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  • WCLC 2013

    15th World Conference on Lung Cancer

    Access to all presentations that occurred during the 15th World Conference on Lung Cancer in Sydney, Australia.

    Presentation Date(s):
    • October 27 - 30, 2013
    • Total Presentations: 2517

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    P1.24 - Poster Session 1 - Clinical Care (ID 146)

    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 53
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      P1.24-001 - Validation of a Novel Superior Vena Cava Syndrome Identification, Classification, and Management Algorithm (ID 307)

      C.R. Thomas, Jr., D. Hampton, C. Gamboa, J. Zatarain, B. Diggs, P.R. Theodore

      • Abstract

      Background
      Superior vena cava (SVC) syndrome results from great vessel extrinsic compression or intraluminal obstruction resulting in facial erythema, edema, or venous distension. This presentation can escalate into a life threatening condition. The Yale SVC classification system and management algorithm was proposed for tumor-related causes. We hypothesized its inclusion criteria may be limited in scope and not capture common causes and symptoms of SVC. The specific aim was to develop a SVC identification, classification, and management algorithm.

      Methods
      Retrospective data from Oregon Health & Science University pts diagnosed with ICD-9 code 459.2, compression of vein, between 2008-11 were collected. Pt demographics, vital signs, physical examination findings, hospitalization records, and outcomes were analyzed. ANOVA and Mann-Whitney U tests were utilized to assess significant between genders, p ≤ 0.05.

      Results
      The study population consisted of 207 pts; 157 were removed due to compression of a vessel other than the SVC. SVC syndrome was secondary to a malignancy (n=30), fibrotic stricture (n=5), or indwelling catheter-related thrombus (n=11). Dyspnea (n=31), facial edema (n=24), and cough (n=18) were the most common physical examination findings. Patients who presented with cough or dyspnea secondary to a malignancy, without facial, neck, or extremity edema (n=7) or those with a post-procedure fibrotic stricture (n=5) or an indwelling catheter-related thrombus (n=11) did not meet the Yale classification system inclusion criteria.

      Conclusion
      A SVC classification system, which accounts for non-oncologic causes and symptoms due to the mass effect on surrounding tissues (vasculature, trachea, and esophagus) is a more comprehensive approach to SVC treatment.

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      P1.24-002 - Efficacy and safety of oral palonosetron compared with IV palonosetron administered with dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with solid tumors receiving cisplatin-based highly emetogenic chemotherapy (HEC) (ID 333)

      M. Karthaus, C. Tibor, V. Lorusso, R. Singh-Arora, A. Filippov, G. Rizzi, M.E. Borroni, G. Rossi, S.M. Grunberg

      • Abstract

      Background
      Cisplatin is a cornerstone of lung cancer treatment and is associated with CINV, which impacts severely quality of life and may cause non-compliance. Palonosetron (PALO) is clinically superior and pharmacologically distinct from old-generation 5-HT3 receptor antagonists. Non-inferiority of 0.50 mg oral PALO (O-PALO) in preventing moderately emetogenic CINV when compared with 0.25 mg intravenous PALO (IV-PALO) has been demonstrated.

      Methods
      This multicenter, multinational, randomized, double-blind, parallel group study investigated the efficacy and safety of single doses of O-PALO and IV-PALO administered prior to HEC. Adult chemotherapy-naive patients with malignant solid tumors and adequate hepatic, renal and hematological function scheduled to receive cisplatin-based HEC were enrolled. Eligible patients received O-PALO (0.50 mg) or IV-PALO (0.25 mg) with oral dexamethasone (Dex) 20 mg (day 1) followed by Dex 8 mg bid (days 2–4). The primary study objective was to demonstrate the non-inferiority of O-PALO vs IV-PALO (O-vs-IV-PALO) as a percentage of patients with complete response (CR: no emesis and no rescue medication) within the acute phase (0–24 hours after chemotherapy administration). Secondary objectives included the assessment of safety and tolerability of O-vs-IV-PALO and CR in the delayed (25–120 hours) and overall (0–120 hours) phases.

      Results
      Of 743 patients randomized 1:1 to receive O-vs-IV-PALO, 739 received study medications and 738 were included in the full analysis set. The majority of patients were male (59.3%) and white (86.7%) with a median age of 59 years; 46.5% of patients had lung/respiratory tract cancer. The CR rate in the acute phase was high for both treatment groups (O-PALO 89.4%; IV-PALO 86.2%). The difference in proportions (stratum-adjusted Cochran-Mantel-Haenszel method) was 3.21% with two-sided 99% Confidence Interval (CI) from ‑2.74% to 9.17%. Non-inferiority of O-vs-IV-PALO was demonstrated since the lower limit of the 99% CI for the difference in proportions was closer to zero than the pre-defined non-inferiority margin of ‑15%. The same conclusion was obtained in the Per-Protocol population. Furthermore, results were similar with no statistically significant differences between treatment groups for delayed CR (O-PALO 76.2% vs. IV-PALO 74.8%, CMH odds ratio 1.09, 95% CI: 0.77–1.52, p=0.637) and for overall CR phases (O-PALO 73.7% vs. IV-PALO 70.2%, CMH odds ratio 1.20, 95% CI 0.87–1.67, p=0.269). Treatment-emergent adverse events (TEAEs) were reported for approximately half of all patients in each treatment arm. TEAEs related to the study drug were low (3.2% and 6.5% for O-PALO and IV-PALO respectively). Serious TEAEs related to the study drug occurred in 2 (0.5%) patients (O-PALO arm only); abdominal pain and constipation (one patient) and diarrhea and asthenia (one patient). No TEAEs related to study drug leading to discontinuation were reported.

      Conclusion
      Non-inferiority of O-PALO compared with IV-PALO was demonstrated. The results of the secondary efficacy endpoints supported the demonstration of non-inferiority based on the primary efficacy endpoint. For both O-PALO and IV-PALO the CR rate in the acute phase was >86% in patients undergoing HEC, nearly 50% of whom had lung/respiratory tract tumors. The safety profile of O-PALO and IV-PALO were comparable, with no concerns.

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      P1.24-003 - A comparison of the Lung Cancer journey - Metropolitan and Non-Metropolitan (ID 674)

      B.J. Page, A. Hanks, H. Marshall, I.A. Yang, R. Bowman, K. Fong

      • Abstract

      Background
      Referrals and diagnostic pathways for people with symptoms of suspected lung cancer vary by where a person lives and ease of accessing services. Lung cancer diagnostic specialist and treatment services are mostly located in major cities, which can make access for people living in regional/rural and remote areas more difficult compared to major cities. Studies have shown that remoteness of residence is associated with an increase of lung cancer incidence and mortality. Hypothesis: The time required for the evaluation of suspected lung cancer is longer for people from regional/rural and remote areas compared to people living in metropolitan Queensland. The aim of the research study is to describe and compare the journey from referral to diagnosis for people with suspected lung cancer from regional/rural and remote areas referred to The Prince Charles Hospital , a tertiary referral center, compared to metropolitan residents.

      Methods
      A retrospective study of consecutive people with suspected lung cancer referred to The Prince Charles Hospital from December 2010 onwards will be reviewed. Data on patient demographics and referral patterns will be collected from medical records and relevant Queensland Health patient information systems. Information systems include Queensland Oncology Online, Queensland Oncology Analysis System (OASys), The Viewer, Hospital Based Corporate Information System (HBCIS), Practix, Outpatient Services Information Management (OSIM), Picture Archive and Communication System (PACS) and Auscare. The following times will be compared between regional/rural/remote (defined as >50km from TPCH) and metropolitan (<50km from TPCH) patients: (A) from receipt of referral to first specialist appointment (FSA), (B) FSA to first pathological (cytology or histology) diagnosis (FPD), (C) FPD to first multidisiciplinary team discussion (MDT) and (D) MDT to first definitive treatment (FDT). .

      Results
      Preliminary results show that there are clear differences in times to first specialist appointments, diagnosis and definitive treatment experienced by patients living in more regional and remote areas compared to patients from the metropolitan area. Patients from more regional and remote areas on average waited longer for their first specialist appointments e.g. Non Metro: N= 103 60% of patients seen within 30 days of a written referral and 28% were seen within 7 days. Metro: N= 60 78% patients seen within 30 days of a written referral and 50% were seen within 7 days There was also a pattern of admitting patients from remote areas to have all diagnostic workup and commence treatment as an inpatient. Admitting patients from remote areas for diagnostic workup appears to have decreased time to treatment for this cohort of patients although the cost effectivenss to the health service is unknown.

      Conclusion
      Lung cancer is a devastating disease and has a poor prognosis. Lung cancer diagnostic and treatment pathways should be developed for patients living in more regional and remote areas of Queensland to ensure times to diagnosis and treatment are optimised. Potentially this will decrease emotional and financial strain suffered by patients and their families as well as being cost effective to health services.

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      P1.24-004 - Characteristics and Prognostic Analysis of Pulmonary Sarcomatoid Carcinoma (ID 727)

      Y. Liang, Y. Lin, H. Yang, G. Ma, Q. Cai, D. Wang, H. Long, J. Fu, L. Zhang, P. Lin, T. Rong, G. Xu

      • Abstract

      Background
      Pulmonary sarcomatoid carcinoma (PSC) is a group of rare tumor .The incidence in previous reports is from 0.1% to 4.7% of all lung malignancies. The recent 2004 WHO classification identified sarcomatoid carcinoma as a group of poorly differentiated non-small cell lung carcinomas that contained a component of sarcoma or sarcoma-like(spindle or giant cell or both) differentiation.There are 5 recognized subgroups: carcinosarcoma, spindle cell carcinoma, pleomorphic carcinoma, giant cell carcinoma, and pulmonary blastoma. Because of its rarity, the actual characteristics and prognosis of PSC is controversial. Some investigations reported PSC having a much more aggressive clinical course and significantly poorer outcome in comparison with other NSCLC, even when disease was diagnosed in early-stage.But others failed to show a poor prognosis for PSC.

      Methods
      We studied a cohort of 69 patients with PSC who received treatment in Sun Yat-sen University Cancer Center from January 1991 to December 2011 retrospectively.We analyzed the clinical characteristics, immunohistochemical profiles, epidermal growth factor receptor (EGFR) mutation status, K-RAS mutation status, treatments, and prognosis.

      Results
      PSC mainly occurred in young, male patients with a history of smoking. Eleven patients were stage I, 26 patients were stage Ⅱ, 23 patients were stage Ⅲ, and nine patients were stage IV at the time of initial diagnosis. The pathology of our patients included pleomorphic carcinoma (4 patients), spindle cell carcinoma (11 patients), giant cell carcinoma (10 patients), carcinosarcoma (34 patients), and pulmonary blastoma (10 patients).Most patients received multimodality treatments and the majority had early stage disease. Fifty patients achieved a complete resection while eleven patients achieved only an incomplete resections for a variety of reasones.Eight patients had inoperable disease when they were diagnosed.Among them, 5 received palliative chemotherapy alone.Eleven patients were tested for EGFR mutations, and all were wild type. Two patients tested for K-RAS mutations and identified 1 KRAS mutation.Five patients received EGFR tyrosine kinase inhibitor(EGFR-TKI) Gifitinib or Erlotinib as palliative salvage treatment: three patients maintained stable disease for 2,3,5 months with gefitinib, respectively; and the other two patients developed progressive disease after receiving treatment with erlotinib for 2 ,4 months , respectively. Median survival time (MST) was not reached, and the 5-year survival rate was 17.4%. Neither neo-adjuvant nor adjuvant chemotherapy improved patient survival for those with early stage disease. The patients without distant metastasis, with normal or higher BMI (≥18.5), with normal HGB, with smaller tumor size (≤4cm), and those who received complete resection had significantly better OS (p<0.05). The patients with pleomorphic carcinoma had much worse prognosis. In a COX regression model, sex, smoking status, BMI, LDH, tumor size, N stage, M stage, pathology and having received a complete resection were independent prognostic factors (p<0.05).

      Conclusion
      PSC is a unique lung malignancy with poor prognosis. Patients receiving complete resection had better prognosis, likely a reflection of early stage disease. Neither neo-adjuvant nor adjuvant chemotherapy improved patient survival for those with early stage disease. Future multi-center collaborations may be necessary to determine the optimal treatment.

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      P1.24-005 - Impressive retinal response to crizotinib in a patient with NSCLC and ALK translocation (ID 740)

      A. Bearz, S. Santarossa, V. Da Ros, U. Tirelli, A. Manfre', I. Sartor

      • Abstract

      Background
      Adenocarcinoma of the lung EML4-ALK-rearranged are about 5-7% of all Non-Small-Cell-Lung Cancer (NSCLC). Treatment for patients affected by metastatic adenocarcinoma of the lung harbouring an EML4-ALK translocation is the oral compound anti-Met, Crizotinib. Crizotinib is considered to be poorly active over cerebral localizations, due to a possible difficult CNS penetration.

      Methods
      Herein we report a case of a patient with adenocarcinoma of the lung and ALK translocation, with bone and retinal metastases at diagnosis and impressive response to Crizotinib in all those sites.

      Results
      In August 2012 a 43-year-old man was hospitalized for a severe impairment in his left eye, onset abruptely the day before. In his medical history no trauma had occurred in the days before hospital admission. He had been reporting cephalea for one month, mostly in the left eye area, with metamorphopsias.He underwent a fluoroangiography,showing signs of left retinal detachment due to multiple, non-primitive, retinal neoplasias, mostly in the left eye, but also in the right retina. CT-scan of the brain showed abnormal tissue in the left retina, with important choroidal swelling. A thorax CT-scan revealed a 5-cm nodule in his right lung, median lobe, with enlargement of right mediastinal lymph nodes. Bone scan showed involvement of several bones, cervical and dorsal vertebral bodies, sternum. Biopsy was done through mediastinoscopy and adenocarcinoma of the lung was diagnosed. Genetic characterizazion was: EGFR and KRAS wild type, EML4-ALK translocation, diagnosed by FISH. Clinical TNM at the diagnosis was T2aN2M1, and distant localizations were at the bone and bilateral retinal tissue, mostly on the left.The patient reported pain at his head, neck, dorsal back, severe asthenia; his left eye was off, he had been spending most of his daily time resting at bed since one week. He started to receive Crizotinib 250 mg BID orally at the beginning of October 2012. Treatment was well tolerated, with few G1 episodes of diarrhoea.In few weeks his symptoms improved with resolution of pain and asthenia, the patient returned progressively to a normal life. CT-scan showed a reduction of the main nodule in the right lung and mediastinal lymph nodes, partial response according to RECIST criteria. Surprisingly he reported an improvement in his left eye vision, he could see the light and some objects in the lower left eye field of view. Ophtalmologist reported a reduction of the temporal nodule in the right retina, while in the left retina there was an impressive reduction of the swelling; for that reason at the end of January 2013 the patient underwent surgery to the left eye for the retinal detachment, gaining a complete left eye field of view. He is still on Crizotinib and no progression of disease has been documented up to now.

      Conclusion
      Crizotinib has induced an impressive response over retinal metastasis from NSCLC; the patient had an eye off at the diagnosis of NSCLC and on treatment gained a complete left eye field of view. Crizotinib is active over cerebral tissue like retina.

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      P1.24-006 - Discussion and analysis of lung cancer among young people at our hospital (ID 767)

      K. Imasaka, Y. Kamata, H. Takakura, A. Komuro, K. Sunada, N. Hamanaka, M. Takahashi, K. Shimizu, Y. Inoue, T. Aoki

      • Abstract

      Background
      The incidence of lung cancer among young people has been increasing in recent years. There are many difficulties in the diagnosis and treatment of this disease in young people, including the need for social support. Therefore, we attempted to clarify the clinical features of lung cancer in young people based on an observation of the clinical course.

      Methods
      A total of about 600 lung cancer patients visited our hospital during the six-year period from April 2007-March 2013. Out of these, we extracted patients of lung cancer who were under the age of 40, and carried out a retrospective analysis of the data based on the medical records. We summarized the diagnosis, treatment and clinical course of the disease in this study population and then analyzed and discussed the characteristic features.

      Results
      There were a total of 10 cases of lung cancer among patients who were under the age of 40, of which 80% were male and 20% were female, 80% were smokers and 20% were non-smokers. The reasons for the first hospital visit was the presence of clinical symptoms, e.g., chest pain, bloody sputum, etc., in 70% of the patients. On the other hand, the remaining 30% of the patients were asymptomatic at the first visit and had been referred to our hospital based on the detection of abnormalities on the chest x-ray during periodic medical examination. Their performance status at the time of diagnosis was as follows: “0” in 6 cases (60%), “1” in 2 cases (20%), “2” in 1 case (10%), “3” in 1 case (10%), and “4-5”in 0 case (0%). Histologically, 7 cases (70%) were diagnosed as having adenocarcinoma, and 3 cases (30%) as having other subtypes (including unknown); classified by the disease stage, 70% patients had Stage 3A or more advanced cancer. Therefore, radical surgery could be performed in only 30%, of which one case showed pathological stage3B, and developed recurrence. Chemotherapy was administered in 9 cases, and 6 cases received 3rd or more advanced-line chemotherapy. Radiation therapy was administered in 7 cases. The remaining patients received alternative therapy, such as immunotherapy and local intra-arterial injection therapy, which was performed in 3 cases, at another medical institution. Clinical psychologist intervention was needed in 5 cases, all of which showed progression or recurrence.

      Conclusion
      Among young patients with lung cancer, the majority were male and smokers. Most of the patients had some symptoms at the first visit, although the performance status was generally good. There were many patients with adenocarcinoma and advanced cancer, and many patients received 3[rd] line or more advanced-line chemotherapy and radiation therapy. Alternative therapy, off-label in respect of insurance coverage, such as immunotherapy was also employed in many cases. In addition, there were many cases needing clinical psychologist intervention. Thus, there were many situations in which the patients required mental care for themselves and/or for their families. In conclusion, among young people with lung cancer, there were many who required a variety of medical and social interventions, including for the diagnosis and treatment, including palliative care.

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      P1.24-007 - Long-term maintenance therapy with bevacizumab for Chinese advanced non-small cell lung cancer: a case report (ID 783)

      Z. Liu, W. Wu, J. Tang, Y. Wu, Q. Meng

      • Abstract

      Background
      Phase IV Safety of Avastin in Lung (SAiL) study was conducted to determine the safety and efficacy of first-line bevacizumab plus standard chemotherapy regimens in a broad patient population. Herein, we report a Chinese female patient enrolled in SAiL study who received chemotherapy and subsequent bevacizumab maintenance for 39 months.

      Methods
      not applicable

      Results
      A 59-year-old female presented with a cough for 6 months, and was admitted to our hospital on December 2007. CT scan showed multiple patchy shadows in both lungs, multiple nodular shadows in the right pleura, and mediastinal lymph node enlargement. CT-guided biopsy of the lower left lung showed adenocarcinoma, and biopsy of the right supraclavicular lymph nodes confirmed metastasis. The patient was a non-smoker, and was negative for EGFR and KRAS gene mutations, and negative for EML4-ALK rearrangement. From January, 2008, this patient was enrolled in the SAiL study and received bevacizumab(15 mg/kg) plus paclitaxel(175 mg/m[2])/carboplatin(AUC=6) for 6 cycles. Re-examination was performed at cycles 2, 4, and 6, and the results showed the target lesion was reduced by 9.4%, 32.9%, and 22.9%, respectively. The non-target lesions were stable and no new lesions were noted. The therapeutic efficacy was defined as PR, and re-examination was carried out every 6 weeks. After 6 cycles of chemotherapy, maintenance bevacizumab was begun (15 mg/kg) every 3 weeks and continued until March, 2011. A total of 42 cycles of bevacizumab were administered, for a total dose of 44,730 mg. CT in April 2011 showed the target lesion and the non-target lesions had increased, and new metastatic nodules were also found. The therapeutic efficacy was defined as PD. The last follow-up visit was in Apr 2012, PFS was 39 months and OS was 52 months. During maintenance therapy with bevacizumab, the main side effects included proteinuria, secondary hypertension, and pneumothorax. Secondary hypertension was observed after 6 months of bevacizumab, and controlled with nifedipine extended-release tablets. At 7 months from beginning bevacizumab, urinalysis showed proteinuria (++) and bevacizumab maintenance was continued with no dose decrease. According to the protocol, a 24-h urine protein level was obtained every 3 weeks. When the urine protein level was <2,000 mg/24h, bevacizumab maintenance was continued, and if the level was ≥2,000 mg/24h, treatment was discontinued and re-examination of the urine protein level was carried out every 3 weeks. Bevacizumab maintenance was continued when the 24-h urine protein decreased to <2,000 mg/24h. After 19 months of bevacizumab, the patient's urine protein level was >2,000 mg/24h, when treatment was discontinued. Between August 2009 and March 2011, bevacizumab maintenance therapy was stopped several times; the longest duration of discontinuation was 3 months. The maximal 24-h urine protein level was 3,926 mg/24h (grade 3), which was noted 33 months after beginning bevacizumab. It is noteworthy that 12 months after discontinuation of bevacizumab, urinalysis still showed proteinuria (+). Spontaneous pneumothorax of her left lung occurred 36 months after initiation of bevacizumab and chemotherapy. The patient experienced no symptoms, and after 1 month CT showed full expansion of the left lung.

      Conclusion
      not applicable

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      P1.24-008 - Are patients' needs being met after-hours? An evaluation of phone calls made after hours for patients with thoracic malignancies. (ID 873)

      M.I. Patel, D. Williams, C. Wohlforth, G.A. Fisher, D. Blayney, H.A. Wakelee

      • Abstract

      Background
      Understanding phone calls that patients with lung cancer make after hours is important as it represents an opportunity to provide improved care for patients and their caregivers. Furthermore, better understanding of after- hours phone calls can help to influence ways to reduce healthcare spending. Therefore, we sought to evaluate the nature of after-hours calls initiated by patients and their caregivers to the thoracic oncology clinic from the hours of 5pm-8am and on weekends.

      Methods
      The study is a retrospective analysis of 4 months of outpatient phone calls made to the Stanford Cancer Institute during the weekends and hours of 5pm until 8am on weekdays. On-call after-hours physicians documented who made the call, chief complaint, age, gender and the advice given. Phone calls were excluded from analysis if there was missing information regarding reason for call or advice given. Differences in proportions were analyzed by Fisher's exact test. A two-sided p value <0.05 was considered significant.

      Results
      There were a total of 271 phone calls made after hours by patients with lung cancer, however after exclusions, there were 215 phone calls for analysis. The majority of phone calls occurred between the hours of 5pm and 11pm (n = 157; 73%) followed by daytime calls made during the weekend (n = 37; 17%). A majority of the phone calls were made by the patient (50%) with a slightly lower proportion made by a family member (46%). The majority of the patients who called were in their 50’s (29%) and female (54%). A high proportion of patients called for more than one chief complaint (30%) although almost all patients complained of more than one symptom on review of systems (95%). The main symptoms patients called for were cough (28%) followed by shortness of breath (27%). Of the phone calls made, 62% (133) were referred to the emergency room. Of those patients referred to the emergency department, 77% (103/133) resulted in a hospital admission.

      Conclusion
      Most after-hours phone calls from patients with lung cancer are related to symptoms. A large proportion of patients who were referred to the emergency department subsequently required an admission. Future studies should evaluate whether there are ways to improve patient triage after hours and improve symptom control to prevent hospitalizations for these patient populations.

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      P1.24-009 - Primary Giant and Destructive Hydatide Disease Mimicking Malign Tumor of the Chest Wall: Case Report and Literature Rewieve (ID 875)

      A. Erdogan, S. Akdeniz, G. Kenar, Y. Toker, A. Demircan

      • Abstract

      Background
      Hydatid disease, a naturally zoonotic disease, is frequently encountered some region; such as Mediterranean Countries. It is generally occupied on the liver and lung; nevertheless, it can pose on all organs. Primary chest wall origin of the Hydatid disease is very rarely observed.

      Methods
      In this report; a sixty five years old female patient who has primary chest wall located, having ribs and soft chest wall tissues destruction giant hydatide disease has been presented due to its so many rare observations, atypical localization and mimicking primary chest wall tumor. She has chest and neck pain continuing for about 5 months. In the examination made, a remarkable finding was not encountered in the patient’s medical history and physical examination. In the computerized thorax tomography, it was reported that there were combined but multiple number of tumoral masses in the giant soft tissue density having dimensions of totally approximately 10*15*10 cm (Figure 1). It was reported that the lesions observed in the whole body PET/CT appearance tomography drawn were not active to the highest degree and their SUX max levels were at the level of 3-5 values (Figure 2).

      Results
      In the exploration, it was observed that the lesions were cystic structures having very high density. Additionally, the thorax wall muscle and soft tissues and the front lateral areas of 2,3 and 4 ribs from above were totally necrotic and destructed. All destructive and necrotic tissues were removed and resected in the operation.

      Conclusion
      In the postoperative period, no complications developed and the patient was discharged with full recovery after 10 days. Hystopathological examination was reported as necrotic hydatid disease. The patient is still under control in the postoperative 3rd year and she has not symptoms.

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      P1.24-010 - Successful rechalenge of erlotinib in patient with non-small cell lung cancer - regain of tyrosine kinase sensitivity. Case report (ID 877)

      E. Chmielowska, M. Studzinski, A. Krause, M. Kwiatkowski

      • Abstract

      Background
      Activating mutation in EGFR gene is a predictive marker for treatment response for tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. These drugs are approved for treatment in any line of advanced stage EGFR-mutated non-small cell lung cancer. The TK domain EGFR mutations are more frequently found in Asian population than Caucasian, and are more prevalent in women than in men. There is scarce data regarding reintroduction of TKI after developing drug resistance during previous treatment.

      Methods
      We report on the case of 56-years old Caucasian, non-smoking woman diagnosed with cancer of the right lung. In 2004 patient underwent lobectomy of lower right lobe with mediastinal lymph nodes sampling – histopathology showed a grade 2 lung adenocarcinoma, pathological stage was pT2N1; no distant metastases were found. Adjuvant chemotherapy has been applied – patient received 4 cycles of PG regimen (Cisplatin with Gemcitabine); radiotherapy was not used. In March 2008, three and a half years after completion of primary treatment regional recurrence was documented by thoracic CT scan – mediastinal lymph nodes and parietal pleura were involved. Sequential chemoradiotherapy was used – patient received 4 courses of pemetrexed and radiotherapy (RTH) 44 Gy in 22 fractions – partial remission was obtained. Six month after RTH completion, in April 2009, the CT scan demonstrated the progression – large lytic lesion on sternum appeared and mediastinal nodes increased in size.

      Results
      Because primary tumor was positive for mutation in EGFR exon 19 by polymerase chain reaction, erlotinib treatment in dose 150 mg/d was initiated. The dose has been reduced to 100 mg after 4 courses due to toxicity – persistent and recurrent genitourinary infection. After dose reduction no adverse events were reported. Erlotinib treatment was continued for 18 months until disease progressed in November 2010 - lytic lesion in sternum increased and became symptomatic. Palliative radiotherapy on sternum was applied and third line of systemic treatment was introduced – six cycles of paclitaxel and carboplatin. Result of treatment was stabilization by RECIST 1.0 criteria and bone pain was gone. For the next 12 months CT scans were performed every 12 weeks – during that period there was no need for anticancer treatment. On February 2012 progression was confirmed – dissemination to both lungs. Because of reports in literature suggesting that EGFR-TKI drug resistance may be result of non-mutational, reversible mechanism that can be overcome by temporarily withholding TKI usage (so called “chemotherapy holidays”), decision was made to restart treatment with erlotinib. Treatment with reduced dose of 100 mg/d was initiated in March 2012 and is continued 15 months later. Every three months CT scans are performed – after initial shrinkage there is a tendency to increase tumor size, but progression criteria by RECIST are not met. 60 months after disease recurrence patient is in good condition, fully active and no adverse events were noticed.

      Conclusion
      Conclusions The intermittent therapy of TKI inhibitors may be beneficial for some patients with lung cancer, given they have reversible TKI-resistance.

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      P1.24-011 - Exercise as a strategy for rehabilitation / palliation in Advanced Stage Lung Cancer Patients (ID 948)

      M. Quist

      • Abstract

      Background
      Potential beneficial effects of physical exercise for cancer patients remains to be demonstrated for lung cancer patients with advanced disease. Advanced lung cancer is incurable, and is the leading cause of cancer deaths world-wide. The aim of the treatment is to improve QoL and prolong life for these patients; therefore interventions with a focus on VO~2~peak and functional capacity are much needed as physical exercise has shown to have a positive impact on QoL. Kasymjanova et al 2009 has been shown that patients with advanced stage lung cancer significantly lowered their functional capacity after two series of chemotherapy. Moreover, patients with low functional capacity before starting chemotherapy had significantly more disease progression and significantly shorter lifespan, compared to those with a higher functional capacity. Another study from Jones et al 2011 supports this and found that functional capacity is a strong independent predictor of survival in advanced NSCLC that adds to the prediction of survival beyond traditional risk factors, which may improve risk stratification and prognostication in NSCLC. Based on these results this study seeks to examine the effect of a 6-week exercise intervention for advanced lung cancer patients.

      Methods
      Patients with inoperable NSCLC (IIIb-IV) and SCLC (ED) were screened for eligibility. Aerobic capacity (VO~2peak~), muscle strength (1RM), functional capacity (6MWD), lung capacity (FEV1), HRQOL, cancer related symptoms (FACT-L) and anxiety and depression (HADS) were measured at baseline and 6 weeks.

      Results
      One-hundred-two patients were included and 72 patients undergoing concurrent systemic treatment were eligible for analysis. There was a significant increase in aerobic capacity - VO~2peak~ (p=0.014) and functional capacity- 6 MWD (p=0.006). There was significant improvement in strength (P<0.001). There was a significant change in the parameter for ‘emotional wellbeing’ (p=0.000) with a moderate effect size of 0.30 and ‘social well-being’ (p=0.000) with a small effect size of 0.23. However, there was no significant improvement or decline in general QOL. Theere was a significant reduction in anxiety (HADS-A) (p=0.008) a significant change in Psychological Morbidity (HADS-T) (p= 0.023). However, there was no significant change in Depression (HADS-D) (p=0.124).

      Conclusion
      The results from this study shows that it is beneficial for advanced lung cancer patients to participate in a 6 weeks exercise intervention. The significant reduction in anxiety has not been found in other studies with advanced lung cancer patients, further research will show the clinical relevance of these findings.

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      P1.24-012 - How to Build a Better Lung Cancer Support Group: Best practices from Australia, the United Kingdom and the United States (ID 1019)

      M. Rigney, L. Dornan, A. Copeland, K. Callaghan, A. Hatton, R. Taylor

      • Abstract

      Background
      Research shows that people diagnosed with lung cancer experience high levels of distress and that their unmet physical and emotional needs are greater than those diagnosed with other types of cancer. One significant unmet need for lung cancer patients is social support. An important way for patients to connect and to know they are not alone is through face-to-face support groups. The benefits to cancer patients attending such groups go beyond support and may include increased feelings of control and confidence and a decrease in depression and distress. For many reasons, the majority of lung cancer patients prefer lung cancer-specific support groups rather than those for all cancers. However, facilitators report that starting and maintaining lung cancer groups is often a challenge. As a result, the number of such groups is insufficient to meet the need. Cancer charities play an important role in fostering lung cancer support groups by directly running groups or supporting those who do. Toward the goal of increasing the number and viability of these groups, a study was conducted to understand the challenges related to starting and sustaining lung cancer support groups and the solutions successful facilitators have found to overcome those challenges.

      Methods
      To understand the challenges of lung cancer specific support groups and how to overcome them, a literature review of research about cancer support groups was conducted. Lung cancer support group faclitators in Australia, the United Kingdom and Australia were surveyed and in-depth interviews were conducted on a sample. Program evaluation data from 37 groups in the UK was also included.

      Results
      An international guide to lung cancer support groups best practices was developed. The guide provides solutions suitable for all facilitator skill levels and addresses resource constraints that facilitators may face. The solutions presented are designed to assist anyone interested in running a successful lung cancer support group anywhere in the world. A second phase of the research will involve formative research to determine desirability and feasibility of adopting best practices in a sample of control groups in the United States that were not involved in the initial survey and interviews. Those results will be presented at future conferences.

