Virtual Library

Abstract:
Usually NSCLC tumors that have invaded the central/mediastinal vascular structures are considered unresectable, and staged as T4 locally-advanced NSCLC and are treated with concurrent platinum-based chemotherapy and thoracic radiation with curative intent (60+Gy). However, subsets of good functional status patients with limited involvement (clinically node-negative; T4N0) have been selectively treated with surgical resection before or after additional therapy. This has been most commonly employed for tumor invasion at the base of one of the pulmonary veins with extension into the proximal left atrium or for right upper lobe tumors with segmental involvement of the superior vena cava. Smaller series exist for resection of lung tumors having primary extension into the cardiac chambers and aortic arch. There are no prospective trials, only manuscripts that detail decades-long retrospective single institution series. This presentation will review the literature and surgical approaches to NSCLC involving the great vessel with and without circulatory support. Surgical management of lung cancer invading the aorta or the superior vena cava. Misthos P, Papagiannakis G, Kokotsakis J, Lazopoulos G, Skouteli E, Lioulias A. Lung Cancer. 2007 May;56(2):223-7. Epub 2007 Jan 16. Extended resection of the left atrium, great vessels, or both for lung cancer. Tsuchiya R, Asamura H, Kondo H, Goya T, Naruke T. Ann Thorac Surg. 1994;57(4):960-5 Results of superior vena cava resection for lung cancer. Analysis of prognostic factors. Spaggiari L, Magdeleinat P, Kondo H, Thomas P, Leon ME, Rollet G, Regnard JF, Tsuchiya R, Pastorino U. Lung Cancer. 2004 Jun;44(3):339-46. 15 years single center experience with surgical resection of the superior vena cava for non-small cell lung cancer. Shargall Y, de Perrot M, Keshavjee S, Darling G, Ginsberg R, Johnston M, Pierre A, Waddell TK. Lung Cancer. 2004:357-63 Superior vena cava resection for lung and mediastinal malignancies: a single-center experience with 70 cases. Spaggiari L, Leo F, Veronesi G, Solli P, Galetta D, Tatani B, Petrella F, Radice D. Ann Thorac Surg. 2007 Jan;83(1):223-9; discussion 229-30 Left atrial resection for T4 lung cancer without cardiopulmonary bypass: technical aspects and outcomes. Galvaing G, Tardy MM, Cassagnes L, Da Costa V, Chadeyras JB, Naamee A, Bailly P, Filaire E, Pereira B, Filaire M. Ann Thorac Surg. 2014 May;97(5):1708-13 Results of primary surgery with T4 non-small cell lung cancer during a 25-year period in a single center: the benefit is worth the risk. Yildizeli B, Dartevelle PG, Fadel E, Mussot S, Chapelier A. Ann Thorac Surg. 2008 Oct;86(4):1065-75; Twelve-year experience with left atrial resection in the treatment of non-small cell lung cancer. Ratto GB, Costa R, Vassallo G, Alloisio A, Maineri P, Bruzzi P. Ann Thorac Surg. 2004 Jul;78(1):234-7. Review. Survival after extended resection for mediastinal advanced lung cancer: lessons learned on 167 consecutive cases. Spaggiari L, Tessitore A, Casiraghi M, Guarize J, Solli P, Borri A, Gasparri R Petrella F, Maisonneuve P, Galetta D. Ann Thorac Surg. 2013;95(5):1717-25 Superior vena caval resection in lung cancer. Lee DS, Flores RM. Thorac Surg Clin. 2014 Nov;24(4):441-7

Abstract:
Chest wall involvement is rare in patients with non-small cell lung cancer (NSCLC), occurring in <8% of patients (1). Invasion of the chest wall accords a T3 designation in both the 7[th] and in the newly proposed 8[th] edition TNM staging systems (2). The overall five-year survival for patients with clinically staged T3N0 NSCLC is approximately 45% (2). With clinically suspected nodal disease, even limited to N1 stations, survival is markedly worse. While cT3N2 NSCLC patients are designated stage IIIA and typically given neoadjuvant therapy, optimal treatment protocols are less clear for cT3N0 or even for cT3N1 patients with chest wall tumors, despite the fact that cT3N1 patients are also classified stage IIIA. An en bloc surgical resection of the involved lung and of the chest wall with or without adjuvant therapy has historically been the treatment algorithm of choice for these patients. Little data exists to determine whether neoadjuvant chemotherapy or chemoradiation might be beneficial in this setting. In contrast, the preferred treatment algorithm for a unique subset of chest wall tumors, Pancoast tumors, has been clearly defined (1). These T3 or T4 superior sulcus tumors arise in the apex of the lung and invade the chest wall at the level of the first rib or above, often with involvement of the brachial plexus, subclavian vessels, or spine. For these patients with clinical T3-4N0-1 disease, two carefully conducted prospective, multi-institutional trials demonstrated that induction chemoradiation therapy was associated with high rates of pathological response, improved resectability, and increased survival over historical controls (3,4). In the Southwest Oncology Group Trial 9416 (Intergroup Trial 0160), following neoadjuvant cisplatin and etoposide with concurrent radiation (45 Gy), 61% of patients had either a pathologic complete response or minimal microscopic residual tumor (3). Among all patients undergoing surgery, 94% were able to undergo an R0 resection. Patients with pathologic complete response had a marked advantage in five year overall survival (median survival not reached for complete responders versus 30 months for those with residual disease). Overall survival of the entire cohort was 44%, but was 54% after complete resection. Similar results were found in a multi-institutional trial from Japan (JCOG 9806), in which 21% of patients experienced a complete pathologic response following neoadjuvant therapy with mitomycin, vindesine, and cisplatin and concurrent radiation of 45 Gy (4). Among surgical patients, 89% underwent an R0 resection. Overall five-year survival for the cohort exceeded 50%, with survival of complete responders again especially favorable. The successful adoption of neoadjuvant therapy followed by surgery for Pancoast tumors raised the question of whether a similar induction strategy should be used in patients with other T3 chest wall tumors outside of the superior sulcus. Previous reports have suggested that prognostic factors for survival in patients with chest wall tumors include lymph node status and depth of chest wall invasion, but also completeness of surgical resection and completion of chemotherapy (5,6). It seems logical that neoadjuvant chemotherapy or chemoradiation may facilitate an R0 resection and that such therapy may be better tolerated preoperatively in patients undergoing potentially morbid chest wall resections. Along those lines, a prospective phase II study of trimodality therapy was performed in Japan (CJLSG 0801) for patients with T3N0 or T3N1 NSCLC involving the chest wall (7). Fifty-one patients were entered into the study, among whom 49 (96%) completed neoadjuvant cisplatin and vinorelbine with concurrent radiation (40 Gy) and among whom 44 (92%) underwent complete resection. Similar to prospective studies in NSCLC patients with superior sulcus tumors, in resected tumors there was a high rate of complete pathological response (25%) and of only minimal residual disease (65%). Treatment was relatively safe. However, one patient did die during neoadjuvant therapy secondary to infection following neutropenia and seven additional patients (16%) experienced grade 4 toxicity. Despite this, 86% of patients completed the induction regimen. Among the 29 patients (66%) who went on to surgery, 5 patients experiencing major complications and there was 1 postoperative mortality. Although median follow up was only 16 months, the 2-year overall and progression-free survival rates were excellent at 85% and 71% respectively. While the results of CJLSG 0801 perhaps make a compelling argument to treat chest wall tumors with neoadjuvant therapy prior to resection, several caveats must be considered. From previous studies, it would seem that nodal disease is the strongest indicator of the need for systemic therapy. However, previously reported rates of nodal disease for chest wall tumors are generally only between 20-40% (5). The rate of nodal disease reported in a recently published review of a Japanese registry of chest wall tumors was only 27% (8). These patients without nodal disease will not clearly benefit from systemic therapy. Furthermore, as opposed to Pancoast tumors, the rate of complete resection of chest wall tumors outside the superior sulcus is high even without neoadjuvant therapy, 88% in the Japanese registry study (8). This ability to obtain an R0 resection calls into question the need to include radiation therapy in the preoperative treatment regimen for most cT3N0 patients, given the potential added morbidity. In conclusion, it would seem most reasonable to utilize neoadjuvant therapy in chest wall tumors with clinical N1 nodal disease. These patients are designated as stage IIIA and need chemotherapy as part of their treatment regimen. Neoadjuvant therapy prior to surgery makes sense, although care should be taken to avoid complications that may prevent surgical resection. For T3N0 patients, the treatment algorithm is less clear. Conceptually, large bulky tumors in which it is expected that difficulty in obtaining negative margins surgically would seem to be good candidates for chemotherapy and radiation preoperatively. Further studies need to explicitly compare neoadjuvant versus adjuvant chemotherapy for T3N0 chest wall tumors and need to better evaluate whether there is any beneficial role of radiation in this challenging group of NSCLC patients. 1. Kozower BD, Larner JM, Detterbeck FC, Jones DR. Special treatment issues in non-small cell lung cancer, diagnosis and management of lung cancer 3[rd] ed: American College of of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5):e3696S-e399S. 2. Rami-Porta R, Bolejack V, Crowley J et al. Proposals for the Revisions of the T descriptors in the forthcoming eight edition of the TNM classification for lung cancer. J Thorac Oncol 2015;10:990-1003. 3. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007;25:313-318. 4. Kunitoh H, Kato H, Tsuboi M, et al. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group Trial 9806. J Clin Oncol 2008;26:644-649. 5. Riquet M, Arame A, Le Pimpec Barthes F. Non-small cell lung cancer invading the chest wall. Thorac Surg Clin 2010;20:519-527. 6. Lee CY, Syun CS, Lee JG, et al. The prognostic factors of resected non-small cell lung cancer with chest wall invasion. World J Surg Onc 2012;10:9. 7. Kawaguchi K, Yokoi K, Niwa H, et al. Trimodality therapy for lung cancer with chest wall invasion: initial results of a phase II study. Ann Thorac Surg 2014;98:1184-91. 8. Kawaguchi K, Miyaoka E, Asamura H, et al. Modern surgical results of lung cancer involving neighboring structures: a retrospective analysis of 531 pT3 cases in a Japanese Lung Cancer Resistry Study. J Thorac Cardiovasc Surg 2012;144:431-7.

Abstract:
Surgical resection offers the best chance of cure for most patients with localized non-small lung cancer (NSCLC). However, the risk-benefit deliberation for surgery becomes less clear in patients with more locally advanced tumors (T4), because the procedures are typically more dangerous (higher risk) and the patient’s prognosis is worse (benefit less clear). That being said, surgery remains a curative option for a significant proportion of patients with T4 tumors. In order to minimize risk and maximize benefit, surgeons should select patients with 1) T4 tumors that can be removed safely, 2) T4 tumors that can be completely removed (R0) and 3) patients that are less likely to experience early systemic failure. The group of T4 NSCLC tumors that have historically been amenable to safe surgical resection include those that invade the spine, trachea, esophagus great vessels, and atrium. The 7[th] edition of the lung cancer stage classification system expanded the T4 designation to include tumors that involve a nodule in a separate ipsilateral pulmonary lobe. The recently released proposal for the 8[th] edition of the lung cancer stage classification system has moved tumors greater than 7cm in maximum diameter and tumors that invade the diaphragm to the T4 category. We have previously stated that changes in staging nomenclature should NOT be taken as justification for changing the way a patient is treated (because the revision only considers prognosis without any regard to treatment). However, these additional members of the T4 staging group pose the same risk-benefit conundrum that the others members pose and are discussed. Global health should be assessed as this is a critical component to the surgical risk calculation for patients. This typically includes an assessment of comorbid condition severity, pulmonary function testing, exercise testing and cardiopulmonary stress testing in patients at risk for cardiac disease. Strategies for safe removal of T4 tumors typically center around preparation for the unexpected. The supporting services should be alerted to not only the planned elements of the case but also possible needs in the event of a more extensive resection. The anesthesia team should be prepared to deal with abrupt bleeding (e.g. appropriate intravenous access that is located away from vessels that are likely to be clamped), the need for alternate ventilation strategies (e.g. jet ventilation). Any surgical specialty that could support an extended resection (e.g. spine service) should be alerted to the possibility. Surgeons should adjust their surgical approach to not only address what is apparent, but possible occult involvement of neighboring structures. Incisions should be placed in a way that allows the surgeon the flexibility to extend the planned resection. If possible, entrance should preserve tissues that can be used to treat surgical complications (e.g. preserving muscle for later use as a muscle flap). The exposure should allow for proximal and distal control of neighboring vessels, the use of cross table ventilation and the urgent use of cardiopulmonary bypass. Complete resection (removing all gross and microscopic disease) is of paramount importance, as the survival of patients is severely compromised by a positive surgical margin. While positive margins are an unfortunate reality to cancer surgery, every effort should be made to estimate the likelihood that a negative surgical margin can be obtained. At times this involves an exploratory phase of the resection (occasionally a minimally invasive approach to start) in order to assess the extent of local involvement (because imaging is notoriously inaccurate for determining the extent of local invasion). Finally the multi-disciplinary team must attempt to select patients that are less likely to develop early systemic failure, as these patients will not benefit from resection. This is of course not knowable with any degree of certainty but an estimate is helpful. Patients should undergo a thorough staging evaluation (brain imaging, PET scanning). While not an absolute contraindication for surgical resection, surgeons should be cognizant of other staging parameters that further compromise the patient’s potential for long-term survival. Most notably this would include the patient’s mediastinal lymph node status. The presence of mediastinal lymph node metastases (N2) is a further indication of the patient’s risk for systemic failure, and is an overall poor prognosticator. While prognosis does not alone define treatment, the patient’s overall prognosis should be considered when attempting to justify surgical risk (which is typically increased for T4 tumor resection). For this reason, it is recommended that surgeons refrain from resecting of T4 tumors associated with N2 disease as their default approach, and rather develop a strategy that attempts to allow patients to declare their potential for early failure. One strategy would be to offer the patient curative-intent nonsurgical therapy (chemoradiation) and observe the patient for a “local only” recurrence. In conclusion, surgical resection of T4 tumors is reasonable and effective in highly selected NSCLC patients. The onus is on surgeons and multidisciplinary care teams to attempt to identify the patients most likely to benefit and least likely to be harmed by surgery.

Abstract:
After definitive CRT, approximately 25-30% of patients with stage III disease will fail at their primary site while the regional and systemic fields are under control. As a result, the question of whether some of these patients may potentially benefit from salvage resection of their primary site is often brought up at multidisciplinary tumor boards. The largest published series is from Duke who reported earlier this year on 31 patients in 17 years who underwent lobectomy after definitive radiation therapy (RT), 29 of whom had also received concurrent chemotherapy. Median dose of RT was 60Gy, ranging from 40 to more than 70. The median interval in between completion of the RT and the lobectomy was 18 weeks, ranging from 8 to 111. The majority of these resections were done open though, to their credit, 6 were done VATS without conversion. There was no operative mortality and 48% patients experienced some complications, only a third of these being major. There were no post op bronchopleural fistulae (BPF) despite only a third of patients having their stumps covered: 30/31 achieved an R0 resection, 19/31 had viable tumor in the specimen as histological confirmation of recurrence / persistent disease was not mandated before resection. Median follow-up (f-up) was 26 months and the median OS was 60 months: 20 months if persistent tumor was present in the resected specimen. For the patients who went to salvage resection for recurrent disease (n=3: DFIs being 240, 300 and 700 days) the OS was 9 months, significantly less than the 26 months of those who had persistent disease after RT. The 5 y survival was 31%, 0 if N1-2 disease was present at resection or if salvage was done for relapse, but very small numbers… (1) In 2013, the Yale group reported on 14 patients in 6 years who underwent salvage resection for biopsy proven persistent/ recurrent T disease after definitive CRT. Most underwent lobectomies (9), 2 pneumonectomies. 36% underwent stump coverage. There was no mortality at 90 days, 43% experienced some complication, including 1 ARDS and I BPF. Median post op survival was 9 months, mean 2 year survival was 49%.(2) Bauman in 2008 reported on 24 patients in 8 years who underwent salvage resection after RT, mean dose of 64 Gy (59 to 70), 22 had received concurrent chemo. The interval from completion of RT to surgery ranged from 5 to 94 weeks (median 21). Most underwent lobectomies but 10 were pneumonectomies, including 4 right sided. 19/24 had stump coverage, 16 by omentopexy. Median OR time was 5.5 hours. There was one post op death due to ARDS, 58% experienced some complications, no BPF. 80% of specimen had viable tumor, 2 had R1 resections, 11/24 had N1-2. Median f-up was 29 months, median OS was 30 months, 43 months if PET information/changes led to salvage resection. The estimated 3 year survival was 47%: 2 patients had were found to have brain metastases within 2 months of the salvage resection, neither had had brain imaging in the re-evaluation leading to salvage surgery.(3) Personal opinion (4): the preoperative evaluation of such candidates should always include fresh CT PET, brain MRI and PFTs including a DCO as well as a quantitative perfusion scan as the possibilities of pneumonectomy are not insignificant in this population. Smoking cessation is mandatory. The location of the tumor at presentation also matters: it may be technically much more difficult to perform a lobectomy for centrally radiated lesions. Though not the topic at hand, in my experience, the technical challenges to salvage after SABR pale in comparison as usually the hilar structures are relatively intact after SABR. These surgeries can be challenging and I would encourage that one obtain as much information as possible upfront before going to resection. This includes that one attempt to obtain histological confirmation of viable cancer before undertaking these surgeries. We now know that after RT, particularly after SABR, the PET information may be falsely positive. Along the same lines, I will get EBUS sampling of the mediastinal and hilar lymph nodes before resection. If negative, I will add mediastinoscopy evaluation even in those who had mediastinoscopy at presentation. (5) Intraoperatively, you need to communicate with anesthesia that these patients do not tolerate excess IV fluid well at all as a result of having had their mediastinum radiated. We prepare/ harvest the intercostal muscle bundle at entry. Early circumferential control of the proximal PA and PVs early on is also favored… just in case. Intrapericardial access to the PVs often helps when the hilum is fibrosed, in such instances, open division of the lobar bronchus will often help accessing the lobar PA branches, particularly with the RUL. We cover all of our stumps with the prepared intercostal bundle. Post-operatively, IV fluid restriction remains a priority. Patients whose left hilar dissection was difficult are kept fasting until the left recurrent nerve function is evaluated or judged to be intact. Any concern prompts immediate laryngoscopic evaluation and temporary medialization of any suspicious “lazy” vocal cord follows. The literature on the topic is sparse and all retrospective but we can conclude from its review that: in experienced hands, such resections can be performed safely with acceptable morbidity, such resections, particularly if one is attempting to perform less than a pneumonectomy can be technically challenging and that selection of the patients who may benefit the most from such surgery is not easy. References: Yang CJ, Meyerhoff RR, Stephens SJ, et al. Long-Term Outcomes of Lobectomy for Non-Small Cell Lung Cancer After Definitive Radiation Treatment. Ann Thorac Surg 2015; 99:1914–20 Kuzmik GA, Detterbeck FC, Decker RH, et al. Pulmonary resections following prior definitive chemoradiation therapy are associated with acceptable survival Eur J Card-Thorac Surg 44 (2013) e66–e70 Bauman JE, Mulligan MS, Martins RG, et al. Salvage Lung Resection After Definitive Radiation (>59 Gy) for Non-Small Cell Lung Cancer: Surgicaland Oncologic OutcomesAnn Thorac Surg 2008;86:1632–9 Page B, Blitz M, Louie BE, et al. Pulmonary Resection of NSCLC can be performed safely following definitive chemoradiotherapy. Oral presentation 13th World Conference on Lung Cancer, San Francisco, CA August 1[st] 2009, J Thorac Oncol. 4(9) Supplement 1:S301, September 2009 Louie BE, Kapur S, Farivar AS, et al. Safety and Utility of Mediastinoscopy in Non-Small Cell Lung Cancer in a Complex Mediastinum, Ann Thorac Surgery 92(1): 278-83, 2011

Background:
This study considers pneumonia risk on children under age 7 in Northern Nigeria exposed to ETS. The numerous adverse effects of Environmental Tobacco Smoke (ETS) on the non-smoking public have being evidenced through decades of research. This does not only affect adults but children. ETS effects on children have shown to be grave as it worsens asthma conditions, increases pneumonia cases and causes Sudden Infant Death Syndrome (SIDS).

Methods:
Most residents in all 44 Local Government Areas (LGAs) in Kano State of Northern Nigeria took part in a population-based large-scale cross-sectional survey in Kano state from 2007-2010. Demographic information coupled with socioeconomic status, smoking status and house environment of each household member, was collected from participants. Pneumonia case reported among children aged 7 years and below in each household in the previous 18 months were recorded based on parent’s/guardian's report.

Results:
Out of a total of 528, 800 people resident in 102,334 homes indentified in the survey areas and visible/present as at the time of the study, 52,888 (10%) were children aged 7 years and below. While the prevalence of ETS exposure on children was 81%, the prevalence of reported pneumonia cases was 3.5%. Multiple logistic regression analysis showed that exposure to ETS was independently associated with reports of pneumonia cases (adjusted odds ratio 1.55, 95% CI 1.25 to 1.92). The prevalence of tobacco smoking was higher among men than women (63.5% vs 44.1%). It is estimated that 32.7% of childhood pneumonia in the northern region of Nigeria is attributable to ETS.

Conclusion:
Attention should be given to reduction to children’s exposure to ETS not only in Nigeria but in all affected areas mostly all parts of the world. If nothing is done to protect children, there will be millions of avoidable deaths attributable to Pneumonia heightened by ETS exposure. This is a case of concern for any one involved in lung cancer/tobacco control.

Background:
Lung cancer remains the leading cause of cancer death in the United States and chemoprevention offers an appealing area of investigation in the face of limited therapeutic success. Improvement in endobronchial histology was recently demonstrated in former smokers after oral iloprost treatment. Of the 48 patients who received iloprost in the chemoprevention trial, 23 had regressive histology and 25 had stable or progressive histology. Identifying markers that predict which patients will respond to treatment will help refine target populations for future trials and clinical applications. In vitro studies of NSCLC indicate that iloprost, a prostacyclin analogue, acts through the G-protein coupled receptor Frizzled 9 (Fzd9) instead of the prostacyclin receptor. We hypothesize that Fzd9 expression status predicts response to iloprost chemoprevention and that current smokers may not respond to iloprost treatment due to carcinogen-induced decreases in Fzd9 expression. Prostacyclin may also induce expression of Fzd9, leading to increased anti-tumor signaling.

Methods:
Fzd9 expression was measured by quantitative real-time PCR in RNA extracted from mouse and human tissues, cultured dysplastic cell lines, and cultured human bronchial epithelial cells (HBEC). In the urethane model, FVB wild type and transgenic mice were exposed to a single dose of urethane and sacrificed after 20 weeks. In the smoking model, FVB wild type and transgenic mice were sacrificed after one week of cigarette smoke exposure. Human matched tumor and normal tissue and dysplastic cell lines were acquired from the University of Colorado SPORE in Lung Cancer Tissue Bank. HBEC were exposed to 5ug/ml cigarette smoke condensate and 10uM iloprost in culture media.

