Virtual Library

Background
In order to improve prognosis and quality of lung cancer care the Danish Lung Cancer Group has developed a strategy consisting of national clinical guidelines and a clinical quality and research database. In 1998 the first edition of guidelines was published and a registry was opened for registrations in the year 2000. This abstract describes the methods used and the result obtained through the collaborative work and discusses how to improve the quality of lung cancer care through the development and monitoring of indicators.

Methods
A wide range of indicators was established, validated and monitored. By registration of all lung cancer patients since the year 2000, more than 40.000 patients have been included in the database. Results are reported periodically and submitted to formal auditing on an annual basis.

Results
Improvements in all outcome indicators are documented and statistical significant. Thus the one year overall survival has between 2003 and 2011increased from 36.6 % to 42.7 %; the 2 year survival from 19.8 % to 24.3 % and the 5 year survival from 9.8 % to 12.1 %. 5 year survival after surgery has increased from 39.5 % to 48.1 %. Improvements in waiting times, accordance between cTNM and pTNM and in resection rates are documented.

Conclusion
The Danish experience shows that a national quality management system including national guidelines, a database with a high degree of data quality, frequent reports, audit and commitment from all stakeholders can contribute to improve clinical practice, improve core results and reduce regional / geographic differences.

Background
One goal of the current French National Cancer Plan is to reduce health inequities in cancer control. In this study, an underprivileged population was investigated to analyze exposure to lung cancer risk factors and health care access in order to highlight ways to improve lung cancer control in that population.

Methods
Within the nationwide observational study EDIFICE 3, conducted by phone interviews among a representative sample of 1603 subjects aged between 40 and 75 years old, we used the “EPICES” validated questionnaire to examine the association of underserved status with lung cancer risk factors, beliefs, and health care access.

Results
Based on the EPICES score, underserved subjects represented 33% of the sample. These subjects subjectively perceived a higher risk of cancer compared to subjects in the served population (21% vs. 14% respectively, p<0.01). Among people with cancer, underserved subjects have a higher rate of lung cancer (10% of cancers vs. 1%, p<0.05). They also have more cancer risk factors: a high BMI (26.0 vs. 24.8, p<0.01), are active smokers (38% vs. 23%, p<0.01) with a higher consumption of cigarettes (16.0 cigarettes/day vs. 10.1, p<0.01) and for a longer period (29.4 years vs. 26.3, p<0.01), and also practice less sport (42% vs. 77%, p<0.01). They have more comorbidities: on average (2.2 vs. 1.8, p<0.01), at least one (76% vs. 65%, p<0.01), hypertension (24% vs. 19%, p<0.05), cardiovascular disease (13% vs. 9%, p<0.05) and respiratory disease (13% vs. 7%, p<0.01). Access to healthcare is not an issue (consultations with a general practitioner are more frequent for the underserved group: 5.4 vs. 3.7 per year, p<0.01). They trust the national health system less (an average score from 1 to 10; 6.0 vs. 6.3, p <0.05). However, 85% of underserved subjects think that lung cancer can be efficiently screened vs. 78% of the served population (p<0.01).

Conclusion
In order to reduce inequities in lung cancer control, the effort of upstream interventions should be focused on prevention, as healthcare access does not discriminate. Underserved subjects have a high level of trust in lung cancer screening but a riskier behavior in terms of smoking. This constitutes new targets for specific communication campaigns and Health authorities’ interventions.

Background
Lung cancer results from the combined effects of smoking exposure and genetic predisposition. Recent studies have shown that susceptibility to chronic obstructive pulmonary disease (COPD) is also relevant to a predisposition to lung cancer. The latter may be mediated in part through exaggerated systemic inflammation secondary to smoking exposure and the innate response to smoking in genetically susceptible people. Recently a large population based study reported that statin therapy was associated with a reduction in mortality from cancer (Nielsen et al. Statin Use and Reduced Cancer-Related Mortality, NEJM 2012; 367: 1792-1802). The aim of this study was to examine the cancer specific effect of statins on mortality.

Methods
Using the raw data from the Nielsen study, we calculated the estimated number of lives saved from statin therapy use according to type of cancer and then estimated the absolute numbers of lives saved.

Results
When we examined the raw data showing hazard ratios according to statin use in each of the cancers described, we found that except for lymphoma, the mortality reductions were significant for smoking related cancers (lung, pharynx, oesophagus, urinary) and obesity-related cancers (colon, prostate, breast - see Figure 1). When we calculated the number of lives saved according to specific cancer type, we found that of all lives saved, 43% could be attributed to a reduction in lung cancer deaths (Table 1). Importantly, mortality for many of these cancers (lung, colon, breast and prostate) has been associated, in large prospective studies, to elevation of the C-reactive protein, a marker of systemic inflammation. Figure 1Figure 2

Conclusion
We conclude that the reduction in cancer mortality attributed to statin therapy by Nielsen et al. is seen almost exclusively in cancers where smoking and/or systemic inflammation is thought to be of significant pathogenic importance. Significantly, the single largest reduction can be attributed to lung cancer where both smoking and systemic inflammation are strongly implicated. We suggest that a reduction in systemic inflammation by statins may be one mechanism underlying the reduction in mortality reported by Nielsen and colleagues.

Abstract not provided

Background
Smokers with a family history of cancer are at higher risk for developing cancer. A diagnosis of cancer within the family may provide an opportunity for smokers to adopt health-promoting behavior. This study examined associations between having a first-degree family history of cancer and smoking status.

Methods
Data from the 2009 California Health Interview Survey (CHIS) on 47,331 adults were used in this cross-sectional study. Sample weights were applied to account for the complex survey design with results generalizable to non-institutionalized adults in California (27.4 million). Smoking status was classified as current, former, or never-smoker. Family cancer history was defined as blood relatives that include biological father or mother, full brothers or sisters, or biological sons or daughters. Demographic characteristics included age, gender, race/ethnicity, marital status, poverty level, education level and health insurance coverage. General health status, physical activity, body weight status and binge drinking status were also included. CHIS defined binge drinking status as ≥5 alcoholic drinks for males or ≥4 alcoholic drinks for females in a single episode in the past year. Body weight status was defined by body mass index as underweight <18.5 kg/m2, normal = 18.5–24.9 kg/m2, overweight = 25.0–29.9 kg/m2, and obesity ≥30.0 kg/m2. Multinomial logistic regression was used to analyze the association between first-degree family history of cancer and smoking status.

Results
In 2009, 13.6% (3.7 million) of the 27.4 million adults were current-smokers, 23.0% (6.3 million) former-smokers and 63.4% (17.4 million) never-smokers. Thirty-five percent (9.6 million) had a first-degree family history of cancer (Table 1). Among those with a first-degree family history of cancer, 13.5% (1.3million) were current-smokers, 29.7% (2.8 million) were former-smokers and 56.8% (5.4 million) were never-smokers. Adults with a first-degree family history of cancer were more likely to be former-smokers compared with adults without a first-degree family history of cancer (29.7% vs. 19.3%, p<.001). Controlling for demographic factors and other risk characteristics (binge drinking, obesity, physical activity), having a first-degree family history of cancer was significantly related to being a current-smoker (OR=1.16; 95% CI=1.01-1.34) and former-smoker (OR=1.17; 95% CI 1.05-1.30).

Conclusion
In California, many adults with a first-degree family history of cancer still smoke which places them at higher risk for poor health outcomes. Smokers with a first-degree family history of cancer may be an important target population for smoking cessation interventions.

Background
Australia established its first national quitline service in 1997 as part of the Australian National Tobacco Campaign (NTC). In 2005 our hospital, an Australian tertiary specialist cancer centre, commenced a multidisciplinary smoking cessation program which included the provision of counselling and behaviour techniques as well as free access to pharmacological smoking cessation agents. In 2007 the hospital went totally smoke free and in 2009 all new patient registrations included collection of information pertaining to smoking behaviours. Cancer patients are known to withhold and underreport details regarding current and previous smoking behaviours however there is limited data on the impact of non-disclosure on the ability to implement interventional smoking cessation programs in the oncology setting. Five years after initiation of an interventional smoking cessation program we present previously uncollected and unreported hospital wide smoking behaviour data (prevalence, magnitude and willingness to report) of cancer patients. We also evaluate our multidisciplinary smoking cessation model including recruitment and quit rates for cancer patients at a specialist oncology centre.

Methods
For the two year period 2009-2011 self-reported smoking behaviors were obtained from hospital registration datasets. A retrospective single arm cohort study, including patients with a cancer diagnosis who accessed the smoking cessation program within the same two year period, was also conducted. Patients and family members are recruited to the program via a multidisciplinary referral system and have access to nurse led counselling and behaviour modification consultations as well as provision of free pharmacological smoking cessation aids. Evaluation of the program was undertaken through and audit of medical and pharmacy records for all patients who participated in the program (n=312) and by phone interviews with a subset of patients (n=30) and compared to data from a previously published study at our institution[1].

Results
50% (n=10,401) of patients newly registered to the hospital identified as having ever smoked with 12% (n=2448) current smokers. Recruitment of self-identified active smokers into the smoking cessation program was low (7.3%). 43% (n=134) of patients enrolled into the program had not disclosed their smoking status at hospital registration. Magnitude of smoking was high; average pack-years of patients who have ever smoked was 22.6 and for current smokers was 27.8; 155 patients reported smoking magnitude as greater than 100 pack years. Provision of free pharmacotherapy equated to a net expenditure of AUD$22,042. Point prevalence smoking cessation rate among patients who participated in follow-up interviews (n=30) was similar to that previously reported following participation in our multidisciplinary smoking cessation program, 33% compared to 37%[1]. 66% of patients reported successful outcomes (cessation or reduction in consumption).

Conclusion
Patient-reported smoking behaviours were grossly underreported impacting on the ability to actively enrol patients into established interventional cessation programs. Despite low recruitment rates and high magnitude of smoking, the multidisciplinary model was able to achieve successful outcomes at minimal cost in this vulnerable patient cohort. Improving disclosure practices may enable future targeted recruitment of patients by health-care professionals and increase the participation of smokers in proven healthcare interventions.

Background
Lung cancer screening programs provide unique opportunities to facilitate smoking cessation in smokers who participate in these programs. However, the effects of screening on motivation to quit might be mediated or modified by other variables. Identifying the participants more likely to quit will allow rapid application of smoking cessation resources to these participants, while those least likely to quit can be afforded experimental interventions. The aim of our study was to assess the impact of lung cancer screening on smoking cessation in current smokers at the time of enrollment and to identify factors that were associated with quitting smoking in this screening population.

Methods
Using data collected from the Pan-Canadian Study of Early Detection of Lung Cancer, both univariate and multivariable logistic regression analysis was used to identify predictors of smoking cessation among current smokers at enrolment. Smoking cessation was defined as quitting for at least a 6 month period, occurring anytime after enrolment.

Results
We analyzed baseline and follow-up questionnaires of 2320 participants, of which 1419 were current smokers. Of these 1419 patients, 392 (27.8%) met the definition of smoking cessation during a median of two annual follow-up visits. In both univariate and multivariable (MV) analysis, greater smoking cessation was associated with four factors: (i) having a diagnosis of lung cancer at any time during the screening process, with a MV Odds ratio (OR) of quitting of 2.4 (95%CI: 1.1-5.0); (ii) lower and medium nicotine addiction as assessed by the Fagerström Nicotine Dependence Scale Score, with MV-ORs of 3.2 (95%CI: 2.2-4.6) and 1.4 (95%CI: 0.9-2.0), respectively; (iii) having higher education, with MV-OR: 1.4 (95%CI: 1.1-1.9); and (iv) having an earlier age of onset of regular alcohol intake, with MV-OR of 1.11 (95%CI: 1.02-1.21) per 5 year decrease in age. Smoking cessation was also associated with (i) previous attempts of quitting [UV-OR 1.8 (95%CI: 1.2-2.7)], willingness to quit smoking within the next month (at baseline screening) [UV-OR 2.2 (95%CI: 1.8-2.9)] or within the next 6 months after baseline screening [UV-OR 1.8 (95%CI: 1.3.-2.4)]. Second-hand smoking exposure, including exposure as a child, or as an adult at work, at home, privately with friends, or in public settings, or a cumulative index of these different exposures, was not associated with smoking cessation. Presence of potential index symptoms for lung disease, including shortness of breath, cough (both dry and productive), hoarseness, audible wheezing or even chest pain, was not associated with an increased chance of smoking cessation.

Conclusion
The diagnosis of a new lung cancer had a major positive impact on screening participants quitting smoking, as were factors such as lower nicotine dependence, higher education, earlier starting alcohol drinking age, and willingness to quit. Whether a new lung cancer diagnosis triggered additional efforts by clinicians to help the person quit will be explored further. Individual lung symptoms and secondhand smoke exposure were not associated with smoking cessation. (Geoffrey Liu and Martin Tamemmagi are co-senior authors)

Abstract not provided

Background
Carboplatin (CBDCA) is used widely against various tumors,including non-small cell lung cancer, small cell lung cancer, which is classified a moderate emetic risk. 5-HT~3~ antagonist and corticosteroid had a great efficacy in patients (pts) treated with CBDCA containing chemotherapy. This randomized trial was conducted to evaluate the efficacy and safety of aprepitant (APR) compared with corticosteroid, based on granisetron (GRA) plus corticosteroid at the first day, in pts treated with CBDCA containing chemotherapy.

Methods
Pts treated with CBDCA (AUC 5 or 6) containing chemotherapy were entered on this trial. Major eligible criteria included more than 20 years old, and ECOG PS 0-2. Patients were randomized either A group (GRA 3 mg, iv, day 1, dexamethasone [DEX] 3.3 mg, iv, day 1, APR 125 mg , po, day 1, and APR 80 mg, po, days 2,3) or D group (GRA 3 mg, iv, day 1, D EX 6.6 mg, iv, day 1, and DEX 8 mg, po, days 2, 3). Randomization was stratified by gender and CBDCA AUC 5 or 6. Study period was 120 hours from administration of CBDCA. During this period, pts recorded the time and date of emetic episodes and severity of nausea by themselves in a survey form. Primary endpoint was complete response rate (CRR), defined as no emetic episodes and no rescue medications during the overall study period. Secondary endpoints included CRR during the acute (0-24 h) and the delayed (24-120 h) phases, no nausea rate, severity of nausea and safety. The planned sample size of 128 provided 80% power to detect a 20% improvement in the CRR at overall period with two-sided α of 0.1. This study was approved by the institutional review board in our institution. All pts provided written informed consent prior to enrollment.

Results
From October 2010 to August 2012, 128 pts were entered in this phase III trial. Three quarters of entered pts were male, and 63% were received CBDCA AUC 6. Baseline factors, such as age, gender, AUC of CBDCA, chemotherapy regimen, and PS, were well balanced between the two groups. The CRR during overall study period were 61.3% and 68.8% in A and D group, respectively (p=0.3799). There was no difference of CRR during both the acute phase (98.4% vs 98.4%) and the delayed (61.3% vs 68.8%). There was no adverse event due to the antiemetic therapy in both groups during the overall study period.

Conclusion
This randomized phase III trial failed to demonstrate that APR was superior to DEX for emesis induced by CBDCA containing chemotherapy which was classified a moderate emetic risk. Combination APR with DEX on days 2 and 3, or more was likely to increase an antiemetic efficacy during delayed phase. Further study was warranted.

Background
Patients with cancer have varying preferences for involvement in decision-making between active, collaborative and passive roles. Previous studies suggest that many patients prefer a more active role than they experienced, and a more active role over time[MSA(1] . We sought the preferred and actual level of involvement in decision-making among patients considering ACT after resection of early NSCLC.