      Conclusion
      People with lung cancer can benefit from in-person support groups in immeasurable ways but many do not have access due to the lack of available groups. While challenges to initiating and maintaining successful lung cancer specific support groups exist, expert facilitators have found creative ways to advertise their groups, keep participants engaged and their groups thriving. With the information provided, professionals at charities and treatment facilities interested in starting lung cancer support groups will know what to consider as they organize their groups and will have at the ready tried and true techniques for making their groups successful. Charities not able to run their own groups will learn the importance of disseminating this information to facilitators as well as understand how to best support them to reach the goal of increasing the number of lung cancer-specific support groups.

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      P1.24-013 - Prophylaxis against pulmonary thromboembolism with unfractionated heparin for the patients undergoing pulmonary resection for lung cancer (ID 1061)

      T. Takemoto, M. Nishino, H. Mizuuchi, K. Sato, K. Suda, T. Iwasaki, K. Minami, T. Mitsudomi

      • Abstract

      Background
      Pulmonary thromboembolism (PTE) is a well-recognized potentially fatal complication after lung cancer surgery. In Japan, PTE had been relatively uncommon. However, it has recently been increasing probably due to changes in lifestyle. In our institution, deep vein thrombosis (DVT) is intensively screened by measuring preoperative D-dimer. Unfractionated heparin (UFH) is routinely administered to the patients having lung cancer surgery in addition to mechanical prophylaxis using elastic stockings(ES) or intermittent pneumatic compression devices(IPC). Here, we retrospectively evaluated efficacy and safety of these strategies to prevent PTE.

      Methods
      We retrospectively reviewed charts of 531 patients who underwent lung cancer surgery from January 2009 through April 2013. The patients who were deemed high-risk for DVT (those with past history of thrombosis, or those with elevated preoperative D-dimer (>1.0μg/ml), or those with varicose veins in their lower extremities), in principle, underwent venous ultrasonography of lower extremities. Among high-risk patients, those with or without DVT were classified as a group A and B, respectively. Those who failed to undergo venous ultrasonography were referred to as a group C. Those who did not meet above-mentioned criteria for high-risk group were classified as a group D. As perioperative prophylactic measures against PTE, all the patients in the group A wore ES from two days before surgery to one month after surgery. The patients also received continuous intravenous UFH (6000 units per day) immediately after surgery to postoperative day (POD) 1, and then received subcutaneous UFH (5000 units twice daily) from POD 2 until the patients became ambulatory. The patients in groups B, C and D wore ES during and after surgery. In addition, IPC was applied intraoperatively. The patients also received continuous intravenous UFH (6000 units per day) immediately after surgery to POD 1.

      Results
      Number of patients in each group were 14, 41, 87, and 389 in the group A, B, C, and D, respectively. In the group A, none was diagnosed as having PTE preoperatively. Eleven patients received postoperative UFH. However, two patients with intrathoracic adhesions did not receive UFH to avoid excessive postoperative bleeding. One patient with coronary artery complications underwent perioperative anticoagulation therapy. In this group, one patient without postoperative UFH administration due to adhesion developed symptomatic PTE. One patient was diagnosed asymptomatic exacerbation of DVT by ultrasonography one week after surgery despite UFH administration. In the groups B, C and D, 473 patients received postoperative UFH. Twenty-one patients with intraoperative bleeding or intrathoracic adhesions did not receive UFH. Twenty-three patients with coronary artery complications underwent perioperative anticoagulation therapy. In these groups, none developed symptomatic PTE. In 4 patients of 473 who received UFH, UFH was discontinued before POD 1 due to increase in sanguineous drainage without further complication.

      Conclusion
      Only one patient of 531(0.19%) developed symptomatic PTE after surgery. This patient had had preoperative DVT. Therefore, we regard that our strategies were effective to prevent PTE at least for patients without preoperative DVT. However, it may be necessary to apply even more intensive prophylactic measures for patients with evidence of preoperative DVT or PTE.

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      P1.24-014 - Metastatic angiosarcoma presenting as haemoptysis and severe pain on the back (ID 1172)

      M.G. Ortakoylu, C. Aslan, A. Bahadir, F. Alkan, A. Kara, C. Ar, O.Ç. Taşkın, E. Çağlar

      • Abstract

      Background
      Angiosarcoma is a rare malignant neoplasm of the vascular or lymphatic endothelium that accounts for 2% of all soft-tissue sarcomas.Angiosarcoma in the lung is a rare disorder and is usually attributable to metastasis from primary site such as skin, soft-tissue, heart, breast or liver.We describe a case of pulmonary metastatic angiosarcoma who presented with episodic haemoptysis and severe pain on the back.

      Methods
      A 21-year-old male was admitted with history of recurrent hemoptysis and pain on the his back for two months.There were no other constitutional symtoms.Thoracic and abdominal computed tomograhy scan revealed left hilar lymphadenopathy and bilateral multiple nodules; the spleen was enlarged and shown multipl hypodense lesions.Hilar lymphadenopathy was sampled by real time convex prob EBUS TBNA and CT guided transthoracic fine needle aspiration was performed.Definitive diagnosis couldnt be obtained with both procedures.PET scan revealed the widespread FDG uptake bone marrow, liver and spleen and lung. The patients underwent bone marrow biopsy and histopathological examination of yields reported angiosarcoma.Immunohistochemistry (CD 31 positivity) confirmed the diagnosis of angiosarcoma.

      Results
      The patient showed progressive deterioration and anemia and thrombositopenia and hemoperitoneum owing to spontaneous liver rupture appeared.He was managed with repeated blood transfusions but he died twenty-seventh days after admitted hospital.

      Conclusion
      We presented a rare angiosarcoma case with aggressive clinical course and a fatal prognosis for the patient.

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      P1.24-015 - Chemoradiotherapy-associated myelosuppression: Analysis of risk factors for patients with non-small cell lung cancer (ID 1298)

      U. Yilmaz, B. Yalcın, C. Anar

      • Abstract

      Background
      Concurrent chemoradiotherapy (CRT) is standard treatment for patients with stage III non–small cell lung cancer (NSCLC). Myelosuppression can be a significant problem in concurrent CRT, but its risk factors remain largely unkown. The aim of the present study was to assess clinical and biological parameters obtained before concurrent CRT to define the risk factors for myelosuppression in patients with locally advanced NSCLC.

      Methods
      We retrospectively analyzed 81 patients with NSCLC who received concurrent platinum-based chemoradiotherapy between January 2008 and December 2012. A total of 78 patients (96.2%) received etoposide (50 mg/m2, intravenously (IV) on days 1-5, 29-33) plus cisplatin (50 mg/m2, IV, on days 1,8,29, and 36) and 3 patients (3.8%) treated docetaxel (20 mg/m2/w, IV, on weeks 1-8) plus cisplatin (20 mg/m2/w, IV, on weeks 1-8) concurrently with thoracic radiotherapy to a total dose of 40-66.6 Gy. The risk factors were examined for their association with myelosupression (grade 3 or 4 leukopenia, neutropenia, thrombocytopenia or anemia) by logistic regression analysis.

      Results
      Grade 3 or higher neutropenia, leukopenia, thrombocytopenia, or anemia occurred in 51.8, 53.0, 8.6, and 7.4 % of the patients, respectively. Multivariate analysis revealed that the risk factors for neutropenia were performance status (odds ratio [OR] , 3,196 ; p=0,032; 95 % confidence interval [CI], 1,104-9,524), white blood cell count (OR, 3,250; p=0,023; 95% CI,1,173-9009 ) and pretreatment creatinine level (OR, 3,325; p=0,018; 95% CI,1,228 - 8,999 ). On multivariate analysis, white blood cell count (OR, 3,311; p=0,027; 95% CI, 1,148-9545 ) was found as significant risk factor for CRT-induced leukopenia. No significant association was found between patient’s characteristics and anemia or thrombocytopenia

      Conclusion
      This information on grade 3-4 neutropenia and leukopenia is considered to contribute significantly to its safe and effective use of concurrent chemoradiotherapy for treatment of locally advanced NSCLC.

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      P1.24-016 - Single agent oral etoposide for elderly and infirm advanced non small cell lung cancer : A reasonable therapeutic option (ID 1317)

      K. Rathnam, K. Kosanam Subramaniam

      • Abstract

      Background
      Background: The use of chemotherapy has been shown to increase the effectiveness of best supportive care (BSC) in elderly patients with non-small cell lung cancer (NSCLC). The use of Intravenous chemotherapy ( IV ) has many times been difficult in elderly patients or patients with poor performance status owing to fear of toxicity.We studied the effectiveness of a non toxic regimen with single agent oral chemotherapy with etoposide plus best supportive care versus best supportive care alone in subjects with advanced non small cell lung cancer unfit for IV chemotherapy

      Methods
      Eighty five cases of advanced non small cell lung cancer and ECOG performance status of 2 to 3 , unfit for IV chemotherapy as per treating physician's discretion were included in the study. Forty three patients received chemotherapy with Tablet Etoposide 50 mg once daily for 14 days along with best supportive care ( BSC )every 21 days for a maximum of 8 cycles in responding patients. Regimen was re challenged on progression. The remaining received BSC only.

      Results
      We measured at least 1 of the following outcomes: Overall survival ( OS ) or treatment-related mortality. Overall, patients that received chemotherapy plus BSC had significant longer OS than those that received BSC alone (HR 0.75; 95%CI, 0.68–0.82; P,0.001). Additionally, chemotherapy plus BSC as compared to BSC alone resulted in a 24% RR reduction (95%CI: 10–38; P = 0.001) in 6-month mortality, 10% RR reduction (95%CI: 8–15; P,0.001) in 12-month mortality and 6% RR reduction (95%CI: 2–9; P = 0.02) in 2-year mortality. Toxicity was not significantly greater in patients who received chemotherapy plus BSC.

      Conclusion
      Chemotherapy with single agent oral etoposide plus BSC is a non toxic therapeutic option in infirm and elderly NSCLC patients unfit to receive intravenous chemotherapy.

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      P1.24-017 - Monitoring of patients under treatment with single fraction of SBRT in lung lesions. (ID 1345)

      D. Najjari, A. Navarro, M.D. Arnaiz, R. Ramos, S. Aso, E. Garcia, F. Guedea, M. Galdeano, R. Piñeiro, F. Cardenal

      • Abstract

      Background
      INTRODUCTION: Oligometastasic pathology has become a usual pathology present in our clinical routine activity.Although invasive treatments are available, SBRT is a non invasive therapy which can be a viable treatment of choice.We introduce our preliminary study of pulmonary lesions treated using a single fraction of 34Gy OBJECTIVES: The main goal of this report is to demonstrate that a fraction of 34Gy is a viable and attainable therapy to treat lesions in oligometastasic patient’s lungs

      Methods
      Seven patients with 7 pulmonary lesions were treated with single dose of 34Gy. Inclusion criteria were : lesion size smaller than 2 cm , distance from the chest wall and main bronchus tree higher than 2 cm , primary tumor under control in PET scan. Mean Age 61.57y (r39-82), Gender distribution 3 women and 4 men, Histology: 4 cases (57.14% were Metastasic lesions from Colon), 1 metastasic from Adenoid Cystic, 1 Adenocarcinoma from Lung and 1 NSCLC. All patients underwent 4DCT for contouring. Inmobilization was done by thermoplastic mask (Lorca Marin) . Dosimetric characteristics: Mean volume of GTV 1.46cc (r 0.6-4.1), mean volume of PTV 11.29cc (r7.1-22.2), D Max oesophagus 5.06 (r 2.6-8.4), D max Heart 4.05 (r6.86-17.0), D max trachea 5.12 Gy (r 0.3-11.1), Dmax skin 10.98(r7.0-14.4). Patients were treated using True Beam machine. In 6 cases treatments were delivered without flattering filter beams

      Results
      After 6 months of follow up (r 6-2.19) no toxicity higher than grade 2 was detected. Local control rates and survival are 100%, 100% respectively. To sum up, even this is a preliminary study, seems than long term results can show us a new perspective in these oligometastasic patients.

      Conclusion
      not applicable

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      P1.24-018 - Characteristics of patients with lung cancer with venous thromboembolism: A post hoc analysis of 676 patients enrolled to the CLOT trial (ID 1402)

      K. Subramaniam, W. Lowe, S. Woodruff, J. Halwagy

      • Abstract

      Background
      Patients with cancer, especially those with lung cancer have an elevated risk for venous thromboembolism (VTE). Importantly, the adjusted risk of VTE is estimated to be 30 % higher among lung cancer patients undergoing chemotherapy with the majority of VTE events occurring within 6 months of initiation of chemotherapy. The presence of a VTE event is significantly associated with an increased risk of mortality[1] [1]Huang et al, J Thromb Thrombolysis. 2012 Nov;34(4):446-56. This study examines the baseline characteristics of patients with lung cancer with VTE, of the participants enrolled to the CLOT trial - a six month multi-centre study involving 676 cancer patients with acute, symptomatic, proximal deep-vein thrombosis (DVT), pulmonary embolism (PE), or both who were randomly assigned at 1:1 ratio to receive dalteparin sodium subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin sodium alone for six months[2] [2]Lee et al N Engl J Med 2003;349:146-53.

      Methods
      Post-hoc analysis aimed at interrogating the descriptive fields of the Intention-To-Treat (ITT) CLOT trial population was conducted to determine the quantitative and qualitative base line characteristics of patients with lung cancer at randomisation.

      Results
      Of the 676 patients with cancer randomised into the CLOT trial, 90 patients had cancer of the lung. Figure 1

      Conclusion
      Baseline characteristics of patients with lung cancer with VTE as randomised in the CLOT trial indicate they were more likely to be males, under 65 years of age, had no previous VTE to the diagnosis of their lung cancer, were receiving treatment for their lung cancer, with surgical pathology and chronic immobilisation not being a significant risk factor for VTE. Review of published literature also suggests that in comparison to the non cancer population, patients with lung cancer experience significant level of pulmonary embolism[3] [3]Shinagare et al Cancer. 2011 Aug 15;117(16):3860-6

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      P1.24-019 - Therapeutic and preventive effects of aprepitant for chemotherapy-induced nausea and vomiting in Japanese patients with thoracic malignancies (ID 1510)

      S. Ito, I. Tsukiyama, M. Ando, M. Tanahashi, R. Hamanaka, K. Kosaka, A. Matsubara, M. Nishimura, H. Tanaka, N. Asai, N. Yokoe, A. Takahashi, K. Baba, K. Matsuura, E. Yamaguchi, A. Kubo

      • Abstract

      Background
      Neurokinin-1 receptor antagonist (NK1RA) in addition to 5-hydroxytryptamine receptor antagonists (5HT3RA) and dexamethasone (Dex) is recommended for chemotherapy-induced nausea and vomiting (CINV) in highly emetogenic chemotherapy (HEC). It had been also reported that 40-60% of patients receiving HEC had not experienced significant nausea and/or vomiting before NK1RA became available. In 2010 NK1RA aprepitant was introduced for CINV prophylaxis in Japan. However, what proportion of patients receiving emetogenic chemotherapy need NK1RA, and whether all patients undergoing HEC truly need NK1RA remain unknown. Increasing medical costs due to uniform use of NK1RA is another concern. The primary objective of this study is the prevalence of patients who require aprepitant. Therapeutic and preventive effects of aprepitant on CINV induced by HEC or moderately emetogenic chemotherapy (MEC), and quality of life (QOL) regarding CINV are secondary objectives. We conducted this single-institute study before fully introducing aprepitant into clinical practice in our institute.

      Methods
      From July 2011 to January 2013, 96 consecutive patients receiving HEC or MEC, with age ≥ 20, able to use Japanese language, and with written informed consent, were enrolled onto the study, and 77 patients were analyzed who received ≥ 2 courses in the same chemotherapy regimen. 5-HT3RA and Dex were administered to prevent CINV. Aprepitant was administered to treat CINV in the first course when CINV occurred, or administered to prevent CINV in the second course. All patients who experienced CINV in the first course received prophylactic aprepitant from the second course. QOL regarding CINV was assessed by Functional Living Index of Emesis (FLIE). Numerical rating scale (NRS) was used to assess the severity of nausea. This study was approved by the Institutional Review Board of Aichi Medical University.

      Results
      Patient characteristics were: median age (range), 67 (38-85); gender (male/female), 64/13; cancer type (lung cancer/thymic tumor/other), 72/3/2; chemotherapy regimen (HEC/MEC), 28/49. Aprepitant was not administered in 57% and 88% of patient who received HEC and MEC, respectively. In patients treated with aprepitant (n=18), therapeutic use of aprepitant after CINV occurred (n=9) decreased average NRS for nausea and average frequency of vomiting per day from 7.44 to 5.44 (p=0.10), and 2.11 to 0.11 (p=0.03), respectively. Prophylactic use of aprepitant in the second course (n=18) increased the proportion of patients with no significant nausea from 6% (first course) to 50% (second course, p=0.007), and those with no vomiting from 33% to 89% (p=0.002). In contrast, in patients who did not require aprepitant (n=59), proportion of patients with no significant nausea and those with no vomiting did not change during the 2 courses (76% to 76% [p=1.00] and 92% to 92% [p=1.00], respectively). In patients who required aprepitant, aprepitant use significantly improved FLIE scores in the second course while these did not change in patients who did not require aprepitant.

      Conclusion
      More than half of patients receiving HEC and 88% of patients receiving MEC did not require aprepitant. Aprepitant showed significant therapeutic and preventive effects on CINV in patients who truly need it.

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      P1.24-020 - Efficacy and safety of carboplatin and pemetrexed for the first line treatment of unfit patients to receive cisplatin with nonsquamous non small cell lung cancer (ID 1563)

      G. Esquerdo, J.L. Fírvida, J. Garde, J.M. Cervera, M. Areses, E. Barrajon, M. Espinoza, R. Peiro, B. Montiel, J. Garcia

      • Abstract

      Background
      Background: Pemetrexed activity is synergistic with both carboplatin and cisplatin in chemonaive NSCLC patients. Two phase II Pem plus carboplatin trials have confirmed the doublet’s activity in NSCLC and response rates were 31% and 24% (Scagliotti and al 2003, Zinner and al 2005). Carboplatin is a good alternative in unfit patients suggesting a balanced benefit/risk profile when combined with Pem.

      Methods
      Sixty-four patients unfit to receive cisplatin with measurable stage III-B IV NSCLC, received at least one dose of chemotherapy. Pem 500 mg/m2 over 10 min on day 1 with folic acid and vitamin B12 supplementation followed by carboplatin AUC 5 on the same day were given every 21 days for 4- 6 cycles. Primary endpoint was safety and efficacy ( progression free survival)

      Results
      Sixty four patients received at least one dose of chemotherapy. Median age was: 71.3 yrs (86−44,3), 90,6% of patients presented comorbilities , mainly cardiopathy (73,4%) . Stages IIIb: 15,6%, IV: 84,4%. Non squamous cell carcinoma: 100.% (adenocarcinoma: 92,2%, large cell carcinoma: 7.8% )Male 76,6%, female 23,4%. The median number of administered cycles was 4. Median progresion free survival and overall survival will be presented at the meeting. Grade 3/4 toxicities related to study drugs were: asthenia 6.1%, skin 3.1%, dyspnea 3.1% .Hematological grade 3/4 events were: neutropenia: 6.1%, thrombocytopenia: 1,6%, anemia: 14.1%. 10,9% of patients need dose reduction

      Conclusion
      In first line NSCLC, the combination of Pem plus carboplatin could be a valuable treatment alternative in unfit patients to recive cisplatin. Anemia is the most frequent toxicity in this combination.

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      P1.24-021 - Bronchoplasty and bronchoangioplasty for primary non-small cell lung cancer (ID 1595)

      N. Yamasaki, T. Tsuchiya, K. Matsumoto, T. Miyazaki, G. Hatachi, K. Tomoshige, H. Sengyoku, H. Watanabe, R. Doi, R. Machino, T. Nagayasu

      • Abstract

      Background
      The objective of this study was to evaluate the operative mortality, morbidity, and survival of bronchoplasty and bronchoangioplasty for non-small cell lung cancer. Multivariate analysis was done to determine potential prognostic factors for both procedures based on our 27-year single-center experience.

      Methods
      Between January 1985 and March 2012, 204 bronchoplastic procedures were done in 1978 patients who underwent lung resections for non-small cell lung cancer at Nagasaki University Hospital. After excluding 18 carino-plasty patients and 13 wedge angioplasty of pulmonary artery, 173 patients (141 bronchoplasty and 32 broncho-angioplasty) were included.

      Results
      In the bronchoplasty group, the postoperative morbidity was 29% (41/141) and the 90-day postoperative mortality was 5.7% (8/141), while in the broncho-angioplasty group the postoperative morbidity was 28% (9/32) and the postoperative mortality was 15.6% (5/32). Eleven patients (6.4%) experienced bronchopleural fistulas. Multivariate analysis demonstrated that induction therapy (p=0.047) and combined multiple organ resection (p=0.012) were risk factors for postoperative anastomotic complication. The 5-year survival rate for all patients was 46.3%. The 5-year survival rate was 69.5% in patients with pathological stage I disease. In patients with stage II disease, the 5-year survival rate was 34.7%. In patients with stage III-IV disease, the 5-year survival rate was 33.2%. The survival rate in stage I disease was significantly better compared with other stage disease (p<0.0003). Multivariate analysis indicated that the type of operation (bronchoplasty versus bronchoangioplasty), postoperative complications, histologic type (squamous cell carcinoma versus non squamous cell carcinoma), and pN status (N0-1 versus N2-3) were significant factors affecting survival.

      Conclusion
      Both bronchoplasty and broncho-angioplasty are useful for the treatment of patients with non-small cell lung cancer and should be performed in stage I. However, careful patient selection is mandatory in patients with advanced tumor stages and in those with nonsquamous cell carcinoma, especially if broncho-angioplasty is being considered.

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      P1.24-022 - mHealth Tool for Lung Cancer - Development and Demonstration (ID 1696)

      J.K. Cataldo

      • Abstract

      Background
      With the rise of technology in health care, the use of electronic or virtual games provides new possibilities for cost effective and individually tailored health care interventions. The advantages of virtual games are the ability and opportunity to incorporate ethnic and cultural diversity and sensitivity, access hard to reach populations, provide motivation and positive feedback for behavior change, and provide information for personalized cancer symptom management. Lung cancer is the leading cause of cancer death in both men and women and is associated with greater levels of psychological distress than any other cancer. Stigma has been found to have a major role in the distress and health outcomes of lung cancer patients. Lung cancer stigma (LCS) is based on the belief that one caused their own cancer (ie, smoking) and negatively impacts patient outcomes. Lung cancer patients report inadequate communication with physicians about important topics such as: symptom experience, prognosis, treatment preferences, practical and financial worries, spiritual concerns, and hospice care. Stigma is a factor that contributes to poor patient-clinician communication and inappropriate referrals. Although palliative care consultation is recommended throughout the trajectory of lung cancer, it is underutilized. Understanding factors that influence communication and referral decisions, such as stigma, can improve integration of symptom assessment and support and palliative care into lung cancer management. Currently there are no interventions to decrease LCS and improve lung cancer patient-clinician communication. The goal of this project was to develop, the mHealth TLC an interactive, immersive 3-dimensional iPad health game that allows individuals to experience first person virtual visits with their clinicians and to conduct initial usability testing.

      Methods
      Because of the innovative nature of an immersive 3D game for lung cancer patients, iterative development/validation was used. Usability was assessed with participation satisfaction questionnaires and focus groups. Four areas were explored: believability and value; technical issues; transparency of goals; and game outcomes.

      Results
      Positive usability results for the mHealth TLC included believable game narrative, minimal game experience interference, participant generation of game and intervention goals, and indications that mHealth TLC will be able to influence lung cancer patient outcomes.

      Conclusion
      mHealth TLC can provide engagement and experiential learning by delivering important information about lung cancer and symptom management and by providing lung cancer patients the opportunity to practice a new communication strategy. Figure 1

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      P1.24-023 - Envoy Service, a form of dignity therapy, designed to assist communication and palliative care decision for patients with advanced cancer: a preliminary report. (ID 1765)

      S.W. Shin, S.Y. Oh, H.J. Jun, Y.H. Kim, S.T. Kim, C.Y. Kim

      • Abstract

      Background
      Patients with advanced cancer experience various difficulties to communicate and express regarding their wishes, personal values and end-of-life care options. These difficulties could be serious obstacles to initiate early palliative care decision and consequently lead to unwanted and/or futile invasive end-of- life care. There is an urgent need to develop innovative approach to address suffering and distress and improve communication between patients and family members, care givers’ and medical providers.

      Methods
      “Envoy Service” was designed to assist patients' own words delivered to family members, friends, care givers in processed and edited form. The assigned patients were interviewed by trained dialogist (2 nurses and 3 clinical psychologists), in individualized and narrative style for 30 to 60 minutes per session up to 3 sessions. During the interview, pre-structured questioned regarding palliative care and end-of-life care options. Additionally, patients are offered to speak what matters most to them, things they would most want remembered. The whole interview process could be videotaped, or voice recorded, or writes down by the dialogist, or in combination upon the patients’ own choices. Once interview sessions completed, the dialogues were reshaped into narrative form and carefully edited in the form of video-audio clip recorded in CDs, or letters. The final products were returned to patients to bequeath to a friend or family member. The responses of patients and family members and caregivers’ and medical provider’s opinions were collected and examined.

      Results
      Twelve patients with advanced cancer (age 40-68, median 57, 5 female, 7 male, 4 lung cancer, 2 head and neck cancer, 5 GI cancer, 1 Gy cancer) received “Envoy service”. It was offered in two hospitals; five patients in Korea University Medical Centre (university Hospital) and seven patients in Seoul Medical Centre (General Hospital) respectively. Interview with dialogist took usually 30-60 minutes (median 40 min) in each session and 1-3 (median 1) sessions. All twelve patients expressed their emotional feeling regarding their illness, fear of death and dying, briefly reviewed their own lives and personal appreciation to their family members and medical providers. Regarding the end-of-life care options, 6 patients choose non-invasive care and 3 patients wished to be chosen by their care giver and physician’s discretion, 3 patients did not evidently spoke about. The edited products, 1 CD, 11 letters were returned to patients to bequeathed to family members. Seven patients reported feeling satisfied. Five patients indicated that the service heightened their physical and psychological well-being. One dialogist reported that completion of services, patients were looked “ready” for dignified end-of-life. Four patients died, 3 without any invasive care, but 1 in ICU.

      Conclusion
      "Envoy service” a form of dignity therapy, is feasible and could be a novel approach to address distress and suffering of patients with advanced cancer. It might help patients to communicate with family members and caregivers and leads to initiate early palliative care and avoid unnecessary invasive procedure near end-of-life.

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      P1.24-024 - Acute Exacerbation of Idiopathic Interstitial Pneumonia After Resection of Lung Cancer: Investigation of Pre Operative CT predictor (ID 1819)

      M.Y. Kim, S.Y. Oh, D.S. Kim, C.M. Choi, S. Kim

      • Abstract

      Background
      To investigate the ‘preoperative CT predictor’ of postoperative acute exacerbation (AE) of lung cancer with underlying idiopathic interstitial pneumonia (IIP) compared to those without AE as control.

      Methods
      The 78 pulmonary resections for lung cancer with underlying IIP in a single tertiary center, 72 males (92.3%) and 6 females (7.7%), aged from 47 to 80 years old, with a median age of 66 years were retrospectively included. This study was approved by the Institutional Review Board and informed consent was waived. Underlying IIP was retrospectively assessed histological (n=46, 59.0%) and clinico-radiological (n=32, 41.0%) according to ATS/ ERS guidelines. We divided them in two groups, one acute exacerbation (AE group) and the other without acute exacerbation (non AE group) after operation of lung cancer. Records of patients who experienced postoperative acute exacerbation were extracted from the clinical data-base. Two independent expert chest radiologists analyzed CT findings in two times (four data sets) for one month interval. We analyzed age, gender, smoking history and pulmonary function test (PFT) differences between two groups. We analyzed HRCT findings as follows; extent of reticulation, honeycombing, ground-glass opacity, and emphysema in overall extent with area percentage. Fibrotic score (sum of reticulation and honeycombing) was also assessed. We performed the correlation between HRCT findings and presence of acute exacerbation. We used binary logistic regression analysis and student t-test with SPSS 21.0 version as statistics.

      Results
      Of the 78 lung cancer patients, six patients experienced postoperative acute exacerbation (7.7%). Smoking history and PFT between two groups were not significantly different except age and gender. Inter- and intra-reader correlation coefficient were 0.496~0.928 and 0.667~0.936/0.657~0.949, respectively, good to fair. Honeycombing (p=0.001; OR, 1.243; CI, 1.087~1.422) and fibrotic score (p=0.007; OR, 1.188; CI, 1.047~1.347) and abnormal area (p=0.042; OR, 1.059; CI, 1.002~1.119) were significantly high in AE group.

      Conclusion
      Physicians should consider the high extent of honeycombing, as well as high fibrotic score in CT, a potential risk factor for acute exacerbation after pulmonary resection for lung cancer.

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      P1.24-025 - Palliation of Malignant Pleural Effusion by Pleurodesis a comparative study (ID 1845)

      A.M. Abdelrahman, F. Aboulkasem, R. Gaafar, A. El Bastawisy, M. Yahia, H. Aziz

      • Abstract

      Background
      Sever dyspnea secondary to persistent or recurrent malignant pleural effusion in terminally ill cancer patients offers great challenge to the treating physicians. It has a significant negative impact on the quality of life which is already poor. The main goal of treating physician is symptomatic relief of dyspnea with the least possible tools. A variety of agents can be used to induce pleurodesis. Multiplicity of those agents indicates that none of them is optimal. Whatever the agent used, it should achieve high success rate with no or minimal side effects and tolerability by the patient. Great care should be taken to properly select patients with malignant effusion for pleurodesis to minimize treatment failure. Unsuccessful pleurodesis my be more problematic and difficult to treat due to conversion of the free effusion into encysted one. The aim of this work is to evaluate the success rate of palliative treatment of malignant pleural effusion comparing talc powder ( either through poudrage or slurry) versus Mistletoe preparation (Viscum Fraxini ~2~). To evaluate also the tolerability of both preparations, coast and the complication rate.

      Methods
      This is a retrospective non randomized study during the period between (Jan. 2008 – Feb 2011). Sixty patients with malignant pleural effusion were included. Patients were divided into 2 groups (30 patients were included in each group) according to the method of pleurodesis used. The first group included patients in whom talc powder ( either through poudrage or slurry) was used for pleurodesis. The second group included patients with Mistletoe preparation (Viscum Fraxini ~2~) used as pleural sclerosant. CT scan of the chest was ordered for all patients prior to treatment. Criteria for potentially successful pleurodesis: There should be no pleural septations or loculation (if present based on CT scan should be lysed pre pleurodesis). The lung should not be entrapped and fully inflated (the presence of residual space will convert the free effusion into encysted one). Response definition : Successful pleurodesis is defined as no recurrence of effusion on clinical and radiologic follow-up 4 weeks after pleurodesis.

      Results
      There were 34 males and 26 females , the mean age was 59 years, right sided effusion was present in 37 patients (61.6%) and left sided effusion in 23 patients (38.4%) . All patients presented with grade I-III dyspnea and 15% also presented with chest pain. In Group I: Twenty three patients had successful pleurodesis (76.7%), while 7 patients showed treatment failure. Treatment related complications developed in 4 patients. In Group II : Pleurodesis was successful in 19 patients (63.3%)(After 2, 6, 7, 8 injections), treatment failure developed in 11 patients after 6 injections. Four patients developed allergic reactions and two patients suffered empyema.

      Conclusion
      Both methods used for pleurodesis were well tolerated by the patients with good success rate with minimal complications. Talc offers higher success rate, less coasty and also considered single use therapy while the use of Mistletoe preparation needs repeated injections.

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      P1.24-026 - Lung Cancer - You can avoid it, get it, survive it; An evaluation of the Irish Cancer Society's annual lung cancer awareness campaign from 2011 - 2013. (ID 1891)

      A. Mc Namara, A. Deegan

      • Abstract

      Background
      Each year almost 2,000 new cases of lung cancer are diagnosed in Ireland (1). It is the biggest cancer killer for Irish men and women (2) and Irish women rate fifth highest in incidence of lung cancer in Europe (3). In 2011 the Irish Cancer Society (the Society) launched a three year advertising and PR campaign to raise awareness of lung cancer in a novel and engaging way. The Society wished to move away from the grim, grey, tobacco led and often frightening messages and imagery normally associated with lung cancer. The campaign directed people to the Society’s National Cancer Helpline.