Results:
Human lung tumors demonstrated reduced Fzd9 mRNA expression compared to matched normal lung tissue. Fzd9 expression is also decreased in human primary dysplastic cell lines, suggesting that loss of Fzd9 expression occurs early in early lung lesions. In a urethane mouse model of lung cancer, Fzd9 mRNA expression is reduced in lung tumors compared to matched, uninvolved lung tissue. Tumors from urethane exposed prostacyclin synthase overexpressing (PGIStg) mice have higher Fzd9 expression compared to tumors from wild type mice. In a one-week smoking model, Fzd9 expression is decreased in lung from wild type smoked mice but higher in PGIStg smoked mice. In HBEC exposed to cigarette smoke, Fzd9 expression decreases and remains low with continued exposure from 1 to 28 weeks. After two weeks of exposure to iloprost alone, HBEC cells demonstrated increased Fzd9 expression.

Conclusion:
These initial studies suggest that Fzd9 expression is lost lung epithelial cells with early smoking-induced damage. Fzd9 expression will be measured in baseline and follow up biopsy tissues from the iloprost clinical trial. This study has the potential to improve iloprost lung cancer chemoprevention by allowing future trials to more effectively target high-risk patients and by providing a clinical biomarker for identification of chemoprevention candidates.

Background:
Lung cancer is the leading cause of cancer related deaths worldwide. The 5-year survival rate for this cancer is only 16%. Chemoprevention can improve prognosis in these patients. However, previous attempts at lung cancer chemoprevention that were soley based on epidemiological data were ineffective. Squamous cell lung cancer develops through a series of bronchial lesions or dysplasia. Persistent dysplasia harbors similar genetic changes as the tumor and has significantly higher chance of progression. Thus, bronchial dysplasia is a risk biomarker for SCC and improvement in dysplasia grade can be used as an outcome for chemoprevention trials. The long-acting prostacyclin analogue, iloprost is the only drug that has improved dysplasia in former smokers (p = 0.006). Despite this positive outcome we have little insight into the mechanisms of iloprost function. Understanding these mechanisms would be essential to identify people who have the highest chance to benefit from iloprost treatment. We propose that this endeavor will require a preclinical model that recapitulates the human disease and is amenable to mechanistic studies.

Methods:
Airway progenitor cells are critical for the maintenance of normal airways, because of their ability to self-renew (i.e. replicate) and differentiate into all cell-types of the airway (i.e. multipotentiality). Together these properties allow progenitors to return injured tissue to normal structure and function. In dysplasia, normal bronchial epithelium is changed into one that contains increased numbers of basal cells and lacks ciliated cells. These findings led to our hypothesis that ‘airway progenitors are malfunctioning in dysplasia’. Previously we showed that Keratin (K) 5/p63-expressing basal cells are the multipotential progenitors of the airway epithelium. During in vitro culture these cells form a unique 3-deimensional structure called the rim clone, which allows them to be distinguished from non-progenitors. To investigate a role of epithelial progenitors in dysplasia, we have collected bronchial biopsies from high-risk smokers and purified rim clone forming basal progenitor cells.

Results:
We demonstrate that both self-renewal and multipotentiality of progenitors is significantly (p < 0.001 for both) decreased in dysplasia. During differentiation in vitro at the air-liquid interface, progenitors from normal biopsies generated a normal epithelium. In contrast, progenitors from dysplasia made a squamous epithelium containing only basal cells and lacking ciliated cells. Mutational analyses of paired samples from epithelial brushings and biopsy-derived progenitors identified the same somatic mutations in p53, Notch 1, Notch 3, Survivin and FGFR1. Thus, epithelial progenitor culture reflects the histologic and genetic changes of dysplasia and therefore can be used as a personalized, preclinical model. A proof of concept study where dysplastic progenitor cells were treated with iloprost resulted in decreased dysplasia in 2 out of 3 cases.

Conclusion:
Thus our data indicate that progenitor cell cultures from a patient’s dysplasia may be used to identify responders versus non-responders to iloprost, as well as other chemopreventives. Future studies could focus on identifying downstream mechanisms via which iloprost exerts its beneficial effect.

Background:
Tobacco use is responsible for 5.4 million deaths every year worldwide and a leading cause of preventable death. Brazil is widely regarded as an international leader in tobacco control. The WHO FCTC aims to protect individuals from the consequences of tobacco use by providing a framework for tobacco control measures. Parties are obligated to implement measures to prevent and reduce all tobacco consumption and to monitor the magnitude and patterns of tobacco use. The ITC Brazil Survey includes several measures to assess smokers’ tobacco use behaviour, such as cigarette consumption and types of products used.

Methods:
The International Tobacco Control Policy Evaluation Survey (ITC) Brazil Survey is a longitudinal cohort survey and was conducted in Brazil with 1,200 adult smokers and 600 adult non-smokers living in three cities. Telephone-administered surveys were conducted using an area stratified random sampling strategy, yielding a representative sample of the four largest cities in Brazil (Rio de Janeiro, Porto Alegre, and Sao Paulo). The Wave 1 Survey (in 2009) and Wave 2 (2012-2013) included questions a variety of tobacco control measures, including use of tobacco products.

Results:
Brazilian smokers in the ITC Survey smoked mainly factory-made cigarettes and five percent reported that they regularly smoke a flavored brand (including menthol). In Wave 2, all respondents were asked about their use of other tobacco products, and the results show evidence of other tobacco product use even among non-cigarette smokers. Thirteen percent of the overall sample (smokers and non-smokers combined) have smoked clove cigarettes, 10% have smoked cigars, 8% smoked shisha, 5% smoked pipes, and 4% smoked bidis. The percentage of smokers and non-smokers in the sample who have tried various tobacco products, by city, shows a significantly higher use of shisha among smokers in São Paulo (18%) compared to Rio de Janeiro (5%) and Porto Alegre (8%), and non-smokers in São Paulo were significantly more likely to smoke cigars than in the other two cities. Despite the prohibition of electronic cigarettes (e-cigarettes) sale, importation, and advertising in Brazil since August 2009, in the ITC Brazil Wave 2 Survey, respondents were asked “Have you ever heard of electronic cigarettes or e-cigarettes?”. The results showed that 35% of smokers and 29% of non-smokers had heard of them. The highest level of awareness of the product was in Porto Alegre where 39% of smokers and 29% of non-smokers had heard of them. Among smokers who had heard of e-cigarettes, 38 smokers (12%) and one non-smoker reported trying these products.

Conclusion:
Daily consumption of cigarettes is relatively high in Brazil for both male and female daily smokers, based on a comparison of the average number of cigarettes smoked per day among 20 ITC countries and an average consumption of 17 cigarettes per day — twice the average consumption of smokers in Mexico, so its recommended to reinforce educational campaigns about the dangers of smoking, and the electronic cigarette use, increase its inspections and mainly reinforce educational campaigns about the dangers of shisha.

Background:
Tobacco use is the single greatest cause of preventable disease, disability, and death in the U.S. Over the last few decades, several states have implemented comprehensive tobacco control programs (CTCP) to reduce tobacco use and secondhand smoke (SHS) exposure. This Community Guide (CG) systematic review was conducted to examine CTCP effectiveness in reducing tobacco use and tobacco-related diseases and deaths.

Methods:
A systematic search was conducted (search period Jan 2000-July 2014) to identify and abstract qualifying studies using standard CG systematic review methods. Studies published prior to 2000 were identified from a previous Community Guide review and added. Summary measures were calculated when possible and narrative results were provided when effect estimates could not be pooled. The review team worked under the guidance of the Community Preventive Services Task Force (CPSTF), a non-federal, independent, volunteer body of public health and prevention experts.

Results:
The review team identified 60 eligible studies; only results from the U.S. studies are reported here (55 studies). Most of the U.S. studies evaluated CTCP at the state level (48 studies from 10 states) with the remaining studies at the city (3 studies) and local or community level (4 studies). States with a CTCP reduced tobacco use prevalence among adults by a median of 2.8 percentage points (pct pts) [Interquartile interval (IQI): -3.5 to -2.4 pct pts; 12 studies]; reduced tobacco use prevalence among young people by a median of 4.5 pct pts (IQI: -6.0 to -0.7 pct pts; 9 studies); reduced cigarette pack sales by a median of 12.7% (IQI: -20.8% to -5.5%; 7 studies); and reduced daily tobacco product consumption by a median of 17.1% (IQI: -43.4% to -13.5%; 6 studies). Narrative results showed that states with a CTCP increased cessation (6 studies) and reduced SHS exposure (4 studies). States with a CTCP decreased tobacco-related diseases and deaths (6 studies), specifically in reduced lung cancer incidence (1 study), and reduced lung cancer (3 studies) and smoking-attributable cancer (1 study) mortality. Results indicated that increased program funding was associated with greater impact on the examined tobacco-related outcomes (16 studies). Stratified analysis showed CTCPs were effective across population groups with diverse racial and ethnic backgrounds (5 studies) and varied education or socioeconomic status (6 studies).

Conclusion:
Based on CG criteria, there is strong evidence that CTCPs are effective for reducing tobacco use prevalence among adults and young people, reducing tobacco product consumption, increasing quitting, reducing SHS exposure, and reducing tobacco-related diseases and deaths, especially lung cancer. These findings are broadly applicable to the U.S. settings and population groups at the state, city, and local levels.

Background:
Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD), which frequently coexists with lung cancer. For non-small cell lung cancer (NSCLC) patients with COPD, the poor prognostic factors after curative surgery and their association with smoking status are unclear.

Methods:
We enrolled 858 patients who underwent curative surgical resection for pathological stage I or II NSCLC in our institute between January 2002 and December 2012. Of these patients, those with COPD, as determined by a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7, were evaluated (n = 302). Clinical and pathological characteristics of the patients were retrospectively analyzed using the Cox regression hazards model to determine those that serve as poor prognostic factors after surgery.

Results:
The mean follow-up time was 49.3 months (±30.8 months; range, 1 to 135 months). The five-year disease-free survival rate was 70.2%, and the overall survival rate was 81.5%. Of 302 COPD patients, 243 (80.5%) had a smoking habit, whereas 59 (19.5%) did not. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion, 143 patients (47.5%) were diagnosed with stage I COPD and 159 patients (52.6%) were diagnosed with stage II COPD. The presence of a smoking habit (p = 0.010, hazard ratio [HR] 3.340, 95% confidence interval [CI] 1.334-8.359), lymphatic permeation (p = 0.001, HR 2.352, 95% CI 1.450-3.814), pathological T2 or T3 disease (p = 0.005, HR 1.666, 95% CI 1.165-2.381), and a preoperative serum carcinoembryonic antigen (CEA) value > 0.5 ng/ml (p = 0.041, HR 1.637, 95% CI 1.021-2.625) were determined to be indicators of poor recurrence-free survival in multivariate analysis. For overall survival rates, a smoking habit (p = 0.048, HR 7.527, 95% CI 1.017-55.738), a preoperative serum CEA value > 0.5 ng/ml (p = 0.001, HR 2.782, 95% CI 1.495-5.175), a histology of squamous cell carcinoma (p = 0.014, HR 2.220, 95% CI 1.175-4.193), and pathological N1 disease (p = 0.031, HR 2.505, 95% CI 1.089-5.762) were determined to be poor prognostic indicators in multivariate analysis. The disease stage as determined by the GOLD criterion was associated with neither recurrence-free nor overall survival rates. With regard to smokers, the number of pack-years did not significantly influence prognosis.

Conclusion:
We identified poor prognostic indicators for resected NSCLC in COPD patients. It should be noted that COPD patients who did not smoke had a better prognosis after surgery than those who did. Neither the number of pack-years in smokers nor the stage of COPD was related to prognosis after surgery.

Background:
Published results, to date, on smoking cessation and lung cancer screening have been from lung cancer screening clinical trials and/or lung cancer screening studies. Most were done before publication of National Lung Screening Trail (NLST) results. To our knowledge, this is the first report on smoking cessation and smoking relapse rates in a clinical lung cancer screening program to assess the influence of initial screening results on smoking behavior.

Methods:
Self-reported smoking status for all individuals enrolled in a clinical CT lung screening program undergoing a follow-up CT lung screening exam between February 1, 2014 and July 31, 2014 was retrospectively reviewed and compared to self-reported smoking status using a standardized questionnaire at time of program entry. Point smoking cessation and relapse rates were calculated across the entire population and compared with exam results.

Results:
682 participants all of which met NCCN high-risk criteria for lung cancer were included in the study. 45% (309/682) were active smokers at program entry. The smoking cessation rate was 18.4%. Overall relapse rate was 9.9% with a relapse rate for former smokers quit for less than or equal to one year (24 of 64) of 37.5%, 14.8% for those quit for more than one year and up to two years (4 of 27), and 3.2% for those quit for more than two years (9 of 282). Initial screening exam results were not predictive of smoking status at the most recent scan (OR = 0.779, 95% CI = 0.415-1.460, p=0.435). In the group of smokers at the initial scan, screening results did not result in increased rates of smoking cessation (OR = 0.704, 95% CI = 0.308 – 1.610, p=0.405). In the group of former smokers at the initial scan, negative initial exam results did not result in increased smoking relapse rates (OR = 1.021, 95% CI = 0.364-2.860, p=0.969).

Conclusion:
Smoking cessation and relapse rates in a clinical CT lung screening program significantly exceed rates observed in the general population and do not correlate with exam results.

Background:
During 1983, 2000 and 2004 the lung cancer deaths attributable to smoking (LCDAS) were 64.1% (>15 years old), 76% (> 35 years old) and 71% (34-65 years old), respectively. Objectives: a) LCDAS; b) Years of Potential Life Lost (YPLL) due LCDAS; c) cost associated with YPLL for the LCDAS.

Methods:
Mortality data of lung cancer (ICD-10, C33-C34) from the National Center for Health Statistics for Puerto Rico (2010) was analyzed. The prevalence of current, former and never smoking by gender was obtained from the Behavioral Risk Factor Surveillance System (2010) (CDC, US) and the Relative Risk of death dues to smoking by gender from the Cancer Prevention Study-II. The Smoke Attributable Fraction (SAF) was calculated as [p~0 ~+ p~cs ~* RR~cs ~+ p~fs ~* RR~fs ~] – 1 / [p~0 ~+ p~cs ~* RR~cs ~+ p~fs ~* RR~fs ~], where p~0 ~= prevalence of never smoker, p~cs ~= prevalence current smoker, p~fs~ = prevalence of former smoker, RR~cs, ~= Relative Risk of current smoker and RR~fs~ = Relative Risk of former smoker. The LCDAS (D~as~) were calculated as D~o~*SAF, where D~o~ = deaths observed of lung cancer 2010. To compare the data of 1983, 2000 and 2010, SAF was calculated by sex for the total population (not by age groups), with correspondent same death-risk LCDAS. YPLL used life expectancy (women=82.56 years old; men=74.85 years old). The method of willingness to pay, using three times the GDP per capita in 2010 (US$82,353), a discount rate of 3% and an annual increase of 1%, to calculate the economic cost.

Results:
In 2010, 50.3% deaths by lung cancer in women were LCDAS, men 83.7% , in 1983 women and men were 65.9% and 91.2% respectively and in 2000, 58.9% and 84.4% women and men respectively; percentage of all LCDAS (2010) was 73.3% (by sex and group of five). Total population, 2010, not by age groups 75.8%, 2000, 76.3% and1983, 82.5%. In 2010, SAF higher in women was in the age group=45-49 (smoker=13%, SAF=0.66); men was in the age group of 50-54 years (SAF=0.86) (smoker= 17.5%). In women, 1% point decreased (1983-2010) in the prevalence of smoking representing 1.5% point of decreasing LCDAS; men 1% point representing 0.3% point. Lung cancer YPLL in >35 years old represented in 2010 a total of 4,597 years [3,239 years (70.5%) were LCDAS], men accounted 2,383 years [2,014 (84.5%) years LCDAS] and women accounted 2,214 years [1,225 (55.4%) years LCDAS]. In 2010 the cost (willingness to pay) associated for men was $166 million [$139 million (84%) LCDAS], and for women was S146 million [$82 million (56%) LCDAS]. The Average Years Life Lost LCDAS for men was 10.6 years and for women 14.2 years.

Conclusion:
LCDAS have been decreasing in Puerto Rico, as demonstrated in the reduction of SAF. LCDAS occur at an earlier age in women than in men. Notwithstanding , the financial cost of LCDAS is greater in men than in women. Total financial cost for LCDAS represented 0.3% of the Puerto Rico GDP in 2010.

Background:
A comparison of lung cancer incidence, mortality, prevalence and survival in two neighbouring regions of Germany, Schleswig-Holstein, and Denmark, Region Zealand, separated by the Fehmarn Belt, was planned based on data recorded as part of routine monitoring with a view to joint research and sharing of patients and treatment facilities

Methods:
Altogether 14,080 lung cancer patients were recorded in 2004-2010 in Schleswig-Holstein and 5,009 in Region Zealand. Excluding cases of age 90+ years or only known from death certificates, 1- and 4-year relative survival by stage and sex for the periods 2004-2006 and 2007-2009 (1-year survival only) were calculated.

Results:
A very high proportion (19%) of cases in Schleswig-Holstein was only known from death certificates contrary to Region Zealand (0%). The incidence of both, age-standardised and age-specific lung cancer, was much higher in Region Zealand versus Schleswig-Holstein (men 73/100,000 versus 68/100,000, women 58/100,000 versus 32/100,000), also reflected in the mortality figures. Lung cancer incidence was increasing among women during the observation period, more so in Schleswig-Holstein (3% estimated annual change) compared to Zealand (1%). Overall relative survival was lower in Zealand than in Schleswig-Holstein for 1-year survival in 2007-2009 (DK: 33% in men and 39% in women, versus G: 43% in men and 49% in women) and 4-year relative survival for 2004-2006 (DK: 9-13% versus G: 16-21%). Stage, sex and period specific relative survival was rather similar between countries. When restricting the analysis to patients with recorded treatment, stage-specific relative survival differences in 2007-2009 nearly disappeared.

Conclusion:
Improved data quality and comparability are needed, especially by lowering the proportion of cases only reported via death certificates in Germany. This would diminish the survival differences as a high proportion of such cases leads to an over-estimation of survival. Smoking is a strong risk factor for lung cancer and smoking prevalence 10 years before our study was high, specifically 37% in men and 22% in women in Germany and 45% in men and 38% in women in Denmark respectively. Smoking prevalence dropped to 24% in men and 21% in women in Denmark 2010, but only to 31% in men and 24% in women respectively in Germany. Such dramatic changes over a short period of time in Denmark are over time expected to be reflected in the overall incidence, mortality and even survival. International benchmarking studies are needed to understand lung cancer trends and to improve prevention and treatment of this serious cancer disease. Research presented here was partly funded by EU INTERREG 4a Fehmarn Belt 2011-2014.

Background:
Smoking and Tobacco kills 15,000 people in Nepal every year. The combined prevalence of smoking and tobacco use is 56.5% in men and 19.5% in women, of whom 32.5% of men and 15.2% of women smoked cigarettes. The estimated incidence of lung cancer is 8000 per year, making it the first commonest cancer in both sexes. Lung cancer accounts for 15.4% of total cancer as per the hospital based cancer registry for both genders in Nepal.

Methods:
This prospective observational study was conducted at National Hospital and Cancer Research Centre, Nepal. Following informed consent, patients with lung cancer attending the hospital for appointments completed pre-set questionnaires about smoking only, and their stage of cancer and histological type were obtained from case notes.

Results:
A total of 116 patients completed the questionnaire between March 2012 and February 2015. 59% of the respondents were male and 41% were female. The mean age was 64 years with ranging from 31 to 81 years. The proportion of patients presenting in the different stages of lung cancer were IB (3%), IIA (2%), IIB (4%), IIIA (30%), IIIB (41%), and IV (23%). The histological type of cancer showed that 53% were Squamous Cell Carcinoma, followed by Adenocarcinoma 28%, Small cell lung Cancer 13% and Neuroendocrine tumors 4%. 85% were smokers. Of the smokers, 14% started smoking before the age of 10, 53% when they were between 11-20 years of age, 13% when they were 21-30 years and only 5% started when they were 40 years or older. Only 4% smoked more than 30 cigarettes per day, 13% smoked 21-30 per day, 32% smoked 10-20 per day and 36% patient smoked less than 10 per day. 68% used local cigarettes, 7% foreign and 10% used both. Further analysis showed that 27% used cigarettes without filters, 50% filtered and 8% used both. 28% were relighting the butt ends, 5% did this occasionally and 52% did not practice this. 13% of patients were still smoking after their diagnosis, 24% quit less than a month later, 11% quit less than a year later, 19% had already quit smoking 5 years before the diagnosis of cancer, 12% had quit 10 years before and 8% had quit 20 years before. Out of 28% of relighting, 48% patient developed cancer in compare to 52% who never relight the butt end.

Conclusion:
The results shows that majority of patients are presenting at stage III and IV. NSCLC is still on the rise in Nepal. This late presentation suggests a lack of education in the community as well as a delayed diagnosis and referral to the specialist. Focus should be given to make the population in Nepal aware about smoking and tobacco use and its link to cancer, as well as the high prevalence of lung cancer in both genders in Nepal. Focus should also be given to educating the population and non-specialist health care professionals about the symptoms of lung cancer and the importance of early presentation to improve prognosis.

Background:
World Health Organization (WHO) recommends radon concentration lower than 100 Bq/m3. Previous studies have demonstrated the correlation between high level of residential radon exposure and lung cancer especially in non-smokers patients (p.). Similarly, most of the advances in personalized therapy in NSCLC p. also occurred in non-smoker. We hypothesized that residential radon could be associated to some specific molecular alterations in NSCLC p.

Methods:
A detector alpha-track was delivered to each p. to measure radon concentration in residence for 3 months and a questionnarie to fill out. The elegible population were NSCLC p. harbouring molecular alterations (EGFR, KRAS or BRAF mutations (m)), ALK or ROS1 rearrangements (r)) and non-smoker p. treated in the Medical Oncology Department, at Hospital Universitario Ramon y Cajal, Madrid. Incident cases and prevalent cases collected from lung cancer patients database have been included from September 2014 to March 2015. We collected demographic information, smoking history, environmental exposure and clinicopathological characteristics including histology, molecular profile, stage, treatment and survival. The radon concentration was analysed using optical microscopy with radosys system 2000. EGFR, KRAS, BRAF mutation (m) were analysed using quantitative real-time polymerase chain reaction (PCR) and ALK and ROS1 rearrangements by fluorescence in situ hybridization (FISH). Statistical analysis was performed using IBM SPSS.

