine the activation and proliferation status of effector CD8[+] T and CD4[+] T-regulatory cells (Tregs), enumeration of dendritic cells and B-cells, as well as the inhibitory pathway programmed death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 on T cells and antigen-presenting cells. Changes in immune parameters will be correlated with overall survival (OS) and radiological response (RECIST 1.1 criteria) at 8 weeks post-treatment.

Results
33 eligible patients were prospectively enrolled. Histopathology was adenocarcinoma (n=23), squamous cell carcinoma (n=7) and NSCLC not otherwise specified (NOS, n=3)). 12 patients had an activating EGFR mutation, 11 were EGFR wild type, and mutation-status was unknown in 10. 6 patients received the TKI gefitinib and 4 received erlotinib as first-line treatment for EGFR-mutation positive disease. 22 patients received erlotinib and 1 patient received afatinib as second or subsequent line therapy. At time of this report, 22/33 patients were deceased. Median OS from study entry was: all patients (7.7 months); mutation-positive (11.1 months); and mutation negative (4.4 months). Samples for 13 patients (2 were mutation-positive) have been analysed for effector T cell and Treg panels and no significant changes were seen between baseline and subsequent time points. Data will be presented for all samples.

Conclusion
This is the first study to explore to the immune effects of EGFR-TKIs. Initial results have not revealed a significant effect on peripheral T-cells, and analysis of remaining patient samples and other panels is in progress. An understanding of the immune effects of targeted therapies will be crucial in the rational development of strategies for incorporating immunotherapy into the anti-EGFR treatment paradigm, in an era of promising immunotherapy and checkpoint blockade approaches.

Abstract not provided

Background
EGFR-tyrosine kinase inhibitor Gefitinib interrupts signaling through the EGFR in non-small-cell lung cancer (NSCLC) cells with EGFR driver mutation and has shown impressive activity in terms of clinical benefit for patients with NSCLC, however, almost all patients develop resistance to this drug. Although much research is focusing on the mechanisms of drug resistance in tumor cell, the role of EGFR signaling in tumor escape from the host immune system is poorly understood. NK cell activity is promoted via NK group 2, member D (NKG2D) on NK cells. The engagement between NKG2D and its ligands enhances cell-mediated cytotoxicity and cytokine production against transformed cells. Both MHC class I-related chain A and B (MICA/B) and UL16 binding protein (ULBP)s are expressed by intestinal epithelial and at low levels also by other non-malignant cell types. Primary tumor cells and tumor cell lines frequently express NKG2D ligands, but the mechanisms responsible for the induction of NKG2D ligands during oncogenesis are also poorly understood. Here we demonstrate Gefitinib downregulates NK group 2 member D (NKG2D) ligand MICA/B and ULBPs, resulting in attenuation of NK cell-mediated cytotoxicity in NSCLC cells.

Methods
Possible influences of Gefitinib on expressions of MHC class I, MICA/B and ULBP1-3 in 5 NSCLC cell lines (A549, PC-9, RERF-LC-KJ, RERF-LC-AI, and LC2/ad) were investigated by flow cytometry. We also assessed whether genetic silencing of EGFR using siRNA of EGFR affected on the expression of NKG2D ligands. To ask the main downstream pathway of EGFR regulating the expression of NKG2D ligands, the cells were treated with PI3K-AKT inhibitor LY294002 or MEK inhibitor PD98059 then the expression of NKG2D ligands was analyzed. NK cell-mediated cytotoxicity against cancer cells was assessed by [51]Cr release assay or flow cytometry based CD107a degranulation assay.

Results
Gefitinib downregulated NKG2D ligands in NSCLC cell lines. In line with these results, siRNA-mediated silencing of EGFR downregulated the expression of NKG2D ligand. Among the major downstream pathways activated by EGFR signaling, the expression of NKG2D ligands was mainly regulated by the PI3K-AKT pathway. Treatment with EGF promoted MICA/B expression in 2 of 5 cell lines, while EGF decreased MICA/B in 1 of 5 cell lines. These observations further emphasize that EGFR signaling is one of the major pathways regulating the expression of NKG2D ligands in NSCLC cells. As expected, inhibition of EGFR signaling-downregulated NKG2D ligands attenuated NK cell-mediated cytotoxicity.

Conclusion
We conclude that EGFR signaling directly regulates the expression of NKG2D ligands and that this may influence the recognition of tumor cells by the innate immune system.

Background
Identifying key molecules in the pathobiology of malignant mesothelioma is needed to develop new therapies and biomarkers. Fibroblast growth factor-9 (FGF-9) is an exciting and novel target uncovered from our global gene profiling of human MPM samples. Recently FGF-9 has been implicated in cancer development and neoplastic transformation of embryonic fibroblasts. We have verified over-expression of FGF-9 in MPM over other cancers and benign pleuritis in five separate cohorts of human pleural tissues and effusions. Our preliminary in vitro work demonstrated that FGF-9 induces mesothelioma cell proliferation and matrix invasion. We therefore hypothesised that antagonising FGF-9 may reduce tumour aggressiveness, growth and induce tumour regression in vivo.

Methods
To study the ‘necessity’ of FGF-9 in MPM development in vivo we transfected the mouse MM cell line, AB1, with shRNA directed against murine FGF-9 (or control vector expressing a scrambled sequence). For the heterotopic model murine AB1-FGF-9 knock-down cells (or controls) were injected (5x10[5 ]cells) subcutaneously into the flank of Balb/c mice. Tumour dimensions were measured thrice weekly and animals sacrificed when tumours reached 100mm[2] and tumour tissues harvested. FGF-9 expression in tumour tissue was determined by immunohistochemistry. For orthotopic experiments, Balb/c mice received a single intraperitoneal injection of 5x10[5 ]AB1-FGF-9 knock-down cells (or controls). At day 13, animals were sacrificed and the number of peritoneal tumour nodules enumerated by blinded investigators. To determine whether the immune system plays a role in the regulation of AB1 MM tumour growth, 5x10[5 ]AB1-FGF-9 knock-down cells (or controls) were injected subcutaneously into nude mice. To elucidate the immune cells involved in AB1 MM tumour growth regulation, T cells were depleted in Balb/c tumour bearing mice using specific antibodies to CD4 and CD8 and tumour growth monitored. T cell depletion was confirmed using flow cytometry.

Results
Heterotopic tumour growth was significantly retarded in mice inoculated with AB1-FGF-9 knockdown cells compared to the scrambled vector and parent MM cells (p<0.001). A significant reduction in the number, and hence tumour burden, of tumour nodules was also observed for AB1-FGF-9 knockdown tumours in the orthotopic peritoneal model compared to controls (p<0.001). When grown in nude mice, which lack a functional T cell repertoire, AB1-FGF-9 knockdown tumours grew at a similar rate to that of the parent and vector controls which was suggestive of a role of the immune response in the regulation of MM tumours lacking FGF-9. AB1-FGF-9 knockdown tumours demonstrated significantly greater tumour burden in mice depleted of CD4+ and CD8+ T cells, either alone or in combination, when compared to saline controls which is highly suggestive of a T cell-mediated immune response to these tumours. These results also suggest that FGF-9 inhibits the tumour-specific immune response in MM.

Conclusion
In combination with our previous in vitro data which clearly demonstrated the proliferative and invasive properties of FGF-9, we suggest that FGF-9 has an important role in the pathobiological characteristics of MM in vivo and represents a novel therapeutic target.

Background
Increasing evidence supports the concept of a unique population of cells within a tumor with stem cell-like characteristics. These cancer-initiating cells (CICs) are thought to be responsible for tumor organization, maintenance, progression and recurrence, as well as contributing to radiation and chemotherapy resistance. In this study we outline a new characteristic of CICs, one in which the CIC can subvert the host immune response. We pose that this characteristic is essential for the establishment of a tumor in an immunocompetent host and may represent a mechanism in which lung tumors may gain resistance to immune based therapies.

Methods
We examined whether lung CICs could be enriched from murine and human cell lines through the use of tumorsphere culture assays. We vaccinated mice against the HPV E7 antigen and challenged mice with HPV E6/7 expressing murine lung cancer cells (TC-1) enriched for CICs. We also examined ex-vivo the capacity of CD8 and NK cells derived from vaccinated mice to lyse CICs. We examined by flow cytometry the expression of MHC-I and NK activating ligands. We examined the effect of interferon gamma (IFN-γ) on MHC-I expression by CICs and determined whether increased MHC-I by CICs would inhibit tumor formation in an immunocompetent animal.