      Methods
      The Society undertook market research in 2011 and 2013 to evaluate the impact of the campaign. The objective of the quantitative survey was to evaluate public awareness of lung cancer as well as prompted awareness of the campaign. This survey was nationally representative and 1,000 interviews were completed. The helpline database was also used to record the number of lung related enquiries during the campaign.

      Results
      Just under three million adults recall some media attention on the issue of lung cancer in February (2013). This is up considerably on 2011 levels (2.1 million Vs. 2.8 million). Whilst just over six in ten are aware of some media attention in January, this figure rises to seven in ten among smokers. In total 34,342 enquiries about lung cancer were recorded during the two week campaign. This included calls and emails to the National Cancer Helpline (167), walk in enquiries to the daffodil centres in hospital settings (670), unique views of the Society’s lung cancer webpages (2315), direct referrals to the National Smokers Quitline (4), likes/ comments/ shares/views of social media posts (9741) and of a live Q&A via Facebook (21,449). Figure 1

      Conclusion
      During the campaign, the National Cancer Helpline received more preventative and undiagnosed enquiries about lung cancer than any other cancer. The majority of contacts were female and aged 50-59yrs; our target audience. A sharp rise in webpage views was noted and social media interaction exceeded expectations considering the young audience. Using traditional as well as online advertising mediums, PR and social media platforms also worked well to reach a wide audience and campaign evaluations show traction with both young and old. Delinking lung cancer from tobacco and going with an empowering message meant that more people engaged with the campaign and it was deemed a success.

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      P1.24-027 - Intrapulmonary recurrence after computed tomography-guided percutaneous needle biopsy of stage I lung cancer (ID 2018)

      Y.K. Kye, Y. Kim, H.W. Jeon, M. Kim

      • Abstract

      Background
      CT-guided percutaneous needle biopsy is a useful diagnostic procedure that is used for the evaluation of pulmonary nodules, and is regarded as a relatively safe procedure. Although tumor seeding along the biopsy needle tract after CT-guided percutaneous needle biopsy is an extremely rare complication with a reported incidence of 0.06% in Japan, it can lead to unnecessary procedures or fatal outcomes. Most of the reported cases of implantation metastasis after CT-guided percutaneous needle biopsy were about the tumor seeding, which occurred in the chest wall or the pleura; however, we present here a case of intrapulmonary recurrence after CT-guided percutaneous needle biopsy.

      Methods
      A 70-year-old woman was admitted to our hospital for the evaluation of a growing lung mass. She had undergone a thoracoscopic lobectomy of the right upper lobe 17 months ago, after CT-guided percutaneous needle biopsy, using a 22-gauge needle, which had confirmed the lung mass as an adenocarcinoma. She was discharged uneventfully and had been followed-up without additional treatment because there was no evidence of metastasis to the lymph nodes or to the distant organs. On the follow-up, a CT scan of the chest revealed a small lung nodule (0.5 cm in the longest diameter), which was located in the superior segment of the right lower lobe. Six months later, a repeat CT scan of the chest showed that the nodule had grown up to 1.2 cm.

      Results
      On admission, we performed successful CT-guided percutaneous needle biopsy of the lesion of the right lower lobe, and pathologic examination revealed an adenocarcinoma, which took the same characteristics as the previous diagnosis from the right upper lobe, which suggested a recurrence. We suspected implantation metastasis, and reviewed the previous biopsy procedures. Finally, we found that the biopsy needle had passed through the superior segment of the right lower lobe to target the right upper lobe lesion, and concluded that the new lesion might be an implantation metastasis, as a result of tumor seeding along the biopsy needle tract. She underwent segmentectomy of the superior segment of the right lower lobe, because there was no evidence of distant metastasis. She recovered well and was followed-up without additional treatment as before.

      Conclusion
      We present a case of implantation metastasis that occurred in the pulmonary parenchyma, after a CT-guided percutaneous needle biopsy of stage I lung cancer. We also present here a lesson from this case that the biopsy needle should not pass through different anatomical compartments other than the target compartment, and this strategy should be kept in mind, especially, when the lesion is located deeply.

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      P1.24-028 - Chemical pleurodesis using mistletoe extraction (ABNOVAviscumⓇ Injection) for malignant pleural effusion (ID 2056)

      J.S. Cho, Y. Kim, H. I, K. Na, Y.J. Lee

      • Abstract

      Background
      Malignant pleural effusion is common in patients with advanced cancer. Several treatment modalities for malignant pleural effusion have known and of those, chemical pleurodesis can be considered for malignant effusion that do not respond to chemotherapy, radiotherapy, or therapeutic thoracentesis. However, which agent is more effective and safe in chemical pleurodesis is not yet clear.

      Methods
      This study was designed as a single arm, multicenter, and open-label phase III clinical trial to evaluate efficacy and safety of chemical pleurodesis using ABNOVAviscum[Ⓡ] Injection (Abnoba GmbH. Germany). Reference of other agents in chemical pleurodesis was investigated to compare efficacy and safety, and decide statistical sample size. Of patients who needed pleurodesis for malignant pleural effusion, the patients who had full expansion of lung within 24 hours after pleural drainage, expected life span more than 2 months, and Karnofsky performance scale of more than 50 were enrolled. Efficacy was evaluated by the amount of pleural effusion in chest x ray taken four weeks after pleurodesis (WHO guidelines of response – complete response; few effusion, partial response; lesser than 50% of initial pleural effusion, no response, or not evaluable), and changes of clinical symptoms and karnofsky performance scale. Safety was evaluated by serious adverse event (SAE) and changes of kidney and liver function (AST, ALT, BUN, or creatinine) after pleurodesis. A follow-up period was 4 weeks after last pleurodesis.

      Results
      A total of 68 patients were enrolled which 7 of them dropped out. Median age of patients was 60 years old [range, 34-80]. The number of male and female was 23 and 38, respectively. 49(80.3%) had complete response, 11(18.0%) had partial response, and one patient had no response. Mean response rate of reference for other agents in chemical pleurodesis was 64%. The mean karnofsky performance scale before the pleurodesis was 79.5 and the mean karnofsky performance scale on fourth week after pleurodesis was 81.9. SAE definitely related to ABNOVAviscum[Ⓡ] Injection was presented in two cases; dyspepsia and generalized muscle weakness. Both of these cases were recovered before the end of this study. SAE probably related to ABNOVAviscum[Ⓡ] Injection was seven cases; dyspepsia, fever (3), constipation, vomiting, and fatigue. These seven cases were recovered before the end of this study as well. No other toxicity related to ABNOVAviscum[Ⓡ] Injection was presented in laboratory findings such as AST, ALT, BUN, or creatinine during a follow-up period.

      Conclusion
      This study suggests that chemical pleurodesis using ABNOVAviscum[Ⓡ] Injection for malignant pleural effusion might be an effective and safe modality.

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      P1.24-029 - Metastatectomy for lung cancer and lung resection for metastases - our experience (ID 2165)

      S. Krishnamurthy, P. Shivappa, V.R. Challa

      • Abstract

      Background
      Metastectomy for lung cancer had shown varied results some showing survival benefit and in some studies as only palliation. But unlike metastatectomy for lung cancer , lung resection for metastases had shown definitive role atleast in some selected cases like colorectal cancer, renal cell carcinoma, breast cancer , etc. Here we would like to share our experience considering the above mentioned topics.

      Methods
      Our study was a retrospective analysis of medical records from January 2006 to March 2012 in a single unit in a teritiary care center in India. Clinicopathological features, treatment, prognosis and disease free survival were assessed.

      Results
      Fourteen patients underwent metastatectomy in lung and five patients underwent metastatectomy for lung cancer (Fig.1). Results were described in Table 1 and 2. Among 14 patients who underwent lung resection for metastases, 5 cases were for osteosarcoma of extremity, 5 for soft tissue sarcoma of extremity, one for pyriform fossa cancer, one for breast cancer, one for gestational trophoblastic neoplasia and one for metastatic gaint cell tumor of bone (Table 1&2). Fig: 2: Clinicopathological features of patients: Figure 1 Figure 2

      Conclusion
      Stage IV disease in cancer though considered as incurable in adult solid malignancies, a selective group of patients can still be cured. The success of the surgery depends on disease free survival from the detection of primary, number of lesions, grade and stage of initial primary and site of primary. Metastatectomy for lung cancer in our study is done with a palliative intent.

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      P1.24-030 - A rare case of synchronous and metachronous lung cancers (ID 2238)

      P.Q.L. Bui, C. Bui, L. Morgan

      • Abstract

      Background
      Multiple primary lung tumours can be either synchronous or metachronous. Clarification between synchronous primary tumours and metastatic lesions is vital given the differing prognosis and therapeutic options. We present a case of a patient with a combination of synchronous and metachronous primary lung malignancies, who did well because she had careful multidisciplinary follow-up.

      Methods
      Not applicable

      Results
      A 63-year-old female ex-smoker, with history of moderately severe chronic obstructive pulmonary disease but good performance status, was found to have pulmonary nodules in the left upper and lower lobes that increased slightly in size over 2 years on serial thoracic CT scans. On FDG-PET, the lesion in the left upper lobe demonstrated marked FDG-avidity (SUVmax 7.5) while the left lower lobe nodule demonstrated much lower FDG uptake (SUVmax 2.5). These were considered synchronous early-stage lung tumours by consensus of our multidisciplinary lung cancer group. Intra-operatively, frozen sections confirmed malignancy in each lesion and the patient successfully underwent wide local excision of both nodules. Histopathology revealed infiltrating moderately differentiated adenocarcinoma in the left upper lobe (T1N0M0) and infiltrating undifferentiated large cell carcinoma in the left lower lobe with no hilar or mediastinal nodal involvement (T1N0M0). The patient remained disease-free until 6 years later, when new right lung opacities were found incidentally on a chest radiograph. Chest CT confirmed 2 new pulmonary nodules in the right upper lobe, one intensely FDG-avid (SUVmax 11.0) and the other poorly avid (SUVmax 1.2). No other FDG-avid foci suspicious of metastatic disease were detected elsewhere. Following multidisciplinary discussion, wedge resections of both lesions were performed. Histopathology revealed high-grade neuroendocrine carcinoma (small and large cell types) in the intensely FDG-avid lesion and adenocarcinoma in situ in the other lesion. The patient was subsequently offered adjuvant chemotherapy and prophylactic whole brain irradiation.

      Conclusion
      This rare case of synchronous and metachronous primary lung cancers illustrates the importance of long-term follow up of patients with previously treated non-small cell lung with curative intent. These patients may develop new metachronous early-stage lung tumours that would benefit from aggressive treatment. New lung opacities may not necessarily represent recurrent metastatic disease with poor prognosis.

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      P1.24-031 - Confirmation of surgical margin of resected pulmonary adenocarcinoma with lepidic growth with thin slice CT of the resected specimen during surgery (ID 2288)

      Y. Hida, K. Kaga, K. Hiraoka, N. Honma, R. Nakada-Kubota, Y. Matsui

      • Abstract

      Background
      Limited resections such as wedge resections for ground-glass opacity (GGO) adenocarcinomas have been proposed and widely performed. However there have been reports of cut-end recurrences after wedge resection of those lesions. One of the major obstacles to solve this problem is a lack of method to achieve thorough confirmation of surgical margin during surgery. Here we report a successful confirmation of cut-end using thin slice CT on resected lung specimen.

      Methods
      A patient with a ground-glass opacity in the right upper lobe underwent a wedge resection under thoracoscopy. The resected specimen was sent for thin slice CT scan, which revealed that there were enough surgical margins from the cut-end to the GGO lesion in any of 0.5mm thick slices. Figure 1 Figure 2

      Results
      Pathological examination confirmed that the cut-end was free from adenocarcinoma as being consistent with CT findings.

      Conclusion
      It is feasible and effective to confirm surgical margin of resected lung tumor with GGO during surgery using CT on the resected specimen.

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      P1.24-032 - Is tuberculosis a challenge for the management of lung cancer? (ID 2391)

      D. Koksal, D. Ozaydin, A.N. Ozcan, O. Safak, N. Kalac, M. Berkoglu

      • Abstract

      Background
      It is well known that old pulmonary tuberculosis (TB) is associated with an increased risk of lung cancer and lung cancer mortality. Malignancy per se and cytotoxic chemotherapy for its treatment both are recognized risk factors for the development of active tuberculosis. Coincidence of tuberculosis and lung cancer at initial diagnosis or development of tuberculosis during the course of lung cancer is a challenge for management of both diseases.

      Methods
      Herein we analyzed 10 male lung cancer cases (9 NSCLC/ 1 SCLC) coincidentally had tuberculosis.

      Results
      The ages were ranging between 43-71 years. Only one of these patients had a pulmonary TB history. The sites of TB were lung in 7 patients, mediastinal lymphadenopathy (LAP), cervical LAP, and subcutanous nodules in 1 patient each. Four patients were diagnosed as tuberculosis and lung cancer simultaneously. The diagnosis was confirmed by mediastinoscopic lymph node biopsy in 1, transthoracic biopsy in 1 and sputum smear positivity in 2 patients. In 4 patients the diagnosis of pulmonary TB were confirmed by sputum culture 2-3 months after the diagnosis of lung cancer. All these 4 patients were suspicious for pulmonary TB at the time of lung cancer diagnosis, but sputum smears were negative for acid-fast bacilli. In 2 patients TB were diagnosed later in the follow-up period of the patient. One was diagnosed as TB lymphadenitis by cervical lymph node biopsy, the other was diagnosed as TB by biopsy of subcutaneous nodules on the right leg. One patient who was surgically resected for lung cancer tolerated antituberculosis therapy well. Another patient who was initially staged as T3N2MO lung cancer clinically and radiologically (including PET/CT evaluation) also tolerated the therapy fairly well. After 6 months of antituberculosis therapy, he was restaged as T2aN0M0 and treated with definitive radiotherapy. He died due to venous thromboembolism 1 week after the completion of radiotherapy. Another patient had progressive lung cancer during antituberculosis therapy. Hepatotoxicity was the leading adverse reaction (in 3 patients, 30%) due to antituberculosis therapy.

      Conclusion
      In conclusion; these cases highlighted the importance of thinking TB in the course of lung cancer especially in countries with high TB prevalence. TB may cause advanced staging of lung cancer at initial diagnosis; chemotherapy may worsen TB course or cause reactivation TB. Reactivation TB may be considered as progression of lung cancer without a tissue diagnosis. The tolerability of antituberculosis therapy is poor in these patients. Guidelines should refer how to manage these patients especially in certain areas with high TB prevalence.

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      P1.24-033 - A rare case: lung cancer and multiple myeloma (ID 2407)

      A. Bahadir, M.G. Ortakoylu, F. Alkan, E. Çağlar, C. Ar, N. Unver, S. Yılmaz

      • Abstract

      Background
      A multiple myeloma (MM) is a malignant disease of plasma cells, which manifests as one or more of lytic bone lesions, monoclonal protein in the blood and/or urine and disease in the bone marrow. The most typical thoracic manifestation of multiple myeloma is bony involvement of the thoracic cage. Other manifestations include pneumonia, intra-parenchymal mass lesions, mediastinal lymphadenopathy, interstitial pattern like reticulonodular shadows and intrapulmonary calcification. The diagnosis of a secondary solid neoplasm in patients with MM is uncommon, and it is debatable whether the MM itself is a risk factor for the incidence of a secondary solid neoplasm.

      Methods
      62 year-old men, former heavy smoker ,treated pulmonary tuberculosis(1977), autologous bone marrow transplantation (BMT) for MM two years ago.He admitted complaints of fever, cough,sputum and nigth sweats for a month. Physical examination was remarkable moderate pallor. Routıne serum biochemistry parameters were within normal limits except hemoglobin (6.6 gm/dl),ESR was 84 mm in the first hour.Chest xray and computed tomography (CT )showed multiple, bilateral,various size, well-circumscribed pulmonary nodules, containing calcification solid nodul 2 cm in diameter and periferal consolidatıon ın the rigth upper lob . Previous chest radiographs and CT had revealed the presence bilateral multiple nodules and low uptake18F‑fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) ( suv max:2.4).

      Results
      The patient underwent wedge resectıon rigth upper lobe for evaluating nodules three years ago.Histological examination demonstared weak -granulom formation and nodüles consisting dystrophic calcification ,multifocal hyalinisation and ossification It was considered sequelae of tuberculosis. Follow –up imaging studies increased in size,the number of pulmonary nodules and newly rigth 8th and left 6th rib hypermetabolik uptake in PET.CT -guided transthoracic needle aspiratıon biopsy performed the increasing nodul in the rigth upper lobe diagnosed adenocarcinoma.The patient is still alive and on follow-up.

      Conclusion
      Studies have shown that people who have had allogeneic transplants have a higher risk of second cancer than people who got a different type of stem cell transplant. In this case it is difficult to conclude whether TB sequelae caused lung cancer or the lung cancer simply associated in a patient with previously known pulmonary TB. Initial diagnosis of tuberculosis in such patients often misleads the physician to abandon further work-up resulting in overlooking or delayed diagnosis of the lung neoplasm,thus affecting their outcome

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      P1.24-034 - Cystic and cavitary appearance:an usual form of pulmonary metastasis of primer lung adenocarcinoma (ID 3040)

      A. Bahadir, M.G. Ortakoylu, F. Alkan, A. Aslan, E. Çağlar, N. Ürer

      • Abstract

      Background
      Cystic and cavitary pulmonary lesions are abnormalities encountered on chest radiography and computed tomography (CT).Malignant lesions, including metastases, rarely present as cystic and cavitary lesions.Due to rarity such cases ,we report here a case of unusual form of pulmonary metastasis of primer lung adenocarcinoma

      Methods
      A 82-year old female patient admitted to hospital with complaints of dry cough,progressive dsypnea for a month .Her past history was unremarkable. Physical exam was normal.Chest X-ray revealed bilateral diffuse multpil cavitary and cystic lesions In routine laboratory tests, all were normal excepting Hb:10.7 g/dl, CRP:43 The thorax CT showed bilateral diffuse cysticand cavitary lesions in 1-3 cm diameter, with no thoracic lymphadenopathy . As the multiple lung nodules were suspected to be metastatic, 18F‑fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) was conducted, which revealed that the nodules had mild uptake of 18F‑FCG ,a metabolic behaviour consistent with bening aetiologies diseases according to the nuclear medicine report.

      Results
      Bronchoscopy with bronchial lavage was performed. Cytology was negative for malignancy. Repeat CT scan of chest showed increase in size of lung lesions and new right-sided pleural effusion .CT-guide transthoracic needle aspiratıon biopsy was performed. The pathological examination revealed a metastasis of adenocarcinoma ,however histological differentiation of primary pulmonary adenocarcinoma from metastatic adenocarcinoma is sometimes difficult because of their phenotypic similarities So immunohistochemistry (IHC) was performed, the IHC of lung tumor: cytokeratin 20 (CK20)(-), cytokeratin7(CK7)(+), thyroid transcription factor(TTF)(-)Because of PET CT was no showed extrathoracic uptake,It was considered primary lung adenocarcinoma for final diagnosis.

      Conclusion
      One of the most important differences in the differential diagnosis of cystic or cavitary lung lesions is the distinction between malignant and benign aetiologies. Primary lung cancer is a common disease, cavitation being detected by CT for up to 22% of primary lung cancers but for near 11% by plain thoracic radiography. However pulmonary metastases can rarely cavitate, with a reported incidence less than 4% on chest radiographs [2]. Even cavitary lung metastases are rare and benign differential diagnosis are more common, clinician should be careful in neoplastic context and investigation should be done In rarity such cases ,we report here a case of unusual form of pulmonary metastasis of primer lung adenocarcinoma

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      P1.24-035 - Times to presentation and treatment : A prospective comparision of rural and urban lung cancer patients in North Queensland (ID 2500)

      A. Joshi, S. Sabesan, P. Beuttner, S. Varma, Z. Otty

      • Abstract

      Background
      Disparities in cancer survival among rural and urban population is known. Time delay from symptom to presentation for medical attention and treatment in rural lung cancer population is partly responsible for lower survival rates in this population. Identification of specific barriers can help form strategies to improve survival. There are no prospective studies evaluating referral pathways and identifying barriers in lung cancer presentation in rural areas . This study's aim was to analyse time delays in management pathways of rural lung cancer patients and explore the influence of various demographic factors on these times.

      Methods
      Lung cancer patients presenting to Townsville Cancer Centre, Cairns Base Hospital and Mackay Base Hospital were prospectively recruited over a 36 month period from 2009 to 2012. As per ASGC (Australian Standard Geographical Classification) guidelines of remoteness patients were classified as regional or remote. Fisher’s test was used to identify differences between these two cohorts. Times along referral pathway were divided into symptoms to first presentation, symptoms to diagnosis, symptoms to specialist visit, specialist to treatment and symptoms to treatment. The influence of clinical and socio-demographic factors like gender, ethnic status, education level, income, remoteness of location and stage of disease on these times were analysed using Kruskal-Wallis and Mann-Whitney tests for statistical significance.

      Results
      A total of 252 lung cancer patients were eligible for recruitment. Of these 180 (71.4%) were classified as urban and rest remote. In remote compared to urban patients there were more males (73.6% vs 60%, p=0.046) and more Caucasians (96.2% vs 90%,p=0.068). Also level of secondary or higher education was significantly more in urban compared to remote cohort (88.5% vs62.7%). Tumour demographics like histology and stage were balanced between the two cohorts. Median time from symptoms to first presentation was significantly affected by ethnicity (indigenous vs non indigenous 92 vs 57 days, p=0.05), older age (<51yr vs >51yr 14 vs 45 days, p= 0.026) and lower level of education (primary/secondary vs tertiary/TAFE 61 vs 23 days, p=0.023). Median time between symptoms to specialist consultation were significantly higher for lower level of education ( primary / secondary vs tertiary/TAFE 140 vs 55 days, p=0.05) and remoteness of location (remote vs urban 113 vs 89 days, p=0.05). Specialist to treatment time was delayed by stage (III vs IV 34 vs 18 days, p=0.021). On multivariate analysis time between symptoms to first presentation was influenced by level of education (primary/secondary vs tertiary/TAFE, p=0.006). For rural compared to urban patients, time between first consultation to specialist visit (p=0.022) and time between symptoms to first treatment (p=0.015) were significantly longer.

      Conclusion
      The demographic profile of lung cancer patients from remote areas is quite smilar to their regional counterparts. In the five time zones from presentation to treatment, median time from symptoms to first presentation was the most susceptible. In the referral pathways, indigenous ethnicity, level of education, remoteness and stage of disease affected time delays but no impact was found for socio-economic status. On multivariate analysis level of education and remoteness of location emerged as significant barriers to presentation.

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      P1.24-036 - Combined Modality Treatment for inoperable Non-Small Cell Lung Cancer - a retrospective study from a New Zealand regional cancer centre. (ID 2593)

      W. Tsai, C. Hardie, D. Chan, G. Forgeson, M. Carr, H.S. Winter, N. Nedev, J. Nel, R. Du Plessis, S. Allan, R. Isaacs

      • Abstract

      Background
      Lung cancer in New Zealand is associated with poor survival and regional inequalities. Non-small cell lung cancer (NSCLC) accounts for 80%–85% of all newly diagnosed lung cancer cases. Forty five percent of these patients present with stage III disease (mediastinal node involvement). The Regional Cancer Treatment Service (RCTS), Palmerston North Hospital is using combined modality treatment (CMT) chemotherapy / radiotherapy protocol for inoperable Stage II and Stage III NSCLC since 2006. The chemotherapy regimen employs 3 cycles of Cisplatinum/Vineralbine. This audit reviews the outcomes and side effects of treatment.

      Methods
      This retrospective study comprises patients with a clinical diagnosis of inoperable NSCLC from the RCTS, Palmerston North Hospital database. Patients confirmed to have stage IIIB and/or inoperable stage II and IIIA NSCLC are included. These patients completed treatment based on the RCTS NSCLC CMT guideline from 1[st] July 2005 to 31[st] May 2012. Information was obtained from Oncology electronic records and paper based clinical notes in RCTS. The treatment protocol includes one neoadjuvant cycle of chemotherapy, given 3 weeks prior to commencing of the radiotherapy. It is followed by further two cycles of Cisplatin/Vinorelbine, given concurrently with radical radiation therapy on day 1 and 22 of the radiotherapy. All patients were treated with 3D conformal radiotherapy to total dose is 60Gy in 30 fractions, over 6 to 7 weeks. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 were applied. Progression free survival (PFS) and median survival were estimated and reviewed.

      Results
      From 1[st] of July 2005 to 31[st] of May 2012, 39 patients completed CMT. All cases in the study had a history of smoking. Thirty two (82%) patients had inoperable stage III NSCLC (IIIA - 15 cases, IIIB - 17 cases). The remaining seven patients had stage II disease, (IIA - 3 cases, IIB - 4 cases), who were deemed inoperable due to significant medical problems. Protocol doses were maintained in 79% of patients, with dose reduction typically used due to transient renal impairment, ototoxicity and myelosuppression. Neutropenia (ANC <1000/mm3) was documented in 21% of patients. Six patients (15%) had neutropenia on day 14-15 and 2 patients (5%) on day 22-23. One patient had hospital admission for febrile neutropenia. Five other patients developed neutropenia but remained asymptomatic. Grade III anaemia (Hb <80 g/L) was noted in 6 patients - all of them had 2 units of blood transfusion. There were no treatment related deaths. 23 patients developed progression of the disease. At the time this study is completed, 16 patients are remaining progression free. The median progression free survival is 9.4 months (mean 12.4), with a median overall survival of 16.6 months. This study demonstrated a 3-year survival rate of just below 20 %.

      Conclusion
      These outcomes and toxicities are comparable to the reported international studies and would support continued use of our current protocol. Further studies may be helpful to identify the optimum chemotherapy regimen in concurrent therapy for inoperable NSCLC. The future role of molecular tailored regimens in subgroups of patients undergoing CMT is evolving.

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      P1.24-037 - Addition of bevacizumab to standard palliative chemotherapy in advanced non squamous cell lung carcinoma: Tata Memorial Hospital experience. (ID 2743)

      A. Joshi, B. Chauhan, V. Noronha, K. Prabhash

      • Abstract

      Background
      Outcome of advanced NSCLC is poor. Platinum based chemotherapy is standard of care. Addition of antiangiogenic agent such as bevacizumab improves the results.

      Methods
      Prospectively collected data of patients received bevacizumab, platin and pemetrexed as initial therapy for 6 cycle followed by maintenance pemetrexede and bevacizumab till disease progression or unacceptable toxicity.

      Results
      We had 18 patients, 14 were males and 4 were females. The age of the patients ranged from 45 to 68 years with a median age of 54 years. About one third of the patients were smokers and most of the patients were of good performance status (ECOG-0/1-94%). The most common symptoms of presentation were, cough in 61% of patients followed by dyspnea in 39% of patients. The chest pain and neck swelling were present in 11% of patients whereas bony pains were present in 39% of patients. Co-morbidities of diabetes and hypertension each were present in 17% of patients. Most of the patients were stage IV(94%). The patients received chemotherapy which comprised of pemetrexed, platin and bevacizumab for 6 cycle followed by pemetrexed and bevacizumab maintenance till progression in responding patients after six cycle. Number of cycle’s received ranged from 2 to 21 with a median of 10 cycles. Response rates achieved were stable disease in 72%, partial remission in 22% with disease stabilization rate of 95%. Grade 3 and 4 toxicities observed were neutropenia 11%,proteinuria 11%, anemia and Hyponatremia were present in 17%.One patient each developed pulmonary thromboembolism and hypertension. Bevacizumab was stopped because of toxicitty in one patint who developed pulmonary throboembolism. Median progression free survival was 7 month and median overall survival for whole group is not reached.

      Conclusion
      Addition of bevacizumab to standard platin based therapy in both initial and maintenance phase is feasible with acceptable toxicities. Some patients have long term disease control.

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      P1.24-038 - Barriers and facilitators to physical activity receiving chemotherapy for lung cancer: an exploratory study (ID 2796)

      S. Mas, X. Quantin, G. Ninot

      • Abstract

      Background
      Physical activities (PA) induce a positive effect on cardiorespiratory fitness, lung cancer symptoms and quality of life of patients suffering from lung cancer. While 92% of patients are interested in participating in a PA program, only 1/3 of them do sufficient amount of PA to provide important health benefits. The aim of our study was to identify barriers and facilitators to PA in patients with lung cancer receiving chemotherapy.

      Methods
      Our study provided data from patients diagnosed with primary NSCLC in advanced stages of the disease receiving chemotherapy. We chose a qualitative approach using a semi-structured interview. We conducted an exploratory analysis, using the thematic analysis technique to process the data.

      Results
      Seven barriers and facilitators to PA were identified (side effects of the disease/cancer-related treatment, other physiological limitation, timing/loss of meaning of projects, kinesiophobia, support/care, social usefulness/useless feeling, nature of the PA) and were grouped into 4 categories: physiological, psychological, social and environmental factors. These factors were identified to have different effects on the barriers to PA. Psychological and social factors mainly have an impact on the willingness and ability to practice PA; while physiological and environmental factors have an impact on the duration, intensity and regularity of PA.

      Conclusion
      Our study highlighted some of the effects that the barriers to PA have on the practice of PA in patients with NSCLC receiving chemotherapy. Our findings may be used by professionals to design an adapted PA program in this population.

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      P1.24-039 - Outcome of a series of 25 consecutive patients aged 84 and more with stage IV NSCLC : an invitation to systemic treatment (ID 2827)

      J. Gantzer, N. Prim, B. Mennecier, M. Beau-Faller, A. Ducoloné, P. Fraisse, C.A. Matau, R. Stenger, A. Molard, A. Purohit, E. Quoix

      • Abstract

      Background
      Elderly patients and even more older elderly with stage IV NSCLC are often not optimally treated.

      Methods
      Not applicable

      Results
      Between april 1[st] 2010 and february 28th 2013, 25 patients ( aged 84 years or more were referred with a stage IV (11 M1a and 14 M1b) non-small cell lung cancer to our university hospital. There were 11 females and 14 males. There were 11 never-smokers. Median age was 87 years (range : 84-92). Histological subtypes were : 8 squamous cell carcinoma, 14 adenocarcinoma and 3 large cell carcinoma. Molecular analyses was performed in 17 cases among which 2 were impossible due to inappropriate biopsy specimen. EGFR- mutations were found in 4 female patients, 1 with exon 19 deletion and 3 with exon 21 point mutations. There were 3 K-RAS mutations and no ALK translocations. 6 patients received TKIs as first line treatment (5 gefitinib and 1 erlotinib). Two patients with no molecular analysis were treated with first-line TKI (both of them had PS 4, one died after 1.1 month, the other recovered very quickly and is still alive after 15.3 months). The other patients were treated with doublet carboplatine AUC 6 and weekly paclitaxel (90 mg/m², D1, 8, 15), with D1 = D29 (12 patients) or single agent therapy (paclitaxel (2), Gemcitabine (1), vinorelbine(1)). Three patients received only best supportive care (BSC). Doses of TKIs had to be lowered due to toxicity in 1 case. Median overall survival was 8.1 months with a one-year probability of survival of 46%. Survival of the 6 patients treated with first-line TKIs was 1.1, 3.1+, 6.43+, 14, 15.33+, 15.9+ months.

      Conclusion
      It must be noted that EGFR-mutations were more frequent compared to younger patients (at least 4/25) paralleling the high proportion of never-smokers (44%) and of female patients (44%). In this unselected consecutive series of older elderly patients, only 3 received BSC as sole treatment, while 4 were treated with single agent chemotherapy, 12 with a carboplatine-based doublet and 6 with TKIs as first line therapy, of which only 4 had proven EGF-R mutations. Survival was very similar to what is observed with younger counterparts and thus, nihilism is not appropriate in this category of patients.

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      P1.24-040 - Management of solid lung malignancy by CT-guided percutaneous catheter ablation --- Does adjuvant chemotherapy help? (ID 2978)

      P. Andrew, S. O'Connor, R. Lee-Ying, S. Jerat

      • Abstract

      Background
      With a burgeoning population of elderly patients with lung cancer deemed non-surgical, increasing utilization of minimally-invasive techniques such as CT-guided percutaneous catheter ablation is occurring for the management of solid tumors. However, it is unknown whether a strategy of ablation plus adjuvant chemotherapy improves locoregional and survival outcomes in aged patients with solid lung malignancy. The aim of this study was to compare local tumor recurrence and survival outcomes of ablation plus adjuvant chemotherapy versus ablation alone for management of primary and metastatic solid lung tumors in patients unsuitable for lung resection.