Results:
So far now, 48 NSCLC adenocarcinoma p. have been enrolled although only 31 have already completed radon measurement. Median age 59 years (range 33- 82); 58,1% female; 77% ECOG 0; 74,4% stage IV; 90,3% living in Madrid. Smoking habits: non-smokers 58% (9p. EGFRm, 7p. ALKr, 2p. BRAFm), light smokers 6,45% (1p. EGFRm, 1p. ALKr) and heavy smokers 35,4% (6p. EGFRm, 5p. KRASm). Median pack-years: light smokers 2,5 (2-3), heavy smokers 44 (20-80). Non-smoker p. reported 27,8% passive-smoking exposure and 44,4% childhood exposure. Radon measurement characteristics: type of building 83.9% flat; building material: 87.1% bricks. Median time of permanence in the same house: 25 years (2-55). Median height of house 3 floors (0-6). Most of measurement at bedroom (93,5%). Median of radon concentration: 103 Bq/m3 (42- 852); 51.6% over WHO recommendation. By molecular alteration: EGFRm median 91 Bq/m3 (42-164), ALKr median 128 Bq/m3 (64-852), BRAFm median 125 Bq/m3, KRASm median 80 Bq/m3 (44-149). ALKr demonstrated association with levels higher than WHO recommendation (p=0.045 Fisher's exact test).

Conclusion:
Our preliminary results show that radon concentrations in NSCLC harbouring molecular alterations are higher than WHO recommendation, particularly in patients with ALK rearrangement. Final results will help to confirm this possible association.

Background:
Stereotactic body radiotherapy (SBRT) has demonstrated high rates of local control with low morbidity and has now emerged as the new standard of care for medically inoperable, early-stage non-small cell lung cancer (NSCLC). However, the impact of lung SBRT on survival in the elderly population is less clear given competing co-morbid conditions. An analysis of the National Cancer Data Base (NCDB) was undertaken to determine whether definitive SBRT in patients 70 and older improves survival relative to observation alone.

Methods:
The NCDB, a retrospective national database capturing up to 80% of all patients treated for cancer, was queried for patients ages 70 or higher with early stage (T1-T3N0M0) NSCLC from years 2003-2006. Overall survival was compared between patients treated with stereotactic body radiotherapy alone and patients receiving no treatment. Extended Cox proportional hazards model was applied to estimate the treatment effect of SBRT.

Results:
A total of 3,147 patients met the selection criteria for this analysis. SBRT was delivered to 258 patients (8.2%) and 2889 patients (91.8%) received no treatment. There was no significant difference in the distribution of Charlson/Deyo comorbidity index scores between the two groups (p=0.076). Multivariable analysis revealed improved overall survival with SBRT compared with observation for the entire cohort (HR 0.64, p<0.001), as well as for each age group as follows: 70-74, HR=0.72; 75-79, HR=0.66; 80-84, HR=0.59; 85 and above, HR=0.56.

Conclusion:
SBRT is associated with improved survival in elderly patients with early stage NSCLC with concurrent comorbid conditions compared to observation alone . The data support the use of SBRT for treatment of elderly patients with early stage NSCLC that have limiting co-morbid conditions.

Background:
To determine the safety and efficacy of lung SBRT in older patients and to compare their outcomes to those of younger patients.

Methods:
Patients with primary lung cancer treated with SBRT were identified from a multi-institutional (5) database of 1192 cases. Details of patient factors, treatment specifics, toxicity and clinical outcomes were extracted from the database. All events were calculated from the end of radiotherapy. Estimates of local (LR), regional (RR), and distant metastases (DM) were calculated using the competing risk method. Cause specific (CSS) and overall survival (OS) were calculated using the Kaplain-Meier method. Outcomes were compared for those <70, 70-79, >=80. Toxicity was graded per CTCAE V3.0. The 90 day mortality was reported for those <70, 70-79, >=80. Univariable analysis was performed to determine associations with CSS in patients aged >70.

Results:
The median follow-up was 1.7years (1-10y) and median age 75 (41-94). There were 364 patients age <70 (28%), 546 age 70-79 (42%) and 387 age ³80 (48%). 621(48%) were female, 1125(87%) were peripheral and 852(66%) were biopsied. There was no difference in baseline SUV (p=0.6), histology (p=0.4), radiation dose (p=0.1), gender (p=0.3) or biopsy rate (p=0.2) among the three age groups. Patients aged >=80 had significantly more T2 tumors 21% vs 23% vs 32 % (p<0.01). There was no difference in 5 year LR (10% vs 11.5% vs 10%, p=0.7), RR (22% vs 10% vs 9%, p=0.1), DM (17% vs 16% vs 21%, p=0.07) or CSS (80% vs 80% vs 75%, p=0.6). Those age ³80 had significantly lower 5 year OS (75% vs 44% vs 23%, p<0.01). The grade 3+ pneumonitis rate was 1.3% vs 1.6% vs 1.5% (p=0.9) in patients ages <70,70-79, >=80 respectively. The 90 day mortality rates for patients aged <70,70-79, >=80 were 1.4%, 2.7%, and 2.6% respectively. In patients aged >70 CSS was associated with tumor size (p<0.01; HR1.4) and baseline SUV max (p=0.03; HR1.04).

Conclusion:
SBRT is a safe treatment modality in elderly patients (aged >80). Despite larger tumor volumes, the tumor control outcome were identical to the younger patients treated with SBRT. All patients, regardless of age, should be considered for treatment of early stage lung cancer (T1-T2) with SBRT.

Background:
An anatomical surgical resection is considered to be the standard of care in fit patients, but non-randomized comparative effectives studies suggest that survival outcomes may be similar following SABR. An antitumor immune microenvironment was found to be a prognostic factor in surgically resected early stage NSCLC. SABR has been reported to activate the immunesystem in malignant diseases via a number of mechanisms. We investigated the impact of both surgery and SABR in early stage NSCLC on the immunesystem, studied in peripheral blood over time.

Methods:
This is a non-randomised trial. Treatment by either surgery or SABR treatment for early stage (cT1-T2aN0M0) were determined by an institutional multi-disciplinary tumorboard, and in accordance with the patient’s preference . SABR was typically delivered in 3-8 fractions in 1-2 weeks, based on risk-adapted radiotherapy schemes that delivered a biologically effective dose of >100 Gy. Surgery generally involved a VATS lobectomy. Blood was collected prior to treatment, and at weeks 1, 2, 3 and 6 after start of treatment. The peripheral blood mononuclear cell (PBMC) fraction was isolated and was stimulated for 4 hours with phorbol 12-myristate 13-acetate (PMA) and ionomycin, to activate the T cells. Subsequently, the T-cells cells were harvested and analyzed by flow cytometry on the expression of CD4 and/or CD8, granzyme B and interferon (IFN) γ. As PD-1 expression is induced in T-cells after antigen exposure the expression of PD-1 was determined. Changes of population proportions between the different time points were analyzed with the related-samples Wilcoxon signed rank test.

Results:
23 early stage non-small cell lung cancer (NSCLC) patients were included in the study. Of these, 13 patients underwent surgical resection at a mean age (±standard deviation) of 62,9± 8,4 years, and 10 patients who underwent SABR at a median age of 70,0 ±10,4 years. SABR patients had more comorbidities, and a poorer WHO performance score, but clinical tumor stage was comparable. A significant increase in the proportion of IFNγ[+]Granzyme B[+] CD8 T cells (p<.05) was observed at week 2 in the SABR treated group, whereas no difference was found after surgical resection. The PD1[+] fraction of CD4[+] T cells was significantly increased at week 2 in the SABR treated group (p<.05), whereas no differences were seen at two weeks after surgical resection. Proportions of PD1[+ ]CD4 T cells remained elevated in the SABR group at week 3 and 6. A similar trend was observed in the CD8[+] T cell population, although this did not reach statistical significance (p<.1).

Conclusion:
SABR but not surgery, enhances T-cell activation and PD-1 upregulation. The results of our study warrant further investigation as to whether SABR induces an anti-tumor response in patients with early stage NSCLC . The upregulation of PD-1 inherently accompanied with this activation of the immune system potentially warrants combination treatment with PD-(L)1 blockade.

Background:
This study aimed to evaluate the importance of interfraction variations in gross tumor volume (GTV) during stereotactic body radiotherapy (SBRT) for early lung cancer patients and assess its impact on dosimetric GTV coverage

Methods:
Forty-seven consecutive patients undergoing SBRT were treated with 48 Gy in 4 fractions (group 1: n=35) or 60 Gy in 8 fractions (group 2: n=12). For each patient, Cone-Beam Computed Tomography (CBCT) imaging obtained at each fraction and initial planning 4DC (CT) were analyzed. GTVs were delineated on all CBCTs, and individual treatment planning was recalculated on each CBCT. Statistical analyses were performed to compare differences between independent samples: the Mann-Whitney U test was used for non-normal continuous variables analyses between groups and the χ2 test for proportions within each SBRT group. Wilcoxon signed rank test was also used to assess changes in volume, dosimetric parameters, and tumor localization. All significance tests were two-tailed and p<0.05 was considered significant

Results:
A total of 236 CBCTs were processed and analyzed. Median total treatment times were 8 days for group 1 and 19.5 days for group 2. There was a significant tumor volume change between the initial CT and the 1st CBCT (p=0.003) in group 1. This was not found in group 2 (p=0.67). GTV was significantly larger at the 2nd CBCT (p=0.003 for group 1 and p=0.049 for group 2) compared to the 1st CBCT. Volume changes were not significantly different at the 3rd fraction compared to 1st CBCT. In group 1, GTV volume significantly decreases at the 4th fraction compared to the 2nd (p=0.047). In group 2, the significant decrease in volume occurs at the 6th fraction (p=0.026). There was no association between the overall treatment time and tumor volume variations. Taken individually (n=47) 83% of tumors have at least one occurrence of a greater than 15% volume change during SBRT compared to the 1[st] CBCT. Variations of more than 20%, 30% and even 40% were observed in ~60%, 40%, and 17% of treatments, respectively. No factor that would predict a significant volume change during SBRT for the patients analyzed could be identified. In group 1, tumor coverage factor (>95%) for any given fraction deviated no more than 5% from optimised coverage obtained in the initial treatment plan. Although sample size is smaller, there was a trend towards lower tumor coverage factors in group 2 compared to group 1. Conformity index for all tumors still ranged from 3.41 to 13.35 in group 1, and 0.95 to 10.48 in group2, without any association with tumor volume variations or treatment time

Conclusion:
There was considerable variation in tumor volumes and more frequent than initially expected for patients undergoing lung SBRT. However, these volume changes did not significantly impact dosimetric parameters. Whether these results affect treatment and/or patient outcome remains to be investigated in prospective clinical trials

Abstract not provided

Background:
Fibrotic changes after SBRT for stage I NSCLC are difficult to distinguish from local recurrences (LR), hampering proper selection for salvage therapy. Huang et al. (1) defined CT high risk features (HRF) for detection of LR. This study attempts to validate these HRFs in an independent patient cohort.

Methods:
From a multicenter combined database of patients treated with SBRT for stage I NSCLC between 2006 and 2012, 53 LR were detected of which 14 were biopsy proven. The biopsy proven LR (N=14) were matched 1:2 to patients without LR (n=28) based on: 1) dose 2) PTV 3) follow up time 4) central/peripheral location 5) lung lobe. Of the resulting 42 patients 18 were male and 24 female with a median age of 73 years (range 56-89years). Median tumor size, PTV and dose were 2.3 cm (range 1.0-4.9cm), 49cc (range 9-166cc), 48 Gy (range 48-60Gy) in 4 fractions (range 3-8) respectively. Most tumors were peripheral (76%) and located in the upper lobes (55%). Median follow up (FU) was 36 months (range 14-78months) and median time to LR was 18 months (range 12-45months). For all patients, planning CT scans and at least two follow up scans were available. Two blinded observers scored eight HRFs for each scan. Sensitivity and specificity in predicting LR were assessed and compared using Fisher’s exact test. Analysis for best fit was done using AUC.

Results:
Results of sensitivity and specificity are shown in Table 1. The best performing HRF was cranio-caudal growth: sensitivity 86%, specificity 82%. The odds of LR increased on average by 2.6 (95%CI1.5-4.3) for each additional HRF detected, while the AUC was 0.86. The presence of ≥ 3 HRFs resulted in the best cut-off with sensitivity 79% and specificity 86%. Loss of linear margin and bulging margin were scored identical and therefore only the latter was included in the model. The two best combinations of HRFs were: 1) bulging margin & cranio-caudal growth, with a sensitivity of 93% and specificity of 82% or 2) bulging margin & enlarging opacity after 12 months, with a sensitivity of 86% and specificity of 89%. Table 1

CT high risk factor for local recurrence	Sensitivity (%)	Specificity (%)	p-value
Any HRF	93	64	.001
enlarging opacity (≥5mm and ≥20%)	86	68	.003
sequential enlarging opacity	57	89	.002
enlarging opacity after 12 months	71	89	<.001
bulging margin	64	100	<.001
loss of linear margin	64	100	<.001
loss of air bronchograms	7	100	0.33
cranio-caudal growth (≥5mm and ≥20%)	86	82	<.001
new pleural effusion	14	93	0.59

Conclusion:
In this matched group of biopsy proven LR and controls, cranio-caudal growth was the best individual predictor of LR after SBRT. Combining HRF bulging margin with either cranio-caudal growth or enlarging opacity after 12 months resulted in higher sensitivities and specificities than number of HRFs. 1)Huang et al. Radiotherapy&Oncology 2013

Background:
A large Canadian multicentre randomized trial (LUSTRE) has recently opened to determine if stereotactic body radiotherapy (SBRT) to 48 Gy in 4 fractions (peripheral) or 60 Gy in 8 fractions (central) improves outcomes compared to conventionally hypofractionated radiotherapy (CRT) to 60 Gy in 15 fractions in early stage non-small cell lung cancer. Given the rapid diffusion of lung SBRT technology across Canada, a unique radiotherapy quality assurance (RTQA) program was devised to minimize variations in practice. This study describes the RTQA experience to date.

Methods:
Centres participating in LUSTRE are required to satisfy three RTQA requirements prior to being accredited: (a) Respond to a survey describing treatment equipment, planning system details and image guidance parameters in order to confirm that their centre is compliant with protocol guidelines; (b) Assess SBRT delivery accuracy using a thoracic phantom produced by IROC (Imaging and Radiation Oncology Core); and (c) Successfully complete four treatment plans from the developed trial planning guide using SBRT and CRT for one centrally and one peripherally located cancer.

Results:
Currently 13 centres are undergoing RTQA: (a) Surveys have been completed in 8 centres, 2 require revision, and 3 are incomplete. (b) Phantom testing has been completed in 9 centres, 2 are incomplete, 1 has results pending, and 1 is being resubmitted. Although 6/13 centres were identified as having active SBRT programs (>3 patients/month), only 2/6 had completed the IROC phantom prior to study accreditation (most having in-house end-to-end tests). (c) 8/13 centres have successfully submitted their test cases. All 8 submitting centres passed on SBRT/CRT distributions and conformality indices. However, 5/8 centres required resubmission for contouring revisions. In one case, the GTV/ITV was incorrectly contoured. In another case, it was contoured on the incorrect dataset. In the remainder, normal organs (lungs, bronchi, esophagus) had contouring errors, particularly the bronchial tree; contours excluded the major bronchi, and in 2 cases, normal lung parenchyma was included. Some centres did not follow standardized nomenclature for targets and normal organs, as they were likely new to this naming convention. Some issues were related to misinterpretation of the planning guide, prompting the trial group to work with centres to ensure a seamless future workflow.

Conclusion:
Preliminary results show that most well-established lung SBRT centres rely on their own in-house standards, while others are using LUSTRE RTQA to implement new SBRT programs. Our experience shows that when centres participate in an independent review, alterations are recommended that can improve their own existing QA processes, and contribute to standardized practice nationwide. Such an RTQA process can be a model worth considering in future radiotherapy randomized trials, and also when instituting new radiotherapy technologies into existing clinical programs.

Background:
Three prospective randomized control trials (RCTs) comparing stereotactic ablative radiotherapy (SABR) and surgery in early stage non-small cell lung cancer (ES-NSCLC) failed to complete accrual. Numerous other comparative effectiveness studies have been published, but such studies may be more prone to bias, and conclusions may vary based on study quality. The goal of this study was to perform a systematic review of comparative effectiveness studies that compare both treatment modalities in this patient population, to assess study quality and conclusions.

Methods:
In accordance with PRISMA guidelines, a systematic review was conducted on studies reporting on comparative outcomes of surgery versus SABR for ES-NSCLC. Studies published in the English language over a 10-year period (April 2006-March 2015) were identified using PUBMED with an inclusive search strategy, using the National Library of Medicine’s medical subject headings. Eligible study designs included RCTs, population analyses, match pair comparisons, propensity-match score comparisons, retrospective case-control series, decision analyses, and cost-effectiveness analyses. Letters, editorial and systematic reviews were excluded. Abstracts identified were independently reviewed by two investigators to determine eligibility, with discrepancies settled by a third investigator. Using a standardized data abstraction form, study, patient, tumor, and treatment characteristics were abstracted. As patients undergoing surgery and SABR often differ in their baseline characteristics, we determined the proportion of studies reporting statistical adjustment for baseline characteristic imbalances (e.g. matching in patient studies, sensitivity analyses in modeling studies). The Fisher’s exact test was used to determine if there was an association between the use of statistical adjustment and differences in overall survival (OS) findings.

Results:
Of the 568 studies identified by our search strategy, 22 were eligible for analysis. Primary study design was retrospective (n=11), population-based (n=7), or model-based (n=4). Most patient studies (n=17) reported on a statistical adjustment for differences in baseline characteristics, with propensity score matching (n=12) being the most common technique employed. All studies, except for 1, reported details of the type of surgery performed. SABR doses employed ranged from 30 Gy in 1 fraction, to 60 Gy in 3 fractions. The weighted average pathologic confirmation of malignancy rate for SABR patients was 72% (range 22-100%). Of the 20 studies reporting on overall survival, 12 found that SABR and surgery were equal, or sensitive to variability in baseline patient, treatment, or tumor factors. The remaining 8 studies reported an overall survival benefit of surgery over SABR, however, 4 of these studies did not employ statistical adjustments for baseline characteristics. In the other 4 studies reporting overall survival superiority of surgery when controlling for various co-variates, at least one other recurrence endpoint (local, regional, or distant) was found to be equal between surgery and SABR. All but 2 studies stated in their conclusion that future clinical trials are warranted to investigate the role of SABR in the potentially operable ES-NSCLC patient.

Conclusion:
A systematic review of the comparative effectiveness literature indicates that the results of well-controlled studies comparing surgery and SABR argue for clinical equipoise. Results of a pooled analysis of two international RCTs that closed prematurely are expected shortly.

Background:
As Stereotactic Ablative Body Radiotherapy (SABR) is increasingly used to treat early non-small cell lung cancer, a larger proportion of elderly patients are now receiving radical therapy. This review aims to assess whether age significantly influences overall survival (OS) in patients with early stage lung cancer treated by SABR according to a standard provincial protocol, and to determine if a maximum age guideline should be introduced.

Methods:
Using a population database all lung-SABR patients were divided into age categories <70 yo (n=45), 70-74 (n=28). 75-79 (n=39),80-84 (n=33) and ≥85 (n=22). Patient and tumor characteristics were collected including: sex, Charlson comorbidity index (CCI), ECOG performance status, tumor diameter, maximum tumor SUV (SUVmax), forced expiratory volume in 1 second (FEV1), and whether a pathologic diagnosis was obtained. For each cohort, OS from date of SABR was calculated. Variability among tumor characteristics between cohorts was evaluated by Chi-squared test and OS was calculated by Kaplan-Meier.

Results:
185 patients were treated from 2009 to 2013. Median age was 76 (range 49-94). The percentage of patients with pathologic diagnoses and the percentage of males was similar among age categories. FEV1 values, ECOG status, SUVmax values and tumor length were not significantly different among the age categories. Older patients had significantly greater CCI scores (see table p=0.001). Median OS for all patients was 36 months and was not reduced in the oldest cohorts (<70: 34 months, 70-74: 24 months: 75-80: 39 months, 80-84:36 months, ≥85: 36 months).

	Age Categories (years old)
	<70	70-74	75-79	80-84	85+
CCI
0-1	5 (%)	0	0	0	0
2-4	59 (%)	39	35	15	10
5-7	34 (%)	54	57	76	60
8 or more	2 (%)	7	8	9	30

Conclusion:
Based on 5 years of population based data, an age cutoff for lung-SABR is not endorsed. In our treated population, patients ≥85 yo have similar OS as younger patients despite greater CCI scores.

Abstract not provided

Background:
Abdominal compression (COMP) for motion management began with our lung stereotactic body radiotherapy (SBRT) practice. From 11/2009, breath hold technique by automatic breath control (ABC) device is selectively employed typically for fit oligometastatic patients (pts). We now compare local failure (LF) results for COMP versus ABC.

Methods:
Our IRB-approved SBRT registry was queried for pts. treated for either a primary lung cancer (PRIME) or an oligometastatic (OLIGO) diagnosis with a minimum 6 months follow up. SBRT was delivered by a stereotactic-specific LINAC platform with vacuum-bag based immobilization, and infrared-based X-ray positioning system+/- CBCT for image-guidance. With COMP, tumor excursion was limited to <1cm and the ITV was created one of two way dependent on treatment era: 1. Fused GTV excursion CTs from free breathing, fixed inhale and exhale travel or 2. by 4DCT, with PTV created from the MIP ITV after adding a 5mm margin. With ABC, 3 serial CT image sets confirmed target immobilization, with the PTV generated after 5 mm was added to the static GTV. SBRT was delivered either with dynamic arcs or step-and-shoot intensity–modulated beams. SBRT dose/fractionation schedules evolved over time and reflected treatment era, tumor location, clinician preference, and trial-based experience. LF was defined as progressive and increasing CT scan abnormalities confirmed by progressive and incremental increases in a lesion’s SUVs on serial PET imaging, with or without biopsy.

Results:
For the interval 10/2003 to 7/2014, 873 pts with 931 lesions were treated. Overall pt. characteristics were: 455 (52.1%) female; 83.9% Caucasian; median age 73 years (range 37-97); median KPS 80 (range 40-100); median BMI 26.2 (range 12.1-56.3). Overall tumor characteristics were: median tumor size 2.2 cm (range 0.7-10.0); median PET SUVmax 7.5 (range 0.8-59), per RTOG 0813 definitions 234 (25.4%) were central lesions, with no significant tumor differences between COMP and ABC cohorts. 830 (89.2%) lesions were PRIME, 101 (10.8%) were OLIGO. ABC was used significantly more for OLIGO vs. COMP (34.4% vs.8.3%, p<0.0001). Median follow-up and SBRT dose were 16.4 months (0-109.5) and 50 G/5 fractions respectively. Overall crude rate of LF was 9.9%. Use of ABC was not associated with increased LF compared to COMP: hazard ratio (HR)=1.043 [95% CI 0.48-2.29; p=0.92] Three-year actuarial rates of LF for ABC vs. COMP were 13.8% and 16.5%, respectively. After stratifying by OLIGO/PRIME, neither ABC nor COMP was significantly associated with LF. There is a suggestion that centrality may be associated with LF with ABC (HR =2.087, p=0.066)On univariate analysis, BMI, tumor size, PET SUVmax and central location were associated with failure, with size the most significant.