Methods
98 patients completed a self-administered questionnaire at baseline (before ACT, if they were having it) and at 6 months (after ACT, if they had it). Preferred and actual level of involvement in decision-making were assessed by the Control Preferences Scale (CPS) and trichotomised into active, collaborative, and passive roles. Health-related quality of life (HRQL) data were assessed by the Patient DATA Form. Differences on the original CPS scale between preferred and actual roles and between preferred roles over time were assessed with the Wilcoxon signed-rank test. Determinants of preference for an active role were assessed with chi-square tests of association in 2x2 tables, summarising by odds ratios (ORs). Wilcoxon rank-sum (WRS) tests were used to assess differences in survival benefits required to make ACT worthwhile between patients preferring active and less active roles.

Results
Most patients were male (55%) with a median age of 64 years (range, 43-79 years), married (74%) and previous smokers (82%). The majority had had a lobectomy (85%), adenocarcinoma histology (63%), and half (46%) had stage II disease. 83 patients decided to have ACT (85%), 15 declined ACT (15%). ACT was most commonly 4 cycles (71%) of cisplatin/ vinorelbine (73%). Preferred role in decision-making at baseline (n=98) was active in 26 (27%), collaborative in 46 (47%), and passive in 26 (27%); and at 6 months (n=73) was active in 15 (21%), collaborative in 37 (51%) and passive in 21 (29%). Preferred decision-making roles were stable over time (p=0.5). Actual decision-making roles at baseline (n=98) were active in 24 (24%), collaborative in 47 (48%), and passive in 27 (28%). There was concordance between preferred and actual decision-making roles at baseline (p=0.4). Preferring a more active role was associated with university education (p=0.02, OR 2.9) and worse HRQL during ACT: physical well-being (p=0.05, OR 4.4), overall well-being (p=0.02, OR 5.5), sleep (p=0.03, OR 8.4) and shortness of breath (p=0.01, OR 7.6). Patients who preferred an active decision-making role judged larger survival benefits to make ACT worthwhile than patients who preferred a passive role (eg extra survival time of 1 year v 6 months, WRS p=0.03; extra survival rate of 17.5% v 2.5%, WRS p <0.01).

Conclusion
Patients with recently resected NSCLC varied in their preferred roles in decision-making about ACT with most patients preferring a collaborative role. Their preferences were stable over time, and were concordant with their perceived actual role in decision-making at baseline. Preferences for an active role in decision-making were associated with judging larger survival benefits necessary to make ACT worthwhile. Clinicians should elicit and consider patients’ preferences for involvement in decision-making when discussing ACT for NSCLC.

Background
Lung cancer, the leading cause of cancer-related death, is associated with poor survival, painful, life-threatening disease attributes, and greater associated economic burden compared with other cancers. The disease also presents multiple challenges for the caregivers of patients with lung cancer, including increased distress, significant impact on social and health-related quality of life (HRQoL), and costs associated with loss of income and time spent on patient care. Little information exists on the extent of this caregiver burden. The current study aims to investigate the HRQoL and the comorbidity burden of caregivers of patients with lung cancer in several European (EU) countries.

Methods
Data were provided from the 2010 and 2011 EU National Health and Wellness Survey (NHWS), an annual, stratified, random, cross-sectional, self-administered Internet-based survey of healthcare attitudes and behaviors among adults in France, Germany, Italy, Spain, and the United Kingdom (n=114,962). Respondents who reported providing care for a patient with lung cancer ("caregivers") were compared with respondents not providing care ("non-caregivers") on measures of HRQoL and self-reports of diagnosis with conditions known to be caused or exacerbated by psychological stress. HRQoL was assessed using the 12-Item Short Form Survey (SF)-12v2, which included Mental (MCS) and Physical (PCS) Component Summary scores; mental and physical functioning subscales; and SF-6D health state utilities (with higher scores indicating better health status and minimally important differences [MIDs] of 3 points in PCS/MCS scores, and 0.03 points in health utilities).The self-reported diagnoses of interest included depression, anxiety, insomnia, headache, migraine, and gastrointestinal (GI) illnesses (ie, gastroesophageal reflux disease, heartburn, and/or irritable bowel syndrome). Regression models were used to predict health outcomes as a function of caregiving vs non-caregiving, controlling for demographics (age, gender, education, income, marital status, employment, body mass index category), health risk behaviors (exercise, smoking), and the Charlson Comorbidity Index (reflecting mortality risk).

Results
No significant differences between caregivers (n=107) and non-caregivers (n=103,868) on sociodemographic and health characteristics were observed. Caregivers and non-caregivers were on average 44.1 and 46.3 years old, respectively, and employed (55.1% and 57.4%, respectively), suggesting care given by children rather than by spouse/partner. Adjusting for covariates, caregivers reported significantly worse HRQoL than non-caregivers, including PCS (-1.91 points, P=.017), MCS (-3.52 points, P <.001, exceeding MID), health utilities (-0.049 points, P <.001, exceeding MID), and all subscales, except vitality (-1.83 to -4.87, all P <.03). In addition, caregivers had about twice the odds of non-caregivers of diagnosis with depression (OR=1.885, P =.018), insomnia (OR=2.190, P =.002), headache (OR=1.997, P =.008), and GI problems (OR=1.970, P =.002).

Conclusion
Adjusting for confounders, caregivers for patients with lung cancer reported significantly lower mental and physical health status, lower health utilities, and higher depression, insomnia, headache, and GI problems than non-caregivers. In addition to confirming and extending knowledge of the caregiver burden of lung cancer in EU, this study highlights a need for increased personalized support for caregivers. Research on other aspects of caregiver burden, such as healthcare resource utilization and work productivity, will help refine estimation of the financial impact of lung cancer on society.

Abstract not provided

Background
Lung cancer affects nearly 40,000 patients per year in the UK of which 5000 (12%) will undergo major lung resection for primary lung cancer. Approximately 15% of patients will have complications post operatively. Once the patient develops a post surgical pulmonary complication mortality increases from 0.5% to 12%, ITU admission rate increases from 1.5% to 26% and the length of stay increases from 5 to 14 days. A Lack of preparedness prevents patients immediately engaging in post operative activities successfully and can result in an increase in patient’s anxiety, post operative complications and length of stay in hospital. The United Kingdom National Lung Cancer Forum for Nurses Thoracic Surgical Group (TSG) has produced this Guideline to aid health care professionals in the preparation and support of patients undergoing a lung resection with an aim to promote patient self management.

Methods
Following a literature review and discussion amongst this specialist group the Guideline was developed focusing on key topic areas and interventions which included: poor nutrition, before and during the healing process is associated with poor wound healing risks of hospital death and pulmonary complications after lung cancer resection are increased by smoking patients who receive a multi-disciplinary rehabilitation and early mobilisation achieve earlier discharge from hospital and significantly reduce in hospital morbidities and complication rates patient’s satisfaction regarding pain management significantly correlates to the preoperative information they have received good quality patient information is vital in reducing patient’s anxiety and improving the overall patient experience

Results
The Guideline was developed to support any health professional involved in the provision of care for patients who are undergoing thoracic surgery. The Guideline includes information for health professionals providing examples of current best practice and information for patients. The aim of the Guideline is to support self management, support patients through the surgical pathway, and improve patient outcomes and patient experience. The full guideline can be found at http://www.nlcfn.org.uk/editorimages/Guidelines%20to%20Prepare%20etc.pdf

Conclusion
The Guideline is relevant to all patients who are undergoing a lung resection. The Guideline includes a series of broad statements and where necessary local procedures should be developed to complement the guidelines in each clinical area. The Guideline compliments the Surgical Follow Up Guideline also produced by the NLCFN Thoracic Surgical Group.

Background
The goal of any intervention in medicine is to return the patient to the “pre-clinical state”. Thoracic surgical intervention remains the most effective way to manage early stage lung cancer. Minimally invasive techniques have substantially reduced the morbidity associated with traditional open procedures and have returned patients to health faster. This has been achieved without compromising the oncologic validity of the operation and when done appropriately, has even proved superior. Our health system instituted a minimally invasive thoracic surgical program 5 years ago to realize these benefits. This was accomplished through the recruitment of minimally invasive trained, dedicated thoracic surgeons; service line focused team development; rigorous training of the team; systematic community awareness; and investment in technology and equipment. Seeing tremendous success in volumetric growth with our minimally invasive program, we began to focus on strategies to return patients to their pre-operative functional state more swiftly. We believed inherently that early post-operative ambulation had several clear benefits: 1) clearance of pulmonary secretions and reduction of atelectasis thereby preventing pneumonia, 2) avoidance of deep venous thromboses and subsequent pulmonary emboli, 3) reduced third space fluid shifts therefore reducing the risk of atrial fibrillation and myocardial infarction, 4) better pain control without narcotics, and 5) a general sense of well being. Therefore, we hypothesized that prompt initiation of ambulation should reduce morbidity and return patients to the pre-operative state expeditiously and with greater predictability.

Methods
Our limitations were pain, nursing motivation and culture. Pain is substantially reduced in minimally invasive approaches. Ambulation inherently reduces pain as the upright position takes tension off the intercostal spaces. Nursing motivation and culture proved to be a bigger challenge given limitations in the time available for “bedside nursing”. However, perhaps more relevant was the skepticism related to the safety of this endeavor. Given these realities, we created an environment to test our hypothesis seeking first to demonstrate safety and feasibility of an endeavor that we believed to be so pivotal. In July of 2010, with the support of nursing leadership, administration and our thoracic oncology team, we began a program of aggressive post-operative ambulation with one simple mandate: every patient must walk 250 feet within 1 hour of extubation.

Results
For this analysis we included all patients recovered in our dedicated unit after VATS, thoracotomy, robotic or laparoscopic interventions. We excluded patients undergoing bronchoscopy or mediastinoscopy as they were routinely discharged within two hours of extubation. From July 2010 through May 2013, a total of 720 patients were recovered in our unit. 553 (77%) were able to walk 250 feet or more. Of these, 328 (59%) were successful within 1 hour of extubation. 74 patients (10%) were unable to ambulate largely due to weakness and hypotension. There have been no adverse events since implementation (0% complication rate).

Conclusion
We conclude that early post-operative ambulation is feasible and safe. We have observed favorable responses from patients and families and have enjoyed a considerable decrement in our overall post-operative length of stay. Further investigation will be necessary to quantify these endpoints.

Background
Clinical trials (CT) are fundamental to improving outcomes in lung cancer. Recruitment to CT in the UK is poor. The National Cancer Research Interest Group, Clinical Studies Group (UK), identified that Lung Cancer Nurse Specialist (LCNS) may have a role in improving recruitment to CT. The National Lung Cancer Audit (England) 2010-2012 identified that patients who access a LCNS are more likely to recieve anti cancer treatment. Therefore could this correlation be applicable to the CT setting? A survey was conducted to understand the role of LCNS in relation to CT, and to investigate the views of LCNS regarding CT involvement of advanced stage patients.

Methods
A questionnaire was emailed to all registered members of the National Lung Cancer Nurses Forum NLCFN(UK) with an explanatory letter,during the month of April 2013. An e-survey was chosen, to facilitate a convenient route for response and to minimise costs. A custom excel database was built for the purposes of data collection and analysis. The audit was pilot tested by 10 LCNS prior to distribution.

Results
138 (50%) responses received. Results support that LCNS have a good understanding of CT availability (92%). Research nurses were regarded as key team members by all respondents, and 81% were dedicated to lung cancer CT. 85% of LCNS discussed CT in the course of treatment option consultations. The vast majority of technical aspects of CT recruitment, was deferred to the Research nurses. Benefits of CT participation identified by the LCNS's included: access to new drugs, closer follow up,benefit for future patients, additional support from Research nurses, a level of decision making regarding treatment. Disadvantages included: excessive time commitment, additional requirement for hospital appointments, travel distance to trial centre, patients deriving false hope, delays commencing therapy due to protocol requirements, increased number of invasive procedures, feeling they will let the doctor down by non-participation, psychological harm if they don’t responsed to therapy. 17% of respondents suggested that CT participation may be unethical. On further analysis concerns were information, selection and appropriate support levels. Responses confirmed that there is uncertainty in relation to the LCNS role in CT management generally. Little reference was made regarding non drug CT, such as radiotherapy or supportive care.

Conclusion
The LCNS community understand and supports the value of CT. This include patients in the advanced stages of the disease. The role of the LCNS is not clearly defined in relation to CT. Most LCNS are comfortable speaking to patients regarding CT and have a good working knowledge of CT availability. The finer detail in terms of recruitment and clinical trial management is seen as the remit of the research nurse. No expressions of serious concern in relation to trial participation or ethical concerns where derived from responses. LCNS’s have reported understanding of CT philosophy in the UK, and the requirement for CT to continue in this patient group, while at the same time demonstrating a strong advocacy role. LCNS’s in the UK support clinical trial recruitment in patients with lung cancer and regard them as ethical.