      Methods
      Searched PubMed, the Cochrane Library, EMBASE, and CANCERLIT databases from January 2000 to December 2012. Blinded duplicate screening was used to extract data from captured clinical studies involving patients with non-surgical solid lung tumors, both primary and/or metastatic. Population was deemed non-surgical, with solid lung tumors, both primary and/or metastatic. Generated aggregate effect estimates from constituent studies for three outcomes (e.g., local tumor progression [LTP], overall survival [OS], and disease-free survival [DFS]) with comparison of pooled fixed effect analyses concerning ablation plus adjuvant chemotherapy versus ablation alone. Data were analyzed using dedicated meta-analysis statistical software (BioStat Inc., NJ, USA).

      Results
      Ablation + chemotherapy group: 684 patients and 1,314 lung tumors. Ablation only group: 1,874 patients and 2,604 lung tumors. Histology was NSCLC >> mets from colorectal cancer > sarcoma > renal > other. Ablation + chemotherapy versus ablation alone: LTP of 15% over median follow-up of 31 months [range 12 to 59] versus 19% over median follow-up of 21 months [range 12 to 29]; odds ratio (OR) 0.73 (95% CI: 0.61-0.86, p<0.05) at 12 month follow-up. OS was 89% versus 78%, respectively, at 12 month follow-up; OR 1.52 (95% CI: 1.16-2.00, p=0.003). DFS was 90% versus 82%, respectively, at 12 month follow-up; OR 3.18 (95% CI: 2.04-4.96, p<0.05). Forrest plots for the outcomes of LTP, OS, and DFS are shown. Sensitivity analyses were robust, publication bias relatively narrow, and Q statistic <21; p>0.13 for all outcomes.Figure 1

      Conclusion
      A strategy of CT-guided percutaneous catheter ablation plus adjuvant chemotherapy delivers the benefit of retarding LTP, and expectedly lengthens both OS and DFS. Elderly patients with solid lung tumors who are most likely to benefit from this strategy would be non-surgical candidates with relatively good performance status who could tolerate both catheter ablation and chemotherapy.

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      P1.24-041 - Follow up of patients with lung cancer: the role of primary care (ID 2981)

      D.P. Weller, C. Campbell, S. Murray, R. Neal

      • Abstract

      Background
      Despite improvements in lung cancer treatments, there is little international agreement over the key elements of follow-up; frequency of visits and investigations, and choice of models of care remain controversial. Worldwide there is an emphasis on survivorship in patients who have been treated for lung cancer. Further, there is growing interest in the role of primary care in cancer survivorship and follow-up; primary care has the potential to provide more comprehensive and coordinated care in cancer patients. To date there have been few studies investigating the role of primary care in lung cancer follow-up and survivorship. As a prelude to developing and trialing a primary care-focused package of care for UK patients with lung cancer, we undertook a descriptive study, based on analysis of audit, database and qualitative data.

      Methods
      Case notes of 183 lung cancer patients from 60 practices in Wales Scotland and England , and data from two Scottish primary care databases (3025 patients) were analysed (attendance patterns in primary care, co-morbidity, investigations, referrals and prescribing). For a subset of database patients, data from control patients, matched for age and sex, were examined. We also interviewed 84 primary and secondary health care professionals from across the UK, and undertook four focus groups of patients and carers. Transcripts were coded thematically using a grounded theory approach; the analysis was conducted inductively, driven by the interview data.

      Results
      Most (90%) of the patients’ cancers were NSCLC; 57% had received treatment with 'curative intent'; the remainder received essentially palliative treatment. Three-quarters of patients had at least one co-morbidity (32% had two or more). Particularly in the first year post-diagnosis, lung cancer patients had significantly higher primary care consultation rates than matched controls - these differences persisted over time. Approximately 80% of presentations to primary care were for lung cancer-related problems; almost 20% of all primary care consultations led to investigations (predominantly blood tests), and 7% led to a referral. Most prescriptions were for antibiotics, analgesia and antidepressants. There was little evidence of structured approaches to lung cancer follow-up and survivorship. Our qualitative data showed some support amongst key stakeholder groups for an enhanced role for primary care in the follow-up of lung cancer patients. There was, however, a strong perception of 'disaggregation' between secondary and primary care services. Care models involving enhanced roles for primary care were particularly favoured for long-term lung cancer ‘survivors’, with a high burden of psycho-social concerns and unmet need; also, the role of specialist lung cancer nurses was consistently emphasised.

      Conclusion
      Much of the care provided to lung cancer patients is already based in primary care. Further, specialist nurses provide expert knowledge, familiarity with and access to hospital-based services and engagement with multi-disciplinary team processes. There is, however, limited evidence from our study or the wider literature that the services needed to meet the broad and complex needs of these patients are well-defined or well-integrated. Models which integrate primary care with other lung cancer services offer the prospect of improved continuity, access, care co-ordination and management of co-morbidities.

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      P1.24-042 - Video-assisted thoracic surgery lobectomy for patient receiving induction chemoradiotherapy for locally advanced non-small cell lung cancer (ID 3015)

      T. Miura, K. Anami, M. Chujo

      • Abstract

      Background
      Video-assisted thoracic surgery (VATS) lobectomy is an accepted oncologic approach for early-stage peripheral typed non-small cell lung cancer (NSCLC).Recently the indication of VATS lobectomy is becoming widely adapted to more complicated cases thanks to development of thoracoscopic instruments and technical aspects.

      Methods
      We here report a case of patient who underwent VATS lobectomy after induction chemoradiotherapy for locally advanced NSCLC.

      Results
      A 56-year-old man with a 35 pack-year history of tobacco use presented with productive cough. A computed tomography (CT) revealed a 6-cm hilar mass with consolidation in the right upper lobe and hilar, interlobar,and single mediasitnal lymphnode metastases. There was a significant mass uptake of FDG (standardized uptake value: 16.1 to 19.2) on Positron emission tomography (PET). Bronchofiberscopy showed an intraluminal extension of the tumor centrally to the orifice of the right upper lobe. Bronchofiberscopic biopsy demonstrated squamous cell carcinoma. This patient have a clinical T2bN2M0 IIIA NSCLC. He received two cycles of CDDP+GEM followed by concurrent CDDP+VNR and 40Gy irradiation. Preoperative assessment by CT and PET revealed marked regression of the tumor. A VATS lobectomy was then performed. One utility incision (4 cm) was made over the 4th intercostal and three ports (0.5-1.5 cm each) were placed without rib spreading. By using bipolar scissors, the major vascular structures and the bronchus were safely dissected from the irradiated surrounding tissue similarly to an open procedure. The bronchus could be divided using a stapling device. An anatomic lobectomy with sysytematic mediasitanal lymphnode dissection was fully and safely performed. The chest tube was removed on the postoperative 1st day. He had an uneventful 9-day hospital course. This final pathological finding revealed microscopically residual tumor only in the bronchial wall and lung parenchema andin the single mediastinal lymphnode. This patient have an yield pathological T3N2M0 StageⅢA NSCLC.He received additional 4 cycles of CDDP based chemotherapy postoperatively and is alive with disease free 25 months after surgery.

      Conclusion
      VATS lobectomy is a feasible approach for selected patients undergoing resection after induction chemoradiotherapy for locally advanced NSCLC.

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      P1.24-043 - Results of a Multidisciplinary Team in the Management of Non-Small Cell Lung Cancer in a Developing Country (ID 3041)

      L. Corrales-Rodriguez, A. Ramos-Esquivel, M. Caballero, S. Antillón, M. Araya, M. Villalobos, T. Soto, M. Juárez-Villegas, I. González, Z. Zeledón, R. Valladares, C. Zúñiga-Orlich, J. Baptista, T. Rivera, C. Campos-Fallas, R. Guadamuz, A. Murillo, E. Jiménez, M. Herrera, C. Arce-Lara

      • Abstract

      Background
      Lung cancer has the highest cancer-related mortality in the World. In developing countries, mortality rates tend to be higher due to deficits of diagnostic and professional resources, and long time intervals between patient’s symptoms and the initiation of treatment. Multidisciplinary teams improve the care of patients with NSCLC, but this practice is not common in developing countries. In Costa Rica more than 90% of cancer patients are treated in a public hospital where resources are limited. To improve patient care a weekly multidisciplinary thoracic oncology meeting was organized in Hospital San Juan de Dios, one of Costa Rica’s three adult general hospitals. This hospital is responsible for the management of more than 40% of Costa Rica’s cancer patients.

      Methods
      A multidisciplinary team including Medical Oncology, Pneumology, Pathology, Thoracic Surgery, Radiology and Radiation Oncology started to meet in a weekly basis since November 2011. All patients with a possible lung cancer in the hospital were evaluated by the team and recommendations were given. Data of patients with NSCLC seen by the multidisciplinary team during 2012 was compared to a historic data of NSCLC patients diagnosed in the same hospital between 2003 and 2008 when there was no multidisciplinary team involved in patient care. Exclusion criteria included insufficient clinical information. Epidemiologic data was analyzed and survival curves were obtained.

      Results
      In the periods 2003-2008 and 2012, 92 and 39 patients respectively with NSCLC were included for analysis. Epidemiologic results are summarized in Table 1 and overall survival is plotted in Figure 1. Figure 1 Figure 2

      Conclusion
      The inclusion of a multidisciplinary team in the management of NSCLC lead to an earlier diagnosis and increased survival of patients. This approach should be considered in the management of NSCLC patients in a developing country.

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      P1.24-044 - Favorable Survival of Women with Non-Small Cell Lung Cancer (NSCLC) after Resection of Brain Metastases (BM) and Whole Brain Radiotherapy (WBRT) (ID 3092)

      P.M. Putora, C. Panje, T. Hundsberger, K. Van Leyen, S. Ess, L. Plasswilm, M. Fruh

      • Abstract

      Background
      In NSCLC, BM are found in 20%-50% overall and 10-18% at initial presentation. Average survival of these patients (pts) is only 3–6 months. The selection of pts who may benefit from surgical resection of BM is challenging. Our goal was to distinguish which pts might benefit from surgical resection of BM.

      Methods
      We retrospectively reviewed all pts receiving surgical resection of BM from NSCLC at our institution between 2000 and 2011. Survival after Brain surgery was measured.

      Results
      A total of 52 pts were identified. Median age was 59 years (35-81). ECOG Performance status was 2 or less in 88%.Only 2 were never smokers, and 94% smoked until < 5 years before diagnosis. Nineteen (37%) were women, 29 (56%) had adenocarcinoma (AC), 14 (27%) squamous cell carcinoma (SCC) and 9 (17%) not otherwise specified NSCLC. In 35 pts (67%) single BM was present, 2 in 6 (12%), 3 in 5 (9 %) and 4 or more in 3 (6%) pts. The stage of the primary lung tumor was T1-3 in 40 (78%) and N0-1 in 25 (48%). Synchronous BM were resected within one month of diagnosis in 29 (56%) pts. Twenty-three (44%) had no other distant metastases at the time of diagnosis of the BM. Distribution of distant metastases was adrenal (21%), liver (19%), bone (15%), lung (13%) and other (19%). Median time from lung cancer diagnosis to resection of BM was 7.5 months (0-63 months). WBRT was applied to 45 (87%) pts post brain surgery and once before surgery. The primary tumor was resected in curative intent in 14 (27%) pts at diagnosis. Thirty four (65%) received first line platinum chemotherapy doublets. Second line systemic therapy was given to 19 (37%) pts. Only 8 pts received tyrosine kinase inhibitors, but no one was treated for longer than 4 months. Eight are still alive. Median survival was 9.1 months with only one patient (initially pT2 pN0) surviving more over 5 years. One year survival was 42%. Median survival for males was significantly shorter (6.7 vs. 14 months [p<0.005]). AC was associated with improved survival compared to SCC (10.6 vs. 6.7 months [p<0.05]) with no correlation between gender and histology. In a multivariate analysis, the use of TKI, age and WBRT were not associated with outcome. Thirteen (25%) died within 3 months after surgery including 4 (8%) within 1 month. Six (46%) of them had other metastatic sites involved. New brain lesions post-surgery were documented in 12 (23%) and 4 (8%) had local progression at the resection site.

      Conclusion
      Resection of BM followed by WBRT lead to good local control. Despite patient selction with almost one third being treated with surgery of the primary tumor "curative intent" as well, only one patient lived > 5 years. The relatively high death rate (25%) within 3 months of surgery indicate the need for further research to better select patients suitable for survery. Female gender and AC histology were associated with better survival after resection of BM. These pts may preferably be considered for resection.

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      P1.24-045 - A case with long term survival following received paclitaxel as fourth line chemotherapy in refractory-relapsed small-cell lung carcinoma. (On behalf of NT-TOG group) (ID 3096)

      B. Chewaskulyong

      • Abstract

      Background
      Small-cell lung cancer constitutes 10-15% of lung cancer cases. Although it is sensitive to chemotherapy and radiotherapy, but usually relapsed and recurred with median survival time less than 6 months after second line therapy. Paclitaxel monotherapy had been reported its efficacy with minimal toxicity in relapsed small-cell lung cancer treatment. This presenting case demonstrated activity of paclitaxel in relapsed-refractory small-cell lung cancer in fourth line of treatment.

      Methods
      This is the case report of paclitaxel monoherapy in fourth line of refractory -relapsed small-cell lung cancer treatment.

      Results
      A 72-year-old woman with a history of ex-smoker and hypertension presented in September 2007 with weight loss and left- sided chest pain.On physical examination revealed bronchial breathsound at left lung .Computed tomography scan of the thorax showed 5.7 * 4.5 cm mass at left hilar region and occlude left middle part of bronchus. Bronchoscopic biopsy was done and histology showed small-cell lung carcinoma. Staging work up was performed and resulted was limited stage disease. The patients was admininistered chemotherapy with standard cisplatin and etoposide regimen. Concurrent chemoradiotherapy was started on 3rd cycle of chemotherapy . She received first line chemotheapy with total 5 cycles of chemotherapy with good clinical response. Chest imaging showed nearly partial response. Before 6th cycle of chemotherapy she developed relapsed small-cell lung carcinoma and was treated with cisplatin plus irinotecan as second line therapy for 2 cycles and third line with cyclophosphamide/adriamycin/vincristine regimen for 1 cycle with no response and had worse lung symptoms . Fourth line chemotherapy was administered with paclitaxel 175 mg/m2 every 3 weeks for 4 cycle between April and July 2008 . After second cycle of paclitaxel her symptoms and chest imaging were improved. After 4 cycle of paclitaxel monotherapy she was evaluated as stable disease and had long survival since 2008 until now with symptom- free and no relapsed of disease for more than 5 years.She had minimal toxicity from paclitaxel with only mild neuropathy.

      Conclusion
      In conclusion this case demonstrated that paclitaxel still had benefit with long-term survival and minimal toxicity eventhough in the fourth line therapy of refractory-relapsed small-cell lung cancer.

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      P1.24-046 - How are treated French patients with metastatic lung adenocarcinoma with "uncommon" EGFR mutations? How could we do better? (ID 3109)

      R. Saffroy, N. Bosselut, P. Validire, P. Slaouti, A. Izadifar, J. Morere, J. Tredaniel, A. Lemoine

      • Abstract

      Background
      The progression-free survival and response rate of patients with EGFR-mutant tumors treated with an EGFR TKI has been reported to be superior to standard chemotherapeutic regimens. These mutations, concentrated in the exons 18 to 21 encoding the tyrosine kinase domain of the receptor. However, TKI sensitivity depends upon the nature and location of the mutations. Eighty to 90% of all lung adenocarcinoma-associated EGFR mutations are short, in-frame deletions in exon 19 and the exon 21 point mutation L858R; 70% of tumors with the latter mutations respond to treatment with the EGFR TKIs. The remaining 10 to 20 % of EGFR mutations include several additional point mutations that can be considered as "uncommon mutations". Their identification is problematic for therapeutic decision. Indeed, it remains unclear whether these mutations have benefit upon progression-free or overall survival. Therefore a comprehensive strategy is required to prioritize treatment decisions by physicians in the routine clinical practice.

      Methods
      By retrospectively analyzing mutational data of 3,200 consecutive patients with metastatic lung adenocarcinomas diagnosed for EGFR mutational status, we have identified those whose tumors had uncommon mutations (mutations that were neither base pair deletion in exon 19 nor the L858R in exon 21). We have contacted the physicians in charge of these patients and asked them the individual therapeutic decision. We have also questioned them about the level of their knowledge on the sensitivity of uncommon mutations to TKIs and how to improve this knowledge.

      Results
      Out of 3,200 metastatic lung adenocarcinomas, 351 tumors (11%) exhibited abnormalities in the exons 18 to 21. Of these 351 EGFR mutated tumors, 171 (48.7%) were base pair deletions in the exon 19: and 129 (36.7%) were the L868R in the exon 21. The 14.5 % remaining tumors showed "uncommon" mutations. There were G719 to A, C, or S mutations in 18 patients (5%), the L861Q mutation in 14 patients (3%) and only 1 Ins 18 pb in the exon 19. In exon 20, the T790M mutations were found in 4 tumors and in-frame insertions of varying lengths that confer resistance to TKI in 2 patients. Ten additional mutations, most of them being double mutations, were observed in 12 patients (3.4%). Of the 51 patients with uncommon mutations, 15 (29%) have received gefitinib or erlotinib whereas at least 32 patients should have received anti-EGFR therapies. Reasons for this difference were 1) the lack of knowledge of the sensitivity of rare mutations, and mostly double mutations, 2) the difficulty of finding the answer, either on the record or in the scientific literature, 3) the possibility of introducing a platinum-based chemotherapy, 4) the lack of experience of the theranostic which includes many gene mutations.

      Conclusion
      Opportunities for improvement could be: 1) better information on the medical report when there is scientific evidence suggesting sensitivity or resistance of the rare mutation. 2) in parallel, a more accurate information on the lack of knowledge on the sensitivity or resistance, 3) a website for quick access to this type of information and changes along with the knowledge evolution.

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      P1.24-047 - A pulmonary neurogenic tumor: Primary pulmonary cellular Schwannoma (ID 3125)

      T. Isitmangil, Z. Kartaloglu, R. Gorur, N. Yiyit

      • Abstract

      Background
      Although primary neurogenic tumors of the lung are very rare, cellular schwannoma is a subtype of the classical schwannoma, which is a tumor of nerve sheath. Despite of pseudosarcomatous appearance, histopathologically, cellular schwannoma is considered as a benign tumor. However, it may carry atypical characteristics and risk of malign degeneration. We are presenting a case of primary pulmonary cellular schwannoma for discussing its clinical presentation and the prognosis.

      Methods
      A 65 years old male patient applied with the symptoms of cough and sputum production and found to have a 3x2.5 cm mass in the upper lobe of the right lung. At that time, retrospective examination of his available chest radiographs suggested a slowly growing lesion during a 4 years period. The mass was removed by extirpation and the histopathological diagnosis was cellular schwannoma. After surgical treatment no residuel lesion was detectable and he was doing well clinically.

      Results
      He had been followed up yearly for 5 years. Eight years after the operation a 3x3x4 cm mass was seen at the same site of the previous lesion but the patient refused any surgical or diagnostic intervention. During follow up the lesion was found to be 6x6x5 cm in diameters 12 years after the operation.

      Conclusion
      In cellular schwannoma the treatment of choice is surgical removal of the mass and the relapse of the disease is very rare. However, in this case the lesion seems to be the relapse of the previous disease. We suggest that in some cases extirpation of the mass may not suffice and surrounding tissue of close contact should also be removed to avoid relapses.

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      P1.24-048 - Stage 1 results of a 2-stage phase II trial of single agent amrubicin in patients with previously treated thymic malignancies (ID 3175)

      H.A. Wakelee, J.W. Riess, M. San Pedro-Salcedo, S.K. Padda, K. Ramchandran, M.A. Gubens, J.W. Neal

      • Abstract

      Background
      There are limited treatment options for patient with advanced thymic malignancies and the utility of many of the available chemotherapies is restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). We designed this study to look at single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, in patients with advanced thymic malignancies.

      Methods
      Eligible patients have confirmed thymic malignancy (thymoma (T) or thymic carcinoma (TC)) with progression or relapse after at least 1 prior chemotherapeutic regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m[2] IV days 1-3 repeated in 3-week cycles. The study is a Simon 2-stage design based on a null hypothesis of a true response rate <5%, with 90% power to detect a 20% true response rate and a plan to accrue 12 evaluable patients in stage 1, then if at least 1 response is seen, to add 25 additional evaluable patients in stage 2 for a total of 39 patients.

      Results
      Enrollment was initiated in July 2011. Here, we report on the first 12 patients, all enrolled at Stanford University over a 19-month period. Of the first 12 patients enrolled, 11 were dosed. All were pre-treated (5 with prior anthracycline). There were 5 women and 7 men; age range of 30-67 years old; 6 were of Asian ethnicity, 5 were non-Hispanic White and 1 was Hispanic. After enrollment of the first 8 patients, of whom 3 were hospitalized with febrile neutropenia (FN) (38%), the study was amended to a starting dose of 35 mg/m[2] days 1-3 repeated in 3-week cycles. Other than FN in the 3 patients mentioned above, G4 thrombocytopenia in 1 patient, and treatment-related G3 fatigue in 2 patients, other toxicities were generally mild and well tolerated. No significant changes in LVEF have been noted on serial echocardiograms. Of the 11 treated patients, there were 3 partial responses (2 T and 1 TC), 7 with stable disease for at least 4 cycles, and 1 with progressive disease (PD) after 2 cycles (TC). Of the 11 treated patients, only 1 patient, with PD after C2, has stopped before completing 6 cycles, and 5 to date have tolerated >10 cycles (with others still on treatment who may receive >10 cycles), with 15 cycles as the highest number to date.

      Conclusion
      Amrubicin, at 35 mg/m[2] IV days 1-3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with thymoma and thymic carcinoma with a 27% RR in the first 11 treated patients. This exceeded the threshold for proceeding to step 2 and the study will now continue to a total of 39 patients and has expanded to other sites including Indiana University.

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      P1.24-049 - Comparison of information provided by the lung cancer pts through the survey with the Physician's evaluation. (ID 3230)

      N.G. Pilnik, O. Mareca, J. Di Rienzo

      • Abstract

      Background
      Various factors such as age, stage and PS may provide prognostic information in advanced NSCLC; however, a better understanding of a patient’s judgement can help the Physician to make appropriate decisions.Purpose:1- To study the information provided by pts in a questionnaire. 2 To study PS evolution obtained by the doctor (DPS) and by the pts themselves (PPS).3-To evaluate the correlation between some different variables with survival.

      Methods
      Patients and Method: 224 pts with stages III and IV NSCLC, age range 38 - 74 years, were studied. The study was prospective. Pts underwent chemotherapy and/ or radiotherapy. They determined their own PS through a questionnaire . Some different variables such as age, stage, DPS, PSP, appetite, food intake, amount of solid food, evening meals, average meal per day, serving size, vomiting frequency, daily work activity , activity restrictions, and hours of rest per day were analyzed . DPS and PPS were studied at diagnosis and at 3 months. Statistical methods: Cox Proportional-Hazards Regression, Chi Square Pearson, Irwin-Fisher,Mac Nemar Wilcoxon tests and Kaplan Meier Curves were used.

      Results
      Results: According to the univariate logrank test applied to the comparison of the Kaplan and Meier survival curves, many factors seem to be related to survival. 9 of all variables studied were statistically significant. There were no complete agreement between DPS and PPS neither at initial evaluation nor at 3 months. Pts’ self assessment showed higher PS score than PS obtained by doctors.(Mac Nemar Test p< 0.0001).The correlation among predictor variables is not taken into account when using the univariate approach, so a Cox hazard model for the proportional risk was adjusted using all the predictor variables available. To eliminate the less prognostic variables a backward regression test was applied It was found that only initial WL and DPS at the third month of evaluation were positively related to the risk of death. However the low correlation between WL as well asDPS provide independent information.there was statistically significant association between response rate with DPS and PPS. Nutritional parameters revealed no significant data.

      Conclusion
      : Although the univariate approach showed that many factors are related to the survival of pts, the simultaneous analysis of these factors through the Cox model revealed that few of them summarize the most relevant prognostic information. These variables are DPS at the third month of evaluation and initial WL.

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      P1.24-050 - Pilot of a weekly dietetic telephone clinic for thoracic oncology outpatients: a UK cancer centre experience. (ID 3251)

      G. Howell, L. Hilwig

      • Abstract

      Background
      Nutritional decline and weight loss are common features in thoracic oncology patients and are independent prognostic indicators for survival in lung cancer. Malnutrition reduces tolerability to treatment and increases both risk of complications and unplanned hospitalisation, all of which lead to increased disability and reduced quality of life (Ravasco et al, 2004). Changes in eating habits and weight loss can also cause significant psychological distress to both patients and carers. Nutritional assessment and support should therefore be an integral component of the lung cancer patient’s care. The UK National Institute for Clinical Excellence recommends that all outpatients are screened for malnutrition at their first visit. We previously reported on a three month nutritional audit which identified that 37% of patients were at risk of malnutrition, confirming the need for dietary intervention (Howell, 2013). Subsequently an online referral system and a weekly dietetic telephone clinic were established to offer interim support to all outpatients. Data is presented here on the first 7 months of our year-long pilot project.

      Methods
      Between November 2012 and May 2013 all patients presenting to the Papworth Thoracic Oncology Service (PATHOS) with suspected thoracic malignancy were screened for malnutrition using the Malnutrition Universal Screening Tool (MUST) as part of a Holistic Needs Assessment. Patients at high risk of malnutrition (i.e. MUST score ≥2) received written and verbal advice on first line nutritional support, were commenced on oral dietary supplements and referred to the dietetic telephone clinic.

      Results
      26 patients were referred to the dietetic telephone clinic. Assessment calls took approximately 30 minutes, whilst follow-up calls took 10-15 minutes. All patients received an initial assessment call, and the majority of patients received at least one additional follow-up call. 13 (50%) patients were subsequently referred to a community dietician for further management. The following comments are examples of the feedback received. Patient A “it was helpful to have confirmation of what I should be eating and the types of foods to focus on”. Patient B “the information I received on food consistency and the different products available really helped”.

      Conclusion
      A multi-disciplinary team approach has been established to support and educate thoracic oncology outpatients about their nutritional requirements. Although the numbers are small, the new service has been well received by both patients and staff. The online referral system is easy to use and the written information leaflet contains details of the referral and when patients will be contacted. Developments: Modify the online referral system to include likely diagnosis and future plans. Maintain continuous audit, also collect data on: Diagnosis and stage of disease Eventual treatment plan Outcome of community referral Introduce an anonymous patient satisfaction questionnaire. Consider using a nutritional screening tool specific to oncology patients. References: Ravasco P. Monteiro-Grillo I. Marques Vidal P. & Camilo ME. (2004) Cancer: disease and nutrition are key determinants of patient's quality of life. Supportive Care in Cancer. 12: 246-252 Howell G. (2013) Nutritional reassessment and dietary support of thoracic oncology patients is a "MUST". Lung Cancer. 79 (suppl 1): S42

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      P1.24-051 - Video-Assisted Thoracoscopic Surgery (VATS) for diagnosis and therapy in primary and secondary pleuro-pulmonary angiosarcoma (ID 3410)

      J. Bodner, S. Kerber, I. Alkoudmani, W. Stertmann, M. Reichert

      • Abstract

      Background
      Angiosarcoma is a rare (1-2% of all soft-tissue tumors) but highly-malignant tumor deriving from the endothelia of small vessels. It primarily affects the skin, mamma, liver and spleen and the lung is the predominant organ of metastatic spread. Symptoms as well as radiologic characteristics are unspecific and diagnosis is made by biopsy and histopathological assessment.

      Methods
      Single-center case series focusing on the role of VATS in diagnosis and (palliative) therapy of primary and secondary pleuro-pulmonary angiosarcoma.

      Results
      From 11/2012 to 04/2013 three male patients (77 (74-78) y/o) underwent VATS for diagnosis and therapy of primary disseminated pleuro-pulmonary angiosarcoma (n=2) or bilateral pulmonary metastases of a cutan angiosarcoma. All patients presented with unspecific symptoms like dyspnoea and chest pain. Primary angiosarcoma was associated with severe and recurrent hemorrhagic pleural effusion, while bilateral pulmonary angiosarcoma metastases led to a bilateral pneumothorax under systemic chemotherapy. Two patients suffered from recurrent hemoptysis. Indication for VATS was diagnosis (pleural biopsies, n=3) and palliative therapy (talcum pleurodesis [n=3] and apical wedge resection with pleurectomy [n=1]). Mean operating time was 62 (31-117) min. Following VATS (and diagnosis) all patient received chemotherapy. One patient died 4 month after primary diagnosis, the two others are alive with stable disease.

      Conclusion
      Multiple unspecific pleural lesions on CT in patients presenting with hemoptysis and recurrent hemothorax may indicate a primary or secondary pleuro-pulmonary angiosarcoma. VATS is a safe minimally invasive single step procedure for both diagnosis and palliative therapy in this highly malignant soft tissue tumor.

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      P1.24-052 - Symptoms and early diagnosis of lung cancer. (ID 3443)

      M.C. Nicolson, N. Price, K.M. Kerr, E. Steven, D. Stuchbury

      • Abstract

      Background
      In the UK, the 5-year survival for lung cancer patients is less than 10%. One of the reasons contributing to this poor survival is the late stage at diagnosis, with approximately 80% of patients presenting with unresectable disease. CT screening of high risk patients may be effective but is expensive and still under investigation in clinical trials. Symptom-driven investigations may be more likely to detect advanced than early disease. We present data of the presenting symptom type and duration in patients diagnosed at an early, potentially curable stage.

      Methods
      Data from available casenotes of patients with resected non-small cell lung cancer were extracted by one data manager (NP) to study the main presenting symptom, other tumour-related symptoms, duration (where documented), smoking history and stage of disease. All patients were treated in a single institution between 2003 and 2008.

      Results
      105 patients’ details are included. 54 were male; age range 40-83 years, mean 67 years. Chest X-ray was abnormal in 103/105 patients. Smoking status was recorded in 83 (79%) cases. Three were never smokers. At time of diagnosis, 32 patients were still smoking and 17 had just quit. Of those who had stopped previously, 7 did so < 5 years before diagnosis, 5 at >5 < 10 years and 19 > 10 years before diagnosis. Pack year estimates were available in 91 patients and ranged from 5 to 180 (mean 40). Tumour stage at resection was 1a in 28, 1b in 29, IIa in 19, IIb in 15 and IIIa in 14. 25 patients had no symptoms (25%). The most common major presenting symptoms are in Table 1. Pre-diagnosis duration of symptoms was recorded in 67 patients (84%). 31 (39%) had >1 symptom.

      Dominant symptom No of patients Duration in months (mean)
      Cough 25 1-24 (3)
      +haemoptysis 10 0.5-6 (1)
      Lower respiratory infections 10 0.5-36 (3)
      Dyspnoea 10 0.25-12 (1)
      Chest/arm pain 9 2 hours – 4months (1)
      Weight loss 4 3-6
      Other 12 1-12 (2)
      None 25 -

      Conclusion
      CXR was abnormal in the majority of these patients with early tumours. The mean time to presentation with a dominant symptom was short. Almost a quarter of patients were asymptomatic and picked up as an icidental finding.The challenge to identify lung cancer patients early, at a curable stage, continues.

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      P1.24-053 - Repeated Pulmonary Resections at Pulmonary Metastases Surgery (ID 3499)

      I. Capov, J. Dolezel, V. Jedlicka, A. Pestal, Z. Chovanec

      • Abstract

      Background
      Repeated pulmonary resections there are predominantly used in sarcomas and colorectal cancers and in young age. Bad prognosis is in patients with reccurency of pulmonary metastases in period to six months. There are exist four prognostic groups according present risk factors (short disease free interval, multiple metastases).

      Methods
      We performed in period I/1997 to XII/2011 165 operations in 149 patients. 10patients had multiple pulmonary resections. According origin histology were – 6x sarcomas. 2x tu Grawitz, 1x Schwannoma malignum, 1x ca laryngis. There are synovialosarcoma, osteosarcoma, rhabdomyosarcoma, alveolar sarcoma and sarcoma uteri in group of sarcomas.

      Results
      As approach we used VATS 2x, clamshel thoracotomy 2x, muscle sparing vertical thoracotomy 7x and posterolateral thoracotomy 6x. We performed extraanatomic resection 13x, lobectomy 4x and completion pneumonectomy 1x. We observed 6x complications (3x small air leak, 3x wound infection) in postoperative period. No necessary rethoracotomy for complications, letality 0.