Results
We showed that both murine and human lung cancer cells can be grown and maintained in tumorsphere culture conditions. The resulting cells were enriched for CICs as evidenced by increased OCT4, NANOG, and/or SOX2 expression. Additionally, tumorsphere cultures of murine tumor lines had increased tumor take in immunocompetent animals, however this was significantly less than that seen in immunodeficient mice; indicating that true CICs must be able to thwart the immune response to establish tumors. In order to further examine this, we vaccinated mice with HPV E7 peptides and challenged with TC-1 non-CICs or CICs. We showed that mice challenged with CICs had no survival advantage compared to non-vaccinated animals; whereas those animals challenged with non-CICs exhibited a vaccine induced survival advantage. Further we showed ex-vivo that CICs were resistant to lysis from CD8+ T-cells compared to the non-CICs. Next, we showed that both murine and human lung CICs have down-regulated expression of MHC-I as well as a number of ligands for NK cell activating receptors, essentially making them “opaque” to the immune system and therefore less susceptible to CTL or NK cell lysis. Further, we demonstrate that IFN-γ increases MHC-I expression on CICs and restores sensitivity to CTL killing. Finally, we demonstrate that decreased MHC-I expression is a critical component of the ability of CICs to establish tumor in immunocompetent hosts.

Conclusion
Increasing evidence indicates that CICs are critical players in the development and establishment of cancers. In this study we demonstrated that these cells also subvert tumor immune surveillance and play a key role in the resistance of tumors to cancer vaccines through their ability to escape host immune responses. Our results demonstrated that modulation of MHC-I on CICs can alter their susceptibility to T-cell mediated lysis thus opening a new target for cancer vaccine strategies.

Abstract not provided

Background
In NSCLC, antitumor immune response may be inhibited by PD-L1 expression. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 binding to its receptors, PD-1 and B7.1.

Methods
Patients with squamous or nonsquamous NSCLC received MPDL3280A IV q3w up to 1 year as part of a phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tumor tissues were evaluated centrally by IHC for PD-L1 and CD8. A qPCR-based gene expression panel measuring ≈90 immune-related genes was used to characterize the tumor immune microenvironment at baseline and during MPDL3280A treatment.

Results
41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy with an ORR of 22%. Baseline tumor samples were available for IHC (n=33) and for gene expression analysis (n=29). Of patients with available tissue, 5 were PD-L1 tumor status positive and 28 were PD-L1 tumor status negative. Relationship between PD-L1 status and EGFR/KRAS status is described below (table). Elevated baseline PD-L1 expression was associated with response to MPDL3280A (80% ORR vs 14% ORR for PD-L1negative patients), and PD-L1 expression coordinated with CD8+ T cells. A Th1-type T-cell gene signature (including CD8, Granzyme-B and EOMES) was associated with treatment response. Non-responders exhibited at least a 2-fold higher ratio over CD8 of genes associated with immunosuppression, including RORC, FOXP3, TGFb1 and IL10 compared with responders. On treatment, responding tumors across indications showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 up-regulation.

Conclusion
PD-L1 expression and a Th1 driven T-cell gene signature correlated with response to MPDL3280A in NSCLC, and MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. Additionally, expression of immune suppressive factors in NSCLC tumors is associated with a lack of benefit from MPDL3280A. These data provide mechanistic insights into immunotherapy and patient selection for MPDL3280A monotherapy. Preliminary observations suggest clinical activity and molecular characteristics may be associated with PD-L1 tumor expression. Updated data will be presented. Table: Relationship between PD-L1 status and EGFR/KRAS mutational status

	PD-L1-Positive (n = 5)	PD-L1-Negative (n = 28)	PD-L1 Unknown (n = 7)	Overall (n = 40)*
EGFRm, n	1	2	1	4
EGFR WT, n	2	20	4	26
EGFR Unknown, n	2	6	2	10
KRASm, n	1	4	1	6
KRAS WT, n	2	8	3	13
KRAS Unknown, n	2	16	3	21
* 1 patient had missing data.

Background
Programmed Death Ligand 1 (PD-L1, CD274, B7-H1) is an immune checkpoint molecule that binds to the receptors PD-1 and B7.1 on activated T cells. Binding negatively regulates T-cell function in both physiological and pathological conditions. Recent clinical studies have suggested that numerous cancers, including NSCLC, may utilize PD-L1 expression to escape T-cell mediated cytotoxic activity. Inhibition of PD-L1 can restore anti-tumor immunity, leading to clinical responses. A better understanding of PD-L1 expression patterns, co-expression with other immune markers and actionable disease associated biomarkers may provide insight into the future design of cancer immunotherapy trials in NSCLC.

Methods
Expression of PD-L1 was measured by immunohistochemistry (IHC) in archival tumors and, in some cases, in paired metastases in 2 FFPE NSCLC tumor tissue collections. Set 1 (N=561) was collected from patients who were eligible for surgery with curative intent from 2003 to 2005 at MD Anderson Cancer Center. The samples from Set 2 (N=300) contained surgically resected NSCLC tissue collected between 2006 and 2011 (UCCC and Norwegian Radium Hospital). PD-L1 expression was analyzed in both malignant and non-malignant cells (e.g., infiltrating immune cells). In addition, a multiplex qPCR assay that measures ≈90 immune-related genes was used to characterize the tumor immune microenvironment in the NSCLC tumor samples. Disease associated biomarkers, including the mutation status of EGFR and KRAS, as well as expression of MET (by IHC) were also evaluated.

Results
Prevalence of PD-L1 was comparable between adenocarcinoma and squamous cell carcinoma (≈30% in tumor cells; ≈45% and ≈50%, respectively, in immune cells). PD-L1 prevalence varied depending on the pathological stage, and was higher in Stages I-IIIA than in Stages IIIB-IV. Similarly, the prognostic value of PD-L1 varied by both stage and histology. In adenocarcinoma, tumors with PD-L1–positive tumor cells had a higher frequency of KRAS mutation and high Met expression, and a lower frequency of EGFR mutation compared with PD-L1–negative tumors. In contrast, tumors with PD-L1–positive and PD-L1–negative immune cells had a comparable frequency of high Met expression. Expression of PD-L1 was frequently co-localized with CD8+ T-cell infiltrates. Gene expression profiling revealed differences in the tumor immune environment, including genes associated with cytotoxic T-cells, between adenocarcinomas and squamous cell carcinomas. PD-L1 protein and immune gene expression associations with patient characteristics will be described in further detail.

Conclusion
These data provide a comprehensive description of PD-L1 expression in the context of disease biology utilizing large independent cohorts of well-characterized lung cancer tissues. The results highlight the complexity of the tumor immune environment in NSCLC with particular emphasis on the association with factors such as pathological stage, histology and oncogenic mutational status. These analyses may help guide future development of immunotherapy trials in NSCLC.

Background
Programmed Death Ligand-1 is a ligand for Programmed cell death protein 1 which is a key receptor regarding one of the immune checkpoints. PD-L1 expression in tumor is known to correlate with post-operative survival in different set of cancer patients. In the present study, we investigated PD-L1 expression of tumor cells in specimens acquired from non-small cell lung cancer patients and analyzed the correlation between the PD-L1 expression and clinicopathological characteristics and postoperative prognosis of 208 Non-Small Cell Lung Cancer patients.

Methods
PD-L1 expression in 208 specimens of NSCLC was assessed through an immunohistochemical process and inspected double-blinded.

Results
PD-L1 expression is associated with clinicopathological features (histology, P=0.047 and differentiation, P=0.023). No significant association observed between PD-L1 expression and post-operative prognosis. However, subgroup analysis of squamous carcinoma patients with positive PD-L1 protein expression showed a tendency of poor overall survival and disease-free survival compared with those with negative PD-L1 protein expression.

Conclusion
we have shown for the first time that PD-L1 expression is associated with clinicopathological features (histology and differentiation). In the subgroup analysis of squamous carcinoma patients, patients with positive PD-L1 expression showed a tendency to be associated with poorer survival compared with those with negative PD-L1 expression, which suggested that patients with squamous carcinoma might be the most benefit population in the anti-PD-1 immunotherapy.

Background
The prognostic significance of the tumor immune microenvironment in lung adenocarcinoma has been established by us (CCR 2011, JCO 2013, Oncoimmunology 2013) and others. Here, we investigate whether tumor-infiltrating immune cells correlate with prognosis, independent from TNM staging, in lung squamous cell carcinoma (SCC).

Methods
All available tumor slides from therapy-naive, surgically resected solitary lung SCCs (n=485; 1999-2009) were reviewed. Tissue microarrays were constructed using 451 cases (stage I, 255; II, 131; III, 65) from 3 representative tumor areas. Immunostaining for CD3 (pan T cell marker), CD45RO (memory T cell), CD8 (cytotoxic T cell), CD4 (helper T cell), FoxP3 (regulatory T cell), CD20 (B cell), CD68 (macrophage), and CD10 (neutrophil) was performed. For each case, the average number of cells positive for T cell markers was recorded as the ratio to CD3+ lymphocytes, and classified as low or high by use of the median. CD20, CD68, and CD10 were classified as low or high by the number of positive cells (≥20, ≥50, and ≥10, respectively) as our recent publication (JCO 2013). Overall survival (OS) was estimated using the Kaplan-Meier method; multivariate analyses were performed using the Cox proportional hazards model.