Conclusion:
Although form of motion control overall did not predict for LF in lung SBRT, LF for central tumors may be associated with ABC use.

Background:
Radiation therapy (RT)-induced lung injury is one of the major causes of morbidity in patients with thoracic cancer. Extensive work has been done to understand the predictors of lung injury in patients receiving conventionally fractionated RT. However, less work has been done in the setting of hypo-fractionation. Further, conventional methods to consider lung injury typically assess global lung function (e.g. symptoms, pulmonary function tests), are affected by many other (non-radiation) factors, and are thus non-specific. Single photon emission computed tomography (SPECT) perfusion imaging affords an objective quantitative manner to assess the effects of RT on regional lung function. We herein report the preliminary results of a prospective study to assess the magnitude of RT-induced reductions in regional lung perfusion following hypo-fractionated stereotactic RT.

Methods:
Four patients undergoing hypo-fractionated stereotactic lung RT (SBRT: 12 Gy x 4 fractions or 10 Gy x 5 fractions) had a pre-treatment SPECT (single-photon emission computed tomography) perfusion scan providing a 3D map of regional lung perfusion. Scans were repeated 3-6 months post-treatment. Pre- and post SPECT scans were registered to the planning CT scan (and hence the 3D dose data). Changes in regional perfusion (counts per cc on the pre-post scans) were computed in regions of the lung exposed to different doses of radiation (in 5 Gy intervals), thus defining a dose-response function. SPECT scans were internally normalized such that total counts in the regions receiving <5 Gy were equal between pre- and post-treatment scans.

Results:
3 months post-RT, changes in perfusion are highly variable. At 6 months, there is a consistent dose-dependent reduction in regional perfusion. Average percent decline in regional perfusion was 10% at 15-20 Gy, 20% and 20-25 Gy, and 30% at 25-30 Gy representing a relatively linear dose response with an approximate 2% reduction per Gray for doses in excess of 10 Gy. Subtle increases in perfusion were seen in lung receiving <10 Gy. Figure 1



Conclusion:
Hypo-fractionated stereotactic RT appears to cause a dose-dependent reduction in regional lung perfusion. There appears to be a threshold effect with no apparent perfusion loss at doses <10 Gy, in both normalized and unnormalized dose-response curves. Additional data is needed from a larger number of patients to better assess this issue. This sort of data can be used to assist optimizing RT treatment plans that minimize the risk of lung injury.

Background:
Comparative effectiveness research has demonstrated similar rates of disease control and overall survival (OS) for patients with stage I non-small cell lung carcinoma (NSCLC) who are treated with either surgery or SABR. It was therefore hypothesized that the introduction of SABR might improve patient selection for surgery, lead to the referral of high operable risk patients for SABR, and consequently reduce the lung cancer surgery perioperative mortality rate.

Methods:
Cancer registry data identified all patients with stage I NSCLC who underwent surgery or SABR between 1993-2014 at a Veterans Affairs medical center. Mortality rates from the pre-SABR and post-SABR (after 2007) eras were compared. Clinical records in the Computerized Patient Record System were queried to analyze rates of disease control and overall survival (OS).

Results:
A total of 284 patients underwent surgery for stage I NSCLC in the pre-SABR (n=171) and post-SABR (n=113) eras. The majority of patients were male (96.6%) and the median follow-up was 4.1 years. Operative procedures included a pneumonectomy (n=10), lobectomy (n=206), or wedge resection (n=68). The 90-day mortality rate was 3.2%, whereas the 6-month mortality rate was 7.0%. Comparing mortality rates in the pre-SABR to post-SABR eras, there were no declines at 90-days (3.5% vs. 2.7%, p=0.47), or 6-months (7.0% vs. 7.1%, p=0.36). Patients referred for SABR have included 27 medically inoperable patients and 0 operable patients. The mortality rate after SABR was 0% at both 90-days and 6 months. Comparing SABR and surgery, the rate of disease progression was similar (p=0.47); found in 18.5% after SABR (1 distant, 4 regional), 23.4% after lobectomy (9 regional, 2 regional and distant, 11 distant), 33.3% after wedge (3 local, 3 distant), and 0% after pneumonectomy. Two-year OS was numerically superior with SABR (69.4% vs. 63.1%), although this was not statistically significant (p=0.52).

Conclusion:
The introduction of SABR neither influenced patient selection for surgery, nor reduced the perioperative mortality rate for patients with stage I NSCLC. These data suggest comparative effectiveness research alone may be insufficient to improve outcomes for this disease. Efforts to complete a prospective randomized trial of surgery vs. SABR should not be abandoned.

Background:
Radiation pneumonitis is a potentially life-threatening complication of curative radiotherapy in individuals with lung cancer. Predicting which patients are at higher risk of pneumonitis is constrained by limited understanding of its causes. The aim of this study was to examine patient characteristics and radiological factors associated with increased risk of radiation pneumonitis in individuals with lung cancer receiving curative radiotherapy.

Methods:
Individuals with lung cancer treated with curative radiotherapy between January and June 2009 were identified from our departmental database. Data were extracted on patient sex, age and smoking status, lobe affected by cancer, pathology, T and N stage, radiation dose delivered, the use of concurrent chemotherapy, and the grade of fibrosis present on the diagnostic CT scan. The CT scans were reviewed and the fibrosis scored by two pulmonary radiologists. CTCAEv3.0 toxicity scores were used to grade the pneumonitis. Mann-Whitney, chi-squared and Fisher exact tests were used to determine the impact of the various factors on the risk of developing pneumonitis.

Results:
84 patients were identified who underwent curative radiotherapy for lung cancer between January and June 2009. The minimum follow-up for the cohort was 5 years. One year and 3 year survival were 61.9% and 29.8% respectively. 8/84 patients (9.5%) developed significant pneumonitis (CTCAEv3 grade 3 - 5). 6/22 (27.3%) patients with fibrosis on their diagnostic CT developed grade 3 - 5 pneumonitis compared with 2/58 (3.4%) of patients with no fibrosis on the diagnostic CT (Fisher exact test, p=0.0042). Low grade pneumonitis had no impact on survival (grade 0, median survival 80 weeks, grade 1 - 2, median survival 78 weeks) whereas median survival was reduced to 16 weeks in those with grade 3 - 5 pneumonitis. One out of 8 patients in this group survived one year. Only the presence of fibrosis on the diagnostic CT scan and continued tobacco use affected the risk of developing pneumonitis with fibrosis increasing the risk of developing pneumonitis (relative risk 7.9, p < 0.04) and continued tobacco use reducing the risk (relative risk 0.3, p < 0.02). There appeared to be a trend between the fibrosis score on the baseline scan and the risk of developing pneumonitis which did not achieve statistical significance

Conclusion:
The data from this small study suggest radiation pneumonitis affects approximately 1 in 10 individuals receiving curative radiotherapy for lung cancer. The presence of pulmonary fibrosis on the diagnostic CT scan increased the risk of developing pneumonitis. Consideration should be given to alternative treatment options for these patients.

Abstract not provided

Background:
We report safety and efficacy results for an institutional prospective phase II trial for medically-inoperable patients with centrally-located early-stage non-small cell lung cancers receiving dose escalated SBRT. The Phase II objectives were to determine the overall survival and patterns of local failure.

Methods:
Eligible patients with biopsy-proven NSCLC within 2cm of the proximal bronchial tree (RTOG definition) were enrolled on an IRB-approved institutional clinical trial between 2006-2015. All patients were medically inoperable. The Phase I portion consisted of 4 radiation dose levels using 5 fraction regimens. Dose levels were 9, 10, 11, and 12 Gy/fraction. Phase I was previously reported (ASTRO 2011). Based on an early analysis of efficacy, the Phase II radiation dose was 11 Gy x 5 fractions.

Results:
64 patients were enrolled to the trial; 23 to Phase I and 41 to Phase II. The median follow up for phase II patients alive is 6.2 months (range 1.3-46.3 months). 41 patients are eligible for toxicity analysis and 37 with at least 1 post-treatment visits are eligible for efficacy. Regarding treatment-related toxicity, 1 patient experienced acute Grade 3 hypoxia (2.4%; 95% CI 0.1-12.8%), 3 patients developed late Grade 3, 2 had late grade 4, and 1 had late grade 5 events. The grade 4 events were lung atelectasis resulting in hospitalization and dyspnea, respectively. The grade 5 event was fatal hemoptysis in a patient with tumor involving the pulmonary artery. The one-year local lobar recurrence rate using 11 Gy x 5 fractions is 4.6% (95% CI 0.7-13.6%). The one-year OS is 81.2% (60.0-91.8%).The predominant causes of death were distant metastasis (N=6), intercurrent illness without recurrence (N=6), and secondary lung cancer (N=2). One patient is alive with gastric cancer. Two patients developed nodal recurrence and two developed local failures.

Conclusion:
SBRT for central tumors using 11 Gy x 5 fractions was tolerable, but can contribute to severe toxicity as shown by others where tumor involves the pulmonary vasculature. The lobar tumor control was excellent using 11 Gy x 5 fractions. The results of RTOG 0813, which was methodologically based on this trial, may help to clarify the preferred dose for central lesions.

Background:
Radiotherapy dose-escalation trials have achieved inconsistent levels of overall survival (OS) for non-small cell lung cancer (NSCLC). For stage III NSCLC, RTOG-0617 reported poorer OS for 74Gy than for 60Gy delivered in 2Gy fractions with concurrent chemotherapy (median OS 20·3 vs 28·7 months). The phase I/II IDEAL-CRT CRUK funded trial (Sponsor: University College London (C13530/A10424)) of isotoxic dose-escalation delivered mean and maximum doses of 67.5 and 73Gy in 30 fractions over 40 days, equivalent to 69 and 75.6Gy in 2Gy fractions (EQD2), and reported 1- and 2-year OS rates 87.8% (95% CI:80.7-94.9) and 67.1% (95% CI:56.3-78.0) respectively. Here we investigate associations between OS and dose-distributions delivered to heart, left ventricle (LV), lung minus gross tumour volume (lung-GTV) and oesophagus.

Methods:
For 80 of 82 IDEAL-CRT patients, heart, LV, lung-GTV and oesophagus differential dose volume histograms (DVHs) were extracted from planning data using CERR. Since prescribed doses-per-fraction varied, physical DVHs were converted to EQD2s using the linear-quadratic equation with an α/β of 3Gy for heart, LV and lung-GTV, and 1.7Gy for oesophagus. Patient-to-patient DVH variability was efficiently represented using a small number of Varimax-rotated principal components (PCs) which explained 95% of the total variance: four for oesophagus, five each for heart and LV, and fourteen for lung-GTV. OS was modelled from the start of treatment using Cox regression.

Results:
On univariate analysis there is evidence that larger planning target volumes (PTVs) and greater Heart-PC3 and LV-PC4 coefficients are associated with worse OS (see table). Heart-PC3 represented heart volumes receiving doses of 65-75Gy, and LV-PC4 represented LV volumes receiving 1-5Gy. No lung-GTV or oesophageal dosimetric parameters were significantly associated with OS (p-values>0.1). Although OS improved with increasing prescribed dose, this trend did not reach statistical significance. The estimates of these effects did not change markedly after adjusting for other covariates in the multivariate analysis, and the relationship between greater Heart-PC3 and worse OS remained highly significant.

Results (n=80)

Mean values
Parameters Mean Minimum Maximum EQD2 lung-GTV dose 12.1Gy 6.2Gy 18.5Gy PTV 448.6cm[3] 138.7cm[3] 1262.2cm[3] Heart volume receiving >5Gy (V5) 33.9% 0% 99.9% Heart volume receiving >30Gy (V30) 11.3% 0% 47%
Univariate Cox model for OS
Covariate Hazard Ratio 95% Confidence Interval p-value EQD2 prescribed dose 0.951 0.883-1.024 0.185 PTV 1.002 1.000–1.003 0.026 Heart-PC3 1.257 1.070-1.478 0.005 LV-PC4 1.257 0.998–1.584 0.052
Multivariate Cox model for OS
Covariate Hazard Ratio 95% Confidence Interval p-value EQD2 prescribed dose 0.977 0.900-1.060 0.570 PTV 1.001 0.999-1.003 0.179 Heart-PC3 1.228 1.039-1.452 0.016 LV-PC4 1.203 0.943-1.536 0.137

Conclusion:
We found strong evidence of an association between lower OS in IDEAL-CRT patients and heart volumes receiving 65-75Gy. There was some evidence of a negative association between OS and LV volumes receiving 1-5Gy. RTOG0617 has reported a negative relationship between OS and heart volumes receiving greater than 5Gy. Thus OS gains potentially achievable through tumour dose-escalation may be offset by associated heart dose increases. Further studies are required to improve understanding of radiation effects on heart substructures, aiming to identify avoidance structures for possible cardiac-sparing dose-escalated NSCLC treatments.

Background:
Traditionally, sparing the heart in chemo-radiotherapy of locally advanced lung cancer has a low priority compared to the lungs and esophagus. Recently, however, the randomized phase III trial RTOG 0617 showed that the volume of the heart receiving a dose of at least 5Gy (V5) was associated with a lower overall survival (OS). The aim of the current study is to validate this in an independent database.

Methods:
Patients treated with IMRT (24x2.75Gy with daily low-dose cisplatin) at our hospital between 2006 and 2014 were retrospectively selected. For the heart both mean dose and Vx denoting the volume receiving x Gy or more (x in range 5-50Gy with 5Gy increments) were calculated. Associations of these parameters with OS were evaluated using univariate and multivariate proportional hazards analysis. In multivariate analysis we separately paired the total GTV (primary tumor plus involved lymph nodes) to Vx and mean dose.

Results:
375 pts were available for analysis. Median follow up was 16 months and median OS was 26 months. Using univariate proportional hazard modeling mean dose and all Vx for x<40Gy were significantly associated (p<0.05) with OS. For V5, which was most significant in the analyzed set, the hazard ratio (HR) was 1.008. When pts are split at the median V5 = 37.0%, the median OS was 29 ± 2.5 months versus 19 ± 2.4 months for pts below and above the median respectively (p=0.03, Log Rank). Similarly, the figure illustrates significant separation in Kaplan-Meier plots of OS with the pts divided in V5 quartiles. In the multivariate analysis the correlation between GTV (median volume 109 cc) and mean dose or Vx was less than 0.15, indicating that a higher heart dose is not the effect of larger tumor volumes and hence a worse survival due to more advanced decease. Both GTV (p<0.001, HR=1.001) and V5 (p=.003, HR=1.007) were significant in multivariate analysis as was the case with GTV (p<0.001, HR=1.001) and mean dose (p=0.033, HR=1.018).

Conclusion:
For pts treated with chemoradiation the dose received by the heart is strongly associated with overall survival. Our results are in accordance with the results of RTOG 0617 [1] for the V5 with similar HR despite the different fractionation scheme and chemo regimen. This indicates that cardial toxicity might be more important in lung cancer patients treated with chemoradiation than previously anticipated. Consequently, better sparing of the heart potentially improves outcome. [1] Bradley et.al. J Clin Oncol 31, 15 pp. 7501

Background:
Thoracic radiotherapy plays an important role in the treatment of lung cancer. However, the safety of thoracic radiotherapy delivery is restricted to the risk of radiation pneumonitis(RP), which is the major dose limiting toxicity for patients undergoing thoracic radiotherapy. Few studies to date have assessed risk factors associated with the development of RP in lung cancer patients treated with volumetric modulated arc therapy (VMAT). This study aimed to report the RP incidence and clinical and dosimetric risk factors associated with RP in lung cancer patients treated with VMAT at a single institution.

Methods:
In this retrospective study, lung cancer patients treated with VMAT from 2013 through 2015 were reviewed. RP was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version.4.0. Clinical factors and dosimetric parameters were evaluated using logistic multivariate regression for estimating the correlation with RP. The results were considered statistically significant when the p-value was<0.05.

Results:
Thoracic radiotherapy with VMAT was administered in 77 lung cancer patients. Of these patients, 58 were men and 19 were women, with a median age of 60 years (range 22-84 years); 25 patients received concurrent chemoradiotherapy, and the median radiation dose was 60Gy (range 45-64Gy). VMAT plans were performed with single arc in 9 patients, double in 55 patients, triple in 4 patients, and the mean (±SD) delivery time was 189.1s±42.0s. VMAT allowed us to respect most planning objectives on target volumes and organs at risk, for PTV V~95% ~= 96.8 ± 6.1%; for lung V~5~ = 41.3 ± 8.7%, V~10~ = 29.9 ± 7.1%, V~20~ = 20.9 ± 5.7%, mean dose=1150.9±277.6Gy. With regard to acute RP after thoracic radiotherapy, 10.4% were grade 1 (G1), 16.9% G2, 9.1% G3, 2.6% G5. The overall incidence rate of symptomatic RP (grade ≥ 2 by CTCAE) was 28.6% in the entire cohort. Based on the clinical data and dosimetric parameters analysis, factors predictive of symptomatic RP were lung volume receiving ≥10Gy (V~10~) [OR: 1.39, 95% CI 1.07–1.80, p=0.014], PS score[OR:5.44, 95% CI 1.29–23.08, p=0.021], concurrent chemotherapy[OR:3.85, 95% CI 1.07–13.86, p=0.039]and CRP changing level[OR:1.06, 95% CI 1.01–1.12, p=0.014].

Conclusion:
VMAT, a novel technique, provides a viable option for the thoracic radiotherapy of lung cancer with acceptable toxicities. However, for patients with higher V~10~, poorer PS score, greater increasing level of CRP and undergoing concurrent chemotherapy, VAMT technique should be administrated with cautions. Several molecular biomarkers have been reported that correlated with the development of RP, which will be tested in our further analysis.

Abstract not provided

Background:
Thoracic radiotherapy is a usual treatment for lung cancer; either at early-stages (stereotactic mode) or at locally advanced stages (conventional radiotherapy mode). Thoracic irradiation appears to have little impact on lung volume such as forced expiratory volume in one second (FEV1) or forced vital capacity (FCV). By contrast, carbon monoxide diffusing capacity (TLCO) may be altered under thoracic radiotherapy. Pulmonary diffusion may be also evaluated by the NO (azote monoxide) diffusion capacity (TLNO). Moreover, double assessment of NO and CO diffusing capacities open the way to understand if alteration of lung diffusion is due to alveolar membrane and/or a pulmonary capillary alteration. CONORT aims at measuring pulmonary function tests (PFTs), in particular the CO and NO diffusing capacity, during thoracic radiotherapy.

Methods:
Prospective multicenter study. CONORT study was approved by the Lyon Sud-Est IV ethics committee and the database was declared to the national information registry authority as required by French laws. Overall 112 patients must be included to estimate a difference of 15% in diffusing capacity test, with a 90% power and a 5% alpha risk. All consecutive patients treated by thoracic radiotherapy in Lyon Sud Hospital were included regardless of histology and radiotherapy technique. PFTs including double diffusion are performed by the same operator and using the same technic, before-, during-, at the end-, six weeks after- and six months after- thoracic irradiation. All included patients gave their consent. Results at PFTs were expressed in % of theoretical value (%th), and were compared using Student t test.

Results:
Between 1[st] February 2014 and 14 April 2015, 88 patients were included and 62 have been analyzed. Patients were male in 73%, mean age was 67.4 years. Radiotherapy technique was intensity-modulated radiation therapy (IMRT) in 61%, stereotactic radiotherapy (SBRT) in 32%, and 3D conformal radiotherapy in 7%. Mean pretreatment FEV1 was 2.06L (78.9% of the standard), mean FCV was 3.17L (94.9%), mean TLCO was 16.5 (64.7%) and mean TLNO was 72.7 (60.3%). FEV1 and FCV were stable during and after radiotherapy. However, mean TLCO decreased by 4.4% (P=0.01) between first and fourth PFT, mean DLNO decreased by 4% (P=0.001) between first and second PFT, mean VC (capillary lung volume) decreased by 6.24% between first and fourth PFT (P=0.011), and DM (membrane diffusing capacity) decreased by 3.6% between first and second PFT (P=0.001).

Conclusion:
CONORT is the first study evaluating the potential impact of thoracic radiotherapy on double measurement of lung diffusing capacity. These preliminary results showed that thoracic radiotherapy has little impact on lung volumes. However, lung diffusion decreases, initially by membrane alteration and then by capillary alteration. Results at 6 months showed that this alteration is fully recovered. Updated data will be presented at meeting.

Background:
The study aimed at investigating the feasibility of shrinking field after complete or partial response during Chemoradiothrapy without surgery for stage III non-small cell lung cancer (NSCLC).

Methods:
This retrospective study was carried on 97 consecutive patients with stage III non-small cell lung cancer (NSCLC), who were good responders to cheomoradiation without surgery between September 2009 and November 2014. Computed tomography scans were performed after 40-50 Gy to evaluate the curative effect. Fifty three-dimensional-conformal treatment or intensity-modulated radiation therapy were redelineated to shrink the radiation volume once or twice during conventionally fractionated radiotherapy, leading to a boost of 6-20Gy delieverd to the shrunk PTV. The gross tumor volume (GTV) and planned target volume (PTV) were messured. The acute symptomatic irradiation-induced pneumonia(ASIP) as well as first progression patterns and overall survival were investigated through follow-up.

Results:
Among 97 patients who obtained complete or partial response with median total dose of 60.0 Gy (range, 46.0-70.0 Gy), 50 patients received shrinking field radiation therapy with a median 184.24 cm[3 ](range, 28.1- 449.7cm[3]) reduction of PTV between the first and last plan. The primary GTV and PTV in shrinking field group was greater than that in non-shrinking field group, as well as the 59Gy-greater radiation dose rate(GTV, 116.8 cm[3] vs 102.9 cm[3 ]; PTV, 493.0 cm[3 ]vs 458.0 cm[3]; 59Gy-greater dose rate, 70 % vs 61.7 %). The incidence of ASIP was 20.6%(20/97) for all the population, shrinking field group of 18%(9/50) and non-shrinking field group of 23.4%(11/47). Fifteen patients progressed locoregionlly, 12 distantly and 3 in both patterns in shrinking field group, while 22 locoregionlly, 16 distantly and 3 in both patterns in non-shrinking field group. Four regional-progression located out of PTV in both groups. The locoregion-progression rate and out-PTV rate were not significant difference(60% vs 61%, P=0.934; 63.3% vs 56.1%, p=0.54). As compared with non-shrinking field group, shrinking field had a similar overall survival(median OS, 29 mouths vs 30 mouths, P=0.546), an improved median progression free survival (median PFS, 19 mouths vs 14 mouths, P=0.945) and a lower incidence of acute irradiation-induced pneumonia, but they were all not statistically significant.