Abstract not provided

Abstract

Abstract
Introduction Lung cancer is a major health problem with no improvement in survival over the last decades. At time of diagnosis, lung cancer is often already in advanced stage, with 5-year survival of no more than 15%. Currently, several lung cancer screening trials investigating whether early detection of lung cancer in high-risk individuals will reduce lung cancer mortality are ongoing. In 2011, the National Lung Screening Trial (NLST), was the first and to date only reporting a 20% decrease in lung cancer mortality when three rounds of annual low-dose computed tomography (CT) were compared with three annual rounds of chest X-ray screening. A major challenge, however, is the high rate of positive test results reported by the NLST (24.2%). No less than 96.2% of these comprised false-positive test results, causing unnecessary patient anxiety, radiation exposure and cost. The Dutch-Belgian lung cancer screening trial (Dutch acronym: NELSON study) was launched in September 2003. The NELSON study is an ongoing multicentre randomized controlled multi-detector low-dose CT lung cancer screening trial. The primary object is to investigate whether chest CT screening in year 1, 2, 4 and 6.5 will decrease lung cancer mortality by at least 25% in high-risk (ex-)smokers between 50 and 75 years of age compared to a control group receiving no screening. The NELSON study is the first lung cancer screening trial in which nodule management is based on nodule volume, instead of transverse cross-sectional nodule diameter for new nodules, and nodule growth in terms of volume doubling time (VDT) for existing ones. In this presentation, different aspects of nodule management in the NELSON study will be discussed. Volume detection thresholds Sensitive pulmonary nodule detection is crucial not to miss any lung cancer in a screening setting. The sensitivity of nodule detection was investigated by scanning a Lungman phantom according to the standard NELSON protocol. Nodules of five different volumes (range 14–905mm[3]) were randomly positioned in the phantom. A sensitivity of 100% was found for nodules with a volume equal to or larger than 65mm[3] (5mm), and a sensitivity of 60–80% was found for solid nodules with a volume of 14mm[3] (3mm). Since the lung cancer probability of lung nodules smaller than 50mm[3] or 4mm is neglectable, the sensitivity of nodule detection using the NELSON protocol is sufficient for accurate detection of malignant lung nodules. Measurement reproducibility For accurate decision making in serial CT studies, nodule measurement reproducibility is essential. A sub-study of the NELSON trial showed a difference in repeatability among three reconstruction settings, demonstrating that the use of consistent reconstruction parameters is important. Volume measurements of pulmonary nodules obtained at 1mm section thickness combined with a soft kernel were found to be most repeatable. Another sub-study showed that variability on volume measurements is related to nodule size, morphology and location. Besides image reproducibility, interobserver variability in performing semi-automated volume measurements is of major importance in the classification of lung nodules. Gietema et al. found that interobserver correlation was very high (r=0.99) in small-to-intermediate size (15-500mm[3]) nodules. Volume criteria for nodule stratification For solid nodules, and solid components of part-solid nodules, volume was calculated by 3-dimensional volumetric computer assessment, using LungCare software (version Somaris/5:VA70C-W; Siemens Medical Solutions). The final screen result was based on the nodule with largest volume or fasted growth. In the NELSON study, nodules were classified as negative if volume was <50mm[3] (4.6mm diameter if the nodule would have been perfectly spherical), leading to an invitation for the regular next-round CT, as positive if nodule volume was >500mm[3] (>9.8mm diameter), leading to direct referral to a pulmonologist for further workup, and as indeterminate in case of volume of 50-500mm[3]. Indeterminate nodules underwent a 6-week to 3-month follow-up low-dose CT for growth assessment. Volumetric growth assessment of pulmonary nodules After a nodule has been selected by a radiologist, the LungCare software automatically calculates nodule volume. Information is saved in the NELSON Management System (NMS), which calculates the growth in case of a pre-existing nodule. Growth is defined as a change in volume of ≥25% between two subsequent scans according to the formula: Percentage volume change (%) = (V2-V1)/V1)*100 V2 = volume at last CT, and V1 = volume at previous examination. Determination of the volume-doubling time For solid nodules, or solid components of partial-solid nodules with PVC≥25%, the VDT is semi-automatically calculated by the NMS according to the formula: VDT (days) = (ln(2)*Δt)/(ln(V2/V1)) The VDT is used to distinguish between positive screens (VDT<400days), requiring additional diagnostic procedures, indeterminate screens (VDT 400-600days), requiring an extra follow-up CT 12 months after the regular round CT and negative screens (VDT>600days). Using this two-step approach of volume and growth assessment, 2.6% of NELSON baseline screens were positive, and compared to other screening trials, a higher proportion (34.6% at baseline) were true-positive. The NELSON study reported a baseline screen sensitivity of 94.6% and a negative predictive value of 99.9%. Comparison between volumetric and diameter assessment of pulmonary nodules For determining pulmonary nodule size, the use of volume measurements has been found to be more reliable than diameter measurements. In the previously mentioned phantom study, measurements of the manually measured maximal transverse diameter and semi-automated measurements of diameter and nodule volume were compared with actual properties. In both methods, diameter and volume of the spherical nodules were significantly underestimated. In diameter evaluation, the overall underestimation for solid nodules was about 10% using the manual method, compared with less than 4% using the semi-automated method. In volumetry, the overall underestimation for solid nodules was about 25% (translates into 8% diameter underestimation) using the manual method, compared with less than 8% (translates into 2.5% diameter underestimation) using the semi-automated method. It is important to keep in mind that a small change in diameter already corresponds to a considerably higher change in volume. Thus, in lung cancer screening we suggest nodule measurements by semi-automated volumetry should be used. Differences between volume and diameter based nodule management protocol in terms of early lung cancer detection, morbidity, mortality, radiation exposure and costs remain to be demonstrated.

Abstract not provided

Abstract not provided

Abstract
In patients receiving radiation for a diversity of diagnoses (e.g. Hodgkin’s Disease, breast cancer, seminoma), multiple studies demonstrate that incidental irradiation of the heart can increase the cardiac morbidity and mortality. While there is limited data in patients irradiated for lung cancer, RT-induced heart disease is likely clinically important and care should be taken to minimize incidental cardiac irradiation. Breast Cancer: Dose-response and evolution of techniques: In patients irradiated for breast cancer, there is a fairly well-defined dose/volume response for radiation-induced cardiac injury. The radiation techniques used to treat patients with breast cancer have evolved over the last several decades with a corresponding marked reduction in incidental cardiac doses (and corresponding decreased cardiac risks). For example, it has been estimated that mean heart doses were in the range of 10-15 Gy with anterior photon fields (directed to the internal mammary nodes), ≈5 Gy with tangents and medial IMN electrons, 1-2 Gy with partly-wide tangents, and <1 Gy with conformal cardiac blocking and breath hold. The cardiac implications for patients with breast cancer can be large. In some older studies the detrimental cardiac effects of radiation totally off-set the improvements in cancer-specific survival provided by RT. More modern radiation techniques clearly reduce the cardiac exposure and appear to reduce the frequency or RT-induced heart disease. However, the follow-up duration in the studies utilizing these modern techniques is not as long as are the follow-up durations in the studies using the older techniques. Thus, the long-term safety of “modern” RT can still be questioned. Timing of RT-associated heart injury in patients irradiated for breast cancer: In a classic meta-analysis (Cuzick; Recent Results Cancer Research 111:108-129, 1988; and JCO 12:452, 1994), post-mastectomy RT was associated with a reduction in overall survival at follow-up times >15 years post-RT. This observation helped fuel the traditional belief (recently being challenged) is that RT-induced cardiac injury is manifest at only extended follow-up intervals. This led our group and others to look for more short-term subclinical surrogates for RT-induced cardiac injury. Summary of our prospective study: We prospectively assessed RT-induced changes in regional myocardial perfusion in patients being treated for left-sided breast cancer using modern CT-based techniques. We noted a volume-dependent new perfusion abnormalities 6-24 months post-RT. These perfusion defects largely persist up to 6 years post-RT. The distribution of the perfusion defects follows the path of the tangential radiation field, and not the territory of a coronary artery, and thus represent microvasculature (rather than named coronary artery) injury. In patients with greater than 5% of the left ventricle within the tangential field, the incidence of new perfusion abnormalities si >50%. The functional consequences of these perfusion defects are uncertain. At short follow-up times, they are associated with a slightly increased rate of regional wall motion abnormalities. These wall motion abnormalities, however, do not always persist long-term. There are minimal, if any changes in ejection fraction noted in patients with perfusion defects. However, in patients with "severe" perfusion defects (scored by the summed rest score, SRS), there is suggestion that there might be a more meaningful reduction in ejection fraction (Marks 63:214, 2005, Lind IJROBP 55:914, 2003, Prosnitz Cancer, 110:1840, 2007). The clinical relevance of these perfusion defects remains uncertain. Perfusion defects may represent a reduction in collateral circulation making the patient more prone to develop ischemia when they (at a much later date) develop coronary artery disease. Therefore, care should be taken to minimize cardiac exposure for patients receiving left-sided RT. The use of conformal blocking (heart block), respiratory gating, and electron beam techniques are often useful to reduce cardiac exposure. Reconsideration of the timing of RT-induced cardiac injury in light of the recent analysis by Darby et al (NEJM 368:11, 2013): Darby’s report suggests that RT-induced cardiac injury in patients with breast cancer is clinically manifest relatively soon post-RT (i.e. within a few years), and that the cumulative risk increases continually up to 20 years post-RT. This suggests that the microvascular changes seen in our study (noted above) might have a clinical relevance in the short post-RT interval. Therefore, an alternative interpretation Cuzick et al (cited above) is that there is a clinically-meaningful increase in cardiac mortality in the 1-15 year post-RT interval, but that this is offset by the reduction in breast-cancer specific mortality during that time (resulting in a no net change in overall survival vs. the control group). At >15 years, the excess cardiac events exceed the cumulative anti-cancer effects, leading to the reduced overall survival noted. Lung Cancer: In patients early-stage lung cancer (N0-1), post-operative RT (PORT) is associated with an excess mortality within 0-5 years (Lancet 352:257; ’98). While the causes of the excess deaths are not noted in most studies, at least one study has noted increased cardiac deaths in this setting (Dautzenberg Cancer 86:265, ‘99). Two more-recent studies of “smaller field-PORT” (Mayer: Chest 112:954, ’97; Tradella Radio Oncol 62:11, 2002) demonstrate an improvement in overall survival with PORT, again suggesting that there is a delicate balance between RT-induced reductions in cancer-specific death and normal tissue-induced injury (Miles, IJROBP 68:1047, ‘07), totally analogous to the situation with breast cancer (Marks & Prosnitz, IJROBP 48:625, 2000). With definitive RT for lung cancer, RT-induced cardiac injury is not often reported. However, this might be under-reported as the symptoms of cardiac dysfunction (e.g. dyspnea) might be ascribed to lung disease. Better sparing of the heart during definitive RT for lung cancer is likely to improve the overall outcome. There are no clear dose/volume limits for the heart in patients with lung cancer (Gagliardi IJROBP 2010). Non-axial beams are often useful in reducing cardiac exposure, especially in patients with lower lobe tumors (Quaranta Journal Applied Clinical Medical Physics, 11:3010, 2010). Some portions of the heart might be particularly important in the genesis of RT-induced cardiac injury (e.g. pericardium, coronary arteries, left ventricle) and thus sophisticated techniques to redistribute incidental cardiac dose might be helpful. Dr Marks’s department receives grants from, or has relations with, from Elekta, Siemens, Accuray, Morphormics. Supported by NIH CA069579.

Abstract
Introduction The improved survival in locally advanced non-small cell lung cancer (NSCLC) patients treated with concurrent chemo-radiation (CCRT) comes at a price of increased esophagus toxicity. Acute esophagus toxicity (AET) occurs within 3 months after CCRT and late esophagus toxicity (LET) consists of symptoms persisting or occurring >3 months after treatment. AET is treated with dietary changes, proton pump inhibitors, analgesics, promotility agents, intravenous fluids, and/or nasogastric- or gastrostomy tube insertion. Patients who develop stenosis, perforation or fistula are categorized as severe LET (grade 3-5). Patients with stenosis are treated by dilatation. Some patients will develop a fistula, which can be treated with intraluminal stenting. However the prognosis for patients with a fistula is grim. Estimation of the probability and severity of radiation esophagitis after CCRT treatment is crucial. This allows the individual prescription of tumor doses. Several prediction models have been reported to estimate the risk of AET based on the planned dose distributions. Currently used models to predict acute esophageal toxicity (AET) in lung cancer patients after Intensity Modulated Radiotherapy (IMRT) and concurrent chemotherapy were derived from patients treated with 3D-conformal-radiotherapy (3DCRT). These models first reduce the dose-volume histograms to a single parameter like the volume of esophagus receiving more than a certain threshold dose (V~x~). In a large multi-institutional study on 1082 patients treated with 3DCRT, or IMRT concurrent with chemotherapy, the high-dose volumes were the most important predictors for radiation esophagitis [ref 1]. The V60 emerged as the best predictor for both moderate and severe esophagus toxicity. A low-risk subgroup was identified with a very low V60 of <0.07%, an intermediate-risk subgroup with a V60 of 0.07%-16.99%, and a high-risk subgroup with a V60 of ≥17%. Severe LET seriously affects the patients’ quality of life or even leads to death. For LET predicting models are lacking. With improved survival in patients treated with CCRT, it is important and feasible to analyze LET. This abstract is a summary from a series of studies conducted at NKI on esophagus toxicity in a large NSCLC patient cohort. The patients were all treated with hypofractionated radiotherapy, 66 Gy in 24 fractions, and concurrent daily low dose cisplatin. The following items were investigated: 1) Comparison of AET incidence in patients treated with 3DCRT and CCRT to sequential chemoradiation and RT only.¨ 2) Compare incidence of AET with 3DCRT to IMRT. 3) Analysis of prognostic factors for AET using IMRT. 4) Correlation of radiotherapy dose to the oesophagus wall and AET by means of post-RT 18FDG-PET scans acquired after CCRT. 5) Relations between severe LET and the clinical and dosimetric variables. Material and methods The dose-effect relation of AET (185 patients) [ref 3] and LET ≥grade 3 (171 patients) [ref 6] and dose-volume parameters of the esophagus after hypofractionated IMRT (66 Gy/24 fractions) and concurrent low dose cisplatin were investigated. The dose distributions were first converted to Normalized Total Doses to account for fractionation effects with an α/β-ratio of 10 Gy (AET) or 3 Gy (LET). Equivalent Uniform Dose (EUD) to the esophagus and the volume percentage receiving more than x Gy (Vx) were evaluated by Lyman-Kutcher-Burman model. The association between AET and severe LET (grade ≥3 RTOG/EORTC) was tested through Cox-proportional-hazards model Clinical parameters, onset and recovery times were analyzed as well. Results Acute Esophagus Toxicity -For NSCLC patients treated with 3DCRT and concurrent chemotherapy, the incidence of AET grade ≥ 2 was 27% and significantly higher compared to patients treated with sequential chemoradiation or radiotherapy only regimens [ref 2]. -The AET incidences were not significantly different between 3DCRT based and IMRT based CCRT patients. In order to illustrate the differences between 3DCRT and IMRT we show the Vx (α/β-ratio=10) in steps of 5 Gy derived from the AET study by Kwint et al, and also for 36 CCRT patients treated in the EORTC 08972 trial. From Figure 1 it can be appreciated that with IMRT the volume of esophagus receiving a dose from 5-40 Gy was significantly smaller, while at 70 Gy it was increased. Moreover, the LKB model based on the V50 was not significantly different between IMRT and 3DCRT [ref 3]. -A total of 22% NSCLC patients developed AET toxicity ≥ grade 3 after IMRT to 66 Gy in 24 fractions and concurrent daily low dose cisplatin. The V50 was identified as most accurate predictor of grade ≥ 3 AET [ref 3]. -The median time to AET grade 3 was 30 days, with a median duration of >80 days. Higher grade of AET was also associated with a lower recovery rate [ref 4]. -Post-CCRT esophageal FDG uptake on 18FDG-PET is associated with AET grade. SUV predictability of grade 2-3 AET was significantly improved by using the derived relation between RT dose and PETpost [ref 5]. Results Late Esophagus Toxicity A total of 6% patients developed LET ≥ grade 3 at a median follow-up of 33 months (95% CI 29~37) with a median overall survival of 24 months (95% CI 16~32) [ref 6]. The median onset time was 5 months (range 3~12). Patients with un-recovered AET had a significantly (p<0.001) higher risk of developing severe LET, compared to patients without AET or with a recovered AET. In the EUD; n=0.03 model, all severe LET patients had an NTD >70 Gy on the esophagus. In the EUD~n~-LKB model, the fitted values and 95% confidence intervals were TD~50=~76.1 Gy (73.2~78.6), m=0.03 (0.02~0.06) and n=0.03 (0~0.08). In the V~x~-LKB model, the fitted values and 95% CIs were Tx~50~=23.5% (16.4~46.6), m=0.44 (0.32~0.60) and x=76.7 Gy (74.7~77.5). Conclusions In routine clinical practice it is possible to provide insight in the probability and severity of esophagus toxicity for each individual lung cancer patient treated with CCRT. Both the maximum grade and the recovery rate of AET were significantly associated with severe LET. In clinical practice, NTD corrected esophagus EUD<70 Gy could be a dose constraint to minimize severe LET. AET was not changed with the use of IMRT.