Results
Five-year OS was 59% for the entire cohort and 68% for stage I patients. Analysis of single immune cell infiltration revealed that high CD10+ neutrophil count was correlated with lower OS (5-year OS, 53%; n=160) than low CD10+ count (5-year OS, 61%; n=286; p=0.006). Analysis of biologically relevant immune cell combinations identified 2 significant factors of prognosis: (1) patients with high CD4+ and high FoxP3+ T cell ratios had worse prognosis (5-year OS, 52%; n=140) than the other groups (5-year OS, 62%; n=304; p=0.008), and (2) patients with high CD10+ neutrophil and low CD20+ B lymphocyte counts had worse prognosis (5-year OS, 43%; n=102) than the other groups (5-year OS, 63%; n=340; p<0.001). These results were confirmed in a subgroup analysis limited to stage I patients (p=0.020 for high CD4/high FoxP3+ ratios; p=0.007 for high CD10+/low CD20+ counts). In multivariate analysis, high CD4+/high FoxP3+ ratios (HR=1.58; p=0.001) and high CD10+/low CD20+ counts (HR=1.71; p<0.001) remained significantly associated with poorer survival (Table).

Table. Multivariate analysis for overall survival

Variable	HR	95% CI	p
High CD4+/high FoxP3+ ratios	1.58	1.21–2.06	0.001
High CD10+/low CD20+ counts	1.71	1.28–2.27	<0.001
Age (>65 years old)	1.51	1.09–2.09	0.014
Sex (male vs. female)	1.31	1.01–1.69	0.043
Smoking pack years (>90)	1.01	1.00–1.01	0.003
Stage (II and III vs. I)	1.53	1.16–2.02	0.002
Lymphovascular invasion	1.38	1.02–1.88	0.040

Conclusion
High CD4+/high FoxP3+ ratios and high CD10+/low CD20+ counts are significant factors of prognosis for lung SCC, independent of TNM staging. Targeting regulatory T cells or enhancing tumor-specific B-cell responses may thus have applicability for the treatment of lung SCC.

Abstract not provided

Abstract
Non-small cell lung cancer (NSCLC) is a highly lethal disease. Despite dose escalation with conformal radiotherapy (RT) in combination with modern chemotherapy, there is still a significantly high rate of intrathoracic failure and poor overall survival in patients with locally advanced disease. Recently, clinical studies have shown that blocking the immune check points such as CTLA4 and PD1 is effective in patients with metastatic NSCLC, resulting in a high response rate and improved both progression-free and overall survival. This generates enthusiasm for further studying the effect of immunomodulation with radiation therapy in earlier stage tumors. However, radiation can cause lymphodepletion, and persistently profound radiation-associated lymphopenia has been linked to poorer tumor control and survival in several solid tumors, including NSCLC. Radiation-induce lymphopenia can potentially counteract the effect of immunotherapy, making it less effective in patients treated with radiotherapy. Unfortunately the mechanism of radiation-induced lymphopenia is poorly understood, and unless we can overcome such effect, it will be difficult to integrate immunotherapy with radiotherapy. Galectin-1 (Gal-1) is a secreted carbohydrate binding lectin that is well known for its role in modulating T-cell homeostasis. More recently, it has been shown to play a major role in cancer progression. It is expressed in many cancers, including NSCLC, where increased Gal-1 expression is closely associated with larger tumors, more nodal metastasis and lower overall survival. In human head and neck cancer, expression of Galectin-1 was inversely related to intratumoral T-cell level and correlated with prognosis. We have previously showed that Gal-1’s secretion is enhanced by both hypoxia and radiation in NSCLC. Using an immunocompetent mouse model, we have also shown that tumor-derived Gal-1 is important for promoting tumor growth and spontaneous metastasis in NSCLC. Further mechanistic studies suggested that Gal-1 mediates its tumor promoting function by enhancing intratumoral T-cell death while protecting hypoxic tumor cells from apoptosis. More recently, using the same mouse model, we found that circulating plasma tumor Gal-1, which is elevated after tumor irradiation, appears to mediate the phenomenon of lymphopenia in mice. In addition, in vitro and in vivo studies indicate that down regulation of Gal-1 expression or blocking its function result in enhanced radiation sensitivity in NSCLC, resulting in more cell kill and tumor shrinkage. Based on these data, we believe that the poor outcome associated with radiation-induced lymphopenia is due to Gal-1’s effect on tumor infiltrating lymphocytes, and it is therefore logical to target Gal-1 in combination with radiation in NSCLC.

Abstract not provided

Abstract
Hypoxia as a cause of treatment failure in NSCLC Odd Terje Brustugun, MD PhD Senior Consultant, The Norwegian Radium Hospital, Oslo, Norway & Assoc. professor, Faculty of Medicine, University of Oslo, Oslo, Norway Well-oxygenated tumors respond better to various therapies than hypoxic tumors. Hypoxia is therefore a predictive factor. However, emerging knowledge has underscored that hypoxia is also a prognostic factor, independently of therapy, and that hypoxia in a tumor’s microenvironment induces a more aggressive tumor phenotype. Here, factors involved in hypoxia-mediated therapeutic failures will be discussed both in the context of therapy resistance and as a tumor biology phenomenon per se. Most tumors (including lung cancer) have a low pO~2~ of 0-7.5 mmHg which can be measured indirectly using tracers as 18F-FAZA PET imaging, or via MR-based techniques. However, due to the heterogenous distribution and temporal instability of hypoxia, such methods are limited by lack of resolution. Oxygen molecules diffuse freely in normal tissues, with a diffusion range of ca 200 um. However, all solid tumors over 1 cm[3] contain hypoxic regions due to several factors: abnormal microvessel structure and function leading to increased diffusion distance from vessel to cell, increased oxygen demand due to increased cellular proliferation, reduced oxygen supply due to vascular constriction and increased interstitial pressure. Anemia, frequently observed in cancer patients, adds to the reduced oxygen supply (1). Radiation kills cells mainly via production of free radicals that bind to DNA and induce strand breaks. Oxygen stabilizes the chemical bond breaks in DNA, and makes the damage permanent. Therefore, in oxygen absence, DNA is less vulnerable to permanent damage, leading to relative radioresistance, and the dose has to be increased substantially to induce the same cell kill. Hypoxia-inducible factor-1 (HIF-1) is an intracellular protein whose transcriptional activity is increased as a response to cellular stresses, including hypoxia (2). HIF-1 consists of a labile unit (HIF-1α) and a stable unit (HIF-1β), which heterodimerize to become transcriptionally active. In normoxia, HIF-1α undergoes proteolysis, resulting in a very low level of HIF-hetereodimers. In hypoxia, degradation of the α-unit is reduced leading to an increased level of the functional heterodimer which via binding to hypoxia response elements (HRE) induces expression of genes. Notably, HIF-1 is also regulated by other factors apart from, or in concert with molecular oxygen. HRE-elements are found in promoter or enhancement regions of various tumor-promoting families of genes, involved in anaerobic metabolism (3), angiogenesis (4), anti-apoptosis (5) and invasion and metastasizing (6). Lysyl oxidase, LOX, is upregulated in hypoxia via HIF-1 and is shown to be an independent prognostic marker also in lung cancer (7). LOX exerts its effect both locally by stimulating migration and invasive behavior, and far away from its secretory origin, preparing the metastatic niche (8). Blockade of LOX is shown experimentally to reduce the metastatic propensity of tumors. HIF-1-mediated signaling regulates virtually every step of the metastatic cascade, from migration towards blood vessels and intravasation through HIF-induced leaky endothelial cells. Further, HIF-1 inhibits anoiokis of circulating tumor cells, and hypoxic primary tumors secrete factors that permeabilize the endothelium at distant premetastatic sites (9). Every element of the stromal compartment is also influenced by hypoxia, including fibroblasts, immune, lymph and blood cells, each playing important roles in tumor progression (10) Of special interest in lung cancer, epidermal growth factor receptor (EGFR) is involved in several aspects of hypoxia. Recently, hypoxia was shown to stimulate invasion via EGFR-activation (11). EGFR is also shown to suppress specific tumor-suppressing microRNAs in response to hypoxic stress through post-translational regulation of a Dicer-regulator, AGO2 (12). A number of HIF-1-upregulated genes contribute to radioresistance, perhaps most important is the shift from glucose metabolism to a glycolytic phenotype (13). This effect increases the cell’s antioxidant capacity via accumulation of redox-buffers, thereby reducing the level of free oxygen radicals produced by radiation and thus protects the DNA from damage. Hypoxic tumors reoxygenate after radiation therapy, as a result of reduced demand because of cell death, and due to increased perfusion in tissues (14). Based on this, one would expect HIF-1α levels to decline after radiation, but the opposite is observed. This phenomenon is primarily caused by 1) increased level of free radicals, and 2) liberation of “stress granula” content, both leading to stabilization of the HIF-1α subunit (15). The initial HIF-1-increase occurs within hours of radiation. A few days thereafter, increased NO produced by infiltrating macrophages induces a second peak of HIF-1 stabilization, via NO-mediated prevention of HIF-degradation (16). Both the initial and the later increase of HIF-levels may contribute to a more aggressive phenotype and ultimately to treatment failure as cells become more prone to invade and metastasize. Several hypoxia sensitizers are in clinical trials, but so far, none are in routine use in lung cancer (17). Both HIF-1-inhbitors, as well as drugs targeting glucose metabolism should be further examined in the context of radiation therapy (13). These studies should not only be confined to fractionated therapy, but may likely also have positive impact on stereotactic ablative radiotherapy. In conclusion, tumor hypoxia is a major cause of therapy failure and tumor aggressiveness, involving a multitude of factors. As knowledge emerges, the opportunities of therapeutic interventions should be ample. References 1. Brown JM et al. Nat Rev Cancer. 2004;4:437-47. 2. Greer SN et al. EMBO J. 2012;31:2448-60. 3. Semenza GL. Semin Cancer Biol. 2009;19:12-6. 4. Jackson AL et al. Expert Opin Ther Targets. 2010;14:1047-57. 5. Lenihan CR et al. Biochem Soc Trans. 2013;41:657-63. 6. Sullivan R et al. Cancer Metastasis Rev. 2007;26:319-31. 7. Wilgus ML et al. Cancer. 2011;117:2186-91. 8. Erler JT et al. Cancer Cell. 2009;15:35-44. 9. De Bock K et al. Nat Rev Clin Oncol. 2011;8:393-404. 10. Casazza A et al. Oncogene. 2013. 11. Arsenault D et al. PLoS One. 2013;8:e55529. 12. Shen J et al. Nature. 2013;497:383-7. 13. Meijer TW et al. Clin Cancer Res. 2012;18:5585-94. 14. Rubin P et al. Clin Radiol. 1966;17:346-55. 15. Moeller BJ et al. Cancer Cell. 2004;5:429-41. 16. Li F et al. Mol Cell. 2007;26:63-74. 17. Harada H. J Radiat Res. 2011;52:545-56.