      Conclusion
      Surgery is part of complex therapy. There are very necessary strict selection of candidates for surgery and experienced team of thoracic surgeons. Surgery is safe and useful procedure at pulmonary metastases surgery.

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    P1.25 - Poster Session 1 - Nurses (ID 248)

    • Type: Poster Session
    • Track: Nurses
    • Presentations: 6
    • +

      P1.25-001 - The National Lung Cancer Forum for Nurses (NLCFN) (ID 785)

      J. White, D. Borthwick

      • Abstract

      Background
      Lung cancer affects nearly 40,000 patients per year in the UK and despite recent improvements in treatments, outcomes remain poor (NCIN 2012). Therefore the delivery of high quality care is vital. Lung Cancer Nurse specialists (LCNS) are well placed to provide holistic care, ensuring needs are addressed throughout the pathway, and there is an improvement in outcomes and experience for patients. The National Lung Cancer Forum for Nurses (NLCFN) was established in 1999 and is a national organisation in the United Kingdom (UK) developed to support lung cancer nurses through education, sharing best practice and peer support through a national network. The Forum has grown inexplicably and its success can be measured by the links and networks for nurses involved in caring for people with lung cancer as well as the strategic groups it is involved with nationally and internationally. The members are from diverse backgrounds of palliative care, respiratory medicine and thoracic oncology which results in a wealth of experience and knowledge. The NLCFN has approximately 280 members.

      Methods
      The NLCFN runs a Research Interest Group (RIG) and a Thoracic Nurses Subgroup (TNS) and both groups are active in improving practice and initiating research projects in lung cancer. The NLCFN proactively supports nursing research and offers a small grant award scheme each year to support lung or thoracic nurses who wish to develop a research project. Collaboration between the Forum and Sheffield Hallam University has led to the development of funding for a part-time PhD studentship. The RIG has been successful in obtaining a research grant to explore in more detail the evaluation of the LCNS role in treatment access. The NLCFN also hosts a website where patients, carers and clinicians can assess up-to-date information on lung cancer management, treatments and interventions and find out about local and national services for lung cancer patients. There is a NLCFN members section which houses guidelines and relevant documents

      Results
      Over the last 10 years the NLCFN has developed into a national voice on clinical and strategic issues and as such is represented on all lung cancer improvement and strategic groups in the UK. The NLCFN have produced several documents and guidelines which are available to all health care professionals.

      Conclusion
      The number of Lung Cancer Nurse Specialists has increased since the introduction of the role in 1995. They play a vital role in supporting patients and carers throughout their pathway from pre-diagnosis to end of life care and ensuring that all their needs are addressed. The NLCFN aims to provide the LCNS with a good infrastructure for networking and support as well as continually striving for better care for their patients.

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      P1.25-002 - Testing the feasibility of a lung cancer nurse coordination model during early treatment: phase II study (Clinical Trial in Progress) (ID 1124)

      A. Serena, A. Griesser, S. Leyvraz, N. Fucina, S. Peters, K. White, M. Eicher

      • Abstract

      Background
      To develop adequate self-care strategies, patients with lung cancer and their families are in need of emotional, informational and behavioural supportive care. Supportive care in cancer can reduce symptom burden and improve patients and their families self-management skills. As lung cancer incidence continues to rise, and increased attention is given to early diagnosis, research on early involvement of lung cancer nurse (LCN) in care, the feasibility and impact on patient outcomes is needed. The primary aim of this study is to assess the feasibility and acceptability of a LCN model of care commenced during first line of chemotherapy, and the impact on patient self-reported changes in self-efficacy, symptoms and supportive care needs. In addition perceived barriers and facilitators for the application of the LCN model will be examined.

      Methods
      An exact single-stage phase II design will be conducted. Lung cancer patients with planned chemotherapy with or without radiotherapy will be recruited at the thoracic cancer center in a Swiss University Hospital. The LCN model of care consists of two face-to-face consultations alternating with two telephone consultations during first line of chemotherapy. LCN consultations will comprise focused assessment of physical and psychological symptoms, information (printed and oral) about disease and its treatment, therapeutic education concerning strategies to manage physical and psychosocial symptoms and review of available support resources. Participants will be invited to complete the validated patient reported Lung Cancer Symptom Scale, Supportive Care Needs Screening Tool 9 and Self-Efficacy Scale for Lung Cancer. Study data will be collected at baseline (day 1 of 1[st] chemotherapy cycle), time 1 (week 3 of 2[nd] cycle) and time 2 (week 3 of 3[rd] cycle). Participants will be categorized as compliant if they complete all their scheduled LCN consultations and questionnaires. For a 5% probability of accepting a poor feasibility (alpha) and a 20% probability of rejecting an acceptable feasibility (beta) we then need to enroll 71 patients. Feasibility will be considered as acceptable for further studies if at least 36 patients will be compliant. Secondary outcomes will be analyzed descriptively for each variable (self-efficacy, symptoms and supportive care needs) across each time point. At the end of quantitative data collection, a focus group will be conducted to explore acceptability of the new role among health professionals working with the LCN in order to identify perceived barriers and facilitators for collaborative work with the new role.

      Results
      N.A.

      Conclusion
      This project is expected to have direct impact on enhancing the quality of supportive care for patients with lung cancer. Findings will provide evidence for refining the LCN model prior to embarking on a full-scale evaluation using a comparative experimental design. Furthermore, phase II designs have rarely been applied to psycho-social interventions. This method could give new insights to the nursing and allied health professionals how to investigate the efficacy and feasibility as well as the needed intensity of newly developed interventions in order to improving supportive care in oncology.

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      P1.25-003 - Characteristics and outcome of unplanned admissions in patients with lung cancer: A longitudinal tertiary center study. (ID 1911)

      C. Oyen, A. Derweduwen, C. Dooms, K. Nackaerts, J.F. Vansteenkiste

      • Abstract

      Background
      Unplanned hospital admissions (UHAs) are frequent in lung cancer patients, but literature on this topic is scarce. The aim of this study is to get better insight in the demographics, patterns of referral, presenting symptoms, and outcome of lung cancer patients with UHA.

      Methods
      Data of all consecutive events of UHA between July 1 and December 31, 2012 were reviewed. Details on the factors listed above were examined.

      Results
      There were 247 UHA events during the 6 month study period. Male/female ratio was 185/62, mean age was 66 years (range 40-90), PS on admission was 0-1 in 79 (32%), 2 in 92 (37%), and 3-4 in 76 (31%). Two thirds were stage IV, and 57% did not have ongoing oncological treatment. On 83 occasions (34%), referral was by the general practitioner (GP-REF), for 101 (41%) own initiative (SELF-REF), and for 63 (26%) specialist advice. The most frequent main presenting symptoms were respiratory (21%), infection (15%), general weakness (15%), and pain (13%). The mean hospitalization duration was 9.5 days, shorter and with more same-day-return in SELF-REF patients (Table). Final diagnoses were categorized in nine groups: infection (22%), respiratory problems (17%), lab abnormalities (13%), pain (12%), abdominal problems (11%), cardiovascular problems, neurological events, general weakness and other (6% each). This differed from the problem as recorded in the ER in one third of the events. Final grading (CTC AE v3.0) of the main event was 1-2 in 38%, 3 in 51%, 4 in 8% and 5 in 2%. Causality was decided as therapy-related (THER-REL) in 59, cancer-related (CANC-REL) in 117, unrelated in 48, and unclear in 23. In the THER-REL events, lab abnormalities (36%), infection (34%) and abdominal complaints (22%) were most common, while this was respiratory problems (23%), pain (18%) and infection (16 %) for CANC-REL events. On subgroup analysis (Table), length of stay was higher in CANC-REL events. Nearly all THER-REL events had medical therapy, while for CANC-REL events this was medical 50%, interventional 33% and supportive only 17%. Figure 1

      Conclusion
      UHA in lung cancer are predominantly cancer- rather than therapy-related, with a variety of symptoms. More than half of the events are not seen by the GP first, and the majority results in hospital stay of 9.5 days on average . Our work is a first step in identifying specific groups of events, where better interaction with GPs and education of patients might reduce the incidence of UHAs.

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      P1.25-004 - Deep venous thrombosis prevention effect of electrical stimulation of acupoint combinations in elderly bedridden patients after major surgery (ID 809)

      L. Hou

      • Abstract

      Background
      not applicable

      Methods
      During November 2010 to October 2011, 160 elderly bedridden patients after major surgery were divided into the conventional care group, “invigorating qi and promoting qi” group, “Blood-activating and Dampness-eliminating” group and acupoint-combination stimulation group. Whole blood viscosity, plasma viscosity, D-dimer, lower limb skin temperature, lower limb circumference and flow velocities of the external iliac vein, the femoral vein, the popliteal vein and the calf deep veins in all patients were documented and compared as four individual groups.

      Results
      Whole blood viscosity, plasma viscosity, D-dimer and lower limb circumference were significant reduced in “Blood-activating and Dampness-eliminating” group compared to conventional care group (P<0.05) and almost equal to the results in acupoint-combination stimulation group (P>0.05). Lower limb venous flow velocities were accelerated in“invigorating qi and promoting qi” group compared to groups other than the acupoint-combination stimulation group (P<0.05).

      Conclusion
      Hemorheological indexes in postoperative bedridden elderly patients were improved after electrical stimulations of Yinlingquan (SP 9) and Sanyinjiao (SP 6) in combination. Electrical stimulations of Zusanli (ST 36) and Taichong (LR 3) in combination, on the other hand, accelerated the lower limb venous flow.

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      P1.25-005 - Patient Safety Framework Role of Oncology nurses in the era of oral cancer treatments in patients with NSCLC: Are we ready? (ID 1740)

      M. Nematollahi

      • Abstract

      Background
      With recent progresses and advances in technology, the number of oral cancer treatment is on the rise. Treatment for NSCLC was once chosen only according to the stage of disease and its histologic classification. Though these are important , but discovery of tumor markers and identification of biomarkers and genetic profiling in lung cancer have led to an added layer of classification. This new evolution have improved lung cancer treatment by providing information that helps oncologist match the right patient with the right treatment which will move majority of these patients from infusion centres to their homes. The concern will show up about how the medication adherence affects the outcomes of cancer treatment and quality of life of people with cancer.

      Methods
      Not applicable

      Results
      Not applicable

      Conclusion
      In this presentation we will discuss the role of tumor biomarkers in designing personalized therapy Identify different oral cancer therapies and how they are named Define adherence Discuss different factors impacting patient adherence and Implications for clinical practice

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      P1.25-006 - Lung Cancer and Comorbidities: A regional population compared with an urban population (ID 3450)

      R. Grundy, D. Bedwell

      • Abstract

      Background
      Li and Girgis (2006) note patients with lung cancer have a higher level of unmet needs than patients with other types of cancer. Wilder et al (2008) found cancer patients report significantly more comorbid conditions, poorer physical and mental health compared to the general population. Lung Cancer Nurses utilise a community wide approach to optimise cancer care for patients, provide patient centred care and promote multidisciplinary care. The implications of lung cancer patients having the presence of multiple comorbidities at diagnosis include; an increased need for nursing education surrounding the more common comorbidities, poly-pharmacy issues, increased clinical needs, increased community supports and psychosocial support. Also the financial implications of increased care needs both to the patient and the community. Data is being collected from two different hospitals, one regional and one urban, from two different states within Australia. Although geography and resources determine the fine tuning of the Lung Cancer Nurse role to individual hospitals, essentially both models of care promote improved patient outcomes.

      Methods
      All new patients presented in the Lung cancer Multidisciplinary team meeting for a twelve monthe period from September 2012 to end of August 2013 will have their comorbidity data collected. Including associated pharmacy, performance status, main carer and smoking status. The same data is being collected at both sites in this study.

      Results
      Results and their implications will be discussed once data collection completed at end of August 2013.

      Conclusion
      Preliminary data is showing that the majority of our patients with lung cancer have multiple comorbidities and thus, poly pharmacy and increased needs. The data between the urban and regional hospitals will be compared and the implications, differences, simliarties and the impact this has on the Lung Cancer Nurse's role at each site will be discussed as well as future directions and what regional and urban areas can learn from each other.

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    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 10
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      MO01.01 - Next generation sequencing of circulating tumour cells captured by antibody-independent enrichment and matched primary tumours/metastases in patients with non-small cell lung cancer (ID 3311)

      Y. Teng, J.Y. Chua, M. Loh, S. Ow, A. Wong, T. Agasthian, J.K.C. Tam, B. Pang, R. Soong, R. Soo

      • Abstract
      • Slides

      Background
      Circulating tumour cells (CTCs) are considered the seeds of metastasis, and characterization of CTCs promises novel insights into metastasis, new targets for intervention, and less-invasive samples for assessing tumour status. CTCs however are rare in circulation and thus highly sensitive tools are required for their reliable capture and analysis. Antibody-based platforms using candidate gene-based approaches have begun to provide insights into CTCs. However tumour heterogeneity and the dependence of these methods on antigen expression has made antibody-independent methods of interest. The Clearbridge ClearCell System is a microfluidic-based platform that enables antibody-independent capture and retrieval of CTCs based on differences in the biomechanical characteristics of blood cells and CTCs. Next Generation Sequencing (NGS) has emerged as a tool to perform massive parallel sequencing of genomic regions with high efficiency and accuracy. The aim of this study was to perform NGS analysis of CTCs captured by antibody-independent methods, and their matched primary tumour or metastases samples, in patients with NSCLC.

      Methods
      Three matched CTC and primary tumour samples and three matched CTC and metastases samples were obtained from patients with NSCLC. Whole blood samples were also obtained from the patients for germline DNA. Five patients had adenocarcinoma and none of the patients had received targeted therapy prior to biospy of the metastatic lesions. CTCs were captured and retrieved from 2ml whole blood using the Clearbridge ClearCell System near the time of tumour sampling. DNA was extracted from CTCs, tumour tissue, and whole blood using the Qiagen QiaAMP DNA Micro Kit, DNAeasy Blood and Tissue kit , and Biorobot EZ1 workstation respectively. NGS was performed on the Ion Torrent PGM Sequencer using the AmpliSeq Comprehensive Cancer Panel targeted to 409 genes prominent in cancer. DNA variants were identified using Ion Torrent Software Suite v3.4, and pathway analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID).

      Results
      After subtraction of DNA variants found in whole blood, the average number of variants in CTC, primary tumour and metastases samples was 283 (range: 110-470), 433 (70-1002), and 242 (81-166) respectively. The concordance in variants between CTC and primary tumour samples was 22% (15-29%) and between CTC and metastases samples was 29% (20-38%). Genes frequently mutated in matched CTCs and primary tumours/metastases included NOTCH2, AKT1, and RET. Pathway analysis of genes with DNA variants revealed an enrichment of genes involved in mTOR signalling in both CTC/primary and CTC/metastases samples. In CTC/metastases samples, pathways including the JAK-STAT and B-cell receptor pathways were additionally enriched.

      Conclusion
      Our results have highlighted a high level of genetic variability between CTCs and their matched tumours, reflective of high tumour heterogeneity. Preliminary analysis has identified genes and pathways with alterations in CTCs that could be potential targets for systemic treatment.

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      MO01.03 - Transitioning To Next Gen Testing Of Lung Carcinoma (ID 2891)

      W.A. Franklin, J. Haney, D.T. Merrick, K.L. Jones, K. Gowan, A. Van Bokoven, Y. Miller, P. Bunn, D. Aisner

      • Abstract
      • Slides

      Background
      The feasibility of multigene testing in a clinical setting has been demonstrated by the Lung Cancer Mutation Consortium (LCMC) which has evaluated over 1000 cases from multiple institutions in a CLIA environment. The initial platforms used by the LCMC were SNaPshot and Ion Torrent, allele specific tests. More recently the sequencing by synthesis method (Illumina) used for whole genome sequencing has been scaled for sequencing of a limited number of targeted genes. In this study we compare the performance characteristics of Next Generation testing on the MiSeq platform with the older allele specific SNaPshot platform and evaluate the applicability of Miseq-based testing to a clinical, CLIA regulated setting.

      Methods
      Two Illumina kits, the TruSeq and TruSight evaluating 221 hotspots in 48 gene and 175 exons in 26 genes, respectively, were compared. To assess analytical sensitivity, cell lines with known mutations and SNPs were titered into liver DNA known to be wild-type for the selected mutations, at tumor cell concentrations ranging from 3% to 50%. In addition, 24 formalin-fixed paraffin-embedded lung tumors that had previously been evaluated by SNaPshot or direct sequencing were tested to compare sensitivities and specificities of methods. Paraffin embedded human tumor tissue samples were enriched for tumor cells by coring of paraffin block or macrodissection using a pneumatic cell collector. DNA was extracted by proteinase K digestion and column chromatography, end repaired and phosphorylated. Libraries were prepared from each sample by ligating index adapters that allow for mixing of samples and binding adapters that link DNA fragments to flow cell. Combined libraries were added to flow cells at an appropriate concentration, clusters generated, and sequencing reaction commenced. Results were evaluated by software developed by Illumina or locally at the University of Colorado.

      Results
      Spiking studies indicated that analytic sensitivity for Miseq at loading quantities of 100 to 300 ng (TruSeq) was ~5% for known KRAS and TP53 mutations and several synonymous polymorphisms in other covered genes, comparable to SNaPshot. For clinical samples, average depth of coverage was 5700 (+/- 2267). Unfiltered results using Illumina software supplied with the Miseq instrument showed an average of 88 heterozygous SNPs, 12 insertions and 17 deletions (uncurated for relevance). All of the mutations that were previously found by SNaPshot were also detected by Miseq TruSeq and TruSight protocols (100% concordance). Variants representing known polymorphisms, synonymous changes and variants identified in the context of low coverage were excluded. Data analysis using locally developed software indicated the presence of 1-9 SNPs in each sample that were not predicted by SNaPshot testing, attributable to the wider coverage of the Miseq platforms. None of the additional mutations represented treatable targets with currently available drugs.

      Conclusion
      Next-generation testing is feasible in a CLIA environment using the Miseq platform. However, rigorous software validation is necessary before this platform can be adopted by a busy clinical laboratory. Software limitations currently being addressed include long turnaround time, inadequate vetting of new and recurrent SNPs for clinical significance and limited software development resources.

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      MO01.04 - Comparison of Microarray and RNA Sequencing Platforms for Profiling MicroRNAs in Formalin-Fixed, Paraffin-Embedded Non-Small Cell Lung Cancer Specimens (ID 3145)

      D. Buitrago, K. Kadota, V.W. Rusch, S.K. Patnaik, P.S. Adusumilli

      • Abstract
      • Slides

      Background
      MicroRNAs are useful biomarkers for various disease states, and their preservation in formalin-fixed, paraffin-embedded (FFPE) tissue makes them particularly useful for clinicogenetic studies. Although global microRNA expression in FFPE samples is routinely measured with microarrays, the utility of RNA sequencing for such profiling has yet to be established. In this study, to appraise the suitability of RNA sequencing, microRNAs in RNA from lung cancer FFPE samples were quantified by both a microarray and a sequencing platform.

      Methods
      The affinity spin column–based Roche High Pure FFPE RNA kit was used to extract total RNA from 8 resected stage I lung adenocarcinoma FFPE tumor specimens (~3 mm[3]) with ≥50% tumor content. RNA was quantified by RiboGreen fluorometric and absorbance spectrometric analysis at 260 nm, and its quality was examined by electrophoresis on an RNA Pico chip in an Agilent Bioanalyzer 2100. MicroRNAs in 120 ng of RNA were profiled using the 8x60K Agilent Human miRNA Microarray (release 16.0) platform. MicroRNAs were also quantified by use of the Illumina HiSeq 2000 sequencing system (1x 50 bp reads), with multiplexed sequencing libraries prepared using 1 ug of RNA with the Illumina Truseq Small RNA Preparation Kit (version 2.0). Microarray data were processed using the AgiMicroRna Bioconductor package in R. Sequencing data were demultiplexed using CASAVA software and were mapped against mature human microRNAs in the miRBase database (version 16) using STAR aligner software. Absolute microRNA count values were then normalized among samples by use of the edgeR Bioconductor package.

      Results
      Results of RiboGreen fluorometric analysis suggested that an average of 16 ug (range, 6-35 ug; SD, 8 ug) of RNA was obtained from the FFPE specimens. Significant degradation of RNA was observed, as expected, with Bioanalyzer RNA integrity number values between 1.9 and 2.5. An average of 1.3 million sequencing reads (range, 9.1-16.9 million; SD, 3.5 million) were obtained, but only 1.4% (range, 0.4%-2.1%; SD, 1.4%) of them mapped to known microRNAs. Of the 1205 human microRNAs detectable with the microarray platform, 302 were identified as expressed in the 8-sample set, and 593 were identified as expressed in the sequencing platform. For the 177 microRNAs detected by both microarray and sequencing methods, the interplatform Spearman correlation coefficient was >0.5 for only 51 of them. Reverse-transcription PCR assays are being performed to identify the platform that yields the most accurate microRNA profile.

      Conclusion
      MicroRNA profiling by RNA sequencing and microarray techniques produced different results. The RNA sequencing method described here does not appear to be suitable for profiling microRNAs in RNA from FFPE samples. It is possible that depletion of ribosomal RNA fragments from FFPE RNA samples may improve the quality of data obtained from RNA sequencing.

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      MO01.05 - DISCUSSANT (ID 3900)

      S. Fox

      • Abstract
      • Slides

      Abstract not provided

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      MO01.06 - Screening for drugs that overcome Gefitnib resistance in EGFR mutation-positive non-small cell lung cancer cells. (ID 2957)

      Y. Xue, C. Wang, Z. Zheng

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients who show an initial dramatic response to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy almost always acquire resistance due to secondary resistance mutations on EGFR or other mechanisms. Strategies to overcome such acquired resistance have therefore become critical to improve TKI-based targeted therapy. One strategy is the development of therapeutic agents to be used in combination with EGFR-TKI to treat EGFR mutation-positive relapsed patients. Although several candidate drugs targeting putative resistance pathways in NSCLC cells have been attempted in combination with EGFR-TKI, a systematic screening has not been reported. We seek to screen a small molecule library for compounds that would specifically enhance the cytotoxic effect of TKIs on EGFR mutation-positive tumor cells bearing acquired resistance mutations.

      Methods
      We have used MTS assay to screen a library containing about 1000 FDA approved drugs, 600 bioactive compounds, and 400 natural products, to identify compounds that when used in combination with 1µM Gefitnib, can result in significantly more toxicity to Gefitnib-resistant NSCLC cell line H1975 than either Gefitnib or the compound alone. The EGFR on H1975 contains both a TKI-sensitive mutation L858R and a resistant mutation T790M.

      Results
      The screening identified one candidate compound 18G06, an experimental natural product that belongs to a family of drugs currently used for heart disease. The compound has an IC50 of 270nM on H1975, and acts synergistically with Gifitnib to affect cell apoptosis, suggesting that the drug can overcome Gefitnib resistance in H1975. Test of 4 other known drugs in this family showed that they all have sub-microM IC50 values against H1975, but only Drug D had synergistic effect with Gefitnib, while other three drugs showed only additive effects. In addition, 18G06 or Drug D can overcome Gefitnib resistance of H1650 cells, a resistant NSCLC cell line with TKI-sensitive exon19 microdeletion and a TKI-resistant PTEN deletion. However, these two drugs, when used alone or with Gefitnib, had little effect on A549 cells, a resistant NSCLC line with wildtype EGFR. Biochemical evidence suggested that the improved Gefitnib sensitivities of H1975 and H1960 were correlated with specific synergistic inhibition of the ERK signaling pathway during combination treatment. Finally, combination therapy with Drug D and Gefitnib inhibited the growth of tumors formed by inoculated H1975 cells in nude mice to a greater extent than did treatment with either drug alone.

      Conclusion
      We identified two specific members of a family of therapeutics for heart disease that, when each combined with Gefitinib, have synthetic lethality effect on H1975 and H1960. The FDA-approved Drug D can be readily tested in clinical trials with Gefitnib to potentially reverse TKI-resistance of EGFR mutation-positive patients in targeted therapy.

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      MO01.07 - Inhibition of the IGF-1R signaling pathway potentiates responses to ALK inhibitors in both ALK TKI naive and ALK TKI resistant lung cancer (ID 1660)

      C.M. Lovly, N.T. McDonald, Y.H. Chen, H. Jin, Y. Suehara, D. Lim, L. Wang, D.H. Johnson, L. Horn, M. Ladanyi, W. Pao

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic fusions involving the gene encoding the anaplastic lymphoma kinase (ALK) define a new clinically relevant molecular subset of lung cancer. The majority of patients with ALK+ lung cancer are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy, however, the efficacy of these ALK inhibitors is limited by the development of acquired resistance. Additional strategies using rationally selected therapeutic agents/combinations of agents are needed to both delay and overcome acquired resistance to ALK inhibition. Based upon an intriguing clinical observation from a patient with ALK+ lung cancer who had an ‘exceptional response’ to an IGF-1R monoclonal antibody (MAb), we report a novel therapeutic synergism between ALK inhibitors and IGF-1R inhibitors.

      Methods
      A series of experimental approaches including cell culture models, in vitro assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy were employed to test the hypothesis that IGF-1R can be targeted therapeutically to enhance anti-tumor responses in ALK+ NSCLC.

      Results
      Across multiple different ALK+ lung cancer cell lines, including a novel ALK+ cell line developed from a patient prior to ALK TKI therapy, IGF-1R inhibitors (TKIs and MAbs) sensitized ALK+ lung cancer cells to the effects of ALK blockade as assessed by standard cell viability assays. Similar to IGF-1R, ALK fusions co-immunoprecipitated with the adaptor protein, IRS-1, and treatment with ALK inhibitors decreased IRS-1 protein levels. Furthermore, siRNA mediated knock-down of IRS-1 impaired the proliferation of ALK+ lung cancer cells and enhanced the anti-tumor effects of ALK inhibitors. The IGF-1R pathway was activated in cell culture models of ALK TKI resistance, and combined ALK/IGF-1R inhibition in the resistant cells blocked reactivation of downstream signaling and markedly improved therapeutic efficacy in vitro. Finally, IGF-1R and IRS-1 levels were increased in biopsy samples from a patient with advanced ALK+ lung cancer post crizotinib therapy.

      Conclusion
      Collectively, these data support a role for the IGF-1R/IRS-1 signaling pathway in both the ALK TKI sensitive and ALK TKI resistant states and suggest that this rationally selected combination of inhibitors may be an effective strategy to attempt to delay or overcome acquired resistance to therapeutic ALK inhibition. Intriguingly, the ‘second generation’ ALK TKI, LDK-378, which has demonstrated an overall response rate of 70% in patients with both crizotinib naïve and crizotinib resistant ALK+ lung cancer, can inhibit both ALK and IGF-1R in vitro. We speculate, based on these data, that this surprising response rate may be due to LDK-378’s ability to simultaneously inhibit both targets.

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      MO01.08 - Identifying Strategies For The Treatment Of Acquired EGFR Tyrosine Kinase Inhibitor Resistance (ID 3187)

      C. Hasovits, A. Hudson, R. Harvie, S. Clarke, N. Pavlakis, V. Howell

      • Abstract
      • Presentation
      • Slides

      Background
      The management of non-small cell lung cancer (NSCLC) is becoming increasingly personalised with the identification of oncogenic drivers of cancer cell growth which are able to be targeted therapeutically. The paradigm of advanced non-squamous NSCLC treatment now incorporates assessment of epidermal growth factor (EGFR) mutations and treatment with EGFR tyrosine kinase inhibitors (TKIs) in cases where sensitising mutations are found, which results in significant prolongation of progression-free survival compared to empirical chemotherapy. However, the emergence of acquired resistance to EGFR TKIs is almost universal and the two most common mechanisms of resistance include the acquisition of a second mutation in EGFR, the T790M mutation, and c-MET amplification. Approximately one-quarter of cases of resistance are yet to be defined mechanistically and furthermore, optimal subsequent treatment remains unknown. Further research is required to understand the molecular origins of the development of acquired resistance in order to develop rational treatment strategies that incorporate both targeted and cytotoxic therapies. This study is evaluating, using in vitro models, pathways involved in the development of acquired resistance to EGFR TKI and chemotherapy and evaluating critical differences according to EGFR mutation status.

      Methods
      A panel of human NSCLC cell lines with varying clinically relevant molecular characteristics is being assessed and used to develop resistance to various cytotoxic agents and EGFR TKIs, through chronic low dose exposure, as outlined in the table below:

      Cell Line Mutation Status EGFR TKI Sensitivity Resistant Cell Line Generated
      HCC827 EGFR Exon 19 deletion Sensitive Erlotinib; Cisplatin; Paclitaxel; Pemetrexed
      H1975 EGFR Exon 21 Point Mutation (L858R) and T790M mutation Resistant Cisplatin; Paclitaxel; Pemetrexed
      H1299 EGFR Wild-Type Resistant Cisplatin; Paclitaxel; Pemetrexed
      A549 EGFR Wild-Type and KRAS Mutation Resistant Cisplatin; Paclitaxel; Pemetrexed, HDAC-inhibitor
      Assessments of proliferation, cytotoxicity and key signalling pathways are being conducted to evaluate mechanisms of chemotherapeutic and targeted therapy resistance.

      Results
      Chronic low dose exposure has been successful in generating resistant cell lines to both chemotherapeutic agents and the EGFR TKI erlotinib. Cross-resistance to taxol in cisplatin-resistant cell lines has been observed, along with evidence of epithelial-to-mesenchymal transition in the development of EGFR TKI resistance. Antibody arrays of key signalling pathways are being conducted to confirm critical pathways of interest.

      Conclusion
      The panel of human NSCLC cell lines with parental lines harbouring various EGFR sensitising and resistance mutations and generated lines resistant to cytotoxic agents and EGFR TKI are a useful in vitro model to understand key pathways involved in the emergence of therapeutic resistance and to understand how both sensitising and resistant EGFR mutations influence response to cytotoxic agents. This will guide treatment strategies selected for evaluation in vivo that may influence future treatment selection for patients.

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      MO01.09 - A novel murine xenograft model using samples obtained by EBUS-TBNA (ID 773)

      T. Nakajima, W. Geddie, Y. Wang, M. Li, N. Pham, T. Anayama, H. Wada, K. Hirohashi, H.M. Ko, G.D.C. Santos, S. Boerner, M. Cypel, G.E. Darling, T. Waddell, S. Keshavjee, I. Yoshino, M. Tsao, K. Yasufuku

      • Abstract
      • Presentation
      • Slides

      Background
      Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive approach for lymph node staging in patients with lung cancer. Although EBUS-TBNA has been utilized for various molecular testing, intrinsic characteristics of different lesions produce variability in the amount of cellular material that can be obtained. In some samples, the quantity of tumor recovered may be limited for subsequent testing. To overcome this problem, we evaluated the feasibility of establishing a murine tumor xenograft model using EBUS-TBNA samples for advanced translational research.

      Methods
      After confirmation of adequate sampling for cytopathological diagnosis during EBUS-TBNA, one additional pass was performed for this study (NCT01487603). The aspirate was stored in cell preservative solution (RPMI1640 with 10% FBS) for inoculation of the tumor for the xenograft model. The sample was transported to the laboratory on ice, then mixed with Matrigel and centrifuged. The pellet which contained tumor fragments was implanted to the subcutaneous pocket on the right flank of a NSG (NOD scid gamma) mouse. Once we confirmed the engraftment of the tumor, we passed the tumor to another mouse until 3 passages were completed. The success rate of tumor xenograft establishment was examined along with histopathology and the cellularity and cytopathologial diagnosis of the primary EBUS-TBNA samples.

      Results
      From December 2011 to June 2012, 19 patients were enrolled in this study. The cytopathological diagnoses were as follows; 12 adenocarcinoma, 3 squamous cell carcinoma, 1 large cell carcinoma NOS, and 3 small cell carcinomas. 8 out of 19 cases (42.1%) showed tumor formation. The mean duration between inoculation and tumor formation was 62.38 days (13-144 days). All engrafted tumors could be passed to the second mouse. The histological types of the engrafted tumors were 3 adenocarcinoma (3/12: 25%), 2 squamous cell carcinoma (2/3: 67%), 1 large cell carcinoma (1/1: 100%), and 2 small cell carcinomas (2/3: 67%). The tumor cellularity of primary EBUS-TBNA samples was sufficient for diagnosis and there was no correlation between engraftment and the degree of blood/lymphocyte contamination or percentage of necrosis.