Abstract
Treatment toxicity not only reduces quality of life, but also may be life threatening (and can be unidentified) when it is severe. Radiation induced lung toxicity (RILT) is among the most important dose limiting toxicity in the treatment of lung cancer, particularly locally advanced non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The current standard of RT techniques considers the whole lung as a uniform organ and uses the same dose limit for all patients with the assumption that all have a SAME sensitivity to radiation damage. However, patients with NSCLC frequently have a respiratory comorbidity such as chronic obstructive pulmonary disease (COPD) that results in heterogeneous function within different lung regions. Patients often respond remarkably differently to the same amount of radiation dose. Furthermore, the presence of the tumor itself often affects local vascular supply and ventilation, and changes function level. In this presentation, I will review the current functional imaging for lung and predictive biomarkers for RILT with an emphasis on recent advances regarding 1) ventilation/perfusion single photon emission tomography (V/Q SPECT) for treatment planning and RILT prediction, and 2) blood markers and its integration with physical and functional dosimetric factors for RILT prediction. Ultimately, we would like to generate Functional Imaging and Biophysical Model (FunBipM) to guide individualized treatment planning to minimize treatment toxicity V/Q SPECT is a commonly available technique in most hospitals to image the perfusion (Q) and ventilation (V) of the lung. It has been proposed that Q-SPECT images can be used to guide RT planning so that radiation is directed to the non-functional lung regions [1-4]. It was known to us that the Q-SPECT-guided plans produced more favorable functional dose volume histograms (DfVHs) compared to non-SPECT guided plans, with the fV20 and fV30 values reduced by an average of 13.6% ± 5.2% and 10.5% ± 5.8%, respectively [2]. We have further demonstrated that 1) NSCLC often presents with defect regions on V/Q SPECT, some of which are from tumor compression that improves with tumor shrinkage during- RT; 2) SPECT defect regions are more resistant to post-RT function reduction; 3) V/Q SPECT guided radiation therapy can reduce dose to functional lung without increasing doses to the total physical lung; 4) V/Q SPECT based DfVHs from during-RT may predict clinical significant RILT more accurately than anatomic CT lung based DVH. From treatment planning point of view, I will use example cases to demonstrate that we can avoid V/Q SPECT functional regions in pre- and during- RT to minimize damage to functional lung, particularly by the combined use of pre- and during-. V/Q SPECT adds lung ventilation mapping on top of the Q-SPECT, providing more information (including the mechanism for lung function defects and their potential for recovery). During-RT V/Q SPECT allows adaptive-RT because lung function changes globally and locally during RT, largely due to RT-induced tumor volume reduction improving the vascular supply and ventilation[5]. The combination of pre- and during- V/Q SPECT can classify the lung into different functional regions and strategize to differentially prioritize certain regions, a technique our group developed to minimize lung damage. Additionally, we can compute DfVHs from both pre- during- SPECT scans to predict post-treatment functional loss and clinically significant RILT. Patients with the same dosimetric parameters have shown very different levels of toxicity largely due to their biologically different intrinsic sensitivity to radiation damage [6]. Many studies have been conducted to understand the correlation between pro-inflammatory and pro-fibrogenic cytokines, including TGF-ß1, IL-1ß, IL-6, IL-8, and TNF-α and radiation-induced normal tissue injury [7]. TGFß1, a fibrogenic and radiation-inducible cytokine, has been known to play a key role in this process. Animal studies demonstrated significantly elevated TGFß1 mRNA and protein expression within type II pneumocytes and fibroblasts in radiation-sensitive mice after thorax radiation [8-11], which subsequently contributed to increased TGFß1 levels in circulation. The Duke University group reported that plasma TGFß1 levels at the end of radiation are correlated with the later onset of symptomatic RILT in patients treated with definitive radiation therapy [9][,][12][,][13]. Though the result was not consistently reproduced by others [14], possibly due to technique issues [15], end-of-treatment TGFβ1 correlation nevertheless has limited value. We have demonstrated that TGFß1 elevation in the middle of treatment (2-4 weeks during-treatment) relative to pre-treatment is highly correlated with late-onset grade >2 RILT in NSCLC patients [16][,][17] . Most recently, we have demonstrated that combining baseline IL-8, during-treatment TGF-ß1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) for RILT compared to either variable alone [16]. The findings on baseline and during-treatment markers are more important than end-treatment markers, as they provide us an opportunity to adjust treatment accordingly. More importantly, an individual’s susceptibility to radiation normal tissue toxicity may be genetically determined, which can be measured pre-RT. Germ-line genetic variations, most often single nucleotide polymorphisms (SNPs), may play an important role in radiation damage pathogenesis. SNPs associated with molecules involved in radiation damage pathways, such as DNA double-strand break repair (ATM, XRCC1) and inflammation (TGF β1 and cytokines) have been studied for their association with clinical toxicity [18][,][19]. It was reported that SNPs in TGFβ1 and NOS3 were associated with a lower risk for radiation pneumonitis [20][,][21] whereas SNPs in ATM, IL1A, IL8, TNFa, TNFRSF1B and MIF were associated with an increased risk of radiation pneumonitis [20][,][22]. TGFβ1 rs1800470 was positively associated with RILT [21]. We also demonstrated that SNPs of TGFβ1 genes may be associated with overall risk of other organs’ toxicity, including esophagus or heart/pericardium [23]. This finding is also very important because after limiting lung toxicity to less than certain level (such as 15-17%), increased dose to the most resistant tumors may increase toxicity of other organs. This is complicated but should be taken into consideration. In summary, we may generate a FunBipM through the combination of pre- and during-RT V/Q functional dosimetric parameters and blood biomarker data to predict the risk of lung toxicity for each individual patient: i.e. using a FunBipM that integrates biologic markers into the existing dosimetry-based model. By identifying high-risk patients, adjusting lung dose limit according to the threshold of tolerance, and applying the FunBipM to optimize radiation planning for dose and dose arrangement, we may anticipate a significant reduction of the incidence of toxicity without compromised tumor control.1. Seppenwoolde Y, Engelsman M, De Jaeger K, et al. Optimizing radiation treatment plans for lung cancer using lung perfusion information. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. May 2002;63(2):165-177.2. McGuire SM, Zhou S, Marks LB, Dewhirst M, Yin FF, Das SK. A methodology for using SPECT to reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung. International journal of radiation oncology, biology, physics. Dec 1 2006;66(5):1543-1552.3. Lavrenkov K, Christian JA, Partridge M, et al. A potential to reduce pulmonary toxicity: the use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of non-small cell lung cancer. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. May 2007;83(2):156-162.4. Lavrenkov K, Singh S, Christian JA, et al. Effective avoidance of a functional spect-perfused lung using intensity modulated radiotherapy (IMRT) for non-small cell lung cancer (NSCLC): an update of a planning study. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. Jun 2009;91(3):349-352.5. Yuan S, Frey KA, Gross M, Hayman J, Arenberg D, Cai X. Changes in global function and regional ventilation and perfusion on SPECT during the course of radiotherapy in patients with non-small-cell lung cancer. International journal of radiation oncology, biology, physics. 2012;82(4):e631-638.6. Kong FM, Ao X, Wang L, Lawrence TS. The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer control : journal of the Moffitt Cancer Center. Apr 2008;15(2):140-150.7. Kong FM, Ten Haken R, Eisbruch A, Lawrence TS. Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis. Seminars in oncology. Apr 2005;32(2 Suppl 3):S42-54.8. Yi ES, Bedoya A, Lee H, et al. Radiation-induced lung injury in vivo: expression of transforming growth factor-beta precedes fibrosis. Inflammation. Aug 1996;20(4):339-352.9. Anscher MS, Kong FM, Marks LB, Bentel GC, Jirtle RL. Changes in plasma transforming growth factor beta during radiotherapy and the risk of symptomatic radiation-induced pneumonitis. International journal of radiation oncology, biology, physics. Jan 15 1997;37(2):253-258.10. Bai YH, Wang DW, Cui XM, et al. Expression of transforming growth factor beta in radiation interstitial pneumonitis. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 1997;16(1):15-20.11. Rube CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation. International journal of radiation oncology, biology, physics. Jul 1 2000;47(4):1033-1042.12. Vujaskovic Z, Marks LB, Anscher MS. The physical parameters and molecular events associated with radiation-induced lung toxicity. Seminars in radiation oncology. Oct 2000;10(4):296-307.13. Kong FM, Anscher MS, Sporn TA, et al. Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury. International journal of radiation oncology, biology, physics. Jan 1 2001;49(1):35-41.14. De Jaeger K, Seppenwoolde Y, Kampinga HH, Boersma LJ, Belderbos JS, Lebesque JV. Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer. International journal of radiation oncology, biology, physics. Apr 1 2004;58(5):1378-1387.15. Zhao L, Wang L, Ji W, Lei M, Yang W, Kong FM. The influence of the blood handling process on the measurement of circulating TGF-beta1. Eur Cytokine Netw. Mar 1 2012;23(1):1-6.16. Stenmark M, Cai X, Shedden K, et al. Combining Physical and Biologic Parameters to Predict Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Definitive Radiotherapy. International journal of radiation oncology, biology, physics. In press.17. Zhao L, Wang L, Ji W, et al. Elevation of plasma TGF-beta1 during radiation therapy predicts radiation-induced lung toxicity in patients with non-small-cell lung cancer: a combined analysis from Beijing and Michigan. Int J Radiat Oncol Biol Phys. Aug 1 2009;74(5):1385-1390.18. Damaraju S, Murray D, Dufour J, et al. Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. Apr 15 2006;12(8):2545-2554.19. Hart JP, Broadwater G, Rabbani Z, et al. Cytokine profiling for prediction of symptomatic radiation-induced lung injury. International journal of radiation oncology, biology, physics. Dec 1 2005;63(5):1448-1454.20. Hildebrandt MA, Komaki R, Liao Z, et al. Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. PLoS One. 2010;5(8):e12402.21. Yuan X, Liao Z, Liu Z, et al. Single nucleotide polymorphism at rs1982073:T869C of the TGFbeta 1 gene is associated with the risk of radiation pneumonitis in patients with non-small-cell lung cancer treated with definitive radiotherapy. J Clin Oncol. Jul 10 2009;27(20):3370-3378.22. Zhang L, Yang M, Bi N, et al. ATM polymorphisms are associated with risk of radiation-induced pneumonitis. Int J Radiat Oncol Biol Phys. Aug 1 2010;77(5):1360-1368.23. Xie C, Yuan S, Ellingrod V, Hayman J, Arenberg D, Curtis JL. The Value of Single Nucleotide Polymorphisms in TGFβ1, TPA and ACE in Survival Prediction in Patients with Non-small Cell Lung Cancer. International journal of radiation oncology, biology, physics. 2010;78(3 suppl):199S - 200S.

Abstract
Overview of acute and late toxicities of brain irradiation Acute side effects of brain irradiation (BI) include common effects such as scalp erythema, alopecia, and fatigue and less common effects such as otitis externa, impaired sense of taste, nausea, and headache. Early delayed and late side effects from BI may include hyperpigmentation of the scalp, alopecia, hearing loss, behavioral changes, somnolence syndrome, radiation necrosis and neurocognitive decline. Brain Metastases (BM) often have a devastating impact on neurocognitive function (NCF). BI has been shown to treat, prevent or delay the incidence of BM in lung cancer. However, it can also cause toxicity resulting in a decline in NCF. To date there is limited data available regarding the effects of BI on NCF in patients with lung cancer. This is due to the lack of intensive NCF testing in lung cancer trials. Mechanisms of injury The pathophysiology of late radiotherapy injury is a dynamic and complex interaction between the vasculature and the parenchyma. The vascular hypothesis of radiation-induced injury describes a process of accelerated atherosclerosis causing vascular insufficiency, resulting in a picture similar to small vessel disease seen with vascular dementia. For this reason there is interest in studying vascular dementia treatments to prevent or reduce radiation-induced NCF decline. Glutamate is the principle excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is involved in learning and memory. Ischemia can induce excessive NMDA stimulation and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia. Memantine, an NMDA receptor antagonist, has been shown to be neuroprotective in preclinical models. Additionally, two placebo-controlled phase III trials found memantine to be well-tolerated and effective in treatment for vascular dementia. On these basis, RTOG launched a placebo-controlled, double-blind, randomized trial to evaluate the potential protective effect of memantine on NCF in patients receiving whole brain radiation (WBRT). The results of this study (RTOG 0614) were recently reported. Predisposing factors It is the therapeutic ratio of benefits vs. risks that helps determine the advisability of a treatment such as BI. Clinical trials of prophylactic cranial irradiation (PCI) can enable us to develop strategies that can potentially increase the benefits and decrease the risks. Potential strategies that can increase the benefits of BI may require better ways of identifying a subgroup of patients with the highest risk of developing BM such as those with small cell lung cancer (SCLC), adenocarcinoma, young age, high volume of disease and predictive markers. These are the patients most likely to benefit from PCI. In order to develop strategies to decrease the risks, we must identify and understand those risks. Identifying a subgroup of patients with the highest risk of developing NCF toxicities, such as older age or other patient factors such as hypertension and diabetes, may also improve the therapeutic ratio. Dose volume determinants Due to the concerns with NCF with WBRT, stereotactic radiosurgery (SRS) approaches are being actively studied. Combined therapy (SRS+WBRT) for BM are favored based on Phase III findings that brain control with combined therapy is significantly better than with SRS alone or WBRT alone. On the other hand, a phase III study found that the risk of neurocognitive deficit is doubled with the addition of WBRT to SRS. The published data demonstrate continued evolution of clinical trials and different management strategies are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following BI. To reduce cognitive injury of conventional WBRT, several groups are exploring modified WBRT approaches, such as hippocampal-avoidance WBRT (HA-WBRT). In this approach, complex planning techniques are used to reduce dose to bilateral hippocampal structures while treating the rest of the brain. Hippocampal-dependent functions of learning, memory, and spatial information processing seem to be preferentially affected by RT. It is argued that since <5% of BM occur within 5 mm of the hippocampus, reducing dose to the hippocampus is safe and feasible. The feasibility of this approach has been studied prospectively in a multi-institutional setting by the RTOG study 0933. Clinical features and diagnosis Publications on radiation-induced neurotoxicity have used different assessment methods, time to assessment, and definition of impairment, thus making it difficult to accurately assess the rate and magnitude of the NCF decline that can be expected. There is a paucity of data on neurocognitive impairment after BI, which has previously been assessed using various different neuropsychological tests, as well as different definitions of neurocognitive impairment. It must be remembered that NCF is affected by a number of factors (i.e. BM volume, disease progression (intra and/or extra-cranial progression), chemotherapy, hormonotherapy, surgery, radiation, prior neurologic disease, medications, paraneoplastic effects, etc.) which should be considered when evaluating of the actual neurocognitive effect of treatments such as BI. In addition, a challenge that plagues most studies in patients with advanced cancers, is the decline in compliance with NCF testing over time. Nevertheless, many studies have been completed and will be presented. Prevention and treatment. Because treatment of NCF decline after radiation is limited, treatments ideally would be developed to prevent the detrimental cognitive effects of BI as discussed above. Determining the impact of BI on NCF would provide support for therapeutic decision making for an individual patient, for which we need to use sensitive cognitive assessments to elucidate the incidence, time course, intensity, domains of NCF changes following BI and their actual impact on patient quality of life (QOL). Selected References Sun A, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: Neurocognitive and quality-of-life analysis. J Clin Oncol 2011;29:279-286. Chang EL, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol 2009;10:1037-1044. Wolfson AH, et al. Primary analysis of a phase III randomized trial radiation therapy oncology group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with LD-SCLC. IJROBP 2011;81:77-84.

Abstract
Chemotherapy is still standard treatment for the majority of patients with advanced NSCLC, who do not have specific molecular markers (i.e. EGF mutations, ALK translocations). Platinum based doublets remain standard treatment for most patients and the choice of regimen is based mainly on side effect profile. There is a preference for pemetrexed based therapies for patients with adenocarcinoma histologies, based on one randomized study. Benefit of chemotherapy can be extented by maintenance chemotherapy (pemetrexed), in terms of increased progression-free survival and overall survival. Maintenance with erlotinib has also been approved, although the largest effects are really seen in EGFR mutant patients. Very few chemotherapy doublet regimens have been improved by addition of a third agent, chemotherapy or biological. Bevacizumab was shown to increase response rate, progression-free survival as well as overall survival in one study where carboplatin-paclitaxel was the backbone. Bevacizumab is continued as maintenance. Cetuximab improved survival in addition to cisplatin-vinorelbine, and again cetuximab was continued after the end of chemotherapy. Unfortunately most of the other combinations of biologicals with chemotherapy have been disappointing. Novel agents with different mechanisms of action from the classical tyrosine kinase inhibitors might obtain better results (e.g. PD-1/PD-L1 antibodies). Results of randomzied studies are awaited. The HSP-90 inhibitor gatenespib, in combination with docetaxel gave promising results in a relatively large randomized phase II study, and a phase III study is now underway.