Abstract
Radiotherapy planning and target volume delineation in lung cancer is largely based on x-ray based imaging such as CT scanning or fluoroscopy. The most widely used functional imaging technique in the diagnosis and characterisation of NSCLC is [18]Fluoro-deoxy-glucose (FDG) position emission tomography (PET). PET acquired with CT on the same scanner (PET/CT) has been shown to be superior to CT alone in the staging of NSCLC. When PET is used to select patients for curative therapy an improvement in overall survival is seen. Many clinical studies describe an impact on the use of PET for target volume delineation (TVD) in NSCLC but none describe an improvement in clinical outcomes. Several staging studies clearly demonstrated the superiority of PET/CT over CT for identification of involved mediastinal nodes. PET based TVD was also shown to improve the identification of involved mediastinal lymph nodes. In areas of atelectasis, PET can help discriminate between areas of collapsed lung and areas of tumour. A number of studies have sought to measure the impact of PET/CT based TVD on inter-observer variation or against a gold standard. When PET/CT is used for target volume delineation alone, and the baseline staging issues are removed, PET/CT reduces the undesirable impact of inter-observer variation. Considering the impact on the resultant radiotherapy plan, PET/CT based target volume delineation has been shown to reduce the dose to normal structures and this may open the possibility of dose escalation. When used in its most basic form, images from the staging PET/CT scan can be visually correlated with the radiotherapy planning (RTP) CT image to identify areas of disease for inclusion within the treatment volume. To improve the accuracy of correlation a staging PET/CT scan can be registered with the planning CT and rigid registration is recommended to undertake this. One option is to acquire a PET/CT exclusively for the purpose of RTP after a staging PET has been acquired and the patient is deemed suitable for radical radiotherapy, requiring a separate PET scan, but removing any staging or patient selection issues. Another approach is to acquire a PET/CT in the radiotherapy treatment position both for the purposes of staging and TVD and this represents a more cost effective approach. Given the nature of PET images a number of investigations have examined the use of automated methods to define the edge of the tumour. These methods include: i) Fixed thresholding based on absolute values were areas of disease above a given value are included within the target volume (e.g. SUVmax >2.5); ii) A contour based on the a percentage of the SUVmax (e.g.40% of SUVmax); iii) The use of the ratio of the SUVmax to the average SUV within a background structure to define the SUV level to generate the auto-contour; iv) More complicated analytical methods such as the watershed method. Auto contours provide consistent contours, but have difficulty dealing with normal tissue adjacent to the tumour with high SUV uptake such as the heart. There is no clear consensus on which method most closely approximates to the tumour position and tumour edge and pathological correlation has proven difficult. Another difficulty with PET based auto-contouring is the variability of SUV values due to factors other than tumour activity such patient biological factors and scanning technical factors. At present it is recommended that any PET based contouring outside of a clinical trial should be based on a visual assessment method. As PET images are acquired over a number of minutes at each table position, it has been suggested that PET could define the entire motion trajectory of a lung tumour also known as the internal target volume (ITV) of a moving lung tumour. It has been demonstrated that a 4D PET/CT generated ITV based on the 4D PET image approximates to a 4DCT ITV. A number of studies have shown sizeable differences in SUV calculation between 3D PET/CT and 4D PET/CT and it is suggested that 4DCT provides a more accurate SUV quantification. This has implications for auto-contouring and may lead to new exciting new methods of PET based TVD based on 4DCT. FDG is the most commonly used tracer owing to its high tumour specificity and the relatively long half-life of [18]F. Other fluorine based tracers have been used to quantify tumour proliferation uisng 18 deoxy-fluoro-l-thymidine (FLT) and tumour hypoxia using Fluoroazomycin Arabinoside (F-FAZA). It has been suggested that these may be used for IMRT based dose painting Work is on-going to optimise dual tracer PET acquisition. A number of recent publications have examined the utility of PET for predicting outcome after stereotactic ablative radiotherapy (SABR) and demonstrated a clear association with SUVmax and poorer outcome. This might help identify those patients who might benefit from adjuvant therapy after SABR treatment. PET may have increased accuracy in detecting recurrence following SABR and should be used in the re-staging process. There is growing evidence of a similar clinical utility for PET in the management of patients with SCLC. PET has been shown to select patients with SCLC appropriately for radical therapy, to be predictive for outcome following therapy and for TVD. In conclusion, functional imaging is an essential part of the radiotherapy planning process for both NSCLC and SCLC. For both disease sites PET is critical for baseline staging and patient selection for radical therapy. PET should be used to inform TVD in NSCLC and to guide TVD in SCLC. PET is useful for identify relapse in patients treated with radiotherapy. It may also be useful as predictor of response and for adaptive radiotherapy. On-going research is still required particularly in the era of 4D PET/CT, given the promise 4D PET/CT has for improved accuracy in quantification and volume delineation.