      Conclusion
      EBUS-TBNA samples can be used for establishment of tumor xenograft model in immunodeficient mice. EBUS-TBNA allows minimally invasive sampling of metastatic lymph nodes in patients with advanced lung cancer which opens up possibilities for translational research. We need to continuously seek better ways to improve and standardize procurement and processing of samples obtained by minimally invasive techniques in order to optimize diagnosis and molecular analysis for improved patient care. Figure 1

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      MO01.10 - Integrated molecular characterization of Patient-Derived Tumorgrafts as innovative model for clinical management of Non-Small Cell Lung Cancer (ID 2919)

      F. Tabbo', F. Guerrera, A. Nottegar, L. Bessone, P. Bartocci, E. Ercole, F. Di Giacomo, K. Messana, M. Gaudiano, M. Todaro, R. Machiorlatti, I. Landra, S. Urigu, L. Delsedime, M. Chilosi, G. Inghirami, E. Ruffini

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer is the leading cause of death for cancer. Although impressive diagnosis and therapeutic achievements have been recently obtained, critical issues remain open. It is now believed that the generation of reliable preclinical models will provide the basis for new discoveries and to validate the clinical efficacy of known and novel compounds.

      Methods
      From 2010 to 2013, we have generated a biorepository of 190 frozen tumor samples and matched normal lung tissues, peripheral blood mononucleate cell collections, serum and plasma samples from patients who had undergone surgery with curative intentions (stage Ia, Ib, IIa mainly). This data set has been enriched with 480 additional archival tumors. The entire library, encompassing all major histotypes [adenocarcinomas (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)], covers the heterogeneous landscape of NSCLC. All tumors were characterized by immunohistochemistry (IHC) (TTF1, SPA, MUC5AC, CK5, CDX2, VILLIN, p53, p63, p16, ABCA3 and SOX2) and molecular analyses (EGFR, KRAS, BRAF and PI3K mutations). Considering that the pathogenetic role of many lesions is only in part elucidated, and that many lung cancers lack targetable mutations, we generated patient-derived tumorgrafts (PDTs), engrafting fresh and/or frozen tumor fragments in highly immunocompromised mice (NSG). Successfully grown tumors were propagated up to the third generation (T3). Primary versus PDT features were studied by histology, IHC and molecular profiling [Single Nucletoide Polimorphism (SNP), WES, RNA sequencing (RNAseq)] and HTP proteomic analyses.

      Results
      A known distribution of mutations within the first 300 ADCs samples (17% EGFR; 35% KRAS; 2% PI3K; 1% BRAF) was observed. 26 PDT lines (9 adenocarcinoma, 14 squamous, 2 sarcomatoid, 1 mixed) have been propagated, showing that the time growth average required from engraftment was significantly longer for the ADC-lines than SCC-lines (ADC-lines 20 weeks vs SCC-lines 11 weeks). We demonstrated the strong correspondence of primary cancers and PDT tumors, highlighting primary tumor’s specific features or biomarkers. The SNP analysis has revealed the occurrence of stress engrafment events (i.e. loss of heterozigosity LOH) at the first PDT passage; these alterations, once acquired remain relatively stable along later passages. Preliminary data from proteomic profiling are demonstrating stable Phospho-Tyrosine-Kinase profiles in primary tumors compared to PDTs, reinforcing the idea that this PDT tumors aren’t drifted so far from primary cancer architecture.

      Conclusion
      To improve bio-molecular stratification, pathological classification and clinical treatments of lung cancers, a multiparametric approach is needed; this should depict a complete and integrated cancer network in each cancer patient. Nonetheless, reliable preclinical models are required to define the best treatment choices and to overcome the boundaries between basic knowledge and the clinical requirements.

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      MO01.11 - DISCUSSANT (ID 3901)

      P. Mack

      • Abstract
      • Presentation
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      Abstract not provided

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    MO02 - General Thoracic and Minimally Invasive Surgery (ID 99)

    • Type: Mini Oral Abstract Session
    • Track: Surgery
    • Presentations: 11
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      MO02.01 - Is Lower Zone Lymph Node Dissection always Mandatory in Patients with Lower Lobe Lung Cancer? (ID 1851)

      H. Ueno, K. Suzuki, A. Hattori, T. Matsunaga, Y. Tsushima, K. Takamochi, S. Oh

      • Abstract
      • Presentation
      • Slides

      Background
      The recent UICC-IASLC classification defines lower zone lymph node metastasis, i.e., paraesophageal and pulmonary ligament lymph nodes metastasis, as p-N2 disease. Due to the relatively rare incidence of lower zone nodal involvement, however, controversies still surround regarding the clinical characteristics and the possible pathway for lower zone lymph node in patients with lower lobe lung cancer.

      Methods
      From 2009 to 2013, 257 consecutive patients underwent lobectomy with mediastinal lymph node dissection for lower lobe lung cancer. For all patients, thin-section CT scan was reviewed to investigate maximum tumor size, location and consolidation status. In a current study, radiologically “solid” tumor was defined as a tumor which constructed only by consolidation without ground glass opacity (GGO) lesions on thin-section CT scan. Several clinical factors were evaluated to identify significant predictive factors of lower zone lymph node metastasis using a multivariate analysis.

      Results
      Twenty (7.8%) patients revealed lower zone lymph node metastasis. Twelve were men and 8 were women. Patients ranged in age from 33 to 81 y, with an average of 63 y. Among them, tumors distributed especially in Segment (S) 10 (50%). All patients showed solid appearance on thin-section CT scan. A univariate analysis revealed that tumor location (S 10 or not) and solid tumors with more than 30mm in diameter were the significant predictors for lower zone lymph node metastasis (p=0.011, 0.033). Based on a multivariate analysis, these two factors were also shown to be independent predictors for lower zone nodal metastasis in patients with lower lobe lung cancer. (p=0.014, 0.034). Furthermore, the frequency of lower zone lymph node metastasis was approximately 24% for patients with solid tumors more than 30mm located in S10. On the other hand, lower zone lymph node metastasis was never seen in patients with c-T1a-b lower lobe lung cancer with GGO component.

      Conclusion
      Although lower zone lymph node metastasis is included in N2 disease, these incidences are extremely rare even in patients with lower lobe lung cancer except for those with radiologically large-sized solid tumor located in S10 field. Thus, selective dissection for lower zone lymph node could be an appropriate operative strategy in patients with small-sized lower lobe lung cancer especially with GGO predominance.

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      MO02.02 - Size decrease of ground-glass nodules should not be end of follow-up, but may be optimal timing of curative surgery (ID 2234)

      H. Kaneda, T. Nakano, Y. Taniguchi, T. Saito, T. Konobu, Y. Saito

      • Abstract
      • Presentation
      • Slides

      Background
      As observed in colon carcinogenesis, recent reports support an atypical adenomatous hyperplasia (AAH)–adenocarcinoma sequence in lung carcinogenesis. Recent accumulating experiences based on pathologic–radiologic correlation show that most cases of AAH, adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant adenocarcinoma can be detected by ground-glass nodules (GGNs)—the radiographic appearance of hazy lung opacity not associated with obscuration of underlying vessels. In this study, we retrospectively reviewed radiological and pathological characteristics of resected GGNs that were radiologically observed for at least 12 months before surgery, and discuss optimal timing of curative surgery.

      Methods
      We retrospectively reviewed clinical charts and chest computed tomography (CT) of patients on whom pulmonary resection was performed between January 2006 and March 2013 at the Kansai Medical University Hirakata Hospital. The definitions of pure GGNs and part-solid nodules were based on the tumor shadow disappearance rate. The histologic classification of adenocarcinoma followed the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma. We evaluated the radiologic findings, such as size change of whole tumor and appearance of solid component, and pathological findings. All statistical tests were performed with JMP software.

      Results
      A total of 568 patients underwent pulmonary resection during the study periods and 404 cases were adenocarcinoma (ADA), including 207 tumors with lepidic growth pattern. Total 32 GGNs of 31 patients were observed in chest CT before surgery for at least 12 months. Mean GGN size before surgery was 18.6 mm and mean follow-up period was 25.8 months. Pathological findings of 32 tumors were 6 AISs, 4 MIAs, 8 lepidic predominant ADA, 13 papillary predominant ADA, 1 acinar predominant ADA. On last CT before surgery, 15 lesions showed pure GGNs and 17 showed part-solid nodules. Thirteen of the 17 tumors showed slight size reduction of GGNs during the follow-up, mostly just before or just after appearance of solid component inside GGNs.

      Conclusion
      Some GGNs showed size reduction during the follow-up with chest CT. Even when mild collapse of the GGNs are observed, you should neither diagnose non-malignant tumors, such as inflammatory nodules, nor decide cessation of follow-up. And instead, we recommend rather careful follow-up in order to identify solid component inside the GGNs. If you confirm appearance of the solid component, the finding would be a sign of progression from AAH/AIS to invasive adenocarcinoma and may be optimal timing of pulmonary resection as curative treatment.

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      MO02.03 - Surgical intervention strategy for postoperative chylothorax after lung resection - clinical analysis of fifty patients who developed postoperative chylothorax (ID 3321)

      S. Uchida, K. Suzuki, Y. Miyasaka, Y. Tsushima, K. Takamochi, S. Oh

      • Abstract
      • Presentation
      • Slides

      Background
      Chylothorax is a rare but well-known complication of general thoracic surgery. This study evaluated our treatment strategy for postoperative chylothorax and identified associated predictors.

      Methods
      We retrospectively reviewed 1235 patients who underwent lung resection and systematic mediastinal lymph node dissection for primary lung cancer at our department from January 2008 to September 2012. Postoperative chylothorax patients were analyzed. Chylothorax was diagnosed by the milky aspect of drainage fluid and confirmed by an elevated triglyceride level (>110 mg/dL) in the drainage fluid. We initially treated chylothorax patients conservatively with low fat diet (fat intake < 20 g/day). If this treatment was judged to be ineffective, we tried to do complete oral intake cessation or surgical intervention. Comparisons between conservative and surgical intervention groups were analyzed using Fisher’s exact test. Univariate and multivariate analysis of predictors for surgical intervention was performed using logistic regression analysis. Value of p<0.05 were considered statistically significant.

      Results
      Fifty patients (4.0%) developed postoperative chylothorax. There were 35 men and 15 women with a median age of 63 years (range 33 to 81 years). The operative procedures were pneumonectomy in 2 cases, bilobectomy in 5 cases, lobectomy in 32 cases, segmentectomy in 1 case, and sleeve lobectomy in 10 cases. Forty-one patients (82%) cured with conservative treatment. These patients continued a low fat diet for one month. The remaining 9 patients (8%) underwent surgical intervention at a median of 5.5 days after diagnosis (range 3 to 12 days). Postoperative chest tube drainage (ml/h) until first oral intake was significantly greater in the surgical intervention group than conservative group (37.4±15.7 ml/h vs. 24.7±9.7 ml/h; p=0.003). In multivariate analysis, postoperative chest tube drainage (ml/h) until first oral intake was significant predictor for the chylothorax patient required surgical intervention (p=0.012, Hazard Ratio 1.110, 95% Confidence Interval 1.024-1.205). Four patients (8%) had chest tube drainage exceeding 45 ml/h until first oral intake. Among them 3 patients (75%) required surgical intervention.

      Conclusion
      Postoperative chest tube drainage (ml/h) was independent predictor for surgical intervention in postoperative chylothorax patients. If postoperative chest tube drainage exceed 45 ml/h until first oral intake, we should suspect postoperative chylothorax and consider early surgical intervention.

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      MO02.04 - Safety and long term outcome of repeated lung resection for ipsilateral second primary lung cancer (ID 3048)

      M. Tsuchida, K. Togashi, T. Watanabe, T. Hashimoto, T. Koike, S. Sato, T. Shirato

      • Abstract
      • Presentation
      • Slides

      Background
      Repeated lung resection for second primary lung cancer is indicated as an effective treatment in properly selected patients. Among repeated lung resections, surgery for ipsilateral lesion is a challenging modality for thoracic surgeons. We report our experience of repeated lung resection, especially focused on ipsilateral reoperation after anatomical major lung resection.

      Methods
      We retrospectively reviewed patients who had undergone a second lung resection for ipsilateral second primary lung cancer at the 3 institutions between 2000 and 2012. The diagnosis of the second primary lung cancer was based on the criteria from Martini. Variables analysis included clinical and pathologic data including age, sex, c-stage, surgical procedure, p-stage, histology, time interval between the two operations, operative findings, operative morbidity and mortality, as well as long term outcomes. Overall survival was calculated using the Kaplan-Meier method.

      Results
      There were 52 reoperations in 50 patients. Of the 50 patients, 35 were male and 15 were female. The median age at the time of a second operation was 69.9 years (range 51 to 85). The first lung resection was lobectomy in 48 patients and segmentectomy in 2 patients. According to the current TNM classification, p-stage of the first lung cancer was IA in 20, IB in 24, IIA in 3, IIB in 1, IIIA in 1, and IV in 1. The mean value of %vital capacity and forced expiratory capacity in one second /forced vital capacity obtained before the second surgery was 94.7% and 72.3% respectively. The second operation was wedge resection in 28, segmentectomy in 9, right middle lobectomy in 4, right upper lobectomy after lower lobectomy in one, and completion pneumonectomy in 7. The mean interval time between the two operations was 64 months (range, 15-156 months). During second surgery, vascular injury was occurred in 2 patients. Mean volume of blood loss during surgery was 354ml (range, 0 to 3440 ml), and blood transfusion was necessary in 6 patients. Intrapericaridial exposure of the main pulmonary artery was employed in 9 patients due to dense vascular adhesions. There was no operative death. Complications occurred in 9 patients (prolonged air leakage in 5, empyema in 2, heart failure in 1, and delirium in 1). One patient died of pneumonia 5 months after the second operation. Therefore morbidity and hospital mortality was 18% and 2%, respectively. Pathological diagnosis of the second primary lung cancer was adenocarcinoma in 41, squamous cell carcinoma in 9, and sarcoma in 1. P-stage of the second lung cancer was IA in 37, IB in 8, IIA in 1, IIB in 2, IIIA in 1, and IV in 1. The 5-year overall survival after the second operation was 67 %, and more favorable 5-year survival of 77% was observed in p-stage IA.

      Conclusion
      Most second primary lung cancer in this retrospective study was treated in p-stage I. Reoperations for a second primary lung cancer on the same side of the first surgery shows an acceptable morbidity and mortality rate, and provides favorable survival in selected patients with adequate physiologic pulmonary reserve.

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      MO02.05 - DISCUSSANT (ID 3919)

      G.E. Darling

      • Abstract
      • Presentation
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      Abstract not provided

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      MO02.07 - Effect of Obesity on Peri-Operative Outcomes after Robotic-Assisted Pulmonary Lobectomy: Retrospecitve Analysis of 227 Consecutive Patients (ID 2440)

      M.R. Thau, K.L. Rodriguez, T. Tanvetyanon, F.O. Velez-Cubian, W.W. Zhang, J. Fontaine, J.R. Garrett, C.C. Moodie, L.A. Robinson, E.M. Toloza

      • Abstract
      • Presentation
      • Slides

      Background
      Attention has increased over the safety and efficacy of robotic-assisted surgeries in recent years. With rates of obesity on the rise, the impact of excessive body weight on surgical outcomes comprises an important concern for administering care. Our purpose was to determine the relationship between preoperative body mass index (BMI) on perioperative complications following robotic-assisted pulmonary lobectomy for at a high-volume tertiary-care referral cancer center.

      Methods
      We retrospectively studied 227 consecutive patients who underwent robotic-assisted pulmonary lobectomy for known or suspected lung cancer. BMI was calculated as being equal to weight in kilograms divided by height in meters squared. We stratified BMI into 4 groups as defined by the World Health Organization (WHO): Underweight (BMI <18 kg/m2), Normal Weight (BMI 18-25 kg/m2), Overweight (BMI 25.01-30 kg/m2), and Obese (BMI >30 kg/m2). Perioperative complications from surgery to discharge from the hospital were assessed and included respiratory failure, hemothorax, pleural effusion, prolonged air leak, subcutaneous emphysema, aspiration, pneumonia, and hypoxia. Hospital length of stay and in-hospital operative mortality were also assessed. Of 227 total patients studied, there were 6 Underweight patients, 87 Normal Weight patients, 71 Overweight patients, and 63 Obese patients. Initially, with the Underweight group omitted due to small sample size, comparison of the remaining three BMI groups revealed that there were no significant increases in peri-operative complication rates, hospital length of stay, or in-hospital operative mortality among the 3 groups, although there were clear trends toward increased morbidity and mortality when patients had higher BMI. Therefore, we compared the peri-operative complication rates, hospital length of stay, and in-hospital operative mortality between Obese and Non-Obese patients.

      Results
      The results are shown in the following table:

      Surgical Complication Non-Obese BMI ≤30 Obese BMI >30 P-value
      N=162, n (%) N=65, n (%)
      Hypoxia or Respiratory failure 6 (3.7) 7 (10.8) 0.04*
      Hemothorax 3 (1.9) 2 (3.1) 0.57
      Effusion or Empyema 2 (1.2) 2 (3.1) 0.34
      Prolonged air leak 30 (18.5) 5 (7.7) 0.04*
      Subcutaneous emphysema 6 (3.7) 2 (3.1) 0.82
      Aspiration 4 (2.5) 2 (3.1) 0.79
      Pneumonia 17 (10.5) 8 (12.3) 0.69
      In-Hospital Operative Mortality 2 (1.2) 2 (3.1) 0.34
      Median Length of Stay (days+SEM) 5 + 0.3 4 + 0.6 0.54
      *statistically significant, p<0.05

      Conclusion
      Our study shows that obesity increases the risk of peri-operative hypoxia or respiratory failure but results in a lower risk of prolonged air leak after robotic-assisted pulmonary lobectomy. However, we found no significant difference in hospital length of stay or in-hospital mortality between obese and non-obese patients. Thus, our study suggests that robotic-assisted pulmonary lobectomy is feasible and safe in obese patients.

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      MO02.08 - The Feasibility of Single-incision Video-assisted Thoracoscopic Surgery in Major Pulmonary Resection (ID 1389)

      H.K. Kim, K.H. Kang, Y.H. Choi

      • Abstract
      • Presentation
      • Slides

      Background
      We performed video-assisted thoracoscopic (VATS) lobectomy with one incision for the treatment of malignant or benign lung diseases, and have evaluated the feasibility and safety of this procedure.

      Methods
      Consecutive patients who underwent major pulmonary resection through VATS, using one incision from March 2012 to May 2013 were included in this study. The incision was placed at the 5th intercostal space in the mid-axillary line, approximately 3~5 cm long.

      Results
      A total of 60 patients (male 39, female 21; mean age 60.2 ± 12.53 years old, range 21~83) were included in this study. The preoperative diagnosis was malignant lung disease in 56 patients (93.3%) and benign lung disease in 4 patients (6.7%). Four patients (6.7%) needed a second port during surgery and conversion to thoracotomy was needed in two patients (3.3%). In 54 cases, which were completed by single-incision VATS, lobectomies were done in 50 patients, segmentectomy in 3, and sleeve lobectomy in 1. The resected lobes or segments were right upper in 15 patients, right middle in 3, right lower in 15, left upper in 10, and left lower in 11. In 50 cases, which were completed by a single-incision VATS lobectomy for primary lung cancer, the mean duration of the operation was 148.2 ± 45.29 minutes, and a total number of dissected lymph nodes per patient were 21.3 ± 10.08 (range, 5~55). The chest tube was removed on postoperative day 4.7 ± 1.8, and there was no occurrence of major perioperative morbidity and mortality.

      Conclusion
      Single-incision VATS lobectomy is applicable in the selected cases, and may obtain similar results with the conventional VATS lobectomy, through a certain period of learning curve.

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      MO02.09 - Needle scopic surgery for primary lung cancer: Reduced port surgery in thoracic surgery using fine scope and forceps (ID 1856)

      T. Omori, M. Tajiri, Y. Ishikawa

      • Abstract
      • Presentation
      • Slides

      Background
      If a surgical approach is less invasive than a conventional method and can maintain a sufficient technical level equal to a conventional one, it will bring more benefits to patients. We have performed thoracoscopic anatomical segmentectomy and lobectomy for primary lung cancer for more than fifteen years. First we use and slide a 5mm-diameter scope through three or four ports. Then we start the needle scopic surgery(1 port+ 3 punctures method)using a 3mm-diameter scope, which we have used since September 2012. Now we would like to explain this operative procedure and effectiveness.

      Methods
      【Patients】Forty one patients underwent the needle scopic anatomical segmentectomy and lobectomy of the lung between September 2012 to May 2013. They had clinical stage IA or IB lung cancer. We compared the operation time, blood loss volume, post-operative creatinine phosphokinase (CK) and other peri-operative parameters of this method with those of the conventional method using a 5mm-diameter scope which were performed on 73 patients from January 2012 to August 2012. 【Operative procedure】1. We make a 2.5 to 3 cm length skin incision on the 4th or 6th intercostal space of the chest trunk and set the polyurethane-made retractor. We use it as the main port. 2. We puncture the skin with three 3mm-diameter trocars. Then we insert and slide a 3mm-diameter scope and fine forceps through them. We observe thoracic lumen and perform various manipulations using them. 3. Endostaplers, energy devices and electric cautery of which diameters are larger than 3mm go into the thoracic lumen through the main port. 4. Finally we set the chest tube within the main port incision at the end of surgery.

      Results
      We performed 8 segmentectomies and 33 lobectomies of the lung using this method in forty-one cases for the lung cancer. We dissected mediastinal nodes in all cases. We had no cases that were converted to the conventional method. However we elongated the incision of one puncture from 3 mm to 10mm in three cases in order to insert endostaplers for dissecting pulmonary veins and arteries. Mean operation time was 219±49 minutes. Mean blood loss volume was 20.5±28.4 ml. They were not significantly different from those of the conventional method. Post-operative peak titers of CK of this method were significantly lower than that of the conventional method. We had no severe intraoperative accidents or postoperative complications. All patients were smoothly discharged.

      Conclusion
      We were able to successfully perform the needle scopic surgery for lung cancer as well as conventional thoracoscopic surgery. Though some surgeons have tried the single port method for thoracic surgery as another less invasive surgery, we think the needle scopic method is more suitable for thoracic surgery. Because thoracic surgery needs observations and manipulations which are in the wider range of the inner space than that of the abdomen. This method would be the optimal and optional method if we appropriately select cases.

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      MO02.10 - Fluoroscopy-assisted thoracoscopic resection of pulmonary nodules after computed tomography-assisted bronchoscopic metallic coil marking (ID 1532)

      T. Miyoshi, M. Aoyama, S. Inoue, N. Hino, M. Tsuyuguchi

      • Abstract
      • Presentation
      • Slides

      Background
      With advances in computed tomography (CT), small pulmonary lesions previously unseen on chest radiographs are being increasingly detected. Among lesions less than 10 mm in size, a considerable number of malignancies have been reported. To localize small and deeply situated pulmonary nodules during thoracoscopy with roentgenographic fluoroscopy, we developed a marking procedure that uses a metallic coil and a coin.

      Methods
      Thirty-two patients underwent video-assisted thoracoscopic surgery for removal of 33 pulmonary lesions. Fluoroscopy-assisted thoracoscopic surgery after CT-assisted bronchoscopic metallic coil marking was performed using an ultrathin bronchoscope under fluoroscopy viewing a coin on a patient’s chest wall. The coin was simulated a pulmonary lesion by the CT findings, and it was put on the patient's chest wall. During thoracoscopy, a C-arm-shaped roentgenographic fluoroscope was used to detect the radiopaque nodules. The nodule with coil markings was grasped with forceps and resected in partial resection or segmentectomy under fluoroscopic and thoracoscopic guidance.

      Results
      The marking procedure took 10 to 49 minutes from insertion to removal of the bronchoscope. There were no complications from the marking, and all 33 nodules were easily localized by means of thoracoscopy. The metallic coil showed the nodules on the fluoroscopic monitor, which aided in nodule manipulation. Nodules were completely resected under thoracoscopic guidance, in partial resection in 19 cases, in segmentectomy in 9 cases and lobectomy after partial resection in 4 cases. The pathologic diagnosis was primary adenocarcinoma in 16 patients, primary lung cancer except adenocarcinoma in 2 patients, pulmonary metastases in 11 patients, an atypical adenomatous hyperplasia in 1 patient, a hamartoma in 1 patient and a nontuberculous mycobacteriosis in 1 patient. One case of a bronchiolo-alveolar adenocarcinoma with an extensive two segments was performed a curative segmentectomy.

      Conclusion
      In this study, CT-guided transbronchial metallic coil marking with an ultrathin bronchoscope with a coin on a patient’s chest wall after CT-assisted stimulation was found to be feasible and safe. In our previous report, CT had been needed at least three times, but this method needed only twice CT scan. It might be a useful method not only for making a diagnosis but also for therapeutic resection in selected early lung cancers.

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      MO02.11 - Video-Assisted Thoracic Surgery, Hybrid, versus Open Thoracotomy for Stage I Non-Small Cell Lung Cancer - A Propensity Score Analysis Based on a Multi-institutional Registry (ID 3034)

      J. He, C. Cao, T.D. Yan, Q. Wang, G. Jiang, W. Shao, L. Liu, D. Liu, Z. Wang, Z. Zhu, Q. Zhao, D. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      We conducted a multi-institutional study comparing VATS lobectomy to Hybrid, and conventional open lobectomy for unmatched and propensity score-matched patients with stage I NSCLC in an attempt to stratify any potential differences in perioperative outcomes and long-term survival outcomes among the three procedures in patients with stage I NSCLC on a homogeneous well-balanced large population from multi-institutions.

      Methods
      Between January 2001 and December 2008 in eight institutions from the People’s Republic of China, a total of 2485 patients with stage I NSCLC who underwent lobectomy via c-VATS, Hybrid, or open thoracotomy were entered into the current multi-institutional registry. One thousand and fifty-six patients (42.5%) underwent c-VATS lobectomy, 273 patients (11.0%) underwent Hybrid lobectomy, and 1156 patients (46.5%) underwent open lobectomy. Of the patients who attempted to undergo c-VATS lobectomy, 65 were converted to assisted-VATS and 49 patients were converted to open lobectomy.

      Results
      After propensity-matching, c-VATS, Hybrid, and open lobectomy patients were similar in regards to age, gender, histological type and pathological TNM staging. Median operative time was 156.16±17.08 min in open lobectomy group, higher than in c-VATS lobectomy group (145.39±13.1 min) and Hybrid lobectomy group (148.86±11.62) before matching (P<0.001), after matching, it was 154.5±16.89 min, 145.41±12.17 min, and 148.81±11.63 min in open, c-VATS, and Hybrid lobectomy group, respectively (P<0.001). Transfusion occurred in 4 (12.9%) patients in c-VATS group and 6 (19.4%) patients in Hybrid group, both of them lower than in open lobectomy group of 21 (67.7%) patients (P=0.003). However, after matching, there was no statistical difference among three groups, 5 (41.7%) patients, 1 (8.3%) patients, and 6 (50.0%) patients in open, c-VATS, and Hybrid group, respectively (P=0.112). After selecting the propensity-matched patients, the 5-year survival of 78%, 74% and 76% in patients who underwent c-VATS, Hybrid, and open lobectomy, respectively. The perioperative mortality rate was 1.1% for the open group, 1.0% for the Hybrid group, and 0.8% for the VATS group. Two prognostic factors were independently associated with improved survival outcome in multivariate analysis: age < 60 (p = 0.01) and smoking history (p = 0.012). When comparing the three propensity-matched populations, patients who underwent c-VATS lobectomy had similar long-term survival outcomes to patients who underwent Hybrid or conventional thoracotomy (p = 0.770).

      Conclusion
      The present multi-institutional study represents the largest dataset evaluating surgical outcomes of patients who underwent c-VATS or Hybrid for NSCLC. VATS lobectomy for NSCLC was not associated with inferior long-term survival compared to Hybrid or conventional thoracotomy.

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      MO02.12 - DISCUSSANT (ID 3920)

      M. Windsor

      • Abstract
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      Abstract not provided

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    MO03 - Thymic Malignancies (ID 123)

    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 11
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      MO03.01 - Outcome of surgical treatment for thymic epithelial tumors based on the nationwide retrospective database of 3033 patients in Japan (ID 2284)

      M. Okumura, Y. Fujii, I. Yoshino, H. Asamura, K. Yoshida, H. Date, K. Nagai, K. Yokoi, J. Nakajima, S. Miyoshi, K. Kondo

      • Abstract
      • Presentation
      • Slides

      Background
      Thymic epithelial tumor, consisting of thymoma, thymic carcinoma and thymic neuroendocrine carcinoma, is a relatively rare neoplasm, and there is not a satisfying consensus in the treatment strategy. Because of lack of TNM staging system and global consensus on pathological classification, global research in these research has been difficult. To participate in movement of establishing the global database, Japanese Association for research of the Thymus (JART) conducted the project of Japanese nation-wide database in 2012.

      Methods
      Patients undergoing surgical treatment during 20 years between 1991 and 2010 in Japan were collected from 32 institutes. 3182 patients were first enrolled, but after exclusion of cases with insufficient information, 3033 cases remained for analysis finally.

      Results
      1435 patients (44%) were male, and 1595 were female (not identified in 3 patients). The age at operation was 13 to 88 years (mean 57 years old). Pathological diagnosis was thymoma in 2505 patients (Type A: 203, Type AB: 710, Type B1: 599, Type B2: 669, Type B3: 329), thymic carcinoma in 381 patients (Squamous cell carcinoma: 223, neuroendocrine carcinomas 66), and unclassified or unknown in 147 patients. According to Masaoka staging system, 1063 patients were in stage I, 1084 were in stage II, 477 in stage III, 197 in stage IVA, 57 in stage IVB (undetermined in 155 patients). Complete resection was achieved in 2753 patients (92%), subtotal resection (mass reduction of more than 80%) in 157 patients (5%), partial resection including biopsy in 86 patients (unknown in 37 patients). 249 patients were alive with tumor. 316 patients were dead during the observation period, and 161 patients died from tumor. Among 2557 patients who underwent complete resection (R0), 269 patients (10.5%) had tumor recurrence. In the patients who underwent complete or subtotal resection, 10-year overall survival rate was 89% in thymoma, 56% in squamous cell carcinoma, 30% in non-squamous thymic carcinoma, 72% in well-differentiated neuroendocrine carcinoma and 29% in poorly-differentiated neuroendocrine carcinoma. According to Masaoka stage, 10-year overall survival rate was 94% in stage I, 93% in stage II, 74% in stage III, 59% in stage IVA and 44% in stage IVB. In thymoma patients who underwent complete resection, recurrence-free survival rate at 10 years was 96% in type A, 99% in type AB, 92% in type B1, 80% in type B2, 72% in type B3. By Cox’ proportional hazard model, involvement of the mediastinal pleura (p=0.01), involvement of the lung (p=0.01), pleural dissemination (p=0.0009), distant metastasis (p=0.01) and WHO histological subtype (p<0.0001) were found to be independent factors for tumor recurrence after complete resection, while nodal metastasis, intrapericardial dissemination, involvement of pericardium, pulmonary artery, SVC, brachiocephalic vein, aorta, or brachiocephalic artery were not.

      Conclusion
      Japanese nation-wide database revealed the oncological difference among thymoma, thymic carcinoma and thymic neuroendocrine carcinoma. In thymoma, involvement of pleura and lung, pleural dissemination, distant metastasis and WHO histological classification were significant factors of tumor recurrence. These results are supposed to contribute to clinical practice for tumor treatment as well as establishment of global TNM classification.

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      MO03.02 - Surgical Outcome of Patients with Stage III Thymoma in the Japanese Nationwide Database (ID 2842)

      Y. Yamada, I. Yoshino, Y. Fujii, H. Asamura, K. Yoshida, H. Date, K. Nagai, K. Yokoi, J. Nakajima, S. Miyoshi, K. Kondo, M. Okumura

      • Abstract
      • Presentation
      • Slides

      Background
      Stage III thymoma has a variety characteristics in terms of involved organs, complex surgery and multimodal strategy, and a careful consideration is required in choices of treatments. Recently the Japanese Association for Research on the Thymus (JART) conducted a nationwide large cohort analysis for thymic epithelial tumors. The aim of this study is to clarify clinical characteristics and therapeutic outcome of patients who underwent surgical resection for stage III thymoma using this database.