Conclusion:
Shrinking field and dose escalation for good responders during chemoradiotherapy seem safe with acceptable toxicity and outPTV relapse, especially for the lung cancer with a bulky mass. More prospective trials are needed to validate these results.

Background:
Accelerated repopulation of tumour cells causes inferior local control in locally advanced NSCLC (non-small cell lung cancer). Hypofractionated radiation schedule with a shorter overall treatment time may address this issue. The current study was aimed at evaluating the feasibility and efficacy of using hypofractionated radiotherapy with concurrent chemotherapy after neoadjuvant chemotherapy in locally advanced NSCLC.

Methods:
Thirty patients of locally advanced NSCLC were enrolled in this randomized controlled study and were allocated to one of the two treatment arms between October 2011 and July 2013. Arm A (n=15) received neoadjuvant chemotherapy (NACT) (paclitaxel 200mg/m2 and carboplatin AUC 5) followed by external radiotherapy (EBRT) (60Gy/30fractions/6weeks). Arm B (n=15) received the same NACT followed by EBRT (48Gy/20fractions/4weeks) with concomitant chemotherapy (cisplatin 30mg/m2 weekly). Quality of life analysis was done using EORTC (European organization for Research and Treatment in Cancer) QLQ C30 and LC13. Toxicity scoring was done using CTCAE (Common Terminology Criteria for Adverse Events) version 3.0. The treatment response between two arms was computed using Fisher’s exact test. The difference in QOL parameters were compared by Wilcoxon signed rank test and Mann-Whitney U test for paired and unpaired samples. Survival time was estimated by Kaplan–Meier survival analysis. Survival pattern was compared using the log-rank test. Factors which had p value <0.25 in univariate analysis were subjected to multivariate analysis using Cox regression analysis. Statistical analysis was carried out using Stata software version 12.0.

Results:
The overall response rate at the time of first follow-up for arm A was 54.55% as compared to 85.71 %( p=0.08) in arm B. At median follow-up duration of 12 months the ORR was numerically superior in arm B though not statistically significant 33% vs 47%).The median PFS in arm A and B were 9.2 and 17.23 months respectively [hazard ratio 2.92 (95% C.I: 1.02-9.11); p=0.05]. No significant difference was discernible in OS between two arms on multivariate analysis. Social functioning showed a trend towards improvement while alopecia showed a trend towards worsening in arm B. The most common grade 3/4 hematological and non-hematological toxicity were neutropenia peripheral neuropathy and dysphagia (arm A: 3; arm B: 1).

Conclusion:
Hypofractionated radiotherapy with concomitant chemotherapy after NACT is feasible for locally advanced NSCLC. Such management approach can expedite treatment with an acceptable morbidity, patient compliance and quality of life and thus reduces the waiting time, machine load, socio-economic burden in patients which is significant in a developing nation.

Background:
Radiation pneumonitis (RP) is the most worrying complication following high dose radiation therapy (RT) for loco-regionally advanced lung cancer. Intensity modulated radiation therapy (IMRT) and intensity modulated proton therapy (IMPT) are expected to reduce RP compared with conventional RT technique. Adaptive re-plan is usually indicated to accommodate tumor shrinkage and position changes during fractionated RT course. This study is to comparatively evaluate dosimetric differences between RT techniques and interval changes of these parameters assuming that initial IMRT and IMPT plans are continued throughout RT course without adaptive re-plan.

Methods:
Ten patients who were given concurrent chemo-radiotherapy by IMRT (66 Gy/33 fractions, weekly Docetaxel/CDDP #6) for having N3(+) stage IIIB lung cancer were selected. Surrogate rival IMPT plan on each patient was generated to compare with initial IMRT plan. Beam numbers used in IMRT and IMPT were 6-7 and 3. Second CT obtained during 3[rd]-4[th] week for adaptive IMRT plan was used to generate second sets of IMRT and IMPT plans, assuming that adaptive plan had not been done. Differences between initial RT techniques and changes in dosimetric parameters including conformity index (CI), homogeneity index (HI) and dose-volume histogram (DVH) of target and normal organs, which could have occurred by 2 RT techniques, were compared.

Results:
When comparing initial IMRT and IMPT plans, IMPT showed advantageous features over IMRT with respects to median HI (1.08 vs. 1.02), mean doses (D~mean~) to lung, esophagus, and heart, lung volumes receiving 5 Gy (V~5~), 10 Gy (V~10~), 20 Gy (V~20~), 30 Gy (V~30~), and 40 Gy (V~40~) and maximum dose (D~max~) to spinal cord (all p<0.05), respectively. Mean gross tumor volumes (GTV) on initial and second CT’s were 90.9 (48.1~163.7) cm[3] and 52.2 (23.1~89.7) cm[3] and median GTV reduction was 42.2% (51.3%-84.4%). More dosimetric parameters could have changed significantly by IMPT (CI, HI, V~5~, V~10~, V~20~, V~30~, D~mean~ to lung and heart, and D~max~ to spinal cord) than IMRT (CI, HI, V~20~, D~max~ to spinal cord and heart), respectively. Absolute increase in D~max~ to spinal cord was estimated as 0.53 Gy by IMRT and 4.79 Gy by IMPT (p=0.003).

Conclusion:
Impact of GTV regression during RT course and need for adaptive re-plan seem evident. More uncertainties on dosimetric parameters and higher doses to spinal cord are expected by IMPT than by IMRT if re-plan is not applied. Optimal timing and frequency of adaptive plans, however, need to be further evaluated.

Abstract not provided

Background:
Despite the increasing number of elderly patients (p) with unresectable stage III NSCLC p presenting to our clinic, there is no consensus on the therapeutic approach to these p. The comprehensive geriatric assessment (CGA) and the comorbidity measurement are relevant tools to identify p who may benefit from tolerable combinations of concurrent chemoradiation (CRT).

Methods:
Elderly p (≥75 years) with stage III NSCLC underwent multidimensional geriatric assessment (MGA) that incorporated validated instruments to assess comorbidity, polypharmacy, functional status, geriatric syndromes (GS), mood, cognition and vulnerability. P were classified according to the MGA results into 3 risk groups: (1) fit p: independent in all ADL and IADL, no comorbidities and absence of GS; (2) vulnerable p: <3 comorbidities and/or <3 IADL but no ADL disability and absence of GS; (3) dependent p: ≥3 disabilities or presence of GS. P classified into group 1 and 2 were considered candidates for antitumoral treatment, whereas patients into group 3 were candidates to best support care. Clinical, GA and follow-up data were prospectively collected. Overall survival (OS) was calculated using Kaplan-Meier method and the median follow-up time was 13.5 months.

Results:
From July 2008 to November 2014, 54 elderly p with stage III NSCLC were identified. The median age was 80 years (74-87) and most p (93%) were males. The most common histological subtype was squamous cell carcinoma (54%), followed by adenocarcinoma (28%) and NOS (18%). MGA classified 20 p (37%) as fit, 23 p (43%) as vulnerable and 11 p (20%) as dependent. Median number of comorbidities: 4 (0-11); median number of drugs: 6 (0-12); median Karnofsky: 80% (60-100); median Barthel: 95 (80-100); Lawton-Brody Scale (<4/≥4): 18%/82%; Pfeiffer (<4/≥4): 89%/11%; Yesavage test (0/≥1): 54%/46%; 1 (0-10); median GS: 1 (1-3); VES-13 (<3/≥3): 50%/50%. Risk groups 1 and 2 had significantly better median OS (20 and 17.5 months, respectively) as compared with group 3 (7.7 months, p=0.004). The number of p treated with concurrent CRT was higher among fit patients (14; 70%) as compared with group 2 (8; 35%) and 3 (0; 0%). Some fit and vulnerable p did not receive concurrent CRT due to patient and physician decision, tumor not amenable for radiotherapy or comorbid conditions. P treated with concurrent CRT received conventional 3D thoracic radiotherapy (2 Gy/fraction) in combination with carboplatin AUC 2.5 and vinorelbine 15 mg/m2 on days 1, 8, 21 and 29. Overall response rate was 68%. Median OS was 22 months (95% CI 10.6 – 33.6). There were no differences in OS when comparing risk groups 1 and 2 (p=0.446). Adverse events (G3-4): neutropenia, 2p (9%); anemia, 1p (4.5%); thrombocytopenia 1p (3%); febrile neutropenia, 1p (3%); pneumonia, 1p (3%); tracheo-bronchial infection, 3p (14%); asthenia 2p (9%); anorexia 1p (4.5%); diarrhea, 1p (4.5%); radiation pneumonitis, 3p (14%) and oesophagitis 0p (0%). Three p (14%) died due to radiation pneumonitis and 1 p (3%) due to a respiratory infection.

Conclusion:
MGA may help in the selection of elderly p for concurrent CRT and appeared to be a valuable tool to avoid undertreatment of those p.

Background:
To analyze acute esophagitis (AE) in a Chinese population receiving 3D conformal radiotherapy (3DCRT) for non-small cell lung cancer (NSCLC), combined or not with chemotherapy (CT), using the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model.

Methods:
157 Chinese patients (pts) presented with NSCLC received 3DCRT: alone (34 pts) or combined with sequential CT (59 pts) (group 1) or with concomitant CT (64 pts) (group 2). Parameters (TD50, n, and m) of the LKB NTCP model predicting for > grade 2 AE (RTOG grading) were identified using maximum likelihood analysis. Univariate and multivariate analysis using a binary regression logistic model were performed to identify patient, tumor and dosimetric predictors of AE.

Results:
Grade 2 or 3 AE occurred in 24% and 52% of pts in group 1 and 2, respectively (p<0.001). For the 93 group 1 pts, the fitted LKB model parameters were: m=0.15, n=0.29 and TD50=46Gy. For the 64 group 2 pts, the parameters were: m=0.42, n=0.09 and TD50=36Gy. In multivariate analysis, the only significant predictors of AE were: NTCP (p<0.001) and V50, as continuous variable (RR=1.03, p =0.03) or being more than a threshold value of 11% (RR=3.6, p =0.009).

Conclusion:
A LKB NTCP model has been established to predict AE in a Chinese population, receiving thoracic RT, alone or combined with CT. The parameters of the models appear slightly different than the previous one described in Western countries, with a lower volume effect for Chinese patients.

Background:
Brain metastases (BM) develop in 22-55% of patients with locally advanced Non-small cell lung cancer (LA-NSCLC) treated with curative intent. Prophylactic cranial irradiation (PCI) reduces the incidence of BM by40- 60% but is not part of standard practice due to a lack of proven survival benefit and concerns regarding toxicity. This study aimed to determine patient preferences with respect to the survival gain or reduction in BM PCI would need to provide and the amount of toxicity considered acceptable for them to accept PCI.

Methods:
A Discrete Choice Experiment (DCE) was used. Patients undergoing definitive chemoradiation therapy for LA-NSCLC were asked to make 15 hypothetical choices between two alternative PCI treatments at each of two time points (i.e. pre- and post their own treatment). Each alternative PCI treatment was described by four attributes: amount of life gained, ability to care for oneself, loss of memory and the chance of BM. Participants were also given the option of no PCI treatment. The choice data were analysed using multinomial and mixed logit regression models, to indicate the relative importance of improvements in each attribute for treatment preference.

Results:
There were 54 and 46 surveys completed pre- and post-treatment respectively. Participants had a mean age of 63.6 (range 39-82) years, 74% were male. Participants chose to accept PCI versus no PCI in approximately one third of the choices (34.8% pre- and 33.3% post - treatment). Overall, participants preferred a treatment alternative if it was associated with a longer survival, better ability to take care of oneself, lower loss of memory, and lower chance of BM. Before treatment, an increase in survival of more than 6 months was the most important benefit (relative importance weight 61.2), followed by avoiding severe problems with memory (39.4), avoiding severe problems with self-care (30.3), and a 15% reduction in risk of BM (15.0). After treatment, the rank order of importance remained similar but a reduction in the risk of BM became more important, relative to gains in the other attributes. Preliminary analysis suggests if PCI is able to reduce BM risk by 15% and increase survival by >6months, participants have a probability of uptaking PCI of 0.66 pre- and 0.55 post-treatment, even if they are left with severe problems caring for themselves and severe memory loss.

Conclusion:
The majority of patients would accept PCI for an increase in survival >6months, with a reduction in BM by 15%, , even if severe memory/self-care problems occurred. Patients would avoid PCI if it caused severe problems with memory/ self-care versus mild-moderate problems with memory/self-care, when survival gain is less than 6 months. Patients care more about avoiding BM following the completion of therapy.

Abstract not provided

Abstract:
When patients with early-stage non-small cell lung cancer (NSCLC) are accurately staged inappropriate surgery is avoided and on the other hand potentially curative surgical resection is not refused. The clinical algorithms using imaging studies for staging lung cancer patients with regard to surgical treatment decision and planning as recommended by current guidelines will be presented and discussed. Low-dose CT screening is now recommended for asymptomatic select patients who are at high risk for lung cancer and an increasing number of patients may come to clinical attention during screening. CT findings suggestive of malignancy in a patient with a solitary pulmonary nodule include larger lesion size, irregular or spiculated borders, upper lobe location, thick-walled cavitation, presence or development of a solid component within a ground glass lesion, and detection of growth by follow-up imaging. The general approach to patients suspected of having lung cancer begins with a thorough history and physical examination (1). Following that, essentially every patient suspected of having lung cancer should undergo a contrast-enhanced diagnostic CT scan of the chest. The diagnostic chest CT scan is an important first step, not only to help define the clinical diagnosis, but to structure the subsequent staging and diagnostic evaluation (1). In patients in whom lung cancer has been demonstrated, consideration must turn toward determining the extent of the disease to identify patients with stage IA, IB, IIA, and IIB disease who can benefit from surgical resection. **Extrathoracic (M) Staging** The purpose of extra thoracic imaging in NSCLC is to detect metastatic disease. Current literature continues to demonstrate that PET and PET-CT scans are superior to conventional staging tests (bone scan and abdominal CT scan) in terms of performance characteristics (1). Recent data confirm the superiority of the performance characteristics of PET and PET-CT scans compared with conventional scans in the evaluation of metastatic disease in key specific distant sites (1). Recommendation (1): In patients with a normal clinical evaluation and no suspicious extra thoracic abnormalities on chest CT being considered for curative-intent treatment, PET imaging (where available) is recommended to evaluate for metastases (except the brain) (Grade 1B). However, positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation (e.g., MRI of bone) (2). Brain MRI (to rule out asymptomatic brain metastases) is recommended for patients with stage II and higher (2). Patients with stage IB NSCLC are less likely to have brain metastases; therefore, brain MRI is only a category 2B recommendation in this setting (2). **Mediastinal Nodal (N) Staging** Mediastinal lymph node staging in NSCLC is particularly important, because in many cases, the nodal status actually determines whether there is surgically resectable disease. If the contrast-enhanced CT scan shows nodal mediastinal infiltration that encircles the vessels and airways, so that discrete lymph nodes can no longer be discerned or measured, non-resectable disease is evident and no further imaging studies are required to determine the exact N status (1). In patients with discrete mediastinal node enlargement further evaluation is recommended (1, 2). The NCCN Panel assessed studies that examined the sensitivity and specificity of chest CT scans for mediastinal lymph node staging. Depending on the clinical scenario, a sensitivity of 40% to 65% and a specificity of 45% to 90% were reported. PET/CT scans may be more sensitive than CT scans (2). However, in patients with discrete mediastinal node enlargement, the risks of false positive test results from either CT scanning and/or PET scanning are too high to rely on imaging alone to determine the mediastinal stage of the patient, and tissue confirmation is necessary (1). Transesophageal EUS-FNA and EBUS-TBNA have proven useful to stage patients or to diagnose mediastinal lesions; these techniques can be used instead of invasive staging procedures in select patients. When compared with CT and PET, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high sensitivity and specificity for staging mediastinal and hilar lymph nodes in patients with lung cancer. In patients with positive nodes on CT or PET, EBUS-TNBA can be used to clarify the results. In patients with negative findings on EBUS-TNBA, conventional mediastinoscopy can be done to confirm the results. **Thoracic Tumor (T) Staging** The size of the tumor, its location and invasion of adjacent structures as reflected in the T status determines resectablity and - in cases with given resectablity - the extent of resection. In patients with T3 tumors or centrally located tumors that may necessitate a pneumonectomy, additional functional evaluation of the patient may be required to determine operability. Contrast-enhanced CT scan is the most commonly used imaging modality for T staging and can provide all the information needed. In select cases (e.g. Pancoast-Tumors) MRI may be useful to diagnose involvement of the brachial plexus and extension into the neural foramina and the spinal canal (3). Infiltration of the mediastinal great vessels, esophagus, trachea, and vertebral body is staged as T4 and usually defines unresectability. Findings on CT scan like obliteration of fat plane between the tumor and the mediastinum, circumference of contact between the tumor and the aorta, and the length of anatomical contact between the tumor and the mediastinum are not definitive signs for invasion. Both CT scan and MRI have similar diagnostic accuracy (56-89% for CT and 50-93% for MRI) in predicting mediastinal invasion, with no modality being considered to be distinctly superior (3). References: 1. Silvestri GA, et al. Methods for Staging Non-small Cell Lung Cancer. Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2013; 143(5)(Suppl):e211S–e250S 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer, Version 7.2015, NCCN.org 3. Nilendu C Purandare and Venkatesh Rangarajan.Imaging of lung cancer: Implications on staging and management. Indian J Radiol Imaging. 2015 Apr-Jun; 25(2): 109–120.

Abstract:
This session reviews considerations of imaging for radiotherapy planning and delivery with particular focus on available completed and active prospective clinical research. State - of - the - art (intensive) treatment approaches, including definitive concurrent radiotherapy and chemotherapy for locally advanced lung cancer, and stereotactic body radiotherapy for treating early stage lung cancer, depend on the ability to precisely identify sites of gross tumor and surrounding critical normal structures. As such, the incorporation of optimal anatomic and functional imaging studies, both three-dimensional (3D) and four-dimensional (4D), in the radiation planning process has become increasing critical. Prospective trials initiated in the late 1990's were the first studies assessing three-dimensional conformal radiotherapy based on computed tomography simulation. These trials directly assessed the ability to adequately dose 3D targets and permitted implementation of tissue heterogeneity dose correction. The routine inclusion of mediastinal lymph node stations that were not pathologically enlarged was also questioned in the design of these studies, and while the initial prospective study from the University of North Carolina mandated elective nodal irradiation (ENI), subsequent studies performed by the RTOG and NCCTG did not include ENI. These single arm prospective studies suggested improved survival in stage III disease with delivery of high dose conventionally fractionated radiotherapy. Somewhat surprisingly, the landmark RTOG 0617 phase III trial did not confirm these results, but perhaps refinement of target volumes through improved imaging (and treatment planning/delivery) would lead to a different result. Functional imaging with FDG-PET (/CT) has had a profound overall impact on the staging and ultimate therapy for patients with lung cancer, and radiotherapy plans are frequently altered by including FDG-PET imaging data in addition to cross sectional imaging. Moreover, while the treatment volume may be increased, such as inclusion of PET avid mediastinal lymph nodes not enlarged on CT, the radiation target volume may also be reduced particularly in instances with atelectasis or tumor obstruction. Prospective studies in the US and Europe have prospectively assessed the impact of PET on radiotherapy planning. For example, RTOG 0515 reported that PET/CT-derived tumor volumes were smaller than those derived by CT alone and that PET/CT changed nodal GTV contours in most patients. Techniques to determine the gross target volume using PET images vary and include simple visualization and a variety of software / hardware based methods including automated solutions. This remains an area of active investigtion and an understanding of potential pitfalls of PET fusion with CT simulation is necessary in defining target volumes. Retrospective series suggest a correlation between the pre-treatment standardized uptake value (SUV) and survival in patients with non-small cell lung cancer. Though the primary objective of ACRIN 6668 / RTOG 0235 was to assess post-treatment SUV for patients receiving radiotherapy as part of their treatment for stage III NSCLC, pre-treatment FDG-PET SUV (mean and max) were also assessed. While pre-treatment FDG-PET SUV did not predict outcomes, active research is assessing the delivery of differential dosing (via IMRT dose painting) based on variation in PET activity. Understanding the impact of tumor and organ motion during respiration is essential when utilizing highly conformal techniques in treating lung cancer. This is a key component of the simulation process and AAPM Task Group 76 describes various options for tumor motion management in detail. Four-dimensional CT-simulation 4D CT is accomplished by correlating the motion of an external surrogate device to the time signature of CT scans. Multiple scans are acquired during each phase of respiration and should provide sufficient motion detail to properly define the internal target volume (ITV). These phase calibrated images can then be processed into average or maximal intensity projections (MIP), or used directly as a cinema image of the tumor motion. In order to incorporate the extent of tumor motion from breathing during SBRT, contouring on the MIP, as opposed to helical or average intensity images, may be optimal. Tumor motion seen on the 4D CT is only representative of the motion at the time of simulation, so further assessment is needed to ensure this will be representative of tumor motion during the actual treatment. Real-time confirmation of tumor location during treatment, whether using the ITV method, respiratory gating, or tumor tracking may be provided by use of “cine” mode or fluoroscopy. Routine real-time imaging should be performed given the potential for variability in breathing and tumor motion over the treatment course. Image guided radiotherapy (IGRT), particularly KV cone-beam CT (CBCT) or MV – CT, is essential for ensuring accurate tumor targeting during radiotherapy. For example, image guidance capable of confirming the position of the target with each treatment was required for the RTOG 0236 trial.While the majority of clinical experience is based on 3D CBCT, 4D (respiration correlated) CBCT is now commercially available and reduces motion artifact and may have additional advantages over 3D CBCT in the treatment of lung tumors. IGRT also allows for routine assessment of tumor response and anatomic changes over time and facilitates implementation of adaptive radiotherapy approaches. Several experiences have detailed changes in tumor volume during the radiotherapy course and the (potential) impact of revising the radiotherapy plan during therapy. An ongoing prospective randomized phase II trial, RTOG 1106, is studying adaptive radiotherapy in stage III non-small cell lung cancer by incorporating changes in both functional and anatomic imaging. Repeat PET/CT and CT simulation in the midst of RT is performed for all patients on study with the “boost” volume in the experimental arm defined by the repeat PET/CT. The total dose for each patient in the experimental arm is dictated by the boost volume and predicted NTCP toxicity. The RTOG 1106 trial includes evaluation of [18]F-fluoromisonidazole (FMiso) PET imaging, which may help identify areas of hypoxia, in a subset of patients. Magnetic resonance imaging (MRI) traditionally has been reserved for assessment of select lung tumors (potentially) invading soft tissue structures such as chest wall, mediastinum, lung apex in proximity to the brachial plexus (pancoast tumors), and lesions in proximity to the spinal cord. The recent development of a commercial hybrid radiotherapy /MRI unit may expand the role of MRI and permits IGRT (without the need for additional patient exposure to ionizing radiation) while also facilitating soft tisse tracking and adaptive radiotherapy.