Abstract not provided

Abstract
Chemo-radiotherapy (CT-RT) is the presently the standard of care in patients presenting with a stage III-N2 NSCLC, with surgery being considered an option in selected patient subgroups [ESMO Guidelines 2013]. Improved local disease control in stage III disease translated into improved overall survival [Auperin A, 2010; Machtay M, 2012]. The best median survival reported to date in a randomized phase III trial of concurrent CT-RT is 28.7 months in RTOG 0617, when concurrent carboplatin-paclitaxel was combined with delivery of 60 Gy in once-daily fractions of 2 Gy [Bradley J, 2013]. At this dose, 25% of patients developed a local failure at 18 months follow-up. Therefore, both the optimization of radiation delivery and dose escalation are areas of active research. Evidence supporting radiation dose escalation comes from retrospective analyses and pooled studies. The randomized RTOG 0617 study compared 60 Gy (in 6 weeks) versus 74 Gy (in 7.5 weeks), in a 2x2 design where patients were also randomized to receive additional cetuximab or none [Bradley J, ASCO 2013]. Analysis of the impact of cetuximab has yet to be reported, but a difference in favor of the 60 Gy arm was seen for progression-free survival (36.6% vs. 26.3% at 18 months), median overall survival (28.7 vs. 19.5 months). A higher incidence of grade 3 esophagitis in the 74 Gy arm (21% vs. 7%, p=0.0003) was not unexpected, but the higher rates of local disease progression (34.3% vs. 25.1%, HR = 1.37, p = 0.0319) was a surprise. The latter raises the possibility of unsafe planning practices being applied when higher (and more toxic) doses have to be delivered. On multivariate analysis, factors predictive of a poorer overall survival were higher radiation doses, higher esophagitis/dysphagia grade, greater gross tumor volume, and heart volumes receiving >5 Gy. While publication of full data from the RTOG 0617 study is awaited, some issues related to toxicity and techniques should considered (below). 1. Improved radiotherapy planning using intensity modulated radiotherapy (IMRT) has permitted some parameters for lung toxicity (V20, mean lung dose) to be improved. However, not all recent or ongoing studies have applied constraints for lung volumes undergoing low-dose irradiation (V5). Furthermore, the choice of chemotherapy may increase lung toxicity, as reported by a recent meta-analysis showing that the risk of radiation pneumonitis is highest after concurrent CT-RT in patients aged >65 years, who also received carboplatin-paclitaxel [Palma D, 2012]. This meta-analysis revealed that predictors of fatal pneumonitis were use of daily dose fractions exceeding 2 Gy, the V~20~ parameter, and lower-lobe tumor locations. 2. Cardiac doses exceeding 5 Gy correlated with poorer survival in RTOG 0617 trial, and future studies must pay more attention to cardiac toxicity. Following concurrent CT-RT, cardiac doses of 45 Gy or higher correlated with myocardial hypoperfusion [Gayed 2006], and a higher risk of ischemic heart disease and cardiac dysfunction was seen patients undergoing CT-RT for left-sided lung cancer [Hardy D, 2010]. 3. After radiation doses of 74 Gy and 86 Gy delivered after chemotherapy, the incidence of bronchial stenosis was 4 and 25%, respectively, (Millar KL, 2005]. This complication may increase in incidence if higher doses of radiation are administered concurrent with chemotherapy. 4. When evaluating the results dose escalation studies, one must also consider the impact of tumor volume on survival in stage III NSCLC. For example, planning target volumes (PTV) correlated significantly with overall survival, with PTV values <350cc, 350-700cc, >700-1050cc and >1050cc having corresponding median overall survivals of 35.6 months (95% CI=0-71.3), 24.2 months (95% CI=18.3-30.2), 15.7 months (95% CI=10.5-20.9) and 10.3 months (95% CI=6.0-14.7), respectively [van Reij E, 2013]. Survival for tumors measuring 350-700cc differed significantly from the groups 700-1050 and >1050 cc (p=0.039 and p=0.002, respectively). In addition, larger tumor volumes are also associated with an increased risk of dying in the first 18 months, independently of T and N stage, but not beyond that time point [Ball D, 2012]. The latter finding suggests that a better characterization of tumor characteristics that correlate with radiocurability should be a research priority. 5. In RTOG 0617, the dose of 74 Gy arm was delivered in 7.5 weeks. A recent meta-analysis suggested that the accelerated delivery of radiation, i.e. delivering a higher higher dose in a shorter overall time, led to superior tumor control [Mauguen 2013]. Such accelerated delivery can be delivered using multiple fractions per day, or larger doses/fraction, both approaches which can increase the toxicity of concurrent CT-RT. For some subgroups of stage III-N2 disease, e.g. large volume tumors, where the benefits of concurrent CT-RT are modest [Wiersma T, 2013], sequential delivery may be a less toxic manner for investigating dose escalation. 6. Tumor volumes not infrequently regress during a course of CT-RT, and may also shift in position during the course of treatment [Lim G, 2011]. Volumetric imaging on modern treatment machines can allow for such changes to be detected, and treatment plans be adapted when required. Many recent clinical studies have not studied this aspect of treatment delivery. With dose escalation in fractions of 2 Gy falling out of favor, some groups are exploring the ‘dose painting’ hypothesis [Bentzen S, 2011]. Briefly, the former assumes that local recurrences arise from relatively radiation-resistant sub-regions; that reliable spatio-temporal mapping of such sub-regions is possible (e.g. using FDG-PET); that boosting radiation delivery to these egions improves local tumor control with acceptable side effects. Others groups are exploring the use of protons to improve local control in stage III NSCLC. A critical evaluation of the results emerging from ongoing trials is required, even if early outcomes from pioneering centers appear promising. Quality assurance data from radiotherapy trials, in which a broad range of institutions participate, reveals that a failure to comply with protocol requirements is associated lead to decreased survival, poorer local control and potentially increased toxicity [Weber DC, 2012].

Abstract
For the past decade, the standard first-line therapy for stage IV non-small-cell lung cancer (NSCLC) patients with adequate ECOG performance status (<2) has been platinum-based doublet chemotherapy with a reported median overall survival (OS) of 8–10 months, which has slightly improved to 12 months with the addition of bevacizumab. More recently, tyrosine kinase inhibitors of epidermal growth factor receptor, gefitinib and erlotinib, and anaplastic lymphoma kinase, crizotinib, have been shown to provide longer progression-free survival (PFS) and fewer side effects as first-line therapy, compared with chemotherapy in patients with certain histological subtypes and activating mutations. However, despite therapeutic developments, palliative treatment is standard for many stage IV NSCLC patients and the prognosis remains poor, with relative 5-year survival rates ≤4%, compared with an average of approximately 17% for all patients with NSCLC. Oligometastatic NSCLC is a subgroup of stage IV NSCLC with a limited number/number of sites of metastatic disease, usually 1–5 metastatic lesions. While only a small subset of patients present with such limited metastases (brain metastasis <50%, adrenal gland metastasis ~7%), they may be suitable for, and achieve long-term survival following, eradication of both the primary and metastatic tumours. For example, reported 5-year survival rates for NSCLC patients with solitary brain or adrenal metastasis who underwent surgical removal of both primary lung and metastatic disease ranged from 7–24% and 25–34%, respectively, which is higher than the average of ≤4% for all stage IV NSCLC patients. In addition to having an adequate performance status, there are additional key prognostic factors for identifying oligometastatic NSCLC patients likely to benefit from aggressive therapy; staging of the metastatic lesions, lymph node involvement and status of the primary lung tumour. A lower number of metastatic sites is predictive of good clinical outcome, with >2 metastatic sites associated with shorter PFS. The organ involved in metastatic spread may also impact clinical outcome as, for instance, patients with brain and adrenal gland metastases are more suitable for surgical intervention compared with bone or liver. Given the importance of number and site of metastatic lesions, positron emission tomography and magnetic resonance imaging are vital for accurate staging of oligometastatic disease. An association between N0 disease and increased long-term survival compared with N1/N2 disease has been observed. For example, following surgical treatment of one cohort of patients with solitary NSCLC adrenal gland metastasis, those with N2 disease had 0% median 5-year survival rate, compared with 52% for N0/N1 patients (P=0.001). Pathologic staging of lymph nodes is therefore critical. The status of the primary lung tumour also impacts clinical outcome, as the primary tumour must itself be resectable. Stage III primary disease is associated with worse survival outcome than stage I or II in patients undergoing surgical excision of brain and adrenal gland metastases, with a reported 5-year survival rate of 0% for stage III, compared with 63% and 77% for stage I and II, respectively. Similarly, patients with oligometastatic disease and a controlled primary site, or ‘oligorecurrance’, have better prognosis than those with an uncontrolled primary tumour. Histological subtype of NSCLC may also impact prognosis in oligometastatic NSCLC, with adenocarcinoma associated with the most favourable outcomes. Although an optimal disease-free interval (DFI) to define synchronous and metachronous disease has not been agreed upon, synchronous oligometastasis is generally associated with poorer survival outcomes. Patients receiving adrenalectomy for oligometastatic NSCLC with DFI ≤6 months had median OS of 12 months versus 31 months for DFI >6 months. Similar results were reported for isolated brain metastasis. Oligometastatic NSCLC is a stage IV cancer and as a guiding principle therapy should be simple and minimally invasive. Furthermore, given the diffuse nature of this disease state, management should ideally involve a multidisciplinary team as the primary and metastatic cancer must be treated, requiring a wide range of expertise. Surgery and radiosurgery (stereotactic radiosurgery [SRS] in the brain and stereotactic body radiotherapy [SBRT] in extracranial sites) are the two most common methods of tumour ablation. In general, radiosurgery is less invasive than surgery and is therefore useful for patients ineligible for surgery. Additionally, evidence suggests SBRT may be more applicable to limited extracranial metastasis to multiple organs compared with surgery. The treatment of limited brain metastases has been evaluated through several randomised clinical trials. Surgical resection plus whole brain radiotherapy (WBRT) of oligometastasis in the brain led to significantly prolonged OS compared with WBRT alone – as high as 40 weeks in one trial, compared with 15 weeks for WBRT (P<0.01). Further, a study of SRS with WBRT in patients with 1–4 brain metastases showed improved survival outcomes for patients with solitary brain metastases and improved clinical outcomes for patients with >1 site of metastatic disease, compared with WBRT alone. Overall, SRS plus WBRT is considered an acceptable choice for those patients with limited brain metastasis who are not suitable for surgery. Adrenalectomy is the standard of care for adrenal gland metastases, with OS ranging from 11–31 months. There have been no randomised trials of the use of SBRT in the adrenal gland setting, although one retrospective study reported OS of 23 months for isolated adrenal metastases treated with SBRT. Further, a recent review article of extracranial oligometastatic disease from various primary cancers suggests that survival following SBRT compares favourably to surgery. One of the key challenges for the management of oligometastatic NSCLC is continuing to improve diagnosis and prognostic factors to more accurately identify those patients with oligometastatic NSCLC who are likely to benefit from ablative treatment, as well as distinguish truly isolated metastatic disease from early-stage metastasis that later develops into widely disseminated disease. Continuing advances in imaging technology will play a role in refining diagnosis and prognosis. From a treatment perspective, challenges include cognitive problems associated with WBRT and the current lack of randomised trial data comparing surgery, radiosurgery and standard of care. To this end, there are several ongoing clinical trials, such as the randomized SABR-COMET study, which compares palliative radiation with stereotactic ablative radiation for ≤3 metastatic tumours to any single organ.