      Methods
      Clinical data of 3,033 thymic epithelial tumor patients of 1991 to 2010 were collected rom 32 Japanese institutes. Medical information registered included patients’ characteristics, types of surgery, pathological diagnosis, perioperative therapy, and clinical outcomes were registered. In this study, stage III thymoma patients who underwent surgery were extracted from the database, and retrospectively analyzed for clinical characteristics and surgical outcome.

      Results
      A total of 340 records of patients were analyzed in this study, which comprised 186 males (54.7%) and 153 females (45.0%), 83 (24.4%) with myasthenia gravis, 42 (12.4%) with induction chemotherapy, 18 (5.3%) with preoperative radiotherapy, and 29 (8.5%) with adjuvant chemotherapies. WHO histologic types comprised 16 A (4.7%), 40 AB (11.8%), 47 B1 (13.8%), 118 B2 (34.7%) and 97 B3 (28.5%). Involved organs were lung in 209 (61.4%), pericardium in 167 (49.1%), chest wall in 7 (2.1%), phrenic nerve in 88 (25.9%) and great vessels in 134 (39.4%). Completeness of resection was R0 in 268 (78.8%), R1 in 35 (10.3%) and R2 in 20 (5.9%). Complications were observed in 85 (25.0%) including arterial fibrillation, phrenic nerve palsy, bleeding and crisis of myasthenia gravis, and 30-day mortality rate was 1.8% (6 cases). Tumor recurrence was experienced in 96 (28.2%), and 39 (11.5%) died during the observation. Overall and disease-free 10-year survival rates were 81.0% and 56.7%, respectively. Involved organs except for chest wall, completeness of resection or myasthenia gravis did not affect the survivals. Number of involved organs (1 vs. >2) and tumor length (<7cm vs. >7cm) affected disease-free survival but not overall survival. Among factors suggested to affect overall survival by univariate analyses such as male, surgical complication, WHO histologic type B1-3, chest wall invasion, induction treatments, and recurrence, independent adverse predictors were revealed by a multivariate analysis to be male (p=0.031, HR=2.47), induction chemotherapy (p=0.034, HR=2.39), postoperative complication (p=0.018, HR=2.41) and recurrence of disease (p=0.041, HR=2.15). Of 96 patients with recurrence, 47 patients who underwent salvage resection showed better prognosis than 49 patients who did not (p=0.009).

      Conclusion
      This nationwide registry study exhibited favorable surgical outcome in Japanese patients with stage III thymoma. Effectiveness of multimodal treatments need to be further investigated in prospective controlled trials.

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      MO03.03 - RYTHMIC: a nationwide network for thymic malignancies in France (ID 2631)

      N. Girard, E. Pichon, P. Thomas, H. Léna, E. Dansin, G. Massard, G. Zalcman, J. Mazières, L. Thiberville, V. Westeel, P. Fournel, C. Clément-Duchêne, X. Quantin, J. Bennouna, T. Molina, B. Besse

      • Abstract
      • Presentation
      • Slides

      Background
      RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a nationwide network for thymic malignancies, which was appointed in 2012 by the French National Cancer Institute, as part of its rare cancer program. The objectives of the network include a territorial coverage by regional expert centers, the dissemination of highest standards for the diagnostic and therapeutic management of patients, and the promotion of collaborative research. Registration in RYTHMIC of all patients diagnosed with thymic malignancy is recommended as part of good clinical practice for oncologists.

      Methods
      Starting January 2012, the management of all patients diagnosed with thymic malignancy in France has been discussed on a real-time basis at a reference national multidisciplinary tumor board (MTB), which is organized twice a month using a web-based conferencing system. Decision-making is based on consensual recommendations, that were originally established using available evidence, and are updated and approved each year by all members of the network. A prospective database of all patients is hosted by the French Thoracic Cancer Intergroup. We report the characteristics and treatment modalities of patients included during the first year.

      Results
      From January to December 2012, 257 patients were enrolled in RYTHMIC. There were 126 (49%) men and 131 (51%) women; mean age at diagnosis was 54.5 years. Among 214 cases, histology was thymoma for 146 (56%) patients (11 (5%) type A, 28 (13%) type AB, 22 (10%) type B1, 35 (16%) type B2, 24 (11%) type B3, 26 (12%) mixed type), and thymic carcinoma for 33 (15%) patients, 8 of which were neuroendocrine carcinomas; other histologies were diagnosed for 35 (16%) patients. Among 144 cases, Masaoka-Koga stage was I, IIA, IIB, III, IVA, and IVB in 34 (24%), 19 (13%), 20 (14%), 22 (15%), 35 (24%), and 14 (10%) patients, respectively. 44 (17%) patients presented with autoimmune disorder, consisting of myasthenia gravis in 28 cases. Surgery was performed for 166 patients, mostly using a median sternotomy approach (52% of cases). Postoperative radiotherapy was delivered to 42 patients; 71 patients received perioperative chemotherapy. Exclusive chemotherapy/radiotherapy was administered to 20 and 4 patients, respectively. Mature data will be presented at the meeting.

      Conclusion
      This first analysis of the RYTHMIC prospective cohort demonstrates the feasibility of a national MTB for thymic malignancies, that, besides ensuring all patients an equal access to highly specialized treatment, provides with a comprehensive tool to monitor dedicated actions to improve the management of patients in the future, increase the quality-of-care, and screen patients for future translational research and clinical trials. Supported by Institut National du Cancer

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      MO03.04 - Analysis of lymphatic metastases of thymic epithelial tumors on Japanese database (ID 3196)

      Y. Nakagawa, K. Kondo, J. Nakajima, M. Okumura, I. Yoshino, Y. Fujii, H. Asamura, K. Yoshida, H. Date, K. Nagai, K. Yokoi, S. Miyoshi, S. Sakiyama, A. Tangoku

      • Abstract
      • Presentation
      • Slides

      Background
      Thymic epithelial tumors sometimes metastasize to lymph nodes (LNs). The frequency of lymph node metastasis, the pattern of node metastasis and the relationship between prognosis and node metastasis are still unclear.

      Methods
      We registered patients with thymic epithelial tumors who had undergone resection between 1991 and 2010 from 29 institutes in Japan by the Japanese Association for Research on the Thymus (JART). We investigated the collected data according to the site of lymphatic metastasis. Yamakawa-Masaoka's paper (Cancer 1991;68:1984–7.) tentatively classified the N factor to 3 groups: metastasis to anterior mediastinal lymph nodes around the thymus were defined as N1, metastasis to intrathoracic lymph nodes other than anterior mediastinal lymph nodes as N2, and metastasis to extrathoracic lymph nodes as N3.

      Results
      The rate of lymphatic metastasis in thymoma was 1.75% (44 cases of 2508). Most of metastatic nodes were located in anterior mediastinal lymph nodes (N1, 78%). There is a significant difference of overall survival between thymomas with LN metastasis and those without LN metastasis (p<0.0001, 10-year survival: 89.8% vs 63.6%). Thymomas with N1 metastasis showed a good prognosis than those with other node metastasis, although there is no significant relationship (5-year survival: 64.4% vs 52.5%). The rate of lymphatic metastasis in thymic carcinoma including thymic carcinoid was 22% (84 cases of 380). Most of metastatic nodes were located in anterior mediastinal lymph nodes (N1, 69%). There is a significant difference of overall survival between thymic carcinomas with LN metastasis and those without LN metastasis (p<0.0001, 10-year survival: 59.5% vs 18.4%). Thymic carcimomas with N1 metastasis showed good prognosis than those with other node metastases, although there was no significant relationship (5-year survival: 55.5% vs 27.5%).

      Conclusion
      The rate of lymphatic metastasis in thymoma and thymic carcinoma was 1.75% and 22%, respectively. Both tumors frequently metastasized to the anterior mediastinal nodes. There was a significant difference of overall survival between tumors with LN metastasis and without LN metastasis in both tumors. And both tumors with N1 metastasis showed good prognoses than those with other node metastases, although there was no significant relationship. We think that it may be reasonable to consider the anterior mediastinal lymph node group (N1) to be a primary lymph node of thymic epithelial tumor.

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      MO03.05 - Impact of VEGF, VEGFR, PDGFR, HIF and ERCC1 gene polymorphisms on thymic malignancies outcome. (ID 2020)

      R. Berardi, A. Brunelli, S. Pagliaretta, V. Paolucci, M. Refai, G. Goteri, C. Pompili, G. Marcantognini, F. Morgese, Z. Ballatore, A. Savini, M. De Lisa, M. Caramanti, M. Santoni, P. Mazzanti, A. Onofri, A. Sabbatini, S. Cascinu

      • Abstract
      • Presentation
      • Slides

      Background
      Thymomas are uncommon tumors of thymic epithelial cells. Thymomas display significant heterogeneity from morphologic point of view, clinical behaviour, expression of immunohistochemical markers and molecular profiling. Improving our understanding of the molecular biology of thymic malignancies represents a key challenge in the treatment of these rare tumors.

      Methods
      The genomic DNA of 57 consecutive patients (31 females and 26 males; 43 thymomas and 14 thymic carcinomas) submitted to total thymectomy at our Institution was extracted from paraffin-embedded tissue. We selected polymorphisms in the following genes: Hypoxia Inducible Factor-1 alpha (HIF1a: rs2057482T>C, rs1951795A>C, rs2301113C>A, rs10873142C>T, rs11158358G>C, rs12434438G>A, rs11549465C>T, rs11549467G>A), Vascular Endothelial Growth Factor-A (VEGF-A: rs2010963G>C, rs699947A>C), VEGF Receptor 2 (VEGFR-2: rs2305948C>T, rs1870377T>A), VEGFR-3 (rs307826T>C, rs307821C>A), Platelet-Derived Growth Factor-A (PDGFR-A: rs35597368C>T) and Excision Repair Cross-Complementing 1 (ERCC1: rs11615A>G). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays.

      Results
      The allele frequency of PDGFR-A rs35597368 T (95.24%) was significantly higher than general population (86%, p=0.012), while the frequency of alleles HIF1-A rs2057482C (76.98%), rs1951795C (68.25%), rs2301113A (68.55%), rs10873142T (68.85%), rs11158358C (74.6%), rs12434438A (65.87%), rs11549465C (83.33%) were significantly lower than those of the control group (90%, 87%, 82%, 87%, 86%, 84%, 92%, respectively, p<0.01). VEGFR-3 rs307821C was significantly higher in thymomas vs. thymic carcinomas (79.5% vs 72%, p=0.0371). The following factors were significantly correlated with a better overall survival: VEGFR-3 rs307826C, VEGFR-2 rs1870377A, PDGFR-A rs35597368T/C, HIF1a rs2301113C, rs2057482C/T, rs1951795C, rs11158358G/C and rs10873142T/C, ERCC1 rs11615A (p<0.05).

      Conclusion
      To the best of our knowledge this is the largest monocentric study analyzing the angiogenetic variants in thymic tumors representing a further asset in the definition of high-risk patients after curative resection. The selection tool deriving from this analysis may allow an optimal use of innovative treatment strategies including targeted agents such as sunitinib, sorafenib or pazopanib.

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      MO03.06 - DISCUSSANT (ID 3974)

      J. Huang

      • Abstract
      • Presentation
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      Abstract not provided

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      MO03.07 - Clinical activity of sunitinib in patients with thymic carcinoma (ID 3114)

      A. Thomas, A. Rajan, A. Berman, B. Scepura, C. Brzezniak, C.A. Carter, U. Guha, Y. Wang, E. Szabo, P.J. Loehrer, G. Giaccone

      • Abstract
      • Presentation
      • Slides

      Background
      There are no standard treatments for patients with advanced thymic epithelial tumors (TET) in whom chemotherapy has failed. A subset of TETs over-express and harbor activating mutations of KIT. Moreover, expression of angiogenic markers correlate with invasiveness of TETs. This two-center phase II study was conducted to evaluate efficacy of sunitinib, a multi-targeted tyrosine kinase inhibitor that blocks angiogenic and other growth factors in TETs.

      Methods
      Patients with TET who had progressive disease following at least one platinum-based chemotherapy were enrolled. Sunitinib was administered orally at 50 mg once daily in 6 week cycles for 4 weeks followed by 2 weeks off until disease progression. Tumor response was assessed by computed tomography scans every 6 weeks. KIT mutations were assessed in archival tissue. Primary end-point was objective response rate in parallel cohorts (thymoma, thymic carcinoma).

      Results
      Between May 2012 and June 2013, 22 patients with thymic carcinoma [median age 58 (40-81); males 59%] and 16 with thymoma [median age 54 (31-74); males 44%] enrolled. Median of 4 (range, 1-7) and 3 (range, 1-8) cycles were administered in patients with thymic carcinoma and thymoma respectively. Among 19 evaluable patients with thymic carcinoma, there were three partial responses (16%) and 10 minor responses (50%) (Figure). Thirteen patients had stable disease (68%) and three progressive disease (16%). After median follow up of 7.8 months, the median progression-free survival was 6.2 months and 6-month survival probability 85%. In contrast, only one out of 16 patients with thymoma had a partial response (6%). Twelve patients had stable disease (75%) and three progressive disease (19%). After median follow up of 6.4 months, median progression-free survival was 5.5 months and 6-month survival probability 90.9%. Grade 3 or 4 sunitinib-related adverse events which occurred in >10% of patients included neutropenia (18%), thrombocytopenia (23%), leucopenia (18%), lymphopenia (45%), fatigue (36%), mucositis (32%) and hypertension (18%). Three patients (14%) has symptomatic decline in left ventricular ejection fraction which improved with medical management and discontinuation of sunitinib. KIT mutations were absent in tumors of 20 patients who underwent mutational analysis.Figure 1

      Conclusion
      In this phase II trial, sunitinib demonstrated anti-tumor activity unprecedented for a targeted agent in previously treated patients with thymic carcinoma. Activity was modest in thymoma. These results are intriguing as response rates of thymic carcinomas are usually lower than that for thymomas. KIT mutations did not predict responses. Ongoing exploratory analyses are evaluating biologic determinants of activity and mechanisms of resistance.

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      MO03.08 - Increased Galectin-1 Expression in a Thymic Epithelial Tumor Tissue Microarray (TMA) and Galectin-1 Knockdown Studies in a Thymoma Cell Line (ID 1238)

      J.W. Riess, P. Kuo, C. Kong, H.A. Wakelee, R. West, Q. Le

      • Abstract
      • Presentation
      • Slides

      Background
      Thymoma is a rare malignancy with a paucity of data on biology. Thymic epithelial tumors are often admixed with developing T-lymphocytes in the microenvironment. Galectin-1 (gal-1) is a beta-galactosidase binding protein involved in T-cell development via thymic stromal and thymocyte interaction as well as thymocyte development through negative selection. Gal-1 also induces apoptosis of effector T-lymphocytes, promotes angiogenesis, and is a poor prognostic indicator when overexpressed in several tumor types. To our knowledge expression of gal-1 has not been examined in thymic epithelial tumors.

      Methods
      A TMA was constructed from 68 patients with thymic malignancies and 8 benign thymic controls at Stanford University School of Medicine (Stanford, CA). Immunohistochemical stains for galectin-1 (1:200 dilution; citrate pre-treatment; mouse monoclonal; Novocastra) were performed on 4 µM-thick TMA sections. Galectin-1 cytoplasmic staining of the epithelial cell component was scored as negative (0), focal positive (1+), or strong positive (2+) by a Stanford pathologist, who was blinded to the clinical data. Gal-1 expression was averaged for each patient sample. Statistical analysis was performed using SAS Enterprise Guide v5.0 (Cary, NC). Non-parametric statistical analyses were used to compare average patient gal-1 expression between thymic tumors and benign thymic controls. Stable gal-1 knockdown was achieved in IU-TAB1, a human thymoma WHO type AB cell line, using the pLKo.1 vector with gal-1 shRNA (Open Biosystems). Lentivirus was produced using the Trans-Lentiviral Packaging System (Thermo Scientific). In vitro proliferation cell counts were performed by hemocytometer. After hypoxia exposure (0.5% O~2~), apoptotic cells were labeled using the APO-Direct kit and quantified by flow cytometry (BD Biosciences).

      Results
      Demographics for 68 patients: M:F (53%/47%), Mean age at diagnosis: 55 years, WHO Histology: A (10%), B (57%), AB (24%), C (4%), unclassified (4%), Pathologic Maseoka Stage: I (46%), IIa (18%), IIb (4%), III (18%), IVa (9%) IVb (6%). Gal-1 expression was increased among thymic tumor tissue compared to unpaired controls (mean avg gal-1 expression 1.5 vs. 0.125, p=0.0012, Kruskal-Wallis test). Logistic regression of tumor vs. control thymus by gal-1 generated a C-statistic of 0.845. A significant increase in gal-1 expression was noted across all WHO thymoma subtypes except thymic carcinoma (type C) (p < 0.05, non-parametric ANOVA with post-hoc ranked Dunnett’s t-test). Among 11 thymic tumors analyzed with paired adjacent resected benign thymus tissue from the same patient, a significant increase was noted in gal-1 expression among tumor compared with adjacent resected normal benign thymus (mean avg gal-1 1.82 vs. 0.35, p=0.004, sign-rank test). In vitro, gal-1 knockdown did not affect IU-TAB1 proliferation. Preliminary results showed gal-1 knockdown increased apoptosis under hypoxia compared to scramble control.

      Conclusion
      Gal1 expression was increased among thymoma compared with benign thymus controls and paired adjacent resected benign thymus. A robust C-statistic of 0.845 indicates that gal-1 expression may discriminate tumor from benign thymus. Increased gal-1 expression was conserved across WHO histologic subtype except for thymic carcinoma—whose analysis was limited due to small sample size. Gal-1 knockdown might increase apoptosis under hypoxia. We are continuing to investigate the biologic and clinical significance of increased gal-1 expression in thymoma.

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      MO03.09 - Detection of Human Polyomavirus 7 in thymomas (ID 1829)

      M. Keijzers, A. Dingemans, D. Rennspies, S. Pujari, M.A. Abdul Hamid, M. Hochstenbag, E.M. Speel, A. Haugg, C. Buck, M. De Baets, A. Zur Hausen

      • Abstract
      • Presentation
      • Slides

      Background
      Thymomic pathologies are associated with the autoimmune disease myasthenia gravis (MG). The thymomagenesis have been studied extensively but the etiology of human thymoma remains poorly understood. Based on the consistent finding that murine polyomavirus induces thymomas in mice we tested the presence of Human Polyomavirus 7 (HPyV7) in human thymic epithelial tumors.

      Methods
      We applied HPyV7 DNA Fluorescence in situ hybridization (FISH), DNA PCR and immunohistochemistry (IHC) in 37 thymomas (19 female, 18 male; mean age 58.3 years; range 34 – 82 years). Of these, 26 were previously diagnosed with MG. In addition, 2 thymic carcinomas, 20 follicular hyperplasia and 20 fetal thymus tissues were tested for HPyV7.

      Results
      HPyV7 FISH revealed specific nuclear hybridization signals within the thymoma cells of 23 thymomas (62.2%). Fifteen thymomas revealed strong to very strong hybridization signals, whereas 8 revealed only weak positivity. With one exception the HPyV7 FISH data highly correlated with the HPyV7 DNA-PCR data. IHC showed the presence of HPyV7 on the translational level and immunohistochemical double stainings confirmed the presence of HPyV7 in the epithelial thymoma cellular compartment. One thymus carcinoma was HPyV7 positive the other negative. All fetal thymus tissues were tested HPyV7 negative. The follicular hyperplasia results are pending.

      Conclusion
      We conclude that HPyV7 is frequently present in human thymic epithelial tumors and absent in fetal thymic tissues. No convincing association on HPyV7 and MG could be found. In as much HPyV7 is of relevance to human thymomagenesis remains to be established.

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      MO03.10 - A multicenter prospective study of carboplatin and paclitaxel for advanced thymic carcinoma: West Japan Oncology Group 4207L (ID 987)

      J. Shimizu, F. Hirai, T. Yamanaka, K. Taguchi, H. Daga, Y. Kogure, T. Kimura, K. Tanaka, Y. Iwamoto, A. Ono, H. Sasaki, J. Fukuoka, K. Nishiyama, K. Takeda, T. Seto, Y. Ichinose, K. Nakagawa, Y. Nakanishi

      • Abstract
      • Presentation
      • Slides

      Background
      Thymic carcinoma (TC) is a rare malignant tumor originated within the thymus gland and is associated with a poor prognosis, differing from thymoma which is the most common type of thymic malignant neoplasm. No results of clinical trials focusing on TC have been reported. This single-arm study evaluated carboplatin and paclitaxel (CbP) in previously untreated patients (pts) with advanced TC.

      Methods
      Pts with Masaoka’s stage III to IVb TC, ECOG PS 0 to 1, and more than 20 years old were eligible. The study treatment consisted of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) by extramural assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. All pts were followed-up until 24 months (mo) after last enrollment. Based on the SWOG 2-stage design, the planned sample size of 40 pts was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05.

      Results
      From May 2008 to November 2010, 40 pts were enrolled from 21 centers. Of 39 evaluable for analysis, the median age was 62 years (range, 36–84); 23/16 males/females; 3/10/26 with Masaoka’s stage III/IVa/IVb; 9/11/19 with squamous cell carcinoma/poorly differentiated neuroendocrine carcinoma/other types. The median number of cycles was 6. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval [CI], 21-53%; P = 0.031). The median PFS was 7.5 mo (6.2-12.3 mo) while OS did not reach the median value. The 1-year and 2-year survival rates were 85% (95% CI, 69-93%) and 71% (95% CI, 54-83%), respectively. Major adverse event was grade 3-4 neutropenia in 34 pts (87%). Two cases (5%) of grade 3 febrile neutropenia, neuropathy, and arthralgia were observed, respectively. There was no treatment-related death.

      Conclusion
      CbP showed high efficacy in advanced TC. Our results established that CbP, one of the standard treatments for non-small cell lung cancer, also serves as a key chemotherapy regimen for TC.

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      MO03.11 - DISCUSSANT (ID 3975)

      H.A. Wakelee

      • Abstract
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      Abstract not provided

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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 8
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      O01.01 - Genetic polymorphisms of inflammatory and DNA repair pathways, radiation-related esophagitis and pneumonitis in definitive chemoradiation treated non-small cell lung cancer patients. (ID 2997)

      K. Barrett, J. Xu, K.S. Woon, K. Boyd, D. Cheng, Z. Chen, A. Bezjak, A. Sun, J. Cho, A. Hope, E.P. Saibishkumar, N. Leighl, F. Shepherd, W. Xu, G. Liu

      • Abstract
      • Presentation
      • Slides

      Background
      The benefits of concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC) are tempered by treatment toxicity. Germline genetic variants have been associated with intrinsic radiosensitivity and radiotoxicity in various cancer settings. We investigated whether variants in genes involved in inflammation response and DNA repair pathways independently influence radiation-induced phenotypes of esophagitis and pneumonitis. From 19 candidate genes, 52 polymorphisms, directed by literature and by tagging procedures, were systematically selected for assessment. The candidate genes were involved in DNA repair (double-strand breaks, homology directed, nucleotide excision) and pro/anti-inflammatory signaling. The this investigation sought to evaluate the association of genetic sequence markers for two clinically significant radiation-induced toxicities - esophagitis and pneumonitis – seen in NSCLC patients treated with a curative intent.

      Methods
      From 312 patients treated at PMCC between 2005-12, a training cohort was defined consisting of 92 definitive concurrent chemoradiation/radiation-treated NSCLC patients with genotype information on the 52 polymorphisms. A second, validation cohort consisted of 209 patients. Multivariate logistic regression was performed for each polymorphism of interest, adjusting for known clinical and dosimetric prognostic factors on the dichotomized outcomes of radiation esophagitis (Grades 0-2 vs 3-5) and pneumonitis (Grades 0-1 vs 2-5). The CTCAEv4.03 grading criteria were used. Additive genetic models were used for genetic association analysis. In the training set, genetic variants, genotyped by IlluminaGoldenGate, with p<=0.05 were identified for validation; HWE was set at p>0.01, a criteria met by all polymorphisms with statistical significance.

      Results
      In the combined training and validation datasets, 63% were males, with median age of 65 years. Specifically in the training dataset, 65% were male, with median age of 62, median mean lung doses of 15.9, median max esophageal dose of 67.1 and median V20 of 27.6. For esophagitis, the final models were adjusted for concurrent chemotherapy, V20 and max esophageal dose. Five genetic variants linked to TNF and IL6 were significantly associated with outcome (each using wild-type genotype as reference) (Table 1). For pneumonitis, the final models adjusted for V20 and smoking status. Eight genetic variants found within four genes (ATM, BRCA2, IL1alpha, IL1RN) were associated with significant pneumonitis (Table 1).

      ESOPHAGITIS
      Function / Pathway Gene refSNP OR 95% CI P value
      pro-inflammatory cytokine TNF rs3093662 3.54 1.9-10.6 0.02
      pro-inflammatory cytokine TNF rs3093664 3.42 1.2-10.2 0.03
      pro-inflammatory cytokine TNF rs3093665 4.95 1.2-21.1 0.03
      anti-inflammatory cytokine IL6 rs1800797 2.53 1.0-6.2 0.04
      anti-inflammatory cytokine IL6 rs1800795 2.45 1.0-5.9 0.046
      PNEUMONITIS
      Function / Pathway Gene refSNP OR 95% CI P value
      double-strand break repair ATM rs664143 2.67 1.3-5.6 0.01
      double-strand break repair ATM rs664677 2.37 1.2-4.7 0.01
      homology-directed repair BRCA2 rs1799955 2.59 1.3-5.3 0.01
      homology-directed repair BRCA2 rs1801406 2.42 1.2-4.8 0.01
      homology-directed repair BRCA2 rs1799943 2.09 1.0-4.2 0.04
      anti-inflammatory cytokine IL1alpha rs17561 2.63 1.2-5.7 0.01
      anti-inflammatory cytokine IL1alpha rs2856863 2.60 1.1-5.9 0.02
      anti-inflammatory cytokine IL1RN rs3087263 0.17 0.04-0.8 0.04

      Conclusion
      In our 92 patient training set, genetic variations in TNF and IL6 are associated with radiation esophagitis, while genetic variations in ATM, BRCA2, IL1alpha and IL1RN are associated with pneumonitis. Results from the 209 patients in the validation dataset will be presented at the meeting (A.H. and G. L are co-senior authors).

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      O01.02 - MicroRNA Signature Predicts Survival in Resectable Small-Cell Lung Cancer (ID 1641)

      N. Bi, J. Cao, Y. Song, J. Fan, J. He, Y. Shi, X. Zhang, N. Lu, L. Wang, Q. Zhan

      • Abstract
      • Slides

      Background
      Small-cell lung cancer (SCLC) is one of the most aggressive types of cancer, yet the molecular mechanisms underlying its devastating clinic outcome remain elusive. In this study, we investigated whether microRNA (miRNA) expression profiles can predict clinical outcomes of SCLC patients.

      Methods
      A total of 82 patients with very limited SCLC, who received surgical resection followed by adjuvant chemotherapy according to the standard of care, were enrolled in this study. All the tumor samples used for miRNA profiling were required to contain at least 60% tumor cells and RNA was isolated from formalin-fixed paraffin-embedded specimens. First, we surveyed 924 miRNAs for their expressions from 42 SCLC patients to discover survival relevant miRNAs and develop prognostic models, which were then validated in an independent cohort of 40 cases. A risk score of miRNA signature for survival prediction was calculated according to a combination of expression level of the miRNA weighted by the regression coefficient derived by univariate Cox regression analysis. Kaplan-Meier overall survival curves were compared using the log-rank test and multivariate Cox regression model was used to test if the miRNA signature was an independent prognostic factor.

      Results
      For all the patients, the median follow up time was 57.2 months. Forty-four patients (53.7%) are still alive. Forty-two patients (51.2%) had recurrent disease and the median time to diagnosis of relapse was 12.3 months. In the training set, we identified that two miRNAs, miR-150 and miR-886-3p, were significantly associated with poor OS. The results compared between NL and SCLC tissues also verified that the miR-150 and miR-886-3p expression levels in SCLC were much lower than in normal lung samples (884±126 vs 2954±1652 for miR-150 and 1873±256 vs 3154±448 for miR-150 ). We then derived a miRNA signature 0.545×miR-150 + 0.617 ×miR-886-3p. Compared with patients with low-risk miRNA signature, patients with high-risk signature had significantly shorter median OS (12.6 months versus not reached, P=0.02). This signature was also demonstrated to be a significant predictor of survival in the validation set. Patients with high risk miRNA signatures had poor overall survival (P=0.005) and progression-free survival (P=0.017) compared to those with low-risk scores. It retained statistical significance in a model adjusting for age, gender and smoking status (HR 0.27, 95% CI 0.10-0.72, P=0.008), which suggesting that the miRNA signature may be an independent predictor of survival.

      Conclusion
      In this study, we developed a prognostic miR-150/miR-886-3p signature and validated in an independent dataset for resectable SCLC. Our results indicated that microRNAs may serve as promising molecular prognostic markers as well as new therapeutic targets for SCLC. Larger sample size studies are needed to further validate our findings.

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      O01.03 - BRM Promoter Variants and Survival Outcomes of Advanced Non-Small Cell Lung Cancer (NSCLC) Patients: A Validation Study in the NCIC Clinical Trials Group (NCIC-CTG) BR24 Clinical Trial (ID 1999)

      S. Cuffe, L. Cheng, A.K. Azad, Y. Brhane, D. Cheng, Z. Chen, X. Qiu, K. Boyd, N. Leighl, W. Xu, B.E. Chen, P. Bradbury, F.A. Shepherd, L. Seymour, M.S. Tsao, D.N. Reisman, G. Liu

      • Abstract
      • Presentation
      • Slides

      Background
      BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in NSCLC. Loss of BRM expression occurs in 15% of NSCLC, and has been linked to adverse outcome. Two BRM promoter insertion variants (BRM-741 and BRM-1321) result in epigenetic silencing of BRM through recruitment of histone deacetylases. The presence of double homozygous BRM variants is linked to loss of BRM expression and function in lung tumors, and double the risk of lung cancer. Pharmacological reversal of the epigenetic changes of BRM is feasible. In this study we evaluated the association between the BRM promoter variants and survival outcomes of advanced NSCLC patients.

      Methods
      The training cohort consisted of 564 stage III-IV NSCLC patients treated at the Princess Margaret Cancer Centre, Toronto 2006-2010. The validation cohort comprised 219 stage IIIb-IV NSCLC patients from the NCIC-CTG BR24 clinical trial, a phase II/III double-blind randomized trial of cediranib versus placebo in patients receiving carboplatin/paclitaxel for the treatment of advanced or metastatic NSCLC. Genotyping for the BRM promoter variants was performed using Taqman. Associations of BRM promoter variants and overall (OS) and progression free survival (PFS) were assessed using Cox proportional hazard models adjusted for clinically relevant variables, and in the case of the BR24 population, stratified by treatment arm.

      Results
      Among the training cohort, 73% were Caucasian, 52% male, median age 63 yrs, 55% stage IV disease, and 67% adenocarcinoma. Median OS was 1.6yrs; median follow up, 3.6yrs. The frequency of homozygosity was BRM-741, 23%; BRM-1321, 21%; both 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 2.5 [95% CI: 1.9-3.3; p=6x10E-10]) and PFS (aHR 2.0 [95% CI: 1.6-2.6; p=9x10E-8]) compared to the wild types. Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS of 2.0 [95% CI: 1.5-2.6; p=2x10E-6]; aHR for PFS of 1.8 [95% CI: 1.4-2.4; p=3x10E-6]). The presence of double homozygous BRM-741 and BRM-1321 variants was strongly associated with worse OS (aHR 2.8 [95% CI: 1.9-4.0; p=7x10E-8]) and PFS (aHR 2.7 [95% CI: 1.9-3.8; p=1x10E-8]). Genotyping was possible for 219/296 BR24 participants. Of these, 59% were male, median age 59 yrs, 83% stage IV, 46% adenocarcinoma, with 50% receiving cediranib. Individuals carrying the homozygous variants of both BRM-741 and BRM-1321 (13% of cases) had a substantially worse OS (aHR 9.0 [95% CI: 4.3-18.5; p=1x10E-9]) and PFS (aHR 3.8 [95% CI: 1.9-7.3; p=3x10E-5]) compared to the wild types, irrespective of whether they were treated with cediranib (aHR for OS of 6.4; p=1x10E-4; aHR for PFS of 2.1; p=0.02) or placebo (aHR for OS of 16.8; p=2x10E-7; aHR for PFS of 8.3; p=1x10E-4).