Abstract:
When response assessment is carried out after definitive high-dose radiation therapy (RT) or chemoRT for patients with locally-advanced non-small cell lung cancer (NSCLC), it should give an early indication of the likely prognosis of the patient. Ideally it should identify those patients most likely to experience long term freedom from progression, who require no further therapy, and it should further identify patients with persistent or progressive disease who could benefit from additional therapy or who may be candidates for clinical trials of investigational treatments designed to improve their poor prognosis. In usual clinical practice, response assessment in NSCLC involves the use of structural imaging with computed tomography (CT), to assess the effect of treatment on tumor volumes. The initial dimensions of tumor sites are compared with their dimensions after treatment, either on a single occasion or with serial images acquired over time. Potential sites of distant disease progression are also sought within the field of view of the restaging CT scan although this is a relatively insensitive test for small volume metastatic tumour. Another possible approach to response assessment is to employ a global measure of the success of therapy, typically by analysing serial blood samples for a tumor-specific biomarker. A sensitive blood-based assay could potentially detect the presence of very small amounts of persistent tumor, beyond the resolution of currently available imaging modalities. A disadvantage of a blood test compared to imaging in a locoregionally confined rather than a metastatic cancer is the absence of any indication of the likely location of persistent or recurrent disease, making it impossible to implement any local salvage therapies without additional information. However, a combination of a sensitive biomarker and state of the art imaging could potentially provide detailed and clinically useful prognostic information after therapy. The use of both local and global approaches to response assessment will be discussed.Using Imaging to assess local Treatment Response in NSCLCStructural Imaging Traditionally, serial imaging with CT has been used to assess treatment response in NSCLC. Serial tumor measurements are compared with specific response assessment criteria, enshrined in systems such as the Response Evaluation Criteria In Solid Tumors (RECIST) [1]. Patients are categorized by RECIST as having either; Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started, or Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Although these categories have prognostic significance, they can be an unreliable predictor of ultimate survival in individual cases. Tumor masses are often slow to resolve after RT and their margins may be obscured by fibrotic or consolidated lung, making accurate measurements impossible. The very concept of remission is hard to define after RT in NSCLC because of the changes in the thorax that occur due to a combination of invasion and destruction of parenchyma by tumor and of the morphological changes that result from atelectasis, radiation pneumonitis and radaition induced pulmonary fibrosis. Fibrotic masses may persist indefinitely even in cured cases. Regions of dense fibrosis can harbor persistent tumor that only becomes apparent when regrowth occurs months or years after treatment is complete. The CR category, with disappearance of all lesions, may be especially hard to define on CT imaging. CT scanning, although it is the standard response assessment modality in clinical trials, has very significant limitations when used for this purpose.Functional Imaging with PET Some of the limitations of CT can be transcended by the use of molecular imaging. The advent of positron emission tomography (PET), using [18]F-fluoro-deoxyglucose (FDG) as the tracer, has provided a means of “seeing inside” areas of fibrosis and persistent mass lesions and identifying focal areas of persistent tumor. Furthermore PET imaging compensates for another major limitation of CT, that of its poor sensitivity and specificity for assessing the true status of mediastinal nodes. Unlike CT, PET can detect tumor in small (<1cm short axis) mediastinal nodes and correctly defines enlarged reactive nodes as non-malignant in the great majority of cases. Several meta-analyses have confirmed the superiority of PET-based mediastinal staging in this regard, making it a logical choice for re-staging the mediastinum after therapy. Prospective data have shown the superiority of PET-based response assessment compared to CT-based response assessment after RT in NSCLC. Our group developed FDG-PET response criteria based on visual assessment and used them prospectively in patients treated with RT/chemoRT [2]. Patients were classified into four metabolic response categories groups, namely; 1) Complete Metabolic Response (CMR): tumor FDG uptake absent or less than mediastinal blood pool. 2) Partial Metabolic Response (PMR): appreciable reduction in the intensity of tumor FDG uptake or tumor volume. 3) Stable Metabolic Disease (SMD): no appreciable change in intensity of tumor FDG uptake or volume. 4) Progressive Metabolic Disease (SMD); any new sites of disease, and/or an appreciable increase in intensity of tumour FDG uptake or volume in known tumor sites. In 73 patients, PET response was evaluated at a median of 70 days post-treatment. PET and CT responses were the same in only 40% of cases and PET response predicted survival much better than CT response. There were many more complete responders on FDG criteria (n=34) compared to CT (N=10), and no patients were inevaluable by PET on compared to 6 on CT. In this study, PET was clearly far superior to CT and in an expanded cohort it was clear that a poor PET response was strongly associated with distant metastasis [3]. Without standardization, the use of visual response criteria may be limited by interobserver variability. The Deauville criteria were developed specifically for use in lymphoma in an effort to standardise visual response assessment by comparing residual tumor FDG uptake with uptake in the liver and mediastinum [4]. Another way to reduce interobserver variability is to use a semi-quantitative method of response assessment, such as by comparing pre- and post treatment standardized uptake values (SUV). Although this is an attractive approach, accuracy may be affected by differences technique on different scanning occasions and by the fact that after treatment, uptake of FDG in radiation penumonitis is often within the range associated with the presence of tumor. This is especially so after high dose hypofractionated stereotactic body radiotherapy (SBRT). It is inappropriate therefore to consider a particular SUV cut-off as being diagnostic of persistent disease. Uptake in lung affected by radiation pneumonitis can also hamper visual response assessment but on a qualitative reading of the scan, pattern recognition can take this into account and still provide valuable prognostic information [5]. Despite the apparent superiority of PET for response assessment, no large prospective studies have yet helped refine how this information might be used. The ideal time for imaging is undecided. A longer interval between treatment and imaging is likely to be associated with greater accuracy but less clinical utility. The use of PET imaging during RT is being actively explored by several groups but remains investigational. In anecdotal cases, patients with resectable PET-detected residual disease have undergone successful salvage surgery after RT but large prospective trials are required to validate this approach.Use of circulating biomarkers to measure global treatment response in NSCLC In some cancers, the use of biomarkers in the blood to monitor disease status is a well established part of standard management. Commonly used circulating biomarkers include paraproteins in multiple myeloma, prostate specific antigen in prostate cancer and alpha-fetoprotein and human chorionic gonadotrophin in germ cell tumors. These markers can be highly specific and sensitive and can be used to guide therapy. However, in NSCLC, the search for a practical circulating biomarker with wide application has been hampered by the extreme heterogeneity of this group of diseases. Two of the most intensely investigated tumor biomarkers in NSCLC have been carcinoemryonic antigen (CEA), which is commonly detected in adenocarcinoma and CYFRA21-1 which can be detected in squamous carcinoma. In a review of the literature in 2012, Grunnet and Sorensen analysed the level of CEA as a prognostic marker in NSCLC in 23 studies of serum and two of plasma [6]. In 18 studies CEA was found to be a prognostic marker for either overall survival OS, recurrence after surgery and/or progression free survival (PFS) in NSCLC patients. The remaining 7 studies contained an excess of patients with squamous carcinoma. One study found that a tumor marker index (TMI), based on preoperative CEA and CYFRA21-1 serum levels was useful as a prognostic marker for OS. Six studies evaluated the use of CEA as a predictive marker. Four of these studies found, that serial CEA measurement had some potential as a predictive marker for recurrence and death. Although a combination of CEA and CYFRA21-1 markers have some value in a proportion of patients with NSCLC the heterogeneity of their expression limits their role in response assessment after RT [7]. Measurement of circulating tumor (ct)DNA has shown promise as a "liquid biopsy" for assessing cancer burden but ctDNA detection methods have to date been insensitive or lacked the broad coverage needed to permit clinical application in NSCLC where genetic variation is extreme. Because background circulating DNA is present in healthy individuals, tumour derived ctDNA can be detected and quantified only if it contains a tumour specific sequence. Diehn and colleagues at Stanford reported a breakthrough in ctDNA in NSCLC, which they called “Cancer Personalized Profiling by Deep Sequencing” (CAPP-Seq) [8]. This is an ultrasensitive method for quantifying ctDNA with clinical applicability. CAPP-Seq was implemented in NSCLC patients with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumours. The method detected ctDNA in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I disease, with 96% specificity for mutant allele fractions down to ~0.02%. At least one, and on average 4, mutations were covered in >95% of patients. Levels of ctDNA detected by CAPP-Seq were highly correlated with tumour volume and helped distinguish between residual disease and treatment-related imaging changes in several cases. A large clinical trial is being planned to establish the utility of ctDNA for monitoring disease status after RT in NSCLC.Conclusions Structural imaging with CT gives useful prognostic information after RT in NSCLC but is inferior to FDG-PET. Of all of the blood based methods for estimating global tumour burden, ctDNA analysis seems the most promising at present. A combination of PET and ctDNA could potentially provide prognostic information of previously unattainable accuracy and utility.References1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-216.2. Mac Manus MP, Hicks RJ, Matthews JP, et al. Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 2003;21:1285-1292.3. Mac Manus MP, Hicks RJ, Matthews JP, Wirth A, Rischin D, Ball DL. Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure. Lung Cancer 2005;49:95-108.4. Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale. Haematologica 2014;99:1107-1113.5. Hicks RJ, Mac Manus MP, Matthews JP, et al. Early FDG-PET imaging after radical radiotherapy for non-small-cell lung cancer: inflammatory changes in normal tissues correlate with tumor response and do not confound therapeutic response evaluation. Int J Radiat Oncol Biol Phys 2004;60:412-418.6. Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer 2012;76:138-143.7. Okamura K, Takayama K, Izumi M, Harada T, Furuyama K, Nakanishi Y. Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. Lung Cancer 2013;80:45-49.8. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014;20:548-554.

Abstract not provided

Background:
This presentation reviews the history of tobacco litigation in the United States.

Methods:
Data for this study comes from industry business records available online through the UCSF Legacy Tobacco Documents Library, transcripts of court proceedings, and news and stock analyst reports on tobacco litigation.

Results:
Litigation against the tobacco industry began in 1954, corresponding to the emerging evidence linking smoking and disease. A total of 109 lawsuits were filed between 1954 and 1970, but only eight were tried and all ended in defense verdicts. Another 150 cases were filed between 1970 and 1985, but none went to trial. There was a second wave of cases filed during the mid-1980s that led to jury trials, but only one, Cipollone v. Liggett Group, was a plaintiff verdict. Cipollone was later overturned on appeal. A third wave of litigation followed in the early 1990s, with several plaintiffs’ verdicts. By 1999, juries were awarding punitive damages against the defendants. The state Attorney General cases against cigarette manufacturers resulted in the Master Settlement Agreement in 1998, which, among other things, required that the cigarette companies release millions of pages of business records. These documents have played a key role in fueling subsequent litigation and winning cases. The Engle v. Liggett Group class action verdict on behalf of injured smokers in Florida in the late 1990s helped to change the industry’s long held position that smoking was unproven as a cause of disease and that nicotine was not addictive. Decertification of the Engle class action lawsuit spawned several thousand individual lawsuits against the cigarette industry in Florida, which have resulted in dozens of verdicts favoring plaintiffs since 2009. Additional litigation against the tobacco industry continues nationwide on the “light” cigarettes fraud and on individual personal injury cases that have resulted in notable verdicts against the tobacco industry.

Conclusion:
In the United States, litigation against the cigarette industry began in 1954 and has accelerated over the past 60 years with a growing number of verdicts favoring plaintiffs since the mid-1990s. Litigation has proven to be a powerful tool for tobacco control efforts helping to change public sentiment about the industry and its products, increasing the costs of cigarettes, and forcing the industry to accept responsibility, in front of a jury, for its deceptive practices.

Background:
Cigarette smoking is the major cause of lung cancer. Many adults smoke at the time of a lung cancer diagnosis and continue to smoke during treatment although doing so adversely affects treatment response, quality of life, and survival time. While authoritative bodies recommend that tobacco use be addressed in lung cancer care, few patients receive effective treatment. The coordinated multidisciplinary model of care delivery, in which patients, their caregivers, and key specialists concurrently develop evidence-based care, offers an ideal setting to integrate high quality cessation treatment. To assess the need for and acceptability of cessation services, we surveyed patients about their smoking status, interest in quitting, and willingness to participate in a clinic-based cessation program.

Methods:
The study was conducted in the Multidisciplinary Thoracic Oncology Program at Baptist Cancer Center, Memphis TN. One-hundred eight consecutive new patients, seen between 7/31/13 and 9/24/14, completed a social history questionnaire. From this history, we extracted data related to sociodemographic characteristics (age, gender, race, marital status), smoking status, age of smoking initiation, and tobacco dependence (using the Heaviness of Smoking Index, consisting of cigarettes smoked per day and time of first cigarette of the day). Current smokers reported their level of interest in quitting, and how likely they would be to participate in a cessation program (‘I would not participate’; ‘I might participate but am not sure’; ‘I would participate’). Chi square tests were used to compare characteristics of those who would participate in the stop-smoking program vs. those who would not or were unsure whether they would participate.

Results:
Average age of patients was 65 years (range: 29-91), 41% were men, 58% were white, 39% black, and 15% had graduated college. Patients’ cancer stage broke down to stage I (16%), stage II (9%), stage III (18%), stage IV (28%), and undetermined (29%). 84% of patients had ever smoked cigarettes, 35% currently smoked, and 11% had quit smoking within the past year. Among current smokers, 71% (n=27) were “very interested” in quitting smoking in the next month and of these, 74% reported that they would be willing to participate in a smoking cessation program in the clinic. Willingness to participate in a cessation program was associated with greater interest in quitting (χ[2][1]= 13.3, p=.0003), but was not associated with sociodemographic characteristics, cancer stage, or smoking-related characteristics (amount smoked, age at smoking initiation, or dependence).

Conclusion:
Nearly half (46%) of patients in a community-based multidisciplinary thoracic oncology program were current cigarette smokers or had quit within the previous year, indicating a considerable need for cessation and relapse-prevention support. Encouragingly, a majority of current smokers were highly motivated to make a quit attempt in the next month, and most indicated that they would take advantage of a clinic-based cessation program. Willingness to participate in a cessation program was similar across a broad range of sociodemographic, cancer stage, and nicotine dependence levels. There is considerable need for, and interest in, smoking cessation services in the setting of community-based multidisciplinary lung cancer care.

Background:
It is well documented that active smoking affects the overall mortality in lung cancer. Smoking cessation has been associated with better prognostic outcomes in patients with early stage non-small cell lung carcinoma (NSCLC) and limited stage small cell lung carcinoma (SCLC). Smoking cessation impact in advanced stage NSCLC is less well characterized. We studied the benefit of smoking cessation, before the initiation of chemotherapy, on overall survival (OS) in advanced NSCLC.

Methods:
We retrospectively reviewed the clinical data of 306 patients with stage IV SCLC and NSCLC between 2008 and 2014 in our centre. The 237 NSCLC patients treated with at least one cycle of chemotherapy are the subjects of this study. Smoking status and smoking cessation duration at the chemotherapy initiation time, number of packs/years, comorbidities, histology, sites of metastases, type and number of cycles of chemotherapy were all collected. Never-smokers were defined by a smoking history of < 100 cigarettes during their entire lifetime. Survival curves were calculated by the Kaplan-Meier method and compared using log-rank test. Cox proportional hazard models were used for multivariable analyses.

Results:
Smoking cessation before the initiation of chemotherapy is associated with a better median overall survival of 16 vs 10 months (p=0.007). This is even seen in heavy smokers of > 30 pq/year, with a median OS of 15 vs 8 months (p=0.008). The multivariable analysis confirms that active smoking is an independent negative factor on survival (51% increase in the risk of death) after adjustment for gender, heart or vascular disease, diabetes, high blood pressure, ECOG performance status, histology, site of metastases (brain, liver, adrenals, lungs and bones). Figure 1



Conclusion:
Smoking cessation, before the initiation of chemotherapy, is associated with a better overall survival in chemotherapy treated stage IV NSCLC patients, even in previously heavy smokers and after adjustments for comorbidities. This retrospective analysis demonstrates the possible magnitude of the effect of smoking cessation on treatment efficacy with a potential gain of 6 months in median overall survival. Efforts to encourage smoking cessation are likely beneficial even among this population of patients.

Abstract not provided

Background:
Cigarette smoking is responsible for 85% of all lung cancers and about 1/3rd of all cancer deaths. Quitting smoking reduces the risk of getting lung cancer and other serious health problems. In 2012, the Joint Commission (JC) which sets quality standards for hospitals in the United States recommended that all current smokers identified upon hospitalization receive tobacco cessation services as an inpatient and be followed up after hospital discharge. However, few hospitals implement JC standards due to extra costs, the voluntary nature of the standards, and the lack of evidence demonstrating financial benefits to the hospital and insurers. In 2014, the Medical University of South Carolina (MUSC), a major tertiary care hospital in South Carolina, implemented an automated in-hospital smoking cessation program using interactive voice recognition (IVR) technology to follow-up with patients after discharge consistent with JC standards. This study reports on the results of the program over the first 12 months of operation between February 17, 2014 and January 31, 2015.

Methods:
Descriptive statistics are used to report on the number of patients screened, number of tobacco using patients seen by a bedside tobacco counselor while hospitalized, the number of tobacco using patients followed-up 3, 14, and 30 days after discharge, and the rate of unplanned hospital readmissions within a month of discharge.

Results:
A total of 30,846 patients aged 18 and older were screened for tobacco on hospital admission and 18% were identified current smokers. Of the 5,546 identified smokers, 2008 (36%) were approached by a single bedside counselor while hospitalized; 29% were unavailable for counseling for various reasons (e.g., discharged, too sick, not in room, deceased), 11% refused counseling, and 3% reported to the bedside counselor that they were non-tobacco users. A total of 4,197 tobacco using patients were enrolled into the automated telephone follow-up to assess smoking status and offer triage to the state quitline for those who wanted help. A total of 1,378 (33%) responded to at least one of the follow-up calls by one month, with 31% reporting that they were not smoking (10% classified as not smoking if non-responders are counted as smoking). The one month nonsmoking rate was 44% (19% based on intent to treat) in those seen by the bedside counselor compared to 24% (7% based on intent to treat) in those merely followed by phone. Unplanned 30-day hospital readmission rates were 9.1% for patients seen by the bedside counselor as compared with 15.7% for patients who did not receive bedside counseling based on the first 6 months of the program.

Conclusion:
An opt-out inpatient tobacco cessation service is feasible, can reduce relapse back to using tobacco after hospital discharge, and may reduce unplanned hospital readmissions.

Background:
Smoking cessation (SC) has rarely been recommended by oncologists in Ontario’s cancer centres. Many believe it is too late to matter or perceive that patients will not be receptive to SC. However, a growing body of literature has identified substantial health benefits from SC in cancer patients including improved general health, improved all-cause and cancer-specific mortality, reduced toxicity, greater response to treatment and decreased risk of disease recurrence and second primaries. Based on this evidence, Cancer Care Ontario (CCO) undertook an initiative to support SC for new ambulatory cancer patients in its Regional Cancer Programs (RCPs) in 2013.

Methods:
A steering committee of experts recommended a framework for SC in 2012 based on the Ottawa Model for Smoking Cessation. The CCO executive leadership and Regional Vice-Presidents supported the initiative which was then piloted in all 14 health regions in Ontario in 2014. Regional SC “champions” participated in monthly web meetings, data calls and in-person meetings led by a secretariat at CCO. Presentations on the health benefits of SC were made to physicians and other health care providers (HCPs) at regional cancer treatment centres and through the Ontario Telehealth Network. Presentations emphasized short, repeated oncologist scripts on the benefits of SC with referral to other HCPs for in-depth SC advice. New ambulatory cancer patients are screened, advised and referred to internal or external SC services dependent on regional resources. A minimum data set of standardized performance metrics is captured by CCO with patient-level data aggregated at the RCP level, presented as a provincial average, and reviewed with the RCPs in quarterly performance management sessions.

Results:
During Q1-Q3 of the 2014/15 fiscal year, 52.9% of all new ambulatory cancer cases were screened for smoking status. Of those screened, 21.3% were current or recent (within the last 6 months) tobacco users. Approximately three-quarters of these individuals were advised of the benefits of SC; a referral for cessation services was recommended in nearly 50%; of these patients, 66.7% accepted the referral to SC services. Of those accepting a referral, 50.4% chose referrals internal to the cancer treatment facility, 32.3% chose external referrals and the remainder (17.2%) used a combination of both referral resources. As part of this initiative a standardized cancer patient resource on SC in a print-ready format has been recently developed in both French and English and will be adapted for Ontario’s Aboriginal population.

Conclusion:
CCO’s centralized yet collaborative approach has led to province-wide implementation of a standardized intervention in a relatively short timeframe with limited financial resources. Ongoing barriers to implementation and sustainability experienced by RCPs include financial constraint, limited SC training resources, reluctant physician buy-in, strained staff and system capacity, and suboptimal inter-departmental communication. Nonetheless, there has been substantial progress. Framing SC as a quality of care issue has been critical to the success to date. Sustainability of the initiative will be dependent on continued committed leadership, buy-in from front-line staff, funding for dedicated SC counselors and other resources, and evidence of program cost-effectiveness.

Background:
In the 1990s Poland was among countries with the highest tobacco exposure and catastrophically high lung cancer mortality. Within the past two decades this situation has dramatically improved as a result of comprehensive national tobacco-control programs. We present the current tobacco exposure and

Methods:
Data on trends in cigarette consumption, smoking rates and lung cancer mortality were analyzed using the per capita sale of manufactured cigarettes, results of nation-wide questionnaire surveys conducted in adult (15+) population, and standardized mortality rates from lung cancer, respectively.