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Abstract
As the prognosis of cancer patients gets better, more individuals are at risk to develop a local recurrence or a new primary tumour in previously irradiated organs. New radiation techniques, better imaging and more knowledge of dose volume relationships have fuelled re-irradiation to high doses. The aim of high-dose re-irradiation is to give the patient a chance for long-term disease-free survival and even cure. Re-irradiation is only expected to be beneficial when a high-dose can be delivered. In order to do this safely, knowledge about the dose-response relation for the organs at risk (OAR) is needed. Here, the first problem starts. Even in patients that have never been irradiated, in-depth individual knowledge about dose-response relations for all AORs is lacking. As is clear from e.g. the QUANTEC reviews, even for widely used parameters such as the mean lung dose (MLD) or the V20, the accuracy of the model to predict subsequent development of radiation pneumonitis is very moderate, with AUC values under the ROC curve of 0.60-0.65. For other organs like the heart, current models score even worse. Functional, imaging and genetic parameters are an area of intensive research, but not usable in standard practice yet. In case of re-irradiation, only limited data coming from retrospective studies with small numbers at risk for late complications are available. Keeping all caveats in mind, it seems that the aorta can tolerate cumulative physical doses of up to 120 Gy (given in 2 Gy fractions), above which dose level lethal bleeding may occur (Evans et al. Radiother Oncol 2013). In other retrospective series, grade 4-5 stenosis, fistula and bleeding occurred only when re-irradiation included central structures (Peulen et al. Radiother Oncol 2011). Even when stereotactic body radiotherapy (SBRT) is used for re-irradiation, the risk for radiation pneumonitis seems to be more than 20 % with cumulative V20 values over 30 % (Liu et al. Int J Radiat Oncol Biol Phys 2012). This points to the importance to obtain composite plans, which should include non-rigid deformation. Whether alpha/beta values that are used for primary irradiation are safe in the re-irradiation setting is not investigated thoroughly, as is the repair of OARs over time, the influence of co-morbidities, medication and anti-cancer drugs. Nevertheless, one prospective ( Wu et al. Int J Radiat Oncol Biol Phys 2003) and several retrospective studies (Okamoto et al. Int J Radiat Oncol Biol Phys 2002; Kruser et al. Am J Clin Oncol 2013; Tada et al. Int J Clin Oncol 2005; Ebara et al. Anticancer Res 2007; Peulen et al. Radiother Oncol 2011; Meijneke et al. Radiother Oncol 2013) have been published. In most series, the median radiation dose of the first treatment was about 60 Gy and that of the second 40-50 Gy in 4-5 fractions in case of re-treatment with SBRT or 60 Gy in 2 Gy daily fractions. The median interval between the first treatment and the second was in most studies between 12 and 24 months. All series indicate that re-irradiation is “feasible”, with after a median follow-up of about one year approximately 25 % of the patients having grade 3 or more toxicities. It comes as no surprise that the median overall survival after re-irradiation is low, ranging from 6-15 months. Because apart from one prospective trial with 23 patients only small, retrospective studies have been presented, it is not clear what the prognostic factors for survival are. Thorough staging, a good performance status, a small GTV and the possibility to give a high dose of radiotherapy seem obvious. In view of all uncertainties and the observation a significant proportion of patients with important toxicity, the time is right to launch prospective studies, randomised or not. These studies should focus on prognostic factors both for survival and toxicity, in order to ultimately be able to identify a subgroup of patients with truly curable disease or in which systemic treatment can be delayed significantly without undue toxicity. In the meantime, an individual patient should clearly understand the limitations and doubts of re-irradiation with regard to survival and toxicity. In case of a limited recurrence in an otherwise good performance patient, SBRT is reasonable if central structures can be avoided and 2 Gy per day, 5 days per week in other cases. A biological dose of at least 60 Gy should be given, taking into account the OARs. Probably the most suited patients are those with a long delay, possibly of more than one year, between the first irradiation and the recurrence.

Abstract

Abstract
The Driving Force of Social Networking According to Facebook executives, the social network reports 1.06 billion monthly active users. This number has been steadily increasing with a 25% increase in monthly users from last year and a rise of 28% in daily users. Now that we know the numbers what is happening in the world of patients. Though the premise exists that Facebook is strictly for social media networking, I wouldn’t hesitate to guess that patients, especially those who are home bound, spend an enormous amount of time on the web. Patients with rare diseases, in particular, have found Facebook to be a useful tool in finding others facing similar circumstances. PatientsLikeMe.com, launched in 2004, uses a number of tools to collect data and derives a hefty profit from selling this data to pharmaceutical companies as well as research institutions. It reports over 200K users on the site covering 1800 diseases. It uses sophisticated questionnaires to gather data about its users. Another active social media network, 23andme.com promotes the selling of an at-home saliva kit to map out genetic codes. They provide users with interactive tools meant “to shed new light on your distant ancestors, your close family and most of all, yourself.” In 2013, this company spent up to $5 million in advertising, further demonstrating that healthcare on the web is a lucrative field. Law firms representing mesothelioma patients spent over $50 million in goggle keyword advertising in 2012, making mesothelioma the most expensive word in Google advertising. Many of the larger firms representing victims of asbestos have now also launched Facebook pages and groups. These are usually marketed as patient support and advocacy sites providing patients with support and referrals to both medical and legal professionals. To the unsuspecting patient, these sites appear to be either VA sponsored or true advocacy sites which could not be further from the truth. Do you really want your patients to receive medical advice and referrals from representatives of legal entities or other for-profit operations with secondary motives? Nurses are the most trusted professionals valued by the public according to numerous surveys. Who is better equipped to engage with patients in social media and help them to understand the “rules of engagement”? The median age for the diagnosis of lung cancer is 72 and for mesothelioma 70. People in their 70s are less likely to be knowledgeable about the risks vs. the benefits of engaging in social media networking. We are all too familiar with the patient or family members who present to the office armed with paperwork obtained during web searches. Some of the information is valuable, but much is not applicable to their current situation and some is entirely misleading. An inordinate amount of time is consumed by those affected by the disease and the practitioner sorting through and commenting on relevancy of such information. I would suggest that if a nurse could guide their navigation of the web and provide accurate medical information and accurate interpretation of this information, the patient and their representatives as well as the provider could have a more focused discussion. Social media provides a unique opportunity to capture large numbers of patients and their advocates which can be used as a tool for both education and support. It would be the role of the nurse to explain the workings of the platform and to set guidelines to assist in protecting privacy to the degree possible when engaging on these sites. Patients need to understand the potential consequences of engaging in online health-related discussions and must be willing to accept the risks associated with membership in a group. It is fairly common for potential employers to peruse Facebook pages to gather additional background information on future employees. It could certainly be feasible that health insurance companies, especially if a dispute arises, might also turn to social media for information. Patients should be encouraged to read the privacy policy on these sites and an open dialogue about privacy within the group should be an ongoing. Patients themselves are the driving force in this healthcare-related online movement. As a result, hundreds of groups run by patients are available for others to join and this is where this trend can become problematic. Patients with the loudest voice on Facebook, or perhaps the miracle responders, can sway a captive patient group into potential risky decisions with the best of intentions. Groups starting off as support groups can quickly and unexpectedly have their conversations shift toward sharing of medical information and practice. As nurses, we know that patients need to be fully informed without bias to be able to practice good decision-making. Nurse-led groups can promote support and can help to guide the conversation to avoid misinformation or “cyber opinion bullying” by the strongest patient leader. Nurses can designate a peer group leader but promote their role within the group as the medical monitor. This provides an opportunity to gently correct misinformation and present new medical information to the group thus maintaining professionalism and the integrity of the group. Patients with rare diseases are often isolated and local support groups may not be applicable to their particular situation. Patients in these groups often express relief that they are able to connect with others in similar circumstances. However, connecting with others in this manner can be bittersweet. The group can celebrate the victories but will also mourn setbacks and death of group members. Having a nursing professional in the group provides access to a trained individual who can assist in emotional healing as well as recognize and refer if group members need one on one counseling. In cancer, less than 10% of all patients enroll in clinical trials. As nurses we can educate patients about clinical trials and promote participation in such trials. Cancer patients are seeking knowledge on the web, and as educators, it is our role to see that this need is met. T