Abstract not provided

Abstract
Optimal adjuvant chemotherapy: selection of patients and agents Patients with early stage, resectable non-small cell lung cancer (NSCLC) have the best chance to be cured with 5 year survival rates ranging from 73% for patients with pathological stage IA disease to 24% for patients with pathological stage IIIA disease. However, the presence of micro-metastases will lead to the development of systemic relapse and death in the majority of patients. To improve survival of these patients adjuvant chemotherapy following complete tumor resection has been studied. Three phase III trials with cisplatin-based regimens and the LACE meta-analysis demonstrated increased cure rates by adjuvant chemotherapy and established adjuvant chemotherapy as the standard of care. Randomized Trials The first trial to demonstrate a survival advantage for adjuvant chemotherapy was the International Adjuvant Lung Cancer Trial Cooperative Group (IALT) study. This trial enrolled 1867 patients; 932 patients were randomized to receive chemotherapy (cisplatin plus etoposide, vinorelbine, vinblastine, or vindesine for 3-4 cycles) and 935 patients were randomized to observation. The 5 year overall survival rate significantly favored the chemotherapy arm (Hazard Ratio [HR] 0.86; 95% CI 0.76-0.98; P <0.03). Disease free survival (DFS) was also superior in the treated arm (HR 0.83; 95% CI 0.74-0.94; P=0.003). With longer follow up of 8 years, the HR for overall survival was not significant (HR 91; 95% CI 0.81-1.02; P=0.10) while the HR for DFS retained significance (HR 0.88; 95% CI 0.78-0.98; P=0.02). In 2005, the National Cancer Institute of Canada Cancer Treatment Group (NCIC CTG) reported the results of JBR10. Patients with completely resected stage IB or stage II NSCLC were randomized to receive cisplatin plus vinorelbine (242 patients) or observation (240 patients). An impressive overall survival benefit was observed for the treated group (HR 0.69; 95% CI 0.52-0.91; P=0.04) corresponding to an absolute survival improvement of 15%. In a subgroup analysis, the survival benefit was restricted to patients with Stage II disease. An update of this study, with > 9 years of follow up continued to show a survival benefit for the treated group with an absolute improvement in the 5 year overall survival (OS) rate of 11% (67% versus 56%, respectively) with a HR of .78; 95% CI 0.62-0.99; P=0.04 (11). Subsequently, the results from the ANITA trial (Adjuvant Navelbine International Trialist Association) solidify the role of adjuvant systemic treatment. A total of 840 patients with Stage IB, II, and IIIA NSCLC were randomized to cisplatin plus vinorelbine versus observation. The HR for death was significantly lower for the chemotherapy group (HR= 0.80, 95% CI 0.66-0.96; P=0.017). The 5 and 7 year overall survival was improved by 8.6% and 8.4% in the chemotherapy group, respectively. No benefit was seen in the subset of patients with Stage IB disease (HR 1.10; 95% CI 0.76-1.57; P=NS). To identify which patients might have the greatest benefit from adjuvant chemotherapy, the LACE (Lung Adjuvant Cisplatin Evaluation) meta-analysis was conducted. Individual patient data was collected and pooled from 4,584 patients in 5 trials (BLT, ALPI, IALT, JBR10 and ANITA). The HR of death was 0.89; 95% CI 0.82-0.96; P=0.005, which corresponded to a 5-year absolute survival benefit of 5.4% with chemotherapy. This benefit varied with stage of disease and was not seen for stage IA patients. A positive chemotherapy effect was seen in patients with performance status (PS) 0-1 whereas chemotherapy was potentially harmful for patients with a PS of 2. Other subgroups analyzed including age, sex, histology, type of surgical resection, planned radiation, dose of cisplatin or the second agent used did not affect overall or disease free survival. Elderly patients Since the majority of patients diagnosed with lung cancer are 70 years old or greater, an additional analysis of the LACE data set by age was conducted. Elderly patients (age > 70 years) accounted for 9% of the patients. Their HR of death was better with treatment at .90 (95% CI 0.74-1.16) and was similar to the HR of death for treated patients < 65 years old at .86 (95% CI 0.78-.94). Elderly patients achieved a survival benefit despite having received lower cisplatin doses and fewer number of chemotherapy cycles than their younger counterparts. Tumor size The Cancer and Leukemia Group B (CALGB) trial 9633 evaluated four cycles of adjuvant paclitaxel and carboplatin versus observation in stage IB patients. With mature follow up of 74 months, overall survival was not significantly different between the two groups (HR 0.83; 95% CI 0.64-1.08; P=0.12). No significant improvement in DFS was observed. In an unplanned subgroup analysis based on tumor size a survival advantage for paclitaxel and carboplatin was seen in patients who had tumors >4 cm (HR, 0.69; 95% CI 0.48-0.99; P = .043). In support of this finding, a retrospective analysis of patients with stage IB disease on JBR 10 was conducted according to tumor size of < or > 4 cms. Patients with smaller tumors did not benefit from adjuvant therapy while treated patients with tumors > 4 cm had a favorable 5 year OS rate of 79% compared to 59% for untreated patients (HR .66; 95% CI 0.39-1.14; P=0.13). It is important to remember that in the 7[th] TNM staging system, patients with tumors of > 4 cm could be Stage IB, IIA or IIB. Chemotherapy regimen In the clinical trials described above vinorelbine plus cisplatin was the most commonly used regimen. In a subgroup analysis of LACE, adjuvant cisplatin plus vinorelbine improved survival at 5 years by 8.9% in the vinorelbine cohort and this outcome was superior to the “other” cohort. Today more modern regimens are frequently used based on their activity in advanced disease including cisplatin and gemcitabine, cisplatin and docetaxel and cisplatin and pemetrexed. In summary, adjuvant cisplatin based chemotherapy is the standard of care for patients with resectable Stage II-III NSCLC with a good performance status and should be considered for patients with tumor size > 4 cm. Current strategies to improve outcome of adjuvant chemotherapy focuses on the integration of targeted therapies, tumor vaccines and the identification of prognostic and predictive biomarkers.

Abstract
At the beginning of 20th century only a few hundred cases of lung cancer were diagnosed annually, but the progressive huge spread of tobacco consumption caused a dramatic increase of the incidence of this disease among men and later on among female smokers. US data shows that the prevalence of smoking in American women peaked in 1965 at 33% and remained at that level throughout the 1970s, before beginning to slowly decrease in 1980. In contrast, more than half of American men smoked before 1965, but the prevalence dramatically decreased during the subsequent 20 years. Currently, 18% of American women smoke compared with 23% of men, reflecting the earlier and more marked decline in the prevalence of tobacco use in men. Nowadays, more women in United States die from lung cancer each year than from breast, ovarian and uterine cancer combined: lung cancer is the leading cause of cancer death with more than 110,000 new cases and more than 72,000 estimated deaths in 2013. In European countries there are more than 79,000 new cases of lung cancer in female sex per year and 82,000 is the estimated death number in 2013, that means 9,024 more than what was reported in 2009. Approximately 80% - 85% of lung cancers in women are caused by cigarette smoking. Wang et al. investigated the association of both active and passive smoking on lung cancer risk in a prospective cohort of more than 90,000 post-menopausal women: the results of the Women’s Health Initiative Observational Study (WHI-OS) have been presented at 2013 ASCO annual meeting and evidenced an higher lung cancer incidence, particularly small cell lung cancers and squamous lung cancers, in current smokers (Hazard Ratio, HR 13.44, 95%, CI 10.80-16.75) and former smokers (HR 4.20, 95% CI 3.48-5.08) compared to never smokers. In the same study, among never smoking women, passive exposure, as an adult at home for > 30 years, was associated with a trend of increased risk (HR 1.61, 95% CI 1.00-2.58) for lung cancer, confirming findings of previous prospective cohort studies. In recent times, an increased proportion of non-smoking female patients, with earlier age at diagnosis and a majority of adenocarcinoma has been observed, particularly in Asian countries. Prevalence of lung cancer in females without history of tobacco smoking is estimated to represent 19% compared with 9% of male lung carcinoma in the United States. Freedman et al. reported, on a cohort of nearly 500,000 individuals, aged from 50 to 71 years, a significant increase in the rate of lung cancer for women who did not smoke, compared with male non-smokers, whereas no increased risk was described in current and former female smokers compared with matched males. Hormonal status is one of the potential explanations for gender differences. Estrogens are involved in lung tumorigenesis and progesterone receptor expression has been described in non small cell lung cancers (NSCLC). Combination of estrogen and progesterone works synergistically in vitro to promote vascular endothelial growth factor secretion increasing tumor-associated angiogenesis. Chlebowski et al. examined estrogen plus progestin (E+P) association with lung cancer incidence and outcome evaluating more than 30,000 postmenopausal women. Results have been presented at 2013 ASCO annual meeting: in non users of E+P, lung cancer incidence and deaths from lung cancer were significantly and substantially greater in current smokers versus never smokers (p< 0.0001 for both comparisons). In current smokers, lung cancer incidence and deaths from lung cancer were significantly and substantially greater in E+P users versus non-users (p=0.0021 and 0.0005, respectively), nearly doubling a smoker’s already high risk of death from lung cancer. Conversely, the role of androgens remains unclear. Harlos et al. evaluated more than 3,000 men with lung cancer evidencing that exposure to androgen deprivation therapy (ADT) is associated with significantly better survival when compared with no exposure. Patients exposed to ADT after their diagnosis were found to have a significantly better survival than those not exposed (HR 0.36 p=0.0007). This effect was also seen in those who received ADT before and after diagnosis (HR 0.53 p<0.0001). With regard to specific gene alterations there are relevant differences in men and women. The most widely recognized is the epidermal growth factor receptor (EGFR) mutation, that is found at a much higher frequency in adenocarcinomas, women, Asians and never smokers. Mutations in HER2 gene, although much rarer, target the same subpopulations. Mutations in EGFR (and HER2) are mutually exclusive of K-ras mutations: these are primarily observed in smokers and historically associated with male sex, but there are also publications demonstrating an higher frequency in women of “non-classical” type of K-ras mutations even if these data need further validations. The echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation has been evidenced to occur more frequently in young patients, light or never smokers, while no major differences have been clearly stated between genders. B-Raf (V600) is described in 2% of patients with lung adenocarcinoma in western countries, related with worse prognosis and it is noted more frequently in women. An analysis of the p53 mutation databases indicated that the different spectra of p53 mutational patterns among smoker and never smoker cancers were almost entirely a result of differences between lung cancers in women, whereas male tumours did not show significant differences. Finally, recent studies investigated the role of telomere shortening in lung cancer. Kim et al. hypothesized that relative telomere length may be associated with recurrence in early stage NSCLC after curative resection. Longer telomeres were significantly associated with higher risk of developing recurrence in female (HR 2.25; 95% CI, 1.02-4.96, P= 0.044) and adenocarcinoma subgroups (HR 2.19; 95% CI, 1.05-4.55). All these findings provide multiple evidence for the specificities of lung cancer in women. The different expression of specific biomarkers, which could be targeted by therapy, will improve research towards personalized sex-based investigations, stimulating the development of further gender-based approaches in thoracic oncology.

Abstract
In 2011, an international multidisciplinary classification of adenocarcinoma was published (2011 IASLC classification) (1) (Table). Pathologists, oncologists, radiologists, and basic scientists in the field of lung cancer are involved in this project. The new concepts of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) in this classification are based on the multistep carcinogenesis of adenocarcinoma (2). Pulmonary adenocarcinoma develops to invasive adenocarcinoma through atypical adenomatous hyperplasia (AAH), AIS, and MIA. The diagnostic criteria for AIS and MIA were first defined in this new classification. AAH is a localized proliferation of mildly to moderately atypical cells lining involved alveoli and, sometimes, respiratory bronchioles. AAH is usually less than 5 mm in diameter and lacks any underlying interstitial inflammation or fibrosis. Before, AAH was detected as incidental findings in the adjacent lung parenchyma in resected lung adenocarcinoma, but recently it is found by thin-slice CT scan examination and shows characteristic ground glass opacity (GGO), similar to AIS. AAH shows positivity for TTF-1 antigen and is a preinvasive lesion of peripheral-type adenocarcinoma, especially the terminal respiratory unit (TRU) type (3). Adenocarcinoma with pure lepidic growth is a special subtype, because it mimics AAH, which is a preinvasive form of adenocarcinoma and has an extremely favorable prognosis. Among the pure lepidic adenocarcinomas, “adenocarcinoma in situ” is defined as localized small (< 3 cm) adenocarcinoma with growth restricted to neoplastic cells along preexisting alveolar structures (lepidic growth), lacking stromal, vascular, or pleural invasion. Differential diagnosis between AAH and AIS is sometimes very difficult. AIS corresponds to type A and B adenocarcinoma according to the 1995 Noguchi classification (4). AIS is usually nonmucinous but rarely may be mucinous. MIA is a small, solitary adenocarcinoma (< 3 cm), with a predominantly lepidic pattern and < 5 mm invasion in greatest dimension in any one focus. By definition, the invasive component is composed of histological subtypes other than the lepidic pattern (i.e. acinar, papillary, micropapillary, and/or solid) or tumor cells infiltrating myofibroblastic stroma (malignant stroma). MIA is excluded if the tumor invades lymphatics, blood vessels, or pleura, or contains tumor necrosis. If the tumor is larger than 2 cm, diagnosis should be done with caution, and the tumor needs to be extensively sampled, especially the solid component. On thin-slice CT examination, MIA reveals pure GGO or a partly solid appearance. MIA corresponds to type C’ adenocarcinoma according to the modified Noguchi classification (5). We believe that the 5-year survival of patients with localized resected MIA is more than 95%, but there are no actual data on the clinical outcome of MIA. In Japan, leading radiologists and pathologists have just started a joint project to clarify the natural history of MIA, supported by the Ministry of Health, Labor and Welfare. First, they are defining the radiological diagnostic criteria for MIA. Then, based on the criteria, they will follow up cases for more than 5 years. In the course of follow-up, the growing cases will be surgically resected and examined histologically. Finally we will understand the radiological and biological characteristics of MIA in more detail. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, micropapillary, and solid patterns. Among the subtypes, lepidic growth represents in situ growth or spreading of invasive adenocarcinoma and the region showing lepidic growth does not influence the patient’s outcome. Therefore, it is very important to report the percentage of the lepidic subtype in the invasive adenocarcinoma. In order to verify the utility of invasive adenocarcinoma classification, interobserver agreement (kappa value) of the diagnostic criteria was assessed (6). Eight Japanese pathologists used the 2011 IASLC classification to independently evaluate the histologic grade of 122 adenocarcinoma cases resected in the National Cancer Center Hospital (Tokyo). The mean (±SD) value of the kappa statistic for the 2011 IASLC classification was 0.46±0.09 (range: 0.24 to 0.61) and the value was not enough for practical use. But, if we modified the classification into low grade (lepidic, acinar, and papillary) and high grade (solid and micropapillary), the mean (±SD) value rose to 0.66±0.09 (range: 0.47 to 0.85) reaching the level of practical use (Figure). Therefore, the modified 2011 IASLC classification shows the clinical outcome of the invasive adenocarcinoma. References (1) Travis WD, Elisabeth B, Noguchi M, et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thoracic Oncol 6:244-285, 2011. (2) Noguchi M. Stepwise progression of pulmonary adenocarcinoma. Clinical and molecular implications. Cancer Metastasis Rev 29:15-21, 2010. (3) Yatabe Y, Kosaka T, Takaashi T, et al. EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol 29:633-9, 2005. (4) Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 75:2844-2852, 1995. (5) Minami Y, Matsuno Y, Iijima T, et al. Prognistication of small-sized primary pulmonary adenocarcinomas by hitopathlogical and karyometric analyasis. Lung Cancer 48:339-348, 2005. (6) Nakazato Y, Maeshima AM, Ishikawa Y, et al. Interobserver agreement in the nuclear grading of primary pulmonary adenocarcinoma. J Thoracic Oncol 8:736-743, 2013