Results:
Between 1995 and 2013 annual cigarette sales in Poland decreased from 101 billion to 47 billion. The proportion of smokers among men dropped from 65% in 1980 to 28% in 2013, and among women from 32% to 18%, respectively. If this trend continues, the cigarette consumption per capita in Poland in 2040 will fall to the level of the 1920s. The age-standardized mortality rates per 100,000 from lung cancer in men declined from 71.1 in 1990 to 56.2 in 2010. The pattern of changes in lung cancer mortality among young Polish men became similar to that observed two decades earlier in the Unites States (Figure). However, Poland is still facing several challenges. Between 2003 and 2012 tobacco production in Poland increased by 90%, of which around two-thirds is exported. There is a persistently high proportion of smoking women, with almost a gender parity in the 35-44 age bracket (34% and 32% in women and men, respectively). Polish middle-aged women belong to the most common smokers in the European Union. The mortality rates from lung cancer among women are still on the rise. Since 2010 lung cancer has become the leading cause of death among women in Poland. Today, differences in smoking rates and lung cancer mortality are mainly generated by education and financial status, and not by gender. Figure 1



Conclusion:
There is an apparent need for further tobacco control efforts in Poland, including enforcement of the effective legislative measures (pictorial health warnings, plain cigarette packages, banning the sale of aromatic and ‘slim’ cigarettes) and implementation of tailored population-based preventive programs for women and socially unprivileged populations.

Abstract not provided

Background:
Previous preclinical studies and a phase I clinical trial suggested myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled, phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia.

Methods:
Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks, and then twice/day for 6 months. The primary endpoint was change in dysplasia rate after six months of intervention on a per participant basis. Other trial endpoints reported herein include Ki-67 labeling index and pro-inflammatory, oxidant/anti-oxidant biomarker levels in blood and bronchoalveolar lavage fluid (BAL).

Results:
Seventy four (n=38 myo-inositol, n=36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (p=0.76). The mean percent change in Ki67 labeling index in bronchial biopsies with dysplasia was -22.8% and -6.2%, respectively, in the myo-inositol and placebo arms (p=0.34). Compared with placebo, myo-inositol intervention significantly reduced IL-6 levels in BAL over 6 months (p=0.03) and had borderline significant effects on BAL myeloperoxidase (p= 0.06) level.

Conclusion:
The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent.

Background:
Prior clinical studies have shown that the oral prostacyclin agonist iloprost improves bronchial dysplasia in former smokers. Prostacyclin is a PPAR gamma agonist, and epidemiologic and pre-clinical studies suggest PPAR gamma agonists like pioglitazone may chemoprevent lung cancer. Based on these promising results, a double-blind, placebo controlled, phase II trial of pioglitazone in subjects at increased risk for lung cancer was sponsored by the Department of Veterans Affairs.

Methods:
Subjects were selected for the trial if they met one the following criteria: current or former smoker (> 10 pack years); biopsy proven endobronchial dysplasia; airflow obstruction (FEV1/FVC < 0.70); or at least mild sputum cytologic atypia. Fluorescent bronchoscopy was performed with biopsy of 6 standard endobronchial sites and all other abnormally appearing areas. Subjects also had pulmonary function testings and quantitative high resolution CT scans at the start and completion of the trial. Subjects were then randomized to oral pioglitazone or placebo for 6 months and then a second fluorescent bronchoscopy with repeat biopsy of all the central airway areas sampled on the first bronchoscopy. The endobronchial biopsies were scored on a 1-8 scale based on WHO criteria. The primary endpoint for the study is change in maximum (worst) endobronchial histology.

Results:
A total of 90 subjects (46 pioglitazone, 44 placebo) have been enrolled in the trial, with 76 completing both bronchoscopies. Subjects are well matched in terms of age, gender, tobacco exposure, and sputum cytology. No significant differences in lung function were observed between the treatment groups. While the investigators remain blinded in regards to treatment group, aggregate data is available. Overall, mild dysplasia or worse was seen in 26% of the initial biopsies. Similar to prior studies, current smokers exhibited more dysplasia at baseline compared to former smokers (32.4% vs. 16.6%) and also had more angiogenic squamous dysplasia (11.7% vs. 3.2%). Our primary endpoint is change in maximum histology, and histologic scores from matched biopsies in all participants showed a change of at least 1 grade in 50.2% (25.9% improved, 24.3% progressed). More histologic changes were observed in current smokers (59.2%) than former smokers (41.7%). Summary data for the non-normal biopsy pairs (ie those with a histologic score of at least 2 on baseline biopsy) showed that the majority of pairs (73.7%) changed by at least one grade. Current smokers exhibited more progression (29.3%) compared to former smokers (14.6%).

Conclusion:
The pioglitazone lung cancer chemoprevention trial is currently in progress. The treatment has been well tolerated and histologic changes were observed in many of the subjects.

Background:
Inflammatory infiltrates show differing capacities to eliminate malignant cells. This capacity is related to the polarization of key inflammatory cells in tumor infiltrates. A pathway analysis of genes that are differentially expressed between persistent and regressive bronchial dysplasia (BD) identified 13 pathways associated with persistence of which 8 were related to inflammation. We have hypothesized that differences in inflammatory infiltrate polarization may contribute to lung carcinogenesis and have employed gene expression and in situ analyses to characterize differences in inflammatory infiltrates related to persistence and regression of pre-malignant BD.

Methods:
Normalized gene expression levels (Affymetrix Hu 1.0) of selected genes related to inflammatory cell polarization features were analyzed to find differences associated with follow-up histology for BD. Validational analyses of these relationships were undertaken in studies of baseline biopsies selected to represent persistent (n=43) and regressive BD (n=39). These biopsies were analyzed by quantitative immunohistochemistry and dual immunofluorescence studies to characterize the overall proportion of subsets of T-lymphocytes and macrophages in each of the groups. Image analysis tools (Aperio) were used to characterize the density of inflammatory cell subsets in the stromal and epithelial compartments of biopsy tissue within defined areas.

Results:
Analysis of expression levels for a subset of inflammatory cell related genes assessed in a global gene expression analysis indicated significantly higher levels of expression of macrophage M1 markers HLA-DRA (p=0.01) and inducible nitric oxide synthetase (iNOS; p=0.02) and T-helper lymphocyte marker CD4 (p=0.04) in regressive BD compared to persistent BD. There was also a trend toward higher expression of cytotoxic T-lymphocyte marker CD8 in regressive BD (p=0.25). Expression of B-lymphocyte and neutrophil markers were not different between regressive and persistent BD. CD68 immunohistochemical stains (IHC) demonstrated a trend toward an increase in macrophages per area of combined dysplastic epithelium and underlying stroma with a mean increase in IHC positivity of 1.75-fold in regressive versus persistent BD (p=0.08). CD4 and CD8 IHC showed 1.36- and 1.19-fold increases, respectively, in regressive BD but these changes were not statistically significant (p=0.36 and p=0.43 respectively). Dual immunofluorescence was undertaken to determine if polarization specific subsets of macrophages correlated with regression or persistence of BD. Analysis of a preliminary subset of regressive (n=3) and persistent (n=3) BD demonstrates a wide range of M1 to M2 ratios (range = 0.84 – 4.82 for ratio of HLA-DRA-CD68 dual positive M1 to CD206-CD68 dual positive M2 macrophages per high power field, 400X). Additional analyses of macrophages are ongoing to determine if the polarization status is related to regression or persistence of BD, and analysis of markers of T-helper lymphocyte subsets are planned.

Conclusion:
Gene expression analyses indicate that increased expression of markers of M1 macrophages and T-helper lymphocytes are associated with regression, and in situ analyses suggest that differences in the amount of inflammatory cell subsets may be related to outcome in BD. These studies could have implications for predicting the behavior of premalignant disease and manipulating inflammatory activity in preventing progression of BD to invasive lung cancer.

Abstract not provided

Background:
Inhalation of asbestos and other carcinogenic mineral fibers cause malignant mesothelioma (MM) and lung cancer. Occupational exposure leads to a MM male to female (M:F) sex-ratio of 4-8:1, with a mean age of diagnosis of 74 years old because of the 30-50 years latency between initial exposure and MM development. In places where people are only environmentally exposed to carcinogenic fibers, the M:F sex-ratio is about 1:1 and the mean age of diagnosis is 50-60 years. In places where both types of exposure exist, the M:F sex ratio decreases and the proportion of young (<55 years old) cases increases, compared to places with occupational exposure only. Therefore, incidence rates cannot distinguish between occupationally- and environmentally-caused mesotheliomas.

Methods:
In order to detect areas with possible environmental exposure to carcinogenic fibers, we studied the geology of Nevada. We compiled and integrated known presence of fibrous minerals in Nevada from published sources. We used the CDC 2006-2010 cancer data to study MM incidence and death rates by state and by gender. We also analyzed MM mortality data from the CDC in different Nevada Counties, per sex and age group, for the 1999-2010 period.

Results:
Several fibrous minerals were identified in Nevada, including actinolite asbestos, other amphiboles such as magnesioriebeckite, winchite and richterite that caused an epidemic of asbestos-related disease in Libby, Montana, and the highly carcinogenic erionite. For the 2006-2010 period, Nevada has a global MM age-standardized incidence rate of 10 cases per million inhabitants-year (95% confidence interval (CI): 8-12), similar to the average MM rate in the US (10 per million; 95% CI: 10-10). We discovered that Clark and Nye counties in southern Nevada had higher proportion of young (<55 years) MM cases (11.28%) and lower M:F sex-ratio (2.69:1), compared with other Nevada counties (M:F sex-ratio=6.33:1, p=0.04; proportion of young MMs=9.09%, p=0.80) and with the US (M:F sex-ratio=4.97:1, p=0.04; proportion of young MMs=6.21%, p=0.02).

Conclusion:
The significant decrease of MM M:F sex-ratio and increase of young cases are indicators of possible environmental exposure to carcinogenic fibers in southern Nevada. In this arid region, naturally occurring asbestos minerals are present in urban and rural areas where people use to enjoy outdoor activities including horseback riding, running, hiking, bicycling, and off-road vehicle (ORV) recreation. Airborne dust is common due to wind erosion. Asbestos fibers have been found in air and dust samples in Clark County. Further research should be conducted in this area to help identify sources of environmental exposure to these mineral fibers, activities that lead to the release of these carcinogenic fibers into the air, and measures to reduce the consequent risk of MM and other cancers.

Background:
Radon is a naturally occurring radioactive gas produced by the breakdown of uranium and uranium progeny in soil and rocks. This colourless and odourless gas moves easily through bedrock and foundations to accumulate within homes (basements) and buildings. Once inhaled, radon gas can decay to solid radionucleotides that deposit within tissue of the airways and lungs and continue to emit alpha particle radiation over the course of >25 years. Exposure to radon gas is thought to be a major epidemiological risk for the development of lung cancer in people who have never smoked, but the precise relationship between exposure and molecular alterations associated with lung cancer are poorly described. In order to explore the relationship between domestic radon gas levels and lung cancer incidence in never-smokers, we set out to identify a cohort of Alberta lung cancer patients who have never smoked and measure radon gas levels of in their homes.

Methods:
The Glans-Look Database, comprised of clinicopathological and outcome data for over 5000 patients with non-small cell lung cancer (NSCLC) consulted at the Tom Baker Cancer Centre between 1999 and 2010, was searched for patients who had developed NSCLC but never smoked. Follow-up information was obtained to determine if the patients or their family members still lived at the address provided at diagnosis. Initial letters of contact were sent explaining the study. Patients and their family members will be notified by mail of the levels of radon gas in their homes, and how best to mitigate levels if high. Radon concentration was examined as a continuous variable and as a dichotomous variable, using the cut point value of 200 Bq/m[3] suggested by Health Canada guidelines. Statistical analysis of data utilizes Cox proportional hazard regression models to examine the independent effects of radon exposure on patient outcome, utilizing IBM SPSS Statistical Package version 19. The model addresses the possible confounding variables of exposure to second hand smoke, type and age of dwelling, family history of lung cancer, profession and hours spent within the home.

Results:
A cohort of 317 patients was identified, 189 of whom met study criteria requirement. As of March 2015, 42 patients or their family members agreed to participate in this study. 30 long term testing radon monitors have been placed in the homes where patients lived for at least five years before developing NSCLC. These monitors are being collected by the study team by: all will be retrieved by June 30, 2015, three months after initial placement.

Conclusion:
This study will contribute significantly to our understanding of residential radon gas exposure in NSCLC, and in the short term, alert patients and their families to potential risk of high level radon gas exposure. In the longer term, as this will be the first study of its type in Alberta, the findings may be seminal in forming the basis of a health program for improved testing for radon gas in the home and educating the public with respect to the dangers of radon gas exposure.

Background:
Chronic inflammation can influence the process of lung carcinogenesis. Dietary factors can modulate inflammation and may modify the effect of tobacco smoke. In this study, we aim to investigate the association between the inflammatory potential of usual diet, as assessed by the novel Dietary Inflammatory Index (DII), and lung cancer and to assess the interactions between the DII and tobacco use.

Methods:
Existing data from the Prostate Lung Colorectal and Ovarian Cancer (PLCO) screening trial was used to test the hypothesis that DII influences lung cancer and modifies the effect of tobacco smoke. PLCO participants were enrolled between 1993 and 2001 and randomized to a control arm or screening arm for four target cancers. Data were collected on cancer diagnoses and deaths from all causes that occurred through December 31, 2009. The baseline DII score for each subject was calculated from self-reports via food frequency questionnaires. A proportional hazards model was used to assess the association between the DII and DII-smoking interaction in relation to the probability of developing lung cancer. To investigate the association between DII and lung cancer prognosis, we explored the distribution of the lung cancer stage by the DII quintiles

Results:
Of 110,317 participants who met our eligibility criteria, 1850 (1.68%) developed lung cancer. The median follow-up time was 8.38 years. The association between DII and C-reactive protein was significant (beta coefficient of Quintile5 vs. Quntile1 =0.45, p-value<0.01). Results from the proportional hazards model show that those at the higher DII quintiles were at higher risk of lung cancer. The risk of lung cancer among Participants at the 5[th] quintile was 1.28 times higher the risk among these at 1[st] quintile (HR~Q5vsQ1~ = 1.28, 95 % CI 1.09–1.51, and P~trend~ <0.03, after controlling for possible confounders (demographics, smoking, family history, intervention and others) . An interaction was observed between DII score and tobacco smoke in relation to lung cancer (p-value for the interaction =0.01). Among current and former smokers combined HR~Q5vs.Q1~ was 2.00, 95 % CI 1.6-2.36 ( P~trend~ <0.001) compared to 0.82, 95 % CI 0.48-1.41 among never smokers. Table 1 shows the distribution of the lung cancer stage. Cases with worse prognosis were more likely to be in the higher DII quintile. Figure 1



Conclusion:
Overall, more pro-inflammatory diets are associated with increased risk of lung cancer, particularly for former and current smokers, suggesting that dietary-mediated inflammation plays an important role in lung carcinogenesis

Abstract not provided

Background:
Surgical resection is the standard treatment for early stage Non-Small Cell Lung Cancer (NSCLC). Anatomical resection with lymphadenectomy is recommended in surgically treated patients with Stage I-IIIA NSCLC. Whether mediastinal lymph node dissection (MLND) or mediastinal lymph node sampling (MLNS) should be performed remains controversial, and there is currently no consensus within the literature. We describe surgical approaches and patterns of disease recurrence in patients enrolled in MAGRIT: a large global randomized study of the MAGE-A3 Cancer Immunotherapeutic versus placebo after complete tumor resection (Phase III trial, MAGRIT, NCT00480025).

Methods:
Study participants were aged ≥18 years, with histologically-proven, MAGE-A3-positive Stage IB, II or IIIA NSCLC (AJCC 6.0) who had undergone R0 anatomic resection of their tumor (lobectomy or pneumonectomy) with mediastinal lymphadenectomy. Patients were randomized to MAGE-A3 or placebo in a 2:1 ratio. A total of 2,272 patients were treated at 556 centers in 34 countries. Because MAGRIT did not demonstrate efficacy overall, and because the number of recurrences in the placebo arm was small (n=271), recurrence patterns by surgical technique are presented in the overall population. An analysis of the placebo population was also conducted as the overall population results are subject to potential bias (a limited treatment effect in small sub-groups cannot be excluded). Cox regression models were used to explore whether lymphadenectomy procedure could be prognostic for disease-free survival (DFS) or overall survival (OS).

Results:
In the total treated population, 76% were men, 52% had squamous cell carcinoma, and 52% received adjuvant chemotherapy. More than half (57%) of patients were enrolled in Europe, with 23% in East Asia, 16% in North America and 4% in other countries. 47% of patients had Stage IB, 6.5% IIA, 30% IIB, and 17% IIIA disease. Lobectomy (including bi- and sleeve-lobectomy) was performed in 85% of patients, and 14% required pneumonectomy. MLNS was performed in 53% and MLND in 47% of patients. MLNS and MLND patients had a similar disease stage distribution. By region, the percentage of patients who underwent MLNS was: 36% in Europe, 65% in East Asia, 94% in North America and 59% in other countries. Among patients who had undergone MLNS or MLND, 37% (n=447/1202) and 36% (379/1067) developed recurrent disease, respectively. Loco-regional recurrence was observed in 40% (177/447) of patients after MLNS and 31% (118/379) after MLND, with distant recurrence observed in 55% (244/447) and 64% (244/379), respectively. There was no difference in the pattern of distant metastases between patients who had MLNS or MLND. Cox modeling showed no impact of the extent of lymphadenectomy on either DFS or OS. A separate analysis of patients in the placebo arm demonstrated similar trends to those of the total study population.

Conclusion:
Lobectomy (including bi- and sleeve-lobectomy) was the most frequently used treatment for patients who participated in the MAGRIT study. Important regional differences in lymphadenectomy were observed. Although the patterns of recurrence varied to some extent with the type of lymphadenectomy, our study did not demonstrate any prognostic impact related to the type of lymphadenectomy performed.

Background:
A previous study of the Society of Thoracic Surgeons database showed that non­-anatomic resection had lower perioperative morbidity than segmentectomy for non­-small cell lung cancer (NSCLC); however the study lacked long­ term outcomes. We tested the hypothesis that segmentectomy for stage T1a N0 NSCLC had better long-­term survival than wedge resection using the U.S. National Cancer Data Base (NCDB).

Methods:
Perioperative outcomes and overall survival (OS) of patients with clinical T1a N0 NSCLC who underwent wedge resection or segmentectomy in the NCDB from 2003-­2011 were assessed using propensity­-score-­matched analysis. Groups were matched for common prognostic co­variates (year of diagnosis, race, sex, age, education, income, insurance status, facility type, distance from facility, Charlson/Deyo co­morbidity score, tumor size and location). Additional propensity-­matched analyses were performed on patients with tumors ≤ 1 cm, patients with no comorbidities, and patients with pathologic T1a pN0 disease.

Results:
Of 40,058 clinical stage T1a N0 NSCLC patients, wedge resection and segmentectomy were performed in 7,517 (19%) and 1,268 (3%) patients, respectively. After matching, all baseline covariates, including comorbidity scores, were balanced between the wedge (n=1,231) and segmentectomy (n=1,231) groups. There were no significant differences between wedge and segmentectomy regarding 30-day mortality (1.6% [n=20] vs 1.5% [n=18], p=0.94). However, wedge was associated with significantly lower long-term survival than segmentectomy (Figure 1); this finding remained consistent even in a propensity-matched analysis of patients with tumors ≤ 1 cm (5 year OS: 56.8% [wedge] vs 78.2% [segmentectomy], log-rank p<0.01). To minimize treatment selection bias due to comorbidities, a propensity-matched analysis was also performed between wedge (n=509) and segmentectomy (n=509) for patients without comorbidities; wedge resection was associated with worse survival when compared with segmentectomy (5 year OS: 65.5% vs 69.5%, log-rank p<0.01). An additional propensity-matched analyses demonstrated that wedge (n=1,099) was associated with worse survival when compared with segmentectomy (n=1,099) for patients with pathologic T1a pN0 disease (5 year OS: 56.8% vs 65.5%, log-rank p<0.01).Figure 1



Conclusion:
In an analysis of a population-­based dataset, a large proportion of patients was found to have received wedge resection for stage T1a N0 NSCLC. Segmentectomy for T1a N0 NSCLC had similar 30­-day mortality but improved long-­term survival when compared to wedge resection, even for patients with very small tumors ≤ 1 cm, for patients with no comorbidities and for patients with pathologic T1a pN0 disease.

Background:
Stereotactic ablative radiotherapy (SABR) is a guideline-recommended therapy for unfit patients with early stage non-small cell lung cancer (NSCLC), and for pulmonary metastases. Experience with SABR for potentially operable patients is also increasing, and salvage surgery may have a role in patients who subsequently develop a local tumor recurrence. However, prior high-dose SABR could theoretically increase local adhesions and compromise wound healing. As the published literature is limited, we describe our experience with salvage surgery in 17 patients who developed a local recurrence after SABR.

Methods:
Patients who underwent surgical salvage for a local recurrence following SABR for pulmonary malignancies were identified from two Dutch institutional databases, as well as cases provided by other Dutch surgeons. Complications were scored using the Dindo-Clavien-classification.

Results:
Seventeen patients who underwent surgery for a local recurrence were identified. Patients were treated with SABR for either primary non-small cell lung cancers (N=9) or solitary metastasis (N=8). Four patients with solitary metastasis underwent surgery twice each for separate recurrences. Median time to local recurrence was 15.6 months. Recurrences were diagnosed with CT- and/or [18]FDG-PET-imaging, with 5 patients also having a pre-surgical pathological diagnosis. Extensive adhesions were observed during 5 resections, requiring conversion from a thoracoscopic procedure to thoracotomy in 3 procedures. Four patients experienced complications post-surgery; grade 2 (N=2) and grade 3a (N=2), respectively. All resected specimens confirmed the presence of viable tumor cells. Median length of hospital stay was 7 days (range 4-15 days) and 30-day mortality was 0%. Lymph node dissection revealed mediastinal metastases in 3 patients, all of whom received adjuvant therapy. Median follow-up after surgery was 41 months and median overall survival was 38 months.

Conclusion:
Experience with 21 surgical procedures for local recurrences post-SABR revealed only two grade IIIa complications, and a 30-day mortality of 0%. Median overall survival after surgery was 38 months. These results suggest that salvage surgery may be safely performed in selected patients following SABR.

Abstract not provided

Background:
Comparison of long-term survival of patients with clinical Stage I non-small-cell lung cancer (NSCLC) with and without mediastinal lymph node resection (MLNR) in the International Early Lung Cancer Action Program, a large prospective cohort in a low-dose CT screening program.

Methods:
All instances of thoracic surgery for first solitary primary non-small-cell lung cancer prompted by low-dose CT screening, performed under an IRB approved common protocol at each of the participating institutions since 1992 to 2014, are included. Follow-up time was calculated from diagnosis to death from lung cancer, last contact, or December 31, 2014, whichever came first. Univariate logistic regression analysis of the demographic, CT, and surgical findings for those with and without MLNR was performed. Kaplan-Meier (K-M) survival rates and Cox regression analysis was performed using all significant univariate variables.