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Abstract
Malignant Pleural Mesothelioma is a global challenge for heath professionals, and the role of surgery is key to that challenge. Surgery has a palliative function and a curative function. The palliative function is to drain the fluid, take a biopsy, optimise lung re-expansion, and prevent fluid recurrence by pleurodesis. Video assisted thoracoscopy (VAT) is the palliative operation of choice because it is less painful, has a reduced hospital stay, and the surgeon can assess the chest cavity for suitability for more aggressive treatment. An important predictor for a successful VAT pleurodesis is lung re-expansion after initial pleural drainage assessed by radiology and a patient response of “I can breath now.” If pleurodesis is ineffective and the fluid recurs, or if lung entrapment prevents lung re-expansion, then open surgery via thoracotomy with partial or subtotal pleurectomy / decortication should be considered, providing the patient is medically fit and has a reasonable life expectancy. Partial pleurectomy /decortication is more invasive, has an increased potential for prolonged air-leak, is more painful and has a longer recovery period, however the patient may benefit from an improved quality of life, living without symptoms related to lung entrapment. Brancatisano (1991) reported our experience of 50 patients having partial pleurectomy / decortication. The median survival was 16 months with a range of 3 to 54 months and 21% of patients survived more than two years. The curative role is less defined. Surgical resection is the curative treatment option for most solid malignant tumours and this ideal underpins the practice of surgeons treating MPM. Cytoreductive surgery, to reduce the burden of disease and prolong disease free living by complete macroscopic surgical resection is offered to patients with early disease in some centers. Here lies the key challenge. There are differing operative techniques aiming for the same outcome: extrapleural pneumonectomy, EPP, and lung sparing pleurectomy/decortication, EPD EPP, offered since the 1970s, involves complete resection en bloc of the lung, parietal pleura, ipsilateral pericardium, and ipsilateral hemi-diaphragm, along with complete excision of thoracic lymph nodes. Defects of the pericardium and hemi-diaphragm are repaired with Gortex mesh to prevent cardiac and visceral herniation. An early publication reported an unacceptable morbidity and mortality of 45% and 31%respecively (Butchart, 1976). David Sugarbaker, determined to improve patient survival, continued offering EPP but high recurrence rates proved surgery alone provided little benefit to survival. With persistence, his team offered EPP in combination with chemotherapy (prior to pemetrexed) and radiotherapy. In 1991 Sugarbaker reported survival rates of 70% at one year and 48% at two years. Morbidity and mortality rates were 19% and 6% respectively. This multimodality treatment required surgery to reduce tumour bulk, while chemotherapy and radiotherapy treated micro-metastatic disease. In 1996, Sugarbaker again reported similar results but added that epithelial cell types had better survival rates compared to sarcomatoid or mixed histology tumours. Other centres around the world reported individual surgical series each contributing to a collection of experiences. Weder (2007) reported on 45 EPP trimodality patients and found epithelial cell type had better survival. Cao (2010), attempted to evaluate the safety and efficacy of EPP found an overall survival of 13 – 23.9 months and concluded/confirmed that selected patients might benefit from EPP especially when combined with neoadjuvant chemo and adjuvant radiotherapy. Controversy about the ability of EPP to affect a cure or contribute to improved survival was to be sorted by the UK Mesothelioma and Radical Surgery feasibility study known as the MARS trial. This randomised control trial concluded that EPP offers no benefit and possibly harms patients. Surgeons, skilled at performing EPP and who had reported their results vehemently opposed this conclusion. The only centre in Australia offering trimodality therapy reported 70 patients having EPP between 1994 and 2008, having a median survival of 20 months, and morbidity and mortality of 37% and 5.7% respectively (Yan, 2009). Pleurectomy / decortication or P/D was the other preferred operation as some surgeons questioned the morbidity and mortality of EPP. Valarie Rusch (1993) pioneered P/D in order remove all visible and palpable tumours and achieve macroscopic complete resection. Other surgeons varied this procedure making comparing results difficult so specific terminology was used to describe 3 approaches. 1) Extended or radical pleurectomy/decortication (EPD); parietal and visceral pleura is resected along WITH diaphragm and pericardium. 2) Pleurectomy/decortication (PD); parietal and visceral pleura is resected WITHOUT diaphragm and pericardium. 3) Partial pleurectomy/visceral decortication as a palliative procedure. Individual cancer centers have reported case series. Flores (2008) compared EPP to pleurectomy / decortication. Nerangi-Miandoab (2008) reported epithelial cell type was a predictor of survival in patients having pleurectomy / decortication compared to no surgery. Nakas (2008) concluded patients not suitable for EPP should be offered radical P/D. Zahid (2011) found P/D may improve survival but at the expense of increased morbidity and is best offered to patients enrolled in prospective trials. Global differences related to the role of surgery in cytoreductive therapy relate to what radical surgical procedure provides the best chance of extended disease free survival. Is it EPP, lung sparing EPD, or P/D? What is certain is that EPP and EPD should be offered as part of trimodality therapy. Furthermore, the procedure must be performed by an experienced surgeon, and supported by a team with proven expertise and experience to care for these patients. Rusch (2012) reminds us that the role of surgery in the management of MPM remains controversial but it also remains a treatment option because of the limited benefits of radiotherapy and chemotherapy. Surgery is offered either as a palliative procedure or with curative intent. There is little need for debate about the palliative option but debate about curative intent continues. Finally, while global differences are important, what is learnt from collective experiences is more important. There is an urgent need to identify patients with favourable prognostic factors, suitable for cytoreductive therapy. We need to provide support, hopeful encouragement, and equitable access to multi modality treatment because there is a growing number of well living long-term survivors.

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Background
Measurement of volume doubling time (VDT) of small pulmonary nodules is clinically useful for discrimination between benign and malignant etiology, because this discrimination capability based only on the initial CT is limited. Recent advancement of CT technology enabled direct 3D measurement of volume of pulmonary nodules using commercially available software and enabled VDT measurement with these data. However, there are only a few reports in which accuracy of the 3D method was assessed with comparing the 3D method with the traditional 2D method. Here, we compared intra- and inter-observer variability (OV) to assess the accuracy of these two methods and compared VDT of pulmonary nodules in 2D-method with those in 3D-method. We also discussed the clinical relevance of our results.

Methods
Forty-two pulmonary nodules of 3 cm or smaller (CT type, 11 of ground-glass opacity, 15 of mixed type, and 16 of solid type) of peripheral lung cancer (37 of adenocarcinoma, 4 squamous cell carcinoma, and one small cell carcinoma) in 41 patients (mean age±SD, 67±10 years; 25 men and 16 women) who underwent 16-slice MDCT with 1-mm collimation twice (mean interval, 369 days, range 60-1119 days) before surgical resection during June 2006 and December 2008 were included in this study. Five examiners independently calculated VDT by 2D (nodule diameter measurement) and 3D methods (nodule volume measurement using in-house programmed software) with the use of Schwaltz equation and repeated the measurements one month after. Thus, intra- and inter-OV in VDT for the two methods was compared using 95% confidence intervals (CI) in Blant-Altman plots, and VDT calculated with the two methods was compared in each examiner. In evaluating inter-OV, averaged values of the two measurements in each examiner were used for analysis. A p of less than .05 was considered to be significant.

Results
As for inter-OV (n=10), 95% CI (mean±SD in days, 398±123) for 3D method was significantly greater than that (231±87) for 2D method (p=0.005). Regarding intra-OV (n=5), 95% CI (291±199) for 3D method tended to be greater than that (195±36) for 2D method (p=0.388). VDT calculated with 3D method was significantly greater than that calculated with 2D method in all of the 5 examiners (all p of <0.05).

Conclusion
Inter-OV in VDT measurement was significantly greater in 3D method than in 2D method and VDT calculated with 3D method was greater than that calculated with 2D method. Therefore, in calculating VDT of pulmonary nodules, the same examiner should evaluate with the same method.

Background
PET is a useful tool in the diagnostic workup of lung cancer. However, its role in lung cancer screening with low dose Computed Tomography (CT), in which small sized nodules are detected, is still to be determined. We present final PET results from the 5 year (2005-2010) randomized Danish Lung Cancer Screening Trial (DLCST).

Methods
DLCST participants with indeterminate nodules mostly between 5 and 15 mm were referred for a 3-month rescan. Between the initial scan and the 3-month rescan, participants were also referred for a PET scan. Uptake on PET was categorized as most likely benign or malignant on a scale from I to IV). Receiver operating characteristic (ROC) analyses were used to determine the sensitivity and specificity of PET. Resected nodules and indolent nodules (i.e. stable for at least 2 years) were included, and the latter was categorized as benign. Nodules were only included once in the study, thus repeat PET scans were excluded.

Results
A total of 90 nodules were included, 50% men, mean age 67 years (58-79), prevalence of lung cancer was 38% (35/90). Mean follow-up time for benign non-resected nodules was approx. 2.8 years in screening. Clinical follow-up in central digital medical logs was done for all participants in 2013. The sensitivity and specificity of PET was 66% and 91%, respectively, with cut-off points for malignancy at PET>II (i.e. categorized as possibly or probably malignant at PET). The positive predictive value was 82% (23/28) and negative predictive value was 81% (50/62). 12 PET results were false negative, and of these 75% (9/12) were either ground glass nodules or partly solid nodules. Figure 1

Conclusion
PET is a valuable tool in lung cancer screening; our results show fair sensitivity and high specificity in a trial with long time follow-up of benign nodules. False negative PET results were found in non-solid nodules. We recommend PET as an integrated part of future lung cancer screening programs.

Background
The objective of this study was to develop a pretreatment prognostic model based on metabolic imaging biomarkers that could be used to predict overall survival (OS) in patients with stage I non–small cell lung cancer (NSCLC).

Methods
We evaluated 198 patients with pathologic stage I NSCLC who underwent pretreatment FDG PET/CT. Metabolic imaging biomarkers included maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and coefficient of variation (COV) for primary tumors. SUV is a semiquantitative index of metabolic activity. TLG is a volumetric measurement of tumor glycolytic activity. COV is an index of tumor uptake heterogeneity. The prognostic significance of clinical variables and imaging biomarkers (age, sex, histologic cell type, tumor size, SUVmax, TLG, COV) was assessed by Cox proportional hazards regression model. Statistically significant clinical variables and imaging biomarkers in the multivariable analysis were used to construct a prognostic model for predicting survival. The predictive accuracy of the prognostic model was evaluated by Harrell's concordance index (C-index).