Abstract
Squamous cell carcinoma is one of the four common types of lung cancer, and is defined as a malignant epithelial tumour showing evidence of squamous differentiation in the form of keratinisation, intercellular bridging or both. The main purpose of a pathological classification is to produce clinically relevant subgroups, in addition being reproducible, thorough, dynamic, and globally applicable, and this talk summarises the current WHO classification and potential new parameters. Current morphological classification: Since the 1999 classification, the recognised variants have been being papillary, clear cell, small cell and basaloid. Pure primary basaloid carcinomas of the lung are rare and the current WHO (2004) classification classifies basaloid carcinomas as variants of large cell carcinoma when they lack evidence of squamous differentiation. When squamous differentiation is present, they are classified as basaloid variants of squamous cell carcinoma. Basaloid morphology has been shown to carry a poorer prognosis than poorly differentiated squamous cell carcinomas for stage I and II disease. Papillary squamous cell carcinomas tend to be endobronchial and most are staged as T1N0 with a 5‑year survival of over 60 percent, which may be due to early presentation at this location rather than the architectural pattern itself. With regard to small cell and clear cell variants, the last decade has seen virtually no publications. Indeed, the primary reason for recognising these variants is to avoid misdiagnosis as metastases or other subtypes of lung carcinoma. Therefore, with the exception of the basaloid variant that appears to carry a worse prognosis, especially given small cell and clear cell variants are cytological parameters, consideration should be given to their removal from the next WHO classification, as well as the papillary variant. Also, given the increased knowledge in relation to immunophenotyping, basaloid and basaloid variant of squamous cell carcinoma could potentially be collapsed into a single subgroup of squamous cell carcinoma. Potential new morphological subgroups: The last decade has seen publications suggesting an architectural classification termed "alveolar filling" pattern. One paper has shown 100% survival when this pattern is present, although the number of cases showing this as a pure pattern is very low, around 1-2%. A more recent paper has suggested that the percentage of alveolar filling (greater than 70%) was significantly associated with a better prognosis, arguing that in tumours less than 30 mm in maximum diameter, a minimally invasive category might be appropriate. Tumours with this predominance would likely be sufficiently frequent (near 25%) to be clinically useful, and more data are required to support its inclusion. Other histological parameters such as extent of background of lymphocytic infiltration and keratinisation do not seem to carry prognostic significance. Classification according to presentation and/or aetiological factors: Publications in the last decade have suggested that the frequency of peripheral squamous cell carcinomas is increasing, with a greater number of stage 1 patients having peripheral presentation, although there was no difference in survival in N0 disease when compared to central tumours in one paper (Funai K et al Am J Surg Pathol 2003:27;978-984) . Indeed, survival was better in N1 disease in central presenting tumours. The alveolar pattern of growth was seen within the peripheral group only. However, unlike adenocarcinomas where those that present peripherally may be never-smokers, nearly all peripheral squamous carcinomas appear to be either current or ex-smokers. The frequency of HPV being present in squamous cell carcinoma of the lung varies extensively in the literature. The same ‘high-risk’ subtypes of HPV for cervical carcinoma are found in invasive bronchial carcinomas. However, although data from oropharyngeal squamous cell carcinomas suggest HPV infection is associated with better prognosis, data in the lung are conflicting. There is also likely synergism between smoking and infection as the preferred site of entry for HPV is at squamo-columnar junctions, and the presence or absence of HPV is unlikely to be recommended as a parameter for subclassification. Pre-invasive lesions: Squamous lesions arising in the airways have been regarded as progenitors of squamous carcinoma for decades and basal cell hyperplasia and squamous metaplasia also likely represent earlier phases in the development of squamous carcinomas. The current WHO/IASLC classification tabulates methodology for such gradation, and the system is sufficiently reproducible for diagnostic usage. The sequence progresses from basal cell hyperplasia through squamous metaplasia and squamous dysplasia to carcinoma-in-situ. Immunohistochemistry and small biopsies: The past decade has seen increasing usage of immunohistochemistry to refine the diagnosis of non-small cell carcinoma, driven by the needs for more accurate subclassification in relation to chemotherapeutic agents. This is not part of the current (WHO 2004) classification, although is recommended for use in biopsies by the IASLC as well as the ATS and ERS in relation subclassifying biopsies hitherto called non-small cell carcinoma, not otherwise specified (NSCLC-NOS) (Travis et al. J. Thor. Oncol. 2011;6:244-85). Therefore, any biopsy with NSCLC showing keratinisation and/or intercellular bridges should be classified as squamous cell carcinoma and, in NSCLCs lacking these or other disciminating morphological features on biopsy, but showing immunohistochemical evidence of squamous differentiation (one or two of CK 5/6, P63, and P40 being the most commonly used antibodies for this purpose) should be classified as NSCLC, favouring squamous cell carcinoma on immunohistochemistry. Similar investigation should also be considered in resected large cell undifferentiated carcinomas. Molecular subtypes: There is a vast literature on the carcinogenesis of squamous carcinoma, in particular preinvasive lesions. However none have yet become part of pathology classification. In relation to targeted therapy for invasive squamous cell carcinoma, data are still primarily related to clinical trials, with low frequencies of identification. Therefore, although targets such as DDR2 show some promise, at present, there is insufficient data to warrant pathological classification of invasive squamous carcinoma in relation to specific genetic abnormalities. Conclusion: Unlike adenocarcinomas, there has not been much advance in the morphogical subtyping of squamous cell carcinoma. There has however been advance in immunophenotyping, especially in relation to NSCLC-NOS, and it is hoped that molecular classification may have a role to play in the next decade.

Abstract
Large cell and sarcomatoid carcinomas account for approximately 10% of all lung cancers. For all practical purposes, each of these diagnoses can only be made with accuracy in surgically resected cases since tumour definitions mandate a feature be excluded from or present in at least 10% of the whole lesion. Although features suggesting a large cell variant or sarcomatoid tumour may be recognised in a small biopsy or cytology sample, these diagnoses are inappropriate in such samples. Large cell carcinoma (LCC) is morphologically defined as comprising large undifferentiated tumour cells lacking any evidence of squamous, glandular or small cell carcinoma (SCLC). Epidemiologically these cases are no different from most other non-small cell carcinomas (NSCLC). They favour a more peripheral location in the lung and necrosis is common. Cells are generally large, with open nuclei, prominent nucleoli and abundant cytoplasm, but some cases show hyperchromatic, granular nuclei, inconspicuous nucleoli and less cytoplasm. In the classical case, the cells show no organisation, just sheets of cells with little intervening vascular stroma, but some cases show cellular stratification with more abundant fibrous stroma. Several variants of large cell carcinoma are described. Large cell neuroendocrine carcinoma (LCNEC) additionally requires demonstration of neuroendocrine differentiation, usually by immunohistochemistry. These are often large, necrotic tumours and share many epidemiological and molecular features with small cell lung carcinoma. Organoid morphology with trabeculae and rosettes are common. A significant proportion of LCNEC are combined with other tumour types in the same lesion, most often adenocarcinoma. These cases would more logically reside in a separate category with other NE tumours. The basaloid variant of LCC largely meets the above definition, but tends to have rather smaller cells, peripheral nuclear palisading around discrete nests/sheets of cells, frequent intercellular basement membrane material, like basaloid carcinomas at other sites. An infrequent and unusual form of small keratin pearl may be seen but basaloid carcinomas lack the larger cells with eosinophilic cytoplasm and intercellular bridges of squamous cell carcinomas (SCC). They share immunohistochemical features (p63, p40, CK5/6, desmocollin3) with SCC and could represent de-differentiated SCC. Defining basaloid carcinoma apart from SCC remains a controversial issue. Lymphoepithelioma-like lung carcinoma (LELC) comprises a syncytium of large undifferentiated cells with indistinct cell borders and a heavy lymphoplasmacytic infiltrate. Commoner in East Asian countries, this tumour is still rare and is closely associated with EBV genome. Distinction from other poorly differentiated carcinomas with a heavy immune cell infiltrate may be impossible in the absence of evidence of EBV infection and the latter should, perhaps, be incorporated into the tumour definition. Clear cell carcinoma of the lung features large cells with clear cytoplasm. This histological feature is, however, seen in a range of other NSCLC and as such, serves little useful purpose, apart from awareness of potential confusion with metastatic renal cell carcinoma. This would be better used as a descriptor rather than defining a separate tumour category. Large cell carcinoma with rhabdoid phenotype is rather ill-defined and extremely rare. A few cases reports or small series reflect the heterogeneity of so-called cases with no clear definition. One common impression is that of an aggressive tumour but again, this terminology is better used as a descriptor rather than defining a separate subtype. Emerging immunohistochemical and molecular data have questioned the nature of large cell carcinoma and our current classification. Many cases share a molecular and/or immunohistochemical phenotype with either squamous cell or adenocarcinoma, suggesting that they should be classified by their molecular profile, effectively deleting the LCC category. This approach has several problems including the following: (a) Not all cases can be so re-classified as squamous cell or adenocarcinoma, (b) these immune/molecular profiles are not specific for either diagnosis, and (c) the definition of these differentiated tumours is based on H&E morphology, not immune/molecular findings. Further confusion stems from the inappropriate use of the term ‘large cell carcinoma’ in the small biopsy/cytology setting. Any sample containing large undifferentiated cells lacking features of small cell carcinoma should be referred to as NSCLC, not otherwise specified (NOS) and not ‘large cell carcinoma’. Most of these cases, if resected, derived from differentiated adeno- or squamous cell carcinomas. The legitimate, recommended use of IHC to predict tumour subtype in small samples is neither validated nor justified in resected tumours under the current classification. However, it may be useful to characterise resected LCC cases by immunophenotype since this may correlate with some targetable mutations but it should not lead to a major change in diagnosis. Mutations of EGFR or KRAS are rarer than in adenocarcinoma but correlate with TTF1 positivity. Sarcomatoid carcinomas show pleomorphic, spindle or giant cells comprising at least 10% of the tumour. Usually all three cell types are seen. They account for 3-4% of resected tumours and are usually large, invasive, necrotic tumours. They are clinically aggressive and frequently chemorefractory, justifying their separation in our classification. Most lesions also show differentiated squamous cell or adenocarcinoma components. As for LCC, this diagnosis should not be made in the small biopsy/cytology setting but if these cell types are present in the sample they should be described in the report. Immunohistochemical and/or molecular studies are few. Most cases show an immunoprofile in the sarcomatoid component consistent with the differentiated tumour also present. Pure sarcomatoid cases may also show a ‘differentiation-associated’ immunoprofile but often it is inconclusive or IHC is negative. KRAS mutations have been consistently reported in a few case series. Carcinosarcoma is an exceptionally rare tumour, defined in the lung as a lesion showing carcinoma plus differentiated, heterologous sarcomatous elements, such as rhabdomyo, osteo or chondrosarcoma. Pulmonary Blastoma is a biphasic lesion combining primitive mesenchymal tumour and well-differentiated adenocarcinoma, the latter described as endometrioid or ‘fetal’ in pattern. Regarding the more typical cases of LCC, sarcomatoid and basaloid carcinoma, the molecular evidence supports the concept that these tumours may represent dedifferentiated carcinomas of the lung. How this emerging concept is reflected in our classification is a matter of ongoing debate.

Abstract
TUMORLETS AND DIFFUSE IDIOPATHIC PULMONARY NE CELL HYPERPLASIA (DIPNECH) Tumorlets are defined as nodular proliferations of NE cells that measure less than 0.5 cm in greatest diameter. Tumorlets typically represent incidental histologic findings found in lung tissues with inflammatory and/or fibrotic lesions such as bronchiectasis, interstitial fibrosis, or infections. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) consists of widespread peripheral airway NE cell hyperplasia and/or multiple tumorlets. These patients are thought to represent a preinvasive lesion for carcinoid tumors because a subset of these patients has one or more carcinoid tumors.[1] DIPNECH may present as multiple pulmonary nodules often mistaken for metastatic cancer or as a form of interstitial lung disease with airway obstruction. Histologically DIPNECH is characterized by prominent NE cell hyperplasia and tumorlets. Some patients also have carcinoid tumors. Tumorlets may cause airway narrowing and/or obliteration. The surrounding lung parenchyma is generally normal.CARCINOID TUMORS Carcinoid tumors most commonly show an organoid growth pattern. The tumor cells show uniform cytologic features with a moderate amount of eosinophilic cytoplasm and finely granular nuclear chromatin. AC are separated from TC by the presence of mitoses between 2 and 10 per 2mm[2] area or the presence of necrosis. Necrosis is usually in the form small punctate foci. Other histologic features such as pleomorphism, vascular invasion and increased cellularity are not as helpful in separating TC from AC. Chromogranin, CD56 and synaptophysin are the most helpful NE immunohistochemical markers. A clear role for Ki-67 in separating TC from AC is not established. However, a low proliferation rate (≤5%) is typically seen in TC compared to AC where it is usually between 5 and 20%. Ki-67 is most useful in addressing the problem of over diagnosis of a high grade tumor in carcinoid tumors where diagnostic criteria are obscured in small crushed biopsies. In this setting a high proliferation rate (>59%) will be found in the high grade LCNEC or SCLC where TC or AC show a much lower proliferation rate.LARGE CELL NEUROENDOCRINE CARCINOMA LCNEC is a high grade NE carcinoma with cytologic features of a non-small cell carcinoma. It was classified as a variant of large cell carcinoma in the 2004 WHO classification.[1] LCNEC are diagnosed according to the following criteria: 1) NE morphology with organoid nesting, palisading or rosette-like structures, 2) high mitotic rate greater than 10 mitoses per 2 mm[2] (average 60-80 mitoses per 2 mm[2]), 3) non-small cell cytologic features including large cell size, low nuclear/cytoplasmic ratio, nucleoli, or vesicular chromatin, and 4) NE differentiation by immunohistochemistry with antibodies such as chromogranin, CD56 or synaptophysin or electron microscopy. The diagnosis of LCNEC is difficult to establish based on small biopsies or cytology. This is because the NE pattern is difficult to see morphologically in small tissue samples or cytology. Also NE differentiation can be difficult to demonstrate by immunohistochemistry in small pieces of tissue. For these reasons the diagnosis of LCNEC requires a surgical lung biopsy. When a LCNEC has components of adenocarcinoma, squamous cell carcinoma, giant cell carcinoma and/or spindle cell carcinoma it is called combined LCNEC. The most common component is adenocarcinoma, but squamous cell, giant cell or spindle cell carcinoma can also occur. If the second component is SCLC the tumor becomes a combined SCLC and LCNEC. NE differentiation must be demonstrated by immunohistochemistry or electron microscopy to diagnose LCNEC. NE immunohistochemical markers are usually best performed as a panel of chromogranin, CD56/NCAM, and synaptophysin. In 41-75% of cases, TTF-1 will be positive. The proliferation index by Ki-67 staining is very with staining of 50-100% of tumor cells .SMALL CELL CARCINOMA The diagnosis of SCLC is established based on small specimens such as bronchoscopic biopsies, fine needle aspirates, core biopsies, and cytology in most all cases, because of the presentation in advanced stages. Fortunately these specimens are diagnostic in most all cases. The diagnosis is based primarily based on light microscopy. Tumor cells appear round to fusiform, growing in sheets and nests. Necrosis is common and is often extensive. Tumor cell cytoplasm is scant and nuclear chromatin is finely granular. Tumor cell size is usually less than the diameter of three small resting lymphocytes. Nucleoli are inconspicuous or absent. A high mitotic rate averages 60-80 per 2 mm[2], however, mitoses can difficult to identify in small biopsy specimens. Combined SCLC is diagnosed when there is also a component of NSCLC such as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, spindle cell carcinoma and giant cell carcinoma. In this setting each of the non-small cell components should be mentioned in the diagnosis. Combined SCLC can be seen in 25% of surgically resected tumors. At least 10% large cells should be present for the diagnosis of combined SCLC/large cell carcinoma; however, for the components of adenocarcinoma, squamous cell or spindle cell carcinoma the amount does not matter. Diagnostic challenges occur in the settings of crush artifact and surgically resected specimens. Crush artifact is common in small biopsy specimens. This can create a problem in separating SCLC from a variety of tumors including non-small cell lung cancer (NSCLC), lymphoma, carcinoid and chronic inflammation. Immunohistochemistry can be very helpful in this setting. In well fixed specimens such as resected specimens the tumor cells of SCLC appear larger than in small biopsies. This often results in over diagnosis of LCNEC. The most important special stain for the diagnosis of SCLC is a good quality H&E stain. However, a panel of immunohistochemical stains is often helpful in the diagnosis. The most common cause of problems in interpretation of biopsies for the diagnosis of SCLC result from sections that are too thick or poorly stained. If the histologic features are classic, it may not be needed. The stains that are useful for the diagnosis of SCLC include a pancytokeratin antibody such as AE1/AE3, CD56, chromogranin and synaptophysin, TTF-1 and Ki-67. If keratin is negative, In 70-80% of SCLC TTF-1 is positive. The main role of Ki-67 is to distinguish SCLC from carcinoids because the proliferation is very high (50-100%) in SCLC.