Results:
The 10-year Kaplan-Meier (K-M) NSCLC-specific survival rate for the 225 patients manifesting as a subsolid nodule was 100%, regardless of whether they had MLNR (N = 169) or not (N = 56). For the 373 NSCLC patients manifesting as a solid nodule, for those who had MLNR (N = 285) and those who did not (N = 88), the K-M NSCLC-survival rate was not significantly different (86 % vs. 93%, P = 0.23). The rate was 95% vs. 96% (P = 0.86) for those whose pathologic tumor diameter was <= 10 mm; 83% vs. 94% (P = 0.19) for 11-20 mm, and 79% vs. 86% (P = 0.67) for 21-20 mm. Cox regression analysis comparing MLNR with no MLNR showed that survival rates were not significantly different (P = 0.33), but significantly survival decreased when the tumor diameter was above 20 mm (HR= 5.1, 95% CI: 1.6-15.7).

Conclusion:
Lymph node evaluation is not necessary for resection of subsolid nodules in patients with screen-detected lung cancer.

Background:
Precise preoperative diagnosis of the in-situ or minimally invasive carcinomas may identify patients that can be treated by limited resection. Though some clinical trials of limited resection for lung cancer have started, it will take much time to get results. We have reported a large scale data of limited resection at the previous WCLC meeting. We report here the data of subclass analysis according to the differences of pathology.

Methods:
Data from multiple institutions was collected on 1,737 patients who had undergone limited resection (segmentectomy or wedge resection) for cT1N0M0 non-small cell carcinoma. As 11 patients without pathological diagnosis were excluded, 1726 patients were analyzed to determine the indication of limited resection in pathological differences. Disease free survival (DFS) and recurrence free proportion (RFP) were analyzed.

Results:
Median age was 63 years. Mean maximal diameter of the tumors was 1.4 ± 0.5 cm. DFS and RFP at 5 years were 91.0 % and 93.6 %, respectively. DFSs and RFPs at 5years in pathology were 92.2% and 94.7% in adenocarcinoma (n=1575), 76.3% and 82.4 % in squamous cell carcinoma (SqCC) (n=100), 100% and 100% in carcinoid (n=16), and 73.6% and 75.9 % in others (n=35). Adenocarcinomas were classified using 2 factors, the ratio of consolidation and tumor diameter (C/T) and tumor diameter into 4 groups, group A (C/T ≤ 0.25 and tumor diameter ≤ 2.0 cm), group B (C/T ≤ 0.25 and tumor diameter > 2.0 cm), group C (C/T > 0.25 and tumor diameter ≤ 2.0 cm), and group D (C/T > 0.25 and tumor diameter > 2.0 cm). DFSs and RFPs at 5 years were 96.7% and 98.8% in group A, 100% and 100% in group B, 89.2% and 92.3% in group C, and 76.7% and 77.8% in group D. In all groups of adenocarcinoma, the prognosis in patients who underwent segmentectomy was not superior to wedge resection.The prognosis in both groups A and B was good. These groups seemed to be good candidates of limited resection. The prognosis of group D were not good. Group D seemed not to be a good candidate of limited resection. Prognosis of group C was not bad, however, we could not conclude indication in group C because group C included both part solid tumors and solid tumors. In SqCC, tumor diameter was not prognostic factor and only segmentectomy was favorable prognostic factor (DFSs and RFPs in segmentectomy vs wedge resection: 78.2% and 85.5% vs 65.5% and 65.5%, respectively). In SqCC, there seemed to be indication of limited resection with segmentectomy. In carcinoid, all tumors except one were resected by segmentectomy. Segmentectomy for cT1 carcinoid seemed to be allowed. As prognosis in other pathologies was worse in limited resection, there seemed to be no indication of limited resection.

Conclusion:
Pathological diagnosis was important to determine the indication of limited resection. Measurement of tumor diameter and C/T was useful to determine the indication of limited resection for adenocarcinoma.

Background:
General anesthesia with intubated ventilation is the standard in thoracic surgery. However, intubated anesthesia is often associated with postoperative discomfort and related complications. Recently, non-intubated anesthesia has emerged as a new option, but has only been assessed by several small-size reports. This study is to evaluate the feasibility and safety of non-incubated video-assissted thoracic surgery (VATS) for NSCLC under combined intravenous anesthesia (spontaneous respiratory status) and to compare it with the endotracheal intubated anesthesia.

Methods:
We retrospectively collected all NSCLC cases who underwent complete VATS lobectomy or segmental resection in our center under either non-intubated or intubated anesthesia. In this study, all non-intubated anesthesia cases were performed under combined intravenous anaesthetics plus analgesics while the intubated anesthesia cases were performed using double lumen endotracheal anesthesia. All procedures were conducted by the same group of surgeons and anesthesiologists from Dec 2011 to Dec 2014. Intra-operative and post-operative outcomes were compared between the two groups.

Results:
A total of 156 non-intubated and 188 intubated cases were included for analyses (Table 1). All non-intubated segment resections and the majority of non-intubated lobectomies were well exposed and were successfully completed; only 9 non-intubated cases planned for lobectomy (9/115, 7.2%) switched to intubated anesthesia. As shown in Table 2, both non-incubated lobectomy and segmentectomy had comparable outcomes with intubated anesthesia, regarding surgical duration, intraoperative blood loss, etc., as well as post-operative complications. Potential advantages were observed when comparing post-operative feeding time, volume of postoperative pleural drainage, and duration of post-operative hospital stay. Table1. Patient Demographics and Baseline Characteristics

		Segmentectomy			Lobectomy
	Intubated	Non-intubated	P- value	Intubated	Non-intubated	P- value
Age (years)	56.5±12.3	51.2±11.8	0.115	58.9±11.7	56.5±10.3	0.179
Sex(male,%)	11(44%)	12(35.3%)	0.087	97（58.4%）	64（55.2%）	0.215
Smoking	5(25)	7（20.6%）	0.161	21（12.7%）	15（13.0%）	0.679
BMI(kg/m2)	22.7±3.1	22.1±2.2	0.412	23.0±3.5	22.6±2.5	0.316
Tumor size	1.2±0.6	1.0±0.4	0.255	2.9±1.5	2.4±1.4	0.207
stage
Ⅰ	25	32		108	87
Ⅱ	0	0	29	8
Ⅲ	0	0	26	20

Table2. Operative results

		Segmentectomy			Lobectomy
	Intubated	Non-intubated	P- value	Intubated	Non-intubated	P- value
Surgical duration(min)	149.8±38.7	157.4±40.5	0.483	186.5±57.5	186.1±56.6	0.730
Intraoperative blood loss (mL)	83.6±64.1	73.9±56.5	0.076	154.7±258.3	130.8±185.7	0.165
Conversion to intubation		0			9
Postoperative feeding time (h)	13.9±4.6	7.6±3.2	<0.001	12.9±2.2	7.2±2.5	<0.001
Volume of pleural drainage (mL)	694.8±768.2	486.9±313.8	0.038	817.7±727.2	647.7±402.0	0.023
Chest-tube dwell time (days)	4.0±6.5	2.9±2.5	0.148	3.6±2.5	3.1±1.7	0.321
Duration of postoperative hospital stay (days)	9.5±7.4	7.1±3.5	0.041	8.8±4.1	7.6±2.4	0.044
Number of dissected lymph nodes	6.6±4.7	9.5±6.2	0.408	16.5±9.4	17.1±9.0	0.574
Stations of dissected lymph nodes	2.7±3.5	3.5±1.0	0.526	4.5±1.1	4.6±1.0	0.619

Conclusion:
This large comparative study demonstrated that complete VATS for resection of NSCLC under non-intubated anesthesia is feasible and safe. Non-intubated anesthesia is comparable to intubated approaches, and might have advanteages in terms of post-operative rehabilitation. However, the comparison regarding the long-term outcome is warranted.

Abstract not provided

Abstract:
Stereotactic ablative radiotherapy (SBRT, or SABR) is the guideline-recommended treatment for a peripheral stage I non-small cell lung cancer in patients who are unfit for surgery, or those who decline surgery. In patients fit to undergo surgery, no phase three randomized trial comparing the two modalities has been completed to date. However, comparative effectiveness research suggests that a similar disease-free survival and loco-regional control can be achieved with the two modalities [Louie AV 2015a]. At present, the only available prospective randomized data available in operable NSCLC reveals a 3 year rate of freedom from local recurrence of 96% (95% CI 89–100) in patients treated using SBRT, compared with 100% (95% CI 100–100) for patients in the surgery group (log-rank p=0.44) [Chang J, 2015]. With a number of new randomized clinical trials now in preparation, it is useful to understand the main reasons for a reluctance to believe that 2 treatment modalities are comparable. The poorer overall survival reported in the SBRT literature led to the suggestion that early deaths may be due to poor disease control and/or unrecognized toxicity. However, patients treated in early studies of SBRT often had multiple comorbidities, a factor which also decreases survival in surgical patients. For example, data from the Danish Cancer registry on resected patients reported a 5-year overall survival of 38% (95% confidence interval 23-53%) for pT1 and Charlson comorbidity score 3+, versus a 5-year overall survival of 69% (CI 62-75%) for pT1 and no comorbidity [Luchtenborg M, 2012]. An externally validated prognostic validation tool consisting of a recursive partitioning analysis (RPA) and nomogram, the Amsterdam prognostic model (APM), has been developed for overall survival after SBRT [Louie AV, 2015b]. While the nomogram retained strong performance across surgical and SBRT external validation datasets, RPA performance was poor in surgical patients, suggesting again that two distinct patient populations are now being treated with these local modalities. It has been argued that the identification of nodal metastases during surgery, followed by adjuvant chemotherapy, can lead to superior survival with surgery, as occult nodal metastases may be missed in patients who undergo SBRT after PET-CT staging. However, even recent surgical publications indicate that guideline-specified nodal staging is not being performed in a significant number of patients, but that this difference was not detrimental. Danish Cancer Registry data revealed that nodal upstaging for clinical stage I NSCLC was lower after VATS than after open lobectomy, but also that that the extent of nodal harvest did not influence overall survival [Licht PB, 2013]. The IELCAP investigators reported on outcomes in 347 patients, where of the patients undergoing sub-lobar resection and lobectomy, more than 40% and approximately one quarter, respectively, did not even have a single mediastinal lymph node biopsied [Altorki NK, 2014]. We previously argued that the benefits of surgical nodal harvest are modest at best in this patient population. The lack of clear benefit for a nodal dissection, particularly in patient groups with a stage I NSCLC at increased risk of postoperative complications will limit the benefits of primary surgery. This is not a totally unexpected finding as recent studies have shown that more extensive nodal surgery was not beneficial in malignancies of the breast, esophagus and stage III melanomas with micrometastasis to the sentinel nodes. Cost-effectiveness analyses have consistently demonstrated that SBRT is cost-effective when compared to sublobar resection [reviewed in Louie AV, 2015]. Survivors of both surgery and SBRT are at risk of a second primary lung cancer, at a rate varying from 3-6% per person year [Lou F, 2013; Verstegen N, in press]. Lung cancer deaths predominate in the first 5 years after treatment, after which the relative contribution of cardiovascular and COPD causes of death increases [Janssen-Heijnen M, 2015]. It has been argued previously that “to expose patients to a hypofractionated SABR without mature evidence of absence of its toxicity would be hazardous” [van Schil P, 2013]. As long-term follow-up data after SABR is now available [Verstegen N, 2015], and as SABR has clearly fewer post-treatment complications than a surgical resection [Chang J, 2015], it is only appropriate to discuss all these findings with patients in the context of shared decision-making. Much of the recent debate has focused on pathological staging and techniques. However, there is growing awareness of the importance of ‘value in healthcare’. Both patients and their insurers increasingly wish to know what their life will be like after treatment, if they will return to work, and if their symptoms will improve [http://www.ichom.org/]. In the near future, patient reported outcome measures (PROMs) are likely to take a complimentary role in decisions about the choice of local therapy for stage I NSCLC, as high-quality data from randomized clinical trials are awaited. References Louie AV. Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: Controversies, insights, and changing horizons. Radiotherapy and Oncology 2015 ;114:138-47. Chang JY. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015;16:630-7. Lüchtenborg M. The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients. Eur J Cancer. 2012 48:3386-95 Louie AV. Predicting Overall Survival following Stereotactic Ablative Radiotherapy in Early-Stage Lung Cancer: The Amsterdam Prognostic Model. Int J Rad Oncol Biol Phys in press. Licht PB. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. Ann Thorac Surg. 2013;96:943-9; Altorki NK. Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules. J Thorac Cardiovasc Surg. 2014 Feb;147:754-62; Lou F. Patterns of recurrence and second primary lung cancer in early-stage lung cancer survivors followed with routine computed tomography surveillance. J Thorac Cardiovasc Surg. 2013 ;145:75-81 Verstegen NE. Patterns of disease recurrence after SABR for early stage non-small cell lung cancer: Optimizing follow-up schedules for salvage therapy. J Thorac Oncol in press Janssen-Heijnen ML. Variation in causes of death in patients with non-small cell lung cancer according to stage and time since diagnosis. Ann Oncol. 2015;26:902-7 van Schil PE. Surgery or radiotherapy for early-stage lung cancer--a potential comparison bias. Lancet Oncol. 2013;14(10):e390.

Abstract:
Surgery vs. SBRT in operable NSCLC Surgery Over the last years stereotactic radiotherapy (SRT) has emerged as an alternative treatment to surgical resection for treatment of localized, early-stage non-small cell lung cancer (NSCLC). Precise delivery of high-dose radiotherapy has become possible to eradicate the primary tumor (1). SRT has mainly been applied for functionally inoperable patients with severe cardiopulmonary morbidity. Recently, the question has emerged whether SRT is also a valid oncological treatment in technically and functionally operable patients. At the present time, no randomized studies are available directly comparing SRT and surgical resection with systematic lymph node dissection. Several trials were initiated but they were closed prematurely due to poor accrual. SRT is certainly emerging as a valid therapeutic option. However, from a thoracic surgical point of view several concerns remain when applying SRT to operable early-stage NSCLC: precise pathology is not obtained in all cases, no precise information is available on locoregional lymph node involvement making it difficult to recommend adjuvant chemotherapy in specific cases, and in general, different criteria are applied when comparing results of surgery and SRT. This applies specifically to the definition of local recurrence which gives rise to a potential comparison bias and limits the accuracy of long-term evaluation (2, 3). Moreover, thoracic surgeons are more and more confronted with “salvage surgery” after previous radiotherapy when no other therapeutic options are available (4). Technically, these resections can be very challenging. As no high-grade evidence is available, different opinions prevail in present-day literature. In a pooled analysis of two randomised trials comparing SRT with lobectomy for stage I NSCLC that closed prematurely due to poor accrual, the authors concluded that SRT could be an option for treating operable stage I NSCLC. However, as the authors indicate themselves, because of small patient sample size and short follow-up time, further randomized studies should be performed before more definite recommendations can be made (5). In contrast, in a recent propensity score analysis 41 patients who underwent video-assisted (VATS) lobectomy were matched with 41 patients treated with SRT for stage I NSCLC (6). Significant differences were found in overall survival, cause-specific survival, recurrence-free survival, local and distant control favoring VATS lobectomy. Conclusion of this study was that VATS lobectomy may offer a significantly better long-term outcome than SRT in potentially operable patients with biopsy-proven clinical stage I NSCLC. In another propensity score analysis long-term survival was compared between SRT and sublobar resection for stage I NSCLC in patients at high risk for lobectomy (7). In 53 matched pairs the difference in overall survival was not significant and the cumulative incidence of cause-specific death was comparable between both groups. Conclusion of this study was that SRT can be an alternative treatment option to sublobar resection for patients who cannot tolerate lobectomy because of medical comorbidities. In June 2015 the “Comité de l’Evolution des Pratiques en Oncologie (CEPO) from Québec, Canada published its recommendations regarding the use of SRT (8). For medically operable patients with T1-2N0M0 NSCLC surgery remains the standard treatment due to the lack of scientifically valid comparative data. For medically inoperable patients with T1-2N0M0 NSCLC or medically operable patients who refuse surgery, SRT should be preferred to external beam radiotherapy, a biological equivalent dose (BED) of at least 100 Gy should be administered, and the choice of using SRT should be discussed within a tumor board. Radiotherapy should not be considered for patients whose life expectancy is very limited because of comorbidities. In conclusion, surgical resection remains the treatment of choice for patients with early-stage NSCLC who are functionally operable. After discussion within a multidisciplinary tumor board SRT may be considered for functionally compromised patients who cannot tolerate lobectomy. Further evidence is needed requiring cooperation between radiation oncologists and thoracic surgeons when designing comparative trials with strict inclusion criteria and precise definitions of endpoints. In this way a scientifically valid comparison between SRT and surgical treatment is provided. References 1. Louie AV, Palma DA, Dahele M, Rodrigues GB, Senan S. Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: controversies, insights, and changing horizons. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2015;114(2):138-47. Epub 2014/12/17. 2. Van Schil PE, Van Meerbeeck J. Surgery or radiotherapy for early-stage lung cancer--a potential comparison bias. The Lancet Oncology. 2013;14(10):e390. Epub 2013/09/03. 3. Van Schil PE. Results of surgery for lung cancer compared with radiotherapy: do we speak the same language. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2013;8(2):129-30. Epub 2013/01/19. 4. Van Schil PE. Salvage surgery after stereotactic radiotherapy: a new challenge for thoracic surgeons. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2010;5(12):1881-2. Epub 2010/11/26. 5. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. The Lancet Oncology. 2015;16(6):630-7. Epub 2015/05/20. 6. Hamaji M, Chen F, Matsuo Y, Kawaguchi A, Morita S, Ueki N, et al. Video-assisted thoracoscopic lobectomy versus stereotactic radiotherapy for stage I lung cancer. The Annals of thoracic surgery. 2015;99(4):1122-9. Epub 2015/02/11. 7. Matsuo Y, Chen F, Hamaji M, Kawaguchi A, Ueki N, Nagata Y, et al. Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage I non-small-cell lung cancer in patients at high risk for lobectomy: A propensity score matching analysis. Eur J Cancer. 2014;50(17):2932-8. Epub 2014/10/05. 8. Boily G, Filion E, Rakovich G, Kopek N, Tremblay L, Samson B, et al. Stereotactic Ablative Radiation Therapy for the Treatment of Early-stage Non-Small-Cell Lung Cancer: CEPO Review and Recommendations. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2015;10(6):872-82. Epub 2015/05/23.

Abstract:
Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has been rapidly adapted as a standard treatment for inoperable early stage non-small cell lung cancer (NSCLC).[1] Due to the potential risks of biopsy and the ability to evaluate and characterize pulmonary nodules on CT and [18]FDG-PET, centers have had differing standards of whether to treat patients without a pathologic diagnosis. In other diseases, there are well established protocols for treating without a pathologic diagnosis. For example, ten years ago, a diagnostic algorithm was developed and subsequently validated for the diagnosis of hepatocellular carcinoma based on imaging.[ 2] If a screened patient has a liver lesion is greater than 2 cm, shows arterial hypervascularity and venous washout, it is considered diagnostic. Two of the main techniques for establishing pathologic diagnosis for lung tumors are bronchoscopy and transthoracic needle biopsy (TTNB). Since solitary pulmonary nodules are frequently in the periphery, TTNB is the more frequently used method of diagnosis. Pneumothorax is a common complication of TTNB with rates varying in the literature from 9 – 54% with an average of around 20%.[3] Approximately 5% of patients undergoing TTNB require chest tube placement. In surgical series, the observed rate of surgical resection of non-malignant nodules ranges from 9 to 40%. Even programs with prospective CT-screening cohorts and nodule management protocols such as the International Early Lung Cancer Action Program report benign disease in 11% of resected patients.[ 4] Centers that have a relatively high proportion of treated patients with only a clinical diagnosis typically use criteria such as a new or growing lesion that is avid on [18]FDG-PET. Additionally, the probability of malignancy of a specific pulmonary nodule can be estimated based on statistical work of Swensen, et al. and Herder, et al. [5,6 ]The are numerous on-line calculators that incorporate these equations for evaluation of an individual patient. The VU University Medical Center in Amsterdam analyzed their results in patients who underwent SABR on whether they had a pathologic diagnosis.[ 7] In their prospective database of 591 patients, 35% had a pathologic diagnosis (biopsy proven) and 65% were diagnosed clinically. In a comparison of the two groups, the patients with a pathologic diagnosis had significantly larger tumor diameters and higher predicted FEV1 values. There was no significant difference seen in overall survival, local control regional or distant recurrences. In a retrospective analysis of 94 lesions (86 patients) treated with SBRT at the Cleveland Clinic, 35% of patients did not have tissue diagnosis.[ 8] They reported no difference in overall survival between these patients and those with pathologic confirmation. A prospective Phase II trial of SBRT from the Nordic Cancer Union was reported by Baumann, et al.[ 9] Nineteen (33%) of the 57 patients on the trial did not have pathologic confirmation of malignancy and only 14 of those 19 had [18]FDG-PET to help establish the diagnosis. Similar to the VU experience, patients with a pathologic diagnosis tended to have larger tumors. They reported no difference in progression-free, overall or cancer-specific survival between the subgroup with pathological confirmation and the whole patient group. The toxicity of lung SBRT is well established. In the VU experience reported above, they report Grade 3 or worse radiation pneumonitis in 3% of patients. Other complications include rib fracture and chest wall pain. As expected, there is no difference in toxicity between patients with or without pathologic diagnosis. There clearly is a role for SBRT in patients with radiographic-only confirmation of early stage NSCLC. In the centers where treatment of these patients is common practice, there is no evidence of differences in outcomes, nor excess toxicity. But the appropriate threshold for treatment of non-biopsied lung nodules is still unknown. Radiation oncologists need further input from our colleagues in diagnostic radiology, thoracic surgery and pulmonary medicine to develop specific guidelines on patients where biopsy could, and perhaps should, be avoided. This is especially true in countries where the potential of medical liability is relatively high since it is inevitable that some patients who actually do not have cancer will be treated with aggressive radiation therapy. References 1. Palma D, Senan S. Stereotactic radiation therapy: changing treatment paradigms for stage I nonsmall cell lung cancer. Curr Opin Oncol 2011;23:133–9. 2. AASLD Guidelines; Hepatology 2011;53:1020-2 3.Boskovic, et al. Pneumothorax after transthoracic needle biopsy of lung lesions under CT guidance. J Thor Dis 2014; 6: S99-107 4. Flores R, Bauer T, Aye R, et al. Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer. J Thorac Cardiovasc Surg. 2014;147(5):1619-1626 5. Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch of Int Med 1997;157:849–55 6. Herder GJ, van Tinteren H, Golding RP, et al. Clinical prediction model to characterize pulmonary nodules: validation and added value of 18Ffluorodeoxyglucose positron emission tomography. Chest 2005;128:2490–6. 7. Verstgen, N., et al., Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: Comparison with a contemporaneous cohort with pathologically proven disease. Radiotherapy and Oncology 101 (2011) 250–254 8. Stephans KL, Djemil T, Reddy CA, et al. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience. J Thorac Oncol 2009;4:976–82. 9. Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290–6.

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