Results
Median follow-up for surviving patients was 7.5 years with a range of 5.2 to 9.9. At the time of analysis, 52 (26.3%) patients had died. Age (HR = 1.05 for 1-year increase, P = 0.007), histologic cell type (HR = 0.54 for adenocarcinoma, P = 0.027), SUVmax (HR = 1.08 for 1-unit increase, P = 0.002), and TLG (HR = 1.23 for a doubling of TLG, P = 0.021) were significantly associated with OS by univariable analysis, whereas only age (HR = 1.07 for 1-year increase, P = 0.005) and SUVmax (HR = 1.04 for 1-unit increase, P = 0.012) were significantly associated with OS by multivariable analysis. The final prognostic model included age as a clinical variable and SUVmax as a metabolic imaging biomarker to predict OS. The predictive performance of the prognostic model for OS was not improved by addition of TLG or COV. The C-index was 0.694 for the final model with age and SUVmax. Kaplan-Meier survival curves stratified by risk score showed high-risk group of patients (n = 58, SUVmax > 12 and age > 60) and low-risk group of patients (n = 48, SUVmax ≤ 12 and age ≤ 60). Figure 1

Conclusion
A new prognostic model based on pretreatment metabolic imaging may have potential clinical utility for risk stratification of stage I NSCLC patients.

Background
During the past decade many studies have used FDG-PET/CT for response evaluation to therapy, both in NSCLC and several other cancer forms. A preferential method for evaluation has not been established as of yet. Two main approaches tend to single out: A visually based model as described by Mc Manus et al in 2003 and semi-quantitative approaches, like the recently proposed PERCIST 1.0 2009, by R. Wahl et al. Few studies have evaluated the interobserver variability when using sequential PET/CT scans for response evaluation, and comparison of qualitative- and semi quantitative approaches are also scarce. The aim of this study is to determine which method will provide the more robust evaluation of response when using FDG-PET/CT, the qualitative approach or the SUV based semi quantitative approach prior to the introduction of routine early response evaluation in NSCLC.

Methods
FDG-PET/CT scans at baseline and after 2 cycles of chemotherapy from 35 patients with locally advanced NSCLC were analysed by 8 different readers using two different methods: PERCIST 1.0 and the qualitative McManus approach. Both methods result in allocating patients into one of four response categories. Observers were given short written presentations outlying the criteria for evaluation by the two methods. The observers represent a wide range in experience with PET evaluation, only half had experience in response evaluation in NSCLC, but most were experienced in similar evaluation in lymphoma patients.

Results
When using PERCIST 1.0, the agreement between observers in determining the percentage change in SULpeak was “almost perfect” with ICC=0.959 similar ICC values were found looking at SUL peak at baseline and follow up scans. There was strong agreement amongst readers allocating patients to the different response categories with Fleiss kappa of 0.761 (0.714-0.808). In 22 of the 35 patients there was complete agreement. When using the qualitative method (A.M. McManus), agreement was lower, down to moderate agreement, with Fleiss kappa of 0.596 (0.554-0.639). And complete agreement was observed in only 10 of the 25 patients. Using chi squared the difference is statistically significant (p < 0.005). No difference was found between experienced and non-experienced observers.

Conclusion
In spite of a wide range of experience among 8 readers receiving minimal introduction to the two methods they were to use, we found rather high kappa values, for both methods compared to its nearest competitor: Size change in CT images, known to be very observer dependent. The more objective, semi-quantitative method showed substantially higher agreement than the more subjective method. We suspect that a more detailed introduction into the methods would have improved the kappa values even further, but believe that our method is more likely to provide an introduction similar to the one you receive when introduced as a new physician at the department. Perhaps then the agreement reflects the long-term agreement.

Abstract not provided

Background
Emerging evidences suggests that diffusion-weighted magnetic resonance imaging (DW MRI) at 1.5-T could be useful for tumor detection, together with N and M staging in patients with lung cancer, especially non-small cell lung cancer (NSCLC), with accuracy as good as, or even better than, that of FDG PET/CT most recently. This investigation prospectively examined whether DW MRI at 3.0-T might be as useful as FDG PET/CT for detection of pulmonary malignant tumors.

Methods
This study was approved by the institutional review board, and written informed consent was obtained from all patients. DW MRI and FDG PET/CT were performed before therapy in 113 patients with pulmonary nodules, including lung cancer, lung metastases, and benign lesions, diagnosed by pathological examination. Apparent diffusion coefficient (ADC), maximal standardized uptake value (SUV~max~), and five-point visual scoring were assessed. Immunohistochemical staining for Ki-67 was performed in 36 patients with lung cancer, and Ki-67 score was evaluated. Receiver operating characteristic (ROC) curve analysis was used to determine feasible threshold values. Diagnostic capabilities for detection of pulmonary malignant tumors were compared with the McNemar test on a per-patient basis, and correlation between malignant degree of lung cancer and ADC or SUV~max~ was analyzed by Spearman rank test.

Results
As for diagnostic capability, area under ROC curve (A~z~) for ADC (0.91) were significantly higher than that for SUV~max~ (0.78, P < 0.05), and A~z~ value for DW MRI (0.94) were not significantly different from that for FDG PET/CT (0.92, P > 0.05). For quantitative assessment, specificity and accuracy of ADC (91.7%, 92.9%) proved to be significantly higher than those of SUV~max~ (66.7%, 77.9%, P < 0.05), although sensitivity of ADC (93.5%) was not significantly different from that of SUV~max~ (83.1%, P > 0.05). When feasible threshold values were used to assess qualitatively, sensitivity, specificity, and accuracy of DW MRI (96.1%, 83.3%, 92.0%) were also not significantly different from that of FDG PET/CT (88.3%, 83.3%, 86.7%, P > 0.05). Significant correlation was found between Ki-67 score and ADC (Spearman coefficient r = -0.66, P < 0.05), as well as ADC and SUV~max~ (r = -0.37, P < 0.05). On the contrary, Spearman coefficient was -0.11 between Ki-67 score and SUV~max~ (P > 0.05).

Conclusion
In conclusion, quantitative and qualitative assessments for detection of pulmonary malignant tumors obtained with DW MRI at 3.0-T are as useful as, even superior to, those obtained with FDG PET/CT. Furthermore, another significant outcome of this study was that ADC in DW MRI at 3.0-T can also play a role in prediction for malignant degree of lung cancer in particular, but SUV~max~ did not in FDG PET/CT.

Background
To compare the diagnostic efficacies of diffusion-weighted magnetic resonance imaging (DWI) and F-18 fluorodeoxyglucose positron emission tomography (PET) findings for the preoperative prediction of mediastinal nodal metastasis in stage N2 disease of non–small cell lung cancer (NSCLC).

Methods
The study included 68 patients (42 men and 26 women; mean age, 62 years) with a supicious stage N2 due to NSCLC. In all patients, DWI (using a sigle-shot echo-planar sequence with diffusion factor of 0-600 s/mm² at 1.5 Tesla) and PET were performed before surgery. In DWI, a patient was regarded to have stage N2 disease when an ipsilateral mediastinal lymph node showed apparent diffusion coefficent (ADC) value of ≤0.98 s/mm², regardless of nodal size. A node was considered as positive for malignancy, if it showed standardized uptake value (SUV) of 3 or higher by PET. Both DWI and PET images were prospectively evaluated for malignancy on a per-node basis by two observers. Histopathologic results served as the reference standard. N2 disease was decided by using the American Joint Committee on Cancer staging system. The results were compared between the two modalities and statistically significant differences in nodal metastasis between DWI and PET were determined with p<.05 obtained by using the McNemar test or with a generalized estimating equation.

Results
Nodes were positive for malignancy in 36 (32%) of 114 nodal stations and 22 (32%) of 68 patients. The N2 staging was correctly diagnosed in 56 (82%) and 52 (76%) patients by DWI and PET (p=.09), respectively. For the depiction of malignant nodes, DWI and PET showed sensitivities of 78% (31 of 40 nodal groups) and 78% (28 of 36), specificities of 93% (69 of 74) and 90% (70 of 78), positive predictive values of 86% (31 of 36) and 78% (28 of 36), negative predictive values of 88% (69 of 78) and 90% (70 of 78) and accuracies of 88% (100 of 104) and 86% (91 of 104), respectively (p=.23, p<.05, p<.01, p=.08, and p=.12). There were nine false-positive interpretations by DWI, compared with eight by PET. Eight false-negative assessments were present on PET images, but only five false-negative results were found in DWI. .Figure 1

Conclusion
DWI has a higher specificity for N2 staging of NSCLC compared with PET and has the potential to be a reliable alternative imaging method with an advantage of radiation-free imaging for the preoperative staging of mediastinal lymph nodes in patients with NSCLC.

Abstract not provided