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Abstract
Over the last decade, combined modality therapy has been established as standard of care for patients with locoregionally advanced unresectable non-small cell lung cancer (1). Both induction chemotherapy followed by radiation as well as concomitant chemoradiotherapy have been shown to be superior to radiotherapy alone and both approaches extend progression-free and overall survival. In direct comparison, concomitant chemoradiotherapy has been shown to be superior to induction in several randomized phase III trials as well as meta-analyses, likely due to enhanced locoregional control due to the chemotherapy radiation sensitization effect (2, 3). Currently about 20 to 30% of patients can be cured. While there are established clinical prognostic factors, very little information exists to more precisely guide prognosis or therapeutic approach for individual patients. In trying to improve survival outcomes induction chemotherapy was added to concomitant chemoradiotherapy but failed to result in superior outcome compared to concomitant chemoradiotherapy alone.(4). Similarly, consolidation chemotherapy or maintenance therapy with erlotinib in patients unselected for molecular characteristics did not improve survival compared with concomitant chemoradiotherapy alone (5,6). Several chemotherapy regimens have been investigated in the concomitant setting including the mitomycin/vinblastine/cisplatin (MVP) regimen, carboplatin/paclitaxel given weekly (and this regimen has consolidation chemotherapy for two cycles built in) and cisplatin/etoposide. The latter two are frequently used standards in control arms for current randomized trials. There has also been interest in the combination of carboplatin and pemetrexed given the superior single modality activity of the platinum/pemetrexed regimen in non-squamous cell tumors (7). It has been demonstrated that this drug combination can be given at full systemic doses in combination with radiation, thus providing good systemic coverage to eradicate micro-metastases as well as locoregional radiation enhancement. Whether any of these regimens is superior to another is not clear and few direct comparisons have been completed. Japanese investigators compared carboplatin/taxol with carboplatin/irinotecan and the MVP regimen in combination with concomitant radiation and reported equivalent outcomes with these regimens(8). In a small trial comparing carboplatin/taxol with cisplatin/etoposide and radiotherapy, the platinum/etoposide regimen appeared to be superior; however, the number of patients was very limited at approximately 30 per arm (9). Cisplatin/pemetrexed vs. carboplatin/pemetrexed has also been compared in a randomized phase II format supporting a trend for superiority of cisplatin-based therapy as has been shown for other stages of non-small cell lung cancer as well (10). A large randomized phase III trial comparing cisplatin/etoposide with cisplatin/pemetrexed each with concomitant radiotherapy to 66 Gy has been completed. This study was closed after a futility analysis at near completion of planned accrual and a full analysis of this trial is awaited for the future. Targeted therapies have also been of interest. While they have matured to be standard therapy for many patients with stage IV disease their role in earlier stages remains under-investigated. In a number of uncontrolled trial, the addition of erlotinib or gefitinib to radiation therapy with or without additional chemotherapy has been shown to be feasible. In the Alliance Cooperative Group (formerly CALGB), a recent trial looking at induction chemotherapy with carboplatin and albumin-bound paclitaxel followed by erlotinib and concomitant radiotherapy for patients with poor-risk stage III non-small cell lung cancer was completed. Median progression-free and overall survival times of 11 months and 16 months respectively were encouraging. However, no comparative arm of radiotherapy alone was included in the trial design (11). Similarly, cetuximab has been integrated into this treatment approach. RTOG 0324 reported encouraging pilot data from the addition of cetuximab to carboplatin/paclitaxel-based concurrent chemoradiation and consolidation chemotherapy(12). A randomized trial comparing the base regimen vs. the base regimen plus cetuximab in this setting has been completed and mature results are expected in the near future. It should be cautioned however, that the larger clinical experience with the addition of cetuximab to concurrent chemoradiotherapy regimens to date has been disappointing. A randomized phase II study conducted by the CALGB (CALGB#30407) found no obvious clinically significant benefit from the addition of cetuximab to carboplatin/pemetrexed radiotherapy (7). Median survival times were 21.2 and 22.4 months respectively for the two study arms. Similarly, controlled trials investigating the addition of cetuximab in patients with esophageal or head and neck cancer to concomitant chemoradiotherapy have not shown a statistically significant benefit compared to chemoradiotherapy alone. Current research interest is focused on the treatment of patients with molecular abnormalities, in particular EGFR mutations or EML/alk translocation. For these patients, a study investigating induction chemotherapy with either erlotinib or crizotinib, respectively followed by standard concurrent chemoradiation vs concurrent chemoradiation alone is about to be activated. Similarly, immunological approaches are of interest. At present, no data from studies investigating CTLA-4 or PD1 inhibitors are available. However, a randomized trial investigating the BLP25 vaccine, a liposome MUC1-based vaccine, has recently been reported. This vaccine attempts to induce a proliferative T-cell response to the MUC1 antigen which is frequently overexpressed and hyper-glycosylated in non-small cell lung cancer. In this trial, patients completed standard combined modality therapy (either induction or concomitant chemoradiotherapy) and were then randomized to either a placebo or the active vaccine. For the overall study cohort a trend in survival was observed which was more pronounced in a planned subset analysis of patients receiving concomitant chemoradiotherapy (13). This study adds support to further investigations to vaccine-based approaches. While current standard therapy approaches do result in consistent cure rates of 20-30% of patients, further progress will depend on the development of more specific combined modality approaches. Immunological and molecularly driven clinical trials will be of particular interest in this regard.

Abstract
For years radiation oncologists have dreamed of being able to dynamically adapt treatment to the response of normal and tumor tissues observed during a protracted course of radiotherapy. An obvious goal is to adjust the PTV as the GTV shrinks during treatment, which may improve dose volume metrics in the organs at risk, especially lung. Reinflation of atelectatic lung in response to tumour size reduction may require adjustment of PTV size and position to avoid geographic miss. Cone beam CT (CBCT) has revolutionised the ability to regularly image soft tissue, although it is less useful for targets within the mediastinum or those defined primarily by FDG PET. The main limiting step is the time required to develop an adaptive treatment plan without interrupting treatment. Experience suggests that tumor reduction needs to be substantial to have a meaningful impact on the dose volume metrics. The use of serial FDG PET during treatment to detect residual activity and to use this as a surrogate for persistent disease for adaptive radiotherapy is under investigation. This is however based on an unproven assumption that such FDG activity is due to tumor and not inflammation. Tumor motion adds further uncertainty, affecting both SUV and intrafraction location of the residual FDG uptake. CBCT may also detect tumor progression. This seems to be uncommon.(1) When it occurs, apart from discontinuing futile treatment to avoid unnecessary toxicity, can anything else be done? Our group has investigated the use of PET tracers to detect functional changes in tumour during treatment, including FDG and the thymidine based tracer FLT which we hypothesise images tumour proliferation. Preliminary results indicate that FLT detects functional changes in the tumour earlier than FDG, but the clinical implications of this are unknown.(2) One patient with clinical progression had increased uptake of FLT detected at 20 Gy, suggesting accelerated repopulation. The rate of treatment was accelerated with twice daily fractionation, resulting in a reduction in FLT uptake, providing anecdotal proof of principle. Accelerated repopulation has also been indirectly observed with induction chemotherapy.(3) Imaging with FLT may present an opportunity to detect altered proliferation pre-radiotherapy which may benefit from accelerated fractionation.(4) A further change that may occur during fractionated treatment is reoxygenation. We have observed changes in uptake of the hypoxia PET tracer FAZA during a course of radiotherapy,(5) indicating that hypoxia is present in some tumors pre-treatment, although surprisingly little use is made of this knowledge in clinical practice. Changes observed in normal tissue response may also present opportunities for adaptive treatment. The patient can be used as a biological dosemeter, and the occasional patient will require truncation of treatment because of esophagitis. Is this increased sensitivity a surrogate for inherently increased radiosensitivity within the tumor, indicating that a higher tumor dose is unnecessary for such patients? Our group has observed changes in normal lung during treatment using ventilation/perfusion imaging, opening up prospects of avoiding functioning (as opposed to anatomical) lung with beam redirection.(6) Conclusions: A number of tools are now available to detect tumor and normal tissue response to radiotherapy during treatment. These changes may be anatomic or functional, including changes in tumor kinetics or the micro-environment. The challenge now is to turn these observations into clinically useful patient benefits. References 1. Lim G, Bezjak A, Higgins J, Moseley D, Hope AJ, Sun A, et al. Tumor regression and positional changes in non-small cell lung cancer during radical radiotherapy. J Thorac Oncol. 2011;6:531-6. 2. Ball D, Everitt S, Hicks R, Callahan J, Plumridge N, Collins M, et al. Differential Uptake of F18-fluoro-deoxy-glucose (FDG) and F18-fluoro-deoxy-l-thymidine (FLT) Detected by Serial PET/CT Imaging During Radical Chemoradiation for Non-Small Cell Lung Cancer (NSCLC). . J Thorac Oncol 2012;7:S238. 3. El Sharouni SY, Kal HB, Battermann JJ. Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy. Br J Cancer. 2003;89:2184-9. 4. Baumann M, Herrmann T, Koch R, Matthiessen W, Appold S, Wahlers B, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol. 2011;100:76-85. 5. Trinkaus ME, Blum R, Rischin D, Callahan J, Bressel M, Segard T, et al. Imaging of hypoxia with (18) F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy. J Med Imaging Radiat Oncol. 2013;57:475-81. 6. Siva S, Callahan J, Hofman MS, Eu P, Martin O, Pope K, Ball D, MacManus M, Kron T, Hicks RJ. Technical considerations and preliminary experience of a pilot study of Gallium-68 VQ 4D-PET/CT in lung radiotherapy. J Thorac Oncol 2012;7: S1182.

Abstract

Abstract
There is no general agreement on the definition of the “borderline” patient with stage III non-small cell lung cancer (NSCLC). Patients judged to be unsuitable for standard treatment could be of advanced age, unable to undergo cisplatin-based chemotherapy, poor performance status, poor pulmonary function and/or bulky tumors requiring large radiation fields. Since the combination of chemotherapy and radiation therapy (RT) has been adopted as the standard of care, there has been an increased portion of elderly patients who receive it. [1]. Cooperative group studies have demonstrated that the elderly have more toxicity then their younger counterparts and that age is a negative prognostic factor for survival. [2, 3, 4] However, the elderly with good PF still have improved survival with combined chemoRT as opposed to radiation only. Prospective studies in the “borderline” patient by cooperative groups in North America and Asia have had various eligibility criteria. [5, 6, 7, 8]. Those studies accrued slowly or poorly, perhaps due to the 6-7 week RT required in most studies. One RTOG study combining celecoxib and RT did allow either 60 Gy in 6 weeks or 45 Gy in 3 weeks but few patients were treated with the short course. [8] A short of course of RT may be more acceptable to patients who are elderly or have a poor performance status. A retrospective study of patients who did not receive concurrent chemoRT showed that similar survival was seen in patients treated with 45 Gy in 3 weeks as in patients treated with >60 Gy in 6 weeks. [9] Few prospective studies have been done in patients with poor pulmonary function. A retrospective study found that pre-treatment FEV1 was not statistically correlated with symptomatic lung toxicity following concurrent chemoradiation.[10] However, the combination of poor FEV1, advanced age and high mean lung dose correlated positively with pulmonary toxicity. Prospective studies are also lacking in patients with bulky disease for whom large radiation fields are required. Retrospective studies suggest that bulky disease is associated with a higher risk for the early development of metastases and death. [11] Future efforts to improve the therapeutic ratio for borderline patients likely involve the improved ability to predict both benefit and risk for an individual patient. Studies are ongoing using molecular methods to better predict distant metastases-free survival and pulmonary toxicity. [12, 13] 1. van der Drift MA, Karim-Kos HE, Siesling S, et al. Progress in standard of care therapy and modest survival benefits in the treatment of non-small cell lung cancer patients in the Netherlands in the last 20 years. J Thorac Oncol. 2012;7(2):291-8. 2. Schild SE, Mandrekar SJ, Jatoi A, et al. The value of combined-modality therapy in elderly patients with stage III non-small cell lung cancer. Cancer. 2007;110(2):363-8. 3. Langer CJ, Manola J, Bernardo P, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst. 2002;94(3):173-81. 4. Non-small cell lung cancer collaborative group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individuals patients from 52 randomized clinical trials.. BMJ. 7;311(7010) 1995: 8099-909. 5. Lau DH, Crowley JJ, Gandara DR, et al. Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer. J Clin Oncol. 1998;16(9):3078-81. 6. Atagi S, Kawahara M, Tamura T, et al. Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812). Jpn J Clin Oncol. 2005;35(4):195-201. 7. Jatoi A, Schild SE, Foster N, et al. A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422). Ann Oncol. 2010;21(10):2040-4. 8. Gore E, Bae K, Langer C, et al. Phase I/II trial of a COX-2 inhibitor with limited field radiation for intermediate prognosis patients who have locally advanced non-small-cell lung cancer: radiation therapy oncology group 0213. Clin Lung Cancer. 2011;12(2):125-30. 9. Amini A, Lin SH, Wei C, et al. Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non-small cell lung cancer. Radiat Oncol. 2012;7:33. 10. Wang J, Cao J, Yuan S, et al. Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity. Int J Radiat Oncol Biol Phys. 2013;85(3):798-804. 11. Wiersma TG, Dahele M, Verbakel WF, et al. Concurrent chemoradiotherapy for large-volume locally-advanced non-small cell lung cancer. Lung Cancer. 2013;80(1):62-7. 12. Yuan X, Wei Q, Komaki R,et al. TGFβ1 Polymorphisms Predict Distant Metastasis-Free Survival in Patients with Inoperable Non-Small-Cell Lung Cancer after Definitive Radiotherapy. PLoS One. 2013;8(6):e65659. 13. Yin M, Liao Z, Yuan X, et al. Polymorphisms of the vascular endothelial growth factor gene and severe radiation pneumonitis in non-small cell lung cancer patients treated with definitive radiotherapy. Cancer Sci. 2012;103(5):945-50.

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.

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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
The cellular hierarchy of the lung is quite complex and it is believed that different progenitor cells and stem cell populations residing within distinct spatial regions of the lung are responsible for orchestrating lung development, regeneration and repair. These different stem cell populations are also likely to be instrumental in the development of the various cancers in lung as particular lung tumour subtypes are almost exclusively found in distinct compartments within the lung. Squamous cell carcinomas are thought to arise from the proximal airways, small cell lung cancer are predominantly located in the bronchioles while adenocarcinomas are more frequently detected the in the distal part of the lung. To investigate the cellular origin of lung cancer, we utilized Cre-loxP recombination technology, which is an effective method for expressing or deleting a target gene in Cre-expressing cells. We generated a series of recombinant adenoviruses expressing Cre recombinase from specific lung epithelial gene promoters. For these studies we chose to target Clara cells, alveolar type 2 (AT2) cells and neuroendocrine (NE) cells. Comprehensive experiments performed in Rosa26R-lacZ and mT/mG reporter animals showed that these viruses exhibit a high level of cell selectivity in the adult mouse lung. To address the cellular origins of small cell lung cancer (SCLC) we have utilised a sporadic mouse model of small cell lung cancer based on the conditional inactivation of the tumour suppressor genes Tp53 and Rb1. We infected Tp53F/F;Rb1F/F animals with our cell type-restricted Adeno-Cre viruses: Ad5-CC10-Cre, Ad5-SPC-Cre and Ad5-CGRP-Cre. Results from these studies show that inactivation of Trp53 and Rb1 can efficiently transform neuroendocrine (CGRP-positive) and to a lesser extent, alveolar type 2 (SPC-positive) cells leading to SCLC. In contrast, CC10-expressing cells were largely resistant to transformation. The results clearly indicate that neuroendocrine cells serve as the predominant cell-of-origin of SCLC in this model. Interestingly a different, cell type specificity was observed when a K-rasG12D oncogene-driven non-small cell lung cancer (NSCLC) model was used to reveal the cell of origin of NSCLC (mostly of adenomas and adenocarcinomas). In this case we noted a difference between K-rasLSL-G12D/+ and K-rasLSL-G12D/+;Trp53F/F animals following infection with our cell type-restricted adenoviruses. In K-rasLSL-G12D/+ mice alveolar type 2 cells appeared to be the most effective target cell for inducing adenomas, whereas in K-rasLSL-G12D/+;Trp53F/F mice multiple cell types had the capacity to give rise to adenomas and adenocarcinomas. Moreover, preliminary data from these experiments indicates that the cell-of-origin may also influence the characteristics and behaviour of the resulting tumours. Taken together, our data show that both cell specific features and the nature of the genetic lesion(s) are critical factors in determining the tumour initiating capacity of lung (progenitor) cells to give rise to various lung cancer subtypes.

Abstract
Small cell lung cancer (SCLC) is a malignant neuroendocrine tumour responsible for 20% of all lung cancer deaths. Despite the effectiveness of platinum-based chemotherapy, the overwhelming majority of patients succumb to a chemoresistant recurrence within 2 years of diagnosis. Therefore, the discovery of novel strategies to prevent disease recurrence may have a significant impact on outcome. Many groups, including our own, have identified the importance of embryonic signaling pathways in promoting tumor-regeneration through the regulation of self-renewal. Activation of self-renewal pathways such as Notch, Hedgehog (Hh) and WNT is also thought to contribute to the survival of cancer cells with innate resistance to chemotherapeutic agents. Since the naturally occurring Hh inhibitor cyclopamine can block self-renewal in SCLC cells in vitro, we postulated that this pathway might be targetable following platinum-based chemotherapy. The Hh pathway is a highly conserved signaling system that specifies cell fate and self-renewal in development and homeostasis. The Hh ligand Sonic Hh (Shh) binds to, and inactivates, the receptor Patched (Ptch). This prevents Ptch from inhibiting Smoothened (Smo), the molecular target of the small molecule Hh inhibitors. Smo activation requires translocation to the tip of the primary cilium, a single, immotile, tubulin-based organelle present on most vertebrate cells. The ciliary motor protein Kif3a is essential for Smo translocation to the ciliary tip, and is required for Smo signaling in development. The importance of primary cilia in cancer is poorly understood. In addition, the formation of cilia is normally restricted to cells in the G0 of G1 phases of the cell cycle. In order to better understand how Hh signaling is regulated in SCLC, we investigated pathway activation in the context of cilia formation, and the expression of Smo protein in these cilia. Using a genetic mouse model of SCLC, we observed that approximately 25% of tumour cells express primary cilia, with a variable number expressing Smo at the cilia tip. Clonal growth of these tumour cells could be inhibited by blocking the Shh ligand with a monoclonal antibody, or by inactivating Smo with the small molecule LDE225 (Novartis). These data suggest that activation of Smo by Hh ligand at the level of the primary cilium is a crucial step in the initiation and self-renewal of SCLC. By contrast, cilia were rarely observed in human SCLC cells, both in vitro and in vivo. Based on our hypothesis that Hh signaling may be important in the regeneration of SCLC stem-like cells following chemotherapy, we employed a primary xenograft model in which we could identify minimal residual disease following treatment with single-agent carboplatin. Following chemotherapy, more than 50% of the residual tumour cells expressed primary cilia, and in the majority of these, Smo could be detected in the tip. In addition, marked upregulation of Shh ligand expression was observed. However, when these tumours were allowed to regrow to their original size, expression of Shh and cilia returned to the same pattern as seen in the treatment naive tumour, once again supporting a role for cilia-dependent activation of Smo by Hh ligand in SCLC stem-like cells. Furthermore, treatment of mice following chemotherapy with several small molecule inhibitors of Smo, including LDE225, delayed the regeneration of these tumours in vivo. One major controversy surrounding the role Hh signaling in cancer relates to the role of tumour stroma as a target of Shh signaling. To exclude this as a potential mechanism, we used two approaches. First, we crossed the mouse genetic model of SCLC referred to above with a reporter mouse in which LacZ activity can be used to measure Hh pathway activation. In this model, heterogeneous LacZ expression was clearly seen in tumour cells, but not stromal cells. Second, we recreated the carboplatin regeneration model of human SCLC in vitro using a three dimensional, stroma-free clonogenic assay. Transient manipulation of Hh signaling at all levels of the pathway by antibody blockade, siRNA, transfection or small molecule treatment dramatically affected long term cloning capacity in SCLC cells. Moreover, SCLC cells that survived an LD~95~ treatment with carboplatin in vitro demonstrated a marked increase in clonal capacity that was even more sensitive to Hh pathway blockade. Confocal immunofluoresence imaging of these cells revealed expression of Smo in the tips of numerous primary cilia, demonstrating that cell autonomous Hh pathway activation could be observed in a subset of innately chemoresistant, stem-like cells. In the last 5 years, targeted deletion of different components of the primary cilium in mice has dramatically expanded our understanding of the role of these structures in cell signaling. Once considered vestigial, cilia are now recognised as key signaling nodes for Hh, WNT, Notch, PDGF and mTOR signaling. In addition, we have identified heterogeneous expression of primary cilia in several other tumour models, most strikingly in osteosarcoma. More recently, we have shown that knockdown of KIF3a, an essential component of cilia assembly, causes a more dramatic loss of cloning capacity than inhibition of Hh signaling alone. These data suggest that in a subset of self-renewing tumour cells, cilia-dependent signaling pathways in addition to Hh are of importance, and may represent novel therapeutic targets. We are currently using genetically modified mouse models of cancer in which we can conditionally knockout Kif3a to address this question.

Abstract
Lung cancer, for its high incidence and mortality, is the most common cause of death from cancer in many developed countries. In contrast to other cancers, there has been almost no improvement in the 5-year survival rates of lung cancer in the past 30 years, rate just above 10% in Europe, primarily because lung cancer is detected in most cases in an advanced stage. Detecting lung cancer at an earlier stage and, ideally, predicting who will develop the disease and particularly the most aggressive forms of cancer are the biggest challenge. Imaging via low-dose computed tomography (LDCT) scanning is being actively evaluated as a screening tool for early detection of lung cancer in high risk patients but, although the positive results in mortality reduction reported in the large NLST trial (1) were very promising, at present, the real efficacy of LDCT lung cancer screening in heavy smokers remains a controversial issue (2). Nonetheless, the high false positive rates of LDCT, leading to multiple screening rounds, the issue of over-diagnosis, the unnecessary and sometimes harmful diagnostic follow-up and the costs underscore the need for non-invasive complementary biomarkers for standardized use. MicroRNAs are small, non coding, endogenous single–stranded ribonucleic acids with regulatory functions that are involved in tuning of many important pathways, including developmental and oncogenic pathways. Because of their fundamental role in development and differentiation, their involvement in the biological mechanisms underlying tumorigenesis, as well as their low complexity, stability and easily detection, they represent a promising class of tissue and blood-based biomarkers of cancer (3). We explored miRNA expression profiles of lung tumors and normal lung tissues from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up (4). We found a panel of deregulated miRNAs discriminating normal lung tissue versus lung cancer and significant association of miRNA expression profiles in both tumor and non-involved lung tissue with clinical-pathological characteristics of the patients such as tumor histotype, tumor growth rate, disease free survival. miRNA expression profile in tumor and normal lung tissues from patients identifed in the first two years of the screening, including mainly Stage Ia ADC with excellent survival, was found to be significantly different from the profile of subjects with more aggressive tumors appearing in later years of screening, independently from tumor Stage. Overall these results indicate that, both in tumors and in non involved lung tissues, miRNA signatures are able to discriminate patients according to tumor aggressiveness, independently from Stage and type. We have then investigated mirRNA profiles in plasma samples from cases and controls belonging to two independent LDCT screening trials with extensive follow-up where multiple plasma samples, collected before and at time of disease detection were available. We reported that miRNA profiling in plasma samples collected 1–2 yrs before the onset of disease, at the time of lung cancer detection by LDCT and in disease-free smokers, resulted in the generation of four miRNA signatures with strong predictive, diagnostic, and prognostic potential (4). Overall, these results suggest that plasma miRNA profiles might be helpful in pinpointing those early stage tumors at high risk of aggressive evolution that would need additional treatments. We recently completed a large validation study where the diagnostic performance of the plasma-based miRNA test was retrospectively evaluated in samples prospectively collected from smoker subjects within the MILD trial. In this study, 1,000 consecutive MILD plasma samples collected from June 2009 to July 2010 among lung cancer-free individuals enrolled in the trial and all patients with lung cancer diagnosed by September 2012 (n=85) were obtained. In patients we analyzed plasma samples collected both pre-disease (four to 35 months before lung cancer detection, median lag time of 15 months) and at the time of diagnosis. Custom-made microfluidic cards containing the 24 microRNAs composing the signatures identified in the exploratory study were created, and on each card eight plasma samples were analyzed per time. Since the goal of this study was to combine the plasma miRNA assay with LDCT results, in order to have a clinical useful tool to classify plasma samples, we developed a three-level miRNA signature classifier (MSC) of Low, Intermediate, or High risk of disease with subject categorization to one of these three risk groups based on pre-defined cut-points of positivity for the four different expression signatures of the 24 miRNAs previously identified. The results of this large validation study indicates that MSC is a significant diagnostic instrument for lung cancer detection with prognostic performance and support the combined use of MSC and LDCT to improve the efficacy of lung cancer screening (5). References 1. Kramer BS, Berg CD, Aberle DR et al. Lung cancer screening with low-dose helical CT: results from the National Lung Screening Trial (NLST). J Med Screen. 2011;18:109-111. 2. Pastorino U, Rossi M, Rosato V, Marchianò A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, Pelosi G, La Vecchia C. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev. 2012 May;21(3):308-15 3. Boeri M., Pastorino U. and Sozzi G. Role of MicroRNAs in Lung Cancer: MicroRNA Signatures in Cancer Prognosis. Cancer J. 2012 May;18(3):268-74 4. Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabrò E, Croce CM, Pastorino U, Sozzi G. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3713-8. 5. Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, Roz L, Conte D, Grassi M, Sverzellati N, Marchiano’ A, Negri, La Vecchia C, Pastorino U. Clinical Utility of a Plasma-based microRNA Signature Classifier within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study. Submitted

Abstract
The process of carcinogenesis is driven by clonally maintained genetic and epigenetic events that lead to aberrant cell proliferation, inhibit cell death, promote cell dissemination, and affect other key pathways. Research in the past decade has led to new insights into the epigenetic mechanisms controlling gene expression, and into the multiple ways in which these mechanisms are specifically disrupted in cancer. Epigenetic control of gene expression is dependent on modifications of the DNA itself, primarily methylation at CpG dinucleotides, and also by a host of site-specific protein modifications of histones, histone modifiers, and transcriptional machinery. Progress in understanding the multiple layers of epigenetic control is leading to the development and clinical testing of anti-cancer agents specifically targeting these aberrant pathways. DNA methylation and histone acetylation are two well established epigenetic control mechanisms that are known to be aberrantly regulated in essentially all cancers, including lung cancer. We conducted an exploratory phase I/II trial combining an inhibitor of DNA methyltransferase, azacitidine, and an inhibitor of histone deacetylase, entinostat, in patients with recurrent metastatic non-small cell lung cancer. DNA methylation of gene promoters, and loss of histone acetylation, are coordinately regulated processes that can lead to selective silencing of gene expression: this mechanism has been implicated in silencing key tumor suppressor genes in cancer. Treatment with the combination of azacitidine and entinostat led to rare but impressive objective responses, including a complete response in a patient with extensively pretreated disease. In addition, a surprising fraction of patients experienced objective responses to the immediate subsequent therapy, including standard cytotoxic agents and investigational agents targeting the PD-1/PD-L1 immune checkpoint pathway. Preclinical data offer some potential explanations for this observation: many relevant immunoregulatory pathways in both tumor cells and immune effectors are markedly affected by azacitidine. We are now following up on the priming hypotheses suggested by these data, in randomized phase II studies assessing whether limited duration epigenetic therapy can enhance subsequent chemotherapy or immunotherapy efficacy in patients with advanced non-small cell lung cancer. This study represents an initial foray into combinatorial epigenetic strategy in lung cancer: many other strategies are now possible and are being pursued. “Second generation” agents targeting DNA methyltransferase, including an oral formulation of azacitidine and a prodrug, SG-110, are in early phase clinical development. So too are newer histone deacetylase inhibitors differing in specificity, selectivity, route of administration, and pharmacokinetics. Among the exciting new horizons in epigenetic therapy are new agents targeting more recently defined modifiers of epigenetic control, including many of the readers, writers, and erasers of histone modification. The recent remarkable expansion in knowledge about epigenetic regulatory pathways, and how they become dysregulated in cancer, is opening new therapeutic opportunities in lung cancer and other diseases.