      Conclusion
      The same two homozygous BRM promoter variants that are associated with increased risk of NSCLC are also strongly associated with adverse OS and PFS in this study of advanced NSCLC patients. We are completing additional studies focusing on the relationship between the BRM promoter variants and BRM protein expression; results will be presented at the meeting.

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      O01.04 - DISCUSSANT (ID 3909)

      G. Sozzi

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      Abstract not provided

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      O01.05 - EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKI (ID 691)

      J. Li, X. Li, S. Ren, X. Chen, C. Zhou

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      • Presentation
      • Slides

      Background
      EGFR mutation is a strong positive predictive factor of EGFR-TKIs therapy. However, at least 10% of patients with wild-type EGFR are responsive to TKIs, suggesting that other determinants of outcome besides mutant EGFR might exist. miR-200c is an important regulator of epithelial-to-mesenchymal transition and might be associated with drug-resistance. Our objective was to characterize miR-200c expression in NSCLC and its role in TKI sensitivity in EGFR wild-type NSCLC.

      Methods
      miR-200c levels in 7 NSCLC cell lines were measured by real-time quantitative reverse transcription-PCR (qRT-PCR). Direct target of miR-200c was identified through the TargetScan database and was validated through qRT-PCR and Western blot analysis. The precursor of miR-200c was up-expressed in H1975 and A549 cells using a lentivirus construct, and miRNA inhibitor was used to down-regulate the expression of miR-200c in PC9 cell line. Effects of miR-200c on cell proliferation and sensitivity to EGFR-TKIs were evaluated by MTT assay in vitro. The expression of proteins correlating with signaling pathway was determined by western blot analysis. 141 FFPE samples of advanced NSCLC patients were enrolled in this study, and miR-200c expression and EGFR mutations were detected by qRT-PCR and amplification refractory mutation system (ARMS), respectively.

      Results
      We identified a tight association between the expression of miR-200c, epithelial phenotype, and sensitivity to TKIs in NSCLC cell lines. Up-expression of miR-200c in A549 and H1975 cells up-regulated E-cadherin levels, down-regulated expression of ZEB1, vimentin, pERK and pAKT. Up-regulated miR-200c increased sensitivity to gefitinib in the primary resistant cell line A549. Analysis of 141 NSCLC specimens indicated that median PFS of EGFR wild-type (n=57) and EGFR mutant NSCLC patients (n=73) treated with second/third line targeted therapy was 1.8m vs. 12.0m respectively (P<0.0001). Patients with high expression level of miR-200c had a positive association towards a longer PFS in NSCLC harboring EGFR wild-type when considering 2[-ΔCt]=0.01128 (median level) as cut-off value (3.95m vs. 1.60m, P=0.015). The objective response rate (ORR) was 7% in the EGFR wild-type cohort, and patients with high miR-200c expression level had better ORR than those with low level (12.5% and 3.0%, P=0.3). In Cox regression analysis, miR-200c expression also present the same trend for benefit from EGFR-TKIs in EGFR-negative NSCLC (HR= 0.375, 95%CI: 0.198-0.712, P= 0.003).

      Conclusion
      miR-200c appears to act as a critical role in EGFR-TKIs sensitivity in NSCLC patients with wild-type EGFR. Up-expression of miR-200c can trigger MET and suppress PI3K/AKT, MEK/ERK pathway, which can also partially overcome EGFR-TKIs resistance. miR-200c might be a predictive biomarker of clinical response to EGFR-TKIs and assist in selecting the subpopulation in patients with wild-type EGFR to benefit from targeted therapy.

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      O01.06 - Dynamic change in plasma EGFR mutation DNA in response to first line therapy for advanced stage non-small cell lung cancer (NSCLC) (ID 2496)

      T. Mok, Y. Wu, J.S. Lee, C. Yu, V. Sriuanpong, W. Wen, J. Tsai, M. Trueman, B. Klughammer, L. Wu

      • Abstract
      • Presentation
      • Slides

      Background
      Diagnostic utility study of EGFR mutation analysis of tumor and plasma from FASTACT 2 confirmed that the plasma EGFR mutation DNA (pEGFRmut) is a sensitive and specific biomarker. (Wu et al, Lancet Oncology 2013; T. Mok, ASCO 2013). Primary objective of this study is to investigate the dynamic change in pEGFRmut during course of treatment. Secondary objective is to study the diagnostic utility of pEGFRmut in patients with distant organ metastasis whom we assumed to have higher level of plasma DNA.

      Methods
      Retrospective EGFR mutation testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific assays, cobas® 4800 EGFR_FFPET test and cobas® EGFR_blood test (in Development). Both tests are designed to detect one or more of the 42 known EGFR mut. One FFPET section was used for tissue test and 2-ml plasma was used for blood test. We studied the plasma samples collected at baseline, post cycle 3 (C3) and at tumor progression according to RECIST criteria (PD).

      Results
      Complete analysis of plasma samples at baseline, C3 and PD was available in 305 of 451 pts(67.6%). Incidence of pEGFRmut positive at baseline, C3 and PD was 35% (106/305),15% (47/305)and 27% (81/305), respectively. 98 of 106 pEGFRmut patients harbor the Exon 19 deletion or L858R at baseline. (C arm 51; CE arm 47). At C3, 21 (41%) pts lose pEGFRmut positivity in C arm comparing to 39 (83%) in CE arm. At PD, 8 of the 21pts in C arm and 18 of the 39 in CE arm regained pEGFRmut positivity. Table 1 summarized the median pEGFRmut copies/PCR. There was a considerable decline at C3 in both C and CE arm. However, pEGFRmut copies/PCR rebounded to high level at PD in C arm only and remained low in CE arm. Correlation of dynamic change in pEGFRmut copies/PCR with clinical tumor response and PFS will be presented at the meeting. We have also identified 93 (out of 224 matched tissue and plasma samples) patients with known distant organ metastasis. Sensitivity of pEGFRmut in this patient subgroup is 91% (41/45), specificity at 98% (47/48) and overall concordance at 95% (88/93). Table 1

      Median pEGFRmut copies/PCR Baseline C3 PD
      C (Exon 19) 27.6 2.3 35.8
      CE (Exon 19) 43.2 0 2.7
      C(Exon 21) 40.9 2.6 63.9
      CE (Exon 21) 87.1 0 3.5

      Conclusion
      This is the first study demonstrating the quantitative dynamic change in pEGFRmut in pts who received C or CE for advanced NSCLC. At RECIST progression, pEGFRmut remained low in patients who received erlotinib but not in patients who received chemotherapy only. pEGFRmut is a potential biomarker for monitoring tumor response.

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      O01.07 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): Secondary Endpoint Analysis (ID 3276)

      V. Gregorc, C. Lazzari, S. Novello, S. Barni, M. Aieta, F. Grossi, T. De Pas, F. De Marinis, M. Mencoboni, A. Bearz, I. Floriani, V. Torri, F. Hirsch, H. Roder, J. Grigorieva, J. Roder, A. Bulotta, S. Foti, M. Viganò, M. Giaj Levra, A. Bachi

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR-TKis are more effective in NSCLC patients with EGFR activating mutations. However, about 90% of non-Asian patients are EGFR wild type, and a test for optimizing treatment in pts with wild-type or in patients with undetectable EGFR mutation status or squamous histology is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility in retrospective studies. PROSE is the first completed multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2[nd]- line NSCLC pts treated with E or CT. As reported at 2013 ASCO[1], VSG pts derived similar overall survival (OS) benefit from both agents (hazard ratio (HR) for E=1.06; p=0.71) whereas CT was the superior option for VSP pts (HR for E=1.72; p=0.02). PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p-value of 0.031. The present report discusses the results for the secondary endpoints, PFS.

      Methods
      285 pts, stratified by ECOG-PS, smoking, and blinded pre-treatment VS classification, were randomized 1:1 to receive E or CT at standard doses. Primary endpoint was overall survival (OS) and the primary hypothesis was a significant interaction between VS status and treatment. Sample size was calculated based on an estimated 65%/35% VSG:VSP ratio and hazard ratio (HR) for interaction of 2.35, with a 2-sided α=0.05 and 90% power.

      Results
      263 pts (129 CT, 134 E) were included in the per protocol primary analysis. 68% of pts in CT arm and 72% in E arm were classified as VSG, and analysis was performed at 226 survival events.VSP classification was significantly correlated with worse PFS as compared to VSG, in overall comparison (HR=1.75, 95%CI: 1.34-2.95, P <0.001) , in the CT (HR = 1.69, 95%CI: 1.15-2.48, P <0.007) and the E (HR = 1.91, 95%CI: 1.340-2.80, P<0.001) arms, demonstrating its prognostic value also in PFS. In VSG median PFS was 4.8 months (m) on CT, and 2.5 m on E (HR = 1.26, 95% CI: 0.94-1.69, P =0.129); in VSP median PFS was 2.8 m on CT and 1.7 m on E (HR=1.51, 95% CI: 0.96-2.38, P =0.078). No statistical significant interaction was detected (p=0.44)

      Conclusion
      The analysis of PFS and OS indicates that the differential treatment benefit in OS related to VS classification is determined by the combination of prognostic and predictive properties of the test.

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      O01.08 - DISCUSSANT (ID 3910)

      D. Gandara

      • Abstract
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      Abstract not provided

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    O02 - NSCLC - Combined Modality Therapy I (ID 111)

    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 8
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      O02.01 - Geographic differences in the combined-modality treatment of stage III unresectable non-small cell lung cancer: Results from a global phase III trial of tecemotide (L-BLP25) (ID 2712)

      N. Thatcher, F.A. Shepherd, P. Mitchell, M.A. Socinski, A. Paredes, M. Lambrechts, M. Thomas, J. Kollmeier, M. Zemanova, P. Sadjadian, N. Peylan-Ramu, C. Helwig, A. Schröder, C.A. Butts

      • Abstract
      • Presentation
      • Slides

      Background
      Chemo-radiotherapy (chemo/RT) is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC), but little is known about differences in clinical practice between regions of the world. The START trial is a global phase III trial of the MUC1-specific cancer immunotherapy tecemotide (L-BLP25), for which key efficacy and safety results have been reported previously. Here we report regional differences in diagnostic procedures and treatment of stage III NSCLC prior to enrolment in START.

      Methods
      The START trial recruited patients (performance status 0/1) with unresectable stage III NSCLC who had not progressed within 28–84 days of completing ≥2 cycles of platinum-based chemotherapy with concurrent or sequential radiotherapy (≥50 Gy). Baseline characteristics, diagnostic procedures and the initial chemo/RT administered of those recruited were compared between centers in different regions.

      Results
      From Jan 2007 to Nov 2011, 1513 patients were recruited at >250 centers in 33 countries: Western Europe 40.3%, Eastern Europe 26.0%, North America 21.8%, Latin America 5.7%, Asia 3.4%, Australia 2.8%. The majority of patients (92.1%) were Caucasian and median age was 61 years. Overall, 6.3% of patients were never-smokers with little inter-regional variation except for Asia (31.4%). The proportion of current smokers upon entry into the trial was highest in Eastern Europe (36.3%) and lowest in Australia (11.6%). Median tobacco consumption by region ranged from 36.2 (Eastern Europe) to 53.6 (Latin America) pack-years. The proportion of patients considered for the START trial who received concurrent rather than sequential chemo/RT varied widely between regions and was highest in North America and Australia, lower in Western Europe, Latin America and Asia, and lowest in Eastern Europe. There were also substantial variations in the diagnostic procedures between the regions, although pathological confirmation of N-status was infrequent in all regions. Detailed results by region for the time from diagnosis to randomization, duration of chemo- and radiotherapy, and chemotherapy agents used will be presented.

      Proportion of patients (%) with:
      Use of concurrent chemo/RT N-status determined with PET or PET/CT N-status determined with mediastinoscopy
      Australia (n=43) 100 74.4 2.3
      North America (n=330) 92.7 37.9 18.5
      Asia (n=51) 66.7 21.5 2.0
      Latin America (n=86) 65.1 7.0 5.8
      Western Europe (n=609) 67.2 32.2 6.9
      Eastern Europe (n=394) 28.9 7.3 3.6

      Conclusion
      Baseline data from the START trial suggest substantial variations in the management of unresectable stage III NSCLC between different regions of the world. While recruited patients from North American and Australian centers mostly received concurrent chemo/RT in accordance with current recommendations, a substantial proportion of patients in Europe, Latin America and Asia received sequential chemo/RT. More frequent use of concurrent chemo/RT as the recommended standard of care should be made across geographic regions.

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      O02.02 - Tecemotide (L-BLP25) in unresectable stage III non-small cell lung cancer in the phase III START study: Further endpoint and exploratory biomarker results (ID 2779)

      P.L. Mitchell, C.A. Butts, M.A. Socinski, N. Thatcher, G. Wickart-Johansson, P.M. Ellis, O. Gladkov, J.R. Pereira, W.E.E. Eberhardt, K. Horwood, A. Szczesna, C. Helwig, A. Schröder, F.A. Shepherd

      • Abstract
      • Presentation
      • Slides

      Background
      The phase III START study evaluated the mucin 1 (MUC1) antigen-specific cancer immunotherapy tecemotide (L-BLP25) vs. placebo in patients with stage III unresectable non-small cell lung cancer (NSCLC) who did not progress following initial chemo-radiotherapy (chemo/RT). The primary objective of overall survival (OS) prolongation was not met, however, pre-defined subgroup analyses revealed a clinically meaningful prolongation of survival with tecemotide in patients previously treated with concurrent chemo/RT (p=0.016). Sensitivity analyses suggested the observed treatment effect may have been under-estimated due to a clinical hold, which resulted in a median suspension of recruitment and investigational treatment of about 4.4 months. Tecemotide was well tolerated and no safety concerns were identified.

      Methods
      From January 2007 to November 2011, 1513 patients with unresectable stage III NSCLC and stable disease or objective response following initial chemo/RT were randomized (2:1, double-blind) to subcutaneous tecemotide (806 µg lipopeptide) or placebo, weekly for 8 weeks and then 6-weekly until disease progression or withdrawal. A single dose of cyclophosphamide (300 mg/m2) or saline was given 3 days prior to first tecemotide/placebo dose. Primary endpoint, OS, and secondary endpoints progression-free-survival (PFS) and time-to-treatment-failure (TTF) used a Cox proportional hazards regression model adjusting for randomization strata. While RECIST 1.0 had to be observed for determination of disease progression, there was no formal imaging schedule to determine disease progression; this was done according to institutional practice. Exploratory analyses were done for treatment interaction for HLA-A02, -DRB4 and -B08. Baseline peripheral blood anti-nuclear antibodies (ANA), serum MUC1 (sMUC1), lymphocyte count and neutrophil:lymphocyte ratio (NLR) currently are being explored.

      Results
      The primary analysis population (N=1239) was defined prospectively to account for the clinical hold and prospectively excluded 274 patients randomized within 6 months prior to onset of the hold. Median PFS was 9.6 months with tecemotide vs. 7.7 months with placebo (HR 0.865, 95%CI 0.755–0.990, p=0.036). In keeping with OS data, tecemotide treatment effects on PFS were more pronounced in patients treated with concurrent chemo/RT (N=806; HR 0.826, 95%CI 0.696–0.980, p=0.029) vs. sequential chemo/RT (N=433; HR 0.947, 95%CI 0.756–1.187, p=0.638). Median TTF was 8.9 months with tecemotide vs. 7.2 months with placebo (HR 0.887, 95%CI 0.777–1.012, p=0.075). A prolongation of TTF with tecemotide was seen in patients with prior concurrent chemo/RT (HR 0.844, 95%CI 0.715–0.996, p=0.045), which was absent in the subgroup with prior sequential chemo/RT (HR 0.977, 95%CI 0.784–1.217, p=0.835). Detailed biomarker results will be presented.

      Conclusion
      While the primary endpoint of prolongation of OS was not met, secondary endpoints PFS and TTF support the previously-reported finding of a more favorable effect of tecemotide in patients treated with concurrent but not sequential chemo/RT. Any potential further clinical investigation of tecemotide in locally advanced NSCLC should focus on patients following concurrent chemo/RT therapy.

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      O02.03 - Value of Adding Erlotinib to Thoracic Radiation Therapy with Chemotherapy for Stage III Non-Small Cell Lung Cancer: A Prospective Phase II Study (ID 2436)

      R. Komaki, P. Allen, X. Wei, G. Blumenschein, X.M. Tang, J..L.J. Lee, J.W. Welsh, I.I. Wistuba, D.D. Liu, W.K. Hong

      • Abstract
      • Presentation
      • Slides

      Background
      The molecular basis for radiation resistance seems to involve an enhanced survival response with increased capacity for DNA repair and suppressed apoptosis. Both properties are controlled in part by upstream signal transduction pathways triggered by activation of the epidermal growth factor receptor (EGFR). Hypothesizing that the response of non-small cell lung cancer (NSCLC) to current standard chemoradiotherapy can be improved through the addition of therapy targeted to the epidermal growth factor receptor (EGFR), we undertook a single-institution phase II trial to test whether adding the EGFR tyrosine kinase inhibitor (TKI) erlotinib to concurrent chemoradiation therapy for previously untreated, locally advanced, inoperable NSCLC would improve survival and response rates without increasing toxicity.

      Methods
      Forty-eight patients with previously untreated NSCLC received radiation (63 Gy/35 fractions) on Monday‒Friday, with chemotherapy (paclitaxel 45 mg/m², carboplatin AUC=2) given every Monday and erlotinib (150 mg orally 1/d) Tuesday–Sunday for 7 weeks, followed by two cycles of consolidation paclitaxel-carboplatin. The primary endpoint was time to progression; secondary endpoints were toxicity; response, overall survival (OS), and disease control rates; and whether any endpoint differed by EGFR mutation status.

      Results
      Of 46 patients (96%) evaluable for response, 40 were former or never smokers; 23 had adenocarcinoma; and 41 were evaluable for EGFR mutations (37 wild-type [wt] and 4 mutations [all adenocarcinomas]). Median time to progression was 14.5 months and did not differ according to EGFR status. Toxicity was acceptable (no grade 5, one grade 4, and eleven grade 3). Fourteen patients (31%) had complete responses (3 mutations and 11 wt), 24 (52%) partial (20 wt and 4 unknown EGFR mutation status), and 8 (18%) had stable or progressive disease (6 wt, 1 mutation and 1 unknown EGFR mutation status); 3 patients with mutations (75%) had complete response vs. 11 wt (30%) (p=0.07 for EGFR mutation vs wt groups). For alive patients, the median follow-up was 44.7 months’ follow-up (range, 29.3–54.6 months). OS rates were 82.6% at 1 year, 67.4% at 2 years, 48.5% at 3 years, and 32.2% at 4 years and did not differ by mutation status (wt vs mutation, p=0.17). For all patients the median follow-up was 30.6 months’ follow-up (range, 3.4–54.6 months). 14 patients were free from progression and 32 had local failure, distant failure, or both. Eleven of the 27 distant failures were in the brain (7 wt, 3 mutation, 1 unknown; P=0.04); the local control rate was 75% among the 4 patients with EGFR mutations. Median time to progression was 13.6 months (95% confidence interval 10.2-20) and did not differ by EGFR status (wt vs mutation p=0.39).

      Conclusion
      Overall survival was promising, but time to progression was disappointing. Toxicity was acceptable. The prevalence of distant failures underscores the need for more effective systemic therapy, perhaps including maintenance EGFR-TKI for patients with mutated EGFR.

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      O02.04 - DISCUSSANT (ID 3945)

      E. Vokes

      • Abstract
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      Abstract not provided

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      O02.05 - Major pathologic response (≤10% viable tumor) following neoadjuvant chemotherapy as a surrogate for overall survival in patients with pathologically documented stage IIIA (N2) lung adenocarcinomas (ID 2345)

      J.E. Chaft, M.D. Hellmann, W.D. Travis, V.W. Rusch, M.G. Kris

      • Abstract
      • Presentation
      • Slides

      Background
      Neoadjuvant chemotherapy improves overall survival in patients with resectable stage IIIA lung adenocarcinomas. The gold-standard endpoint for clinical trials evaluating curative therapies is overall survival. Unfortunately, these trials take nearly a decade to complete and this prolonged timeline hinders the approval of promising therapies in the curative realm. Alternative endpoints that can act as a surrogate for overall survival have been evaluated, including nodal downstaging, nodal clearance, and pathologic response. We evaluated the degree to which these endpoints associate with overall survival in patients with pathologically proven stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy.

      Methods
      An electronic database search engine was used to identify all patients with resectable stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy at Memorial Sloan-Kettering Cancer Center between 1/2007-8/2012. Nodal downstaging was defined as no residual tumor tissue in the N2 nodes. Nodal clearance was defined as no residual tumor tissue in N1 and N2 nodes. Pathologic response was systemically assessed by a dedicated thoracic pathologist (WDT) who reviewed at least 1 section per centimeter of greatest gross tumor diameter. The percent viable tumor tissue in each slide was estimated to the nearest 10%. Major pathologic response (MPR) was defined as ≤10% viable tumor tissue. All pathologic analyses were performed by a dedicated thoracic pathologist (WDT). Patients with residual N2 disease at resection were offered post-operative radiation and routinely monitored thereafter. Survival proportions were estimated by the Kaplan-Meier method and compared using the log-rank test.

      Results
      69 patients with pathologically confirmed IIIA(N2) disease were identified and 46 (67%) ultimately underwent R0 resection. Among these patients, 16 had nodal downstaging, 14 had nodal clearance and 5 had a MPR. In both intention to treat analyses (N=69) and including only those who underwent resection, only MPR significantly associated with overall survival. The table below details findings from the population who had complete cancer resection.

      Endpoint (N=46) Yes (A) No (B) NA (C) HR (95% CI) ITT (A vs B+C) HR (95% CI) Resected(A vs B)
      Nodal downstaging 16 30 23 0.68 (0.32-1.56) 0.73 (0.24-2.10)
      Nodal clearance 14 32 23 0.57 (0.27-1.36) 0.96 (0.32-2.81)
      MPR 5 41 23 0.28 (0.1-0.78) 0.26 (0.07-0.95)
      NA = not assessable; ITT = intention to treat

      Conclusion
      MPR (≤10% viable tumor) effectively identifies patients with good clinical outcomes after neoadjuvant chemotherapy and can serve as a surrogate endpoint for overall survival. Furthermore, lack of MPR identifies a patient population at high risk of recurrence. Neither nodal downstaging nor nodal clearance effectively discriminated those with improved survival. Adaptive clinical trials designed to target those not achieving MPR are encouraged in attempt to improve the rate of cure in this disease.

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      O02.06 - Predictors of trimodality therapy use and overall survival in patients with stage III non-small cell lung cancer (NSCLC) in the National Cancer Database (ID 1736)

      M.J. Fidler, M. Liptay, P. Bonomi, D. Sher

      • Abstract
      • Presentation
      • Slides

      Background
      The optimal locoregional therapy for stage III non-small cell lung cancer is controversial, with definitive chemoradiotherapy (CRT) and trimodality therapy (chemoradiotherapy followed by surgery, TMT) serving as competing strategies. The implementation of TMT and resultant survival outcomes in routine United States clinical practice has not been closely examined. In this study, we used the National Cancer Database (NCDB) to determine predictors of TMT and compare overall survival (OS) among a large cohort of stage III NSCLC patients treated with CRT or TMT.

      Methods
      Patients included were stage III NSCLC patients who received concurrent CRT with or without subsequent surgical resection at Commission on Cancer-accredited programs between 1998 and 2010; survival data were available for patients treated through 2005. High-volume (HV) center was defined as the upper decile. Per NCDB coding, treatment centers were stratified into academic, comprehensive, and non-comprehensive community cancer center (CCC). Logistic regression was used for univariable analyses, and multivariable models were prepared using stepwise selection to determine demographic, clinical and non-clinical predictors of TMT use and overall survival. Propensity score matching was used to estimate treatment effect and to minimize the effect of confounding variables.

      Results
      The overall cohort consisted of 49,534 patients, 25,679 of whom also had available survival data. Trimodality therapy was delivered in 7.8% of patients. Multivariable clinical predictors of TMT included: white race (OR 1.36), younger age (lowest [LQ] vs highest [HQ] quartile, OR 4.31), high school education or higher (HQ vs LQ, OR 1.37), stage IIIA vs IIIB, (OR 3.02) and squamous histology (OR 1.26). Non-clinical variables associated with TMT included: early treatment era (first vs last 3 years, OR 1.30), private insurance (OR 1.53), increasing distance from the treatment center (HQ vs LQ, OR 1.81), geography (Northeast vs. other, OR 1.35), treatment at academic research programs (ARP) over comprehensive CCC or non-comprehensive CCC (OR 1.53 and 2.01, respectively), and HV institution (OR 1.26). The median, 3- and 5-year OS were 12.3 months, 17% and 9.6%, respectively. Univariable comparison between CRT and TMT showed OS benefit with TMT (median 26.1 vs 11.7 months, log rank p<0.001). On MVA, stage IIIA (hazard ratio, HR, 0.85), squamous histology (HR 0.97), young age (HR 0.74) , female gender (HR 0.86), non-white race (HR 0.90), higher income (HQ vs LQ HR 0.76), farther distance from treatment center (HR 0.93), more recent treatment era (HR 0.80 vs. first 2 time periods) and TMT (HR 0.49) were significantly associated with improved OS. ARP was significantly associated with superior OS (HR 0.92 vs. CCP) if TMT was not in the Cox model. After propensity matching, TMT was still associated with improved OS (HR 0.62, p<0.001).

      Conclusion
      The use of TMT was strongly associated with markers of higher socioeconomic status and treatment at high-volume and academic centers. These data further support a significant survival benefit in patients undergoing TMT, and treatment at academic centers may improve OS via increased use of TMT.

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      O02.07 - Is there a survival benefit in patients with stage IIIA(N2) non-small cell lung cancer under neoadjuvant chemotherapy and/or radiotherapy followed by surgery administration: a systematic review and meta-analysis (ID 2164)

      Y. Xu, B. Li, X. Xu, X. Yu, Q. Chen, W. Mao

      • Abstract
      • Presentation
      • Slides

      Background
      Optimal management of clinical stage IIIA (N2) non-small cell lung cancer (NSCLC) is controversial despite the conduct of several randomized controlled trials (RCTs). This article contributes to this problem by conducting a systematic review and meta-analysis of published RCTs.

      Methods
      A comprehensive literature search was performed in the Pubmed, Embase, Medline database (last search updated in May 2013) for relevant studies comparing patients with stage IIIA (N2)NSCLC undergoing surgery alone, chemotherapy and/or radiotherapy alone, or resection after neoadjuvant treatment with chemotherapy and/or radiotherapy. A systematic review and meta-analysis of available data were conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards.

      Results
      The comparison contained two components. In the comparison of neoadjuvant therapy followed by surgery and radical chemoradiotherapy/radiotherapy, a fine homogeneity (χ[2]=2.26, p=0.52, I[2]=0.0%) between four studies with a total of 803 selected cases was detected between the overall survival (OS), and the combined hazard ratio (HR) was 0.95 (95% confidence interval [CI]: 0.81-1.10; p=0.47). Progression-free survival (PFS) was investigated in two studies and there was also no significant difference for the combined HR was 0.90 (95% CI: 0.77-1.05; p=0.19). In the comparison of neoadjuvant chemoradiotherapy (Neo-ChRT) and neoadjuvant chemotherapy(Neo-ChT) alone, three studies with a total of 229 selected cases were detected, with the combined HR of OS and PFS 0.79 (95% CI: 0.57–1.09; p=0.15) and 0.67 (95% CI: 0.39-1.15; p=0.15) respectively, but it did not reach the statistical significance. Observing the short-term therapeutic effect, these studies revealed that Neo-ChRT had increased the rate of mediastinal pCR by 15.48% (OR: 3.61, 95%CI: 1.07–12.15; P = 0.04). Comparing the incidence of main complications and mortality, there was no significant difference between neoadjuvant therapy followed by surgery and radical chemoradiotherapy /radiotherapy alone. Neoadjuvant chemoradiotherapy followed by surgery achievered higher response rates and similar postoperative mortality as compared to neoadjuvant chemotherapy followed by operation, without adding significant adverse events.Figure 1

      Conclusion
      Neoadjuvant chemotherapy and/or radiotherapy followed by surgery is not superior to that followed by definitive radiotherapy. Neoadjuvant chemoradiotherapy dose not improve survival compared to neoadjuvant chemotherapy alone. But it can increase the rate of downstaging and mediastinal pCR which were correlated with the better PFS and OS. Neoadjuvant treatment has not increased the incidence of postoperative complication and motality. Further studies should be conducted to determine the patients who will benefit from various administrations.

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      O02.08 - DISCUSSANT (ID 3946)

      E. Vallieres

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      Abstract not provided

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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 8
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      O03.01 - GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. (ID 1715)

      S.S. Ramalingam, G. Shapiro, V. Hirsh, B. Zaric, T. Ceric, E. Poddubskaya, J. Goldman, T. Ciuleanu, F.R. Khuri, J. Spicer, O. Skrylnik, E. Felip, C. Manegold, Z. Andric, R. Rosell, S. Badovinac, T. Pieters, M.R. Modiano, V.M. Vukovic, I. Yalcin, F. Teofilovici, I. El-Hariry, W. Guo, S.R. Bahcall, G. Goss, D. Fennell

      • Abstract
      • Presentation
      • Slides

      Background
      Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).

      Methods
      We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.

      Results
      Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.

      Conclusion
      Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.

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      O03.02 - Randomized Phase-3 trial (INSPIRE) of Necitumumab plus Cisplatin-Pemetrexed versus Cisplatin-Pemetrexed Alone as First-Line Therapy in Stage IV Non-Squamous NSCLC (ID 2337)

      L. Paz-Ares, J. Mezger, T. Ciuleanu, J.R. Fischer, J. Von Pawel, M. Provencio, A. Kazarnowicz, G. Losonczy, G. Castro Jr., A. Szczesna, L. Crino, M. Reck, R. Ramlau, E. Ulsperger, C. Schumann, J.E. Miziara, A. Lessa, H. Depenbrock, V. Soldatenkova, B. Balint, F.R. Hirsch, M.A. Socinski

      • Abstract
      • Presentation
      • Slides

      Background
      Necitumumab is a human IgG1 anti-EGFR1 monoclonal antibody that competes for the binding of natural ligands to this receptor and prevents receptor activation. EGFR1 is detectable in approximately 85% of advanced NSCLC tumors. This phase 3 study investigated necitumumab in combination with first-line chemotherapy in advanced non-squamous NSCLC.

      Methods
      Patients with histologically or cytologically proven stage IV non-squamous NSCLC were randomized 1:1 to either Arm A: cisplatin 75mg/m[2] i.v.-pemetrexed 500mg/m[2] i.v. (Cis + PEM) on Day 1+ necitumumab 800mg i.v. on Days 1 and 8 of a 21-day cycle or Arm B: Cis+PEM alone. Patients received these regimens for up to six cycles. For patients in Arm A with at least stable disease, necitumumab continued until PD or intolerable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and EGFR protein expression level by immunohistochemistry (H-score) utilizing archived tumor tissue based on a mandatory tissue collection. The planned sample size of this study was 947 patients (assuming a hazard ratio [HR] of 0.8 would allow 85% power at 2-sided alpha level of 0.05). After 633 patients, enrollment was stopped (after Feb 2011) following an Independent Data Monitoring Committee (IDMC) recommendation.

      Results
      Between Nov 2009 and Feb 2011 633 patients were randomized (315 Arm A; 318 Arm B). Baseline characteristics were balanced between the arms; 67.0% were male and 33.0% female; ECOG-PS 0/1 94.2 % and PS 2 5.7 %. No difference between treatment arms was observed for OS (median 11.3 vs 11.5 months; HR 1.01 95%-CI [0.84, 1.21]), PFS (median 5.6 vs 5.6 months, HR 0.96 95%-CI [0.80, 1.16]) and ORR (31.1 vs 32.1%; Odds ratio 0.96 95%-CI [0.68, 1.34]). The exploratory analysis in 490 patients assessable for H-score revealed no association between H-score and differences in efficacy between treatment arms (H-score < 200: mOS 8.97 vs 9.72 months, HR 1.07, mPFS 4.90 vs 4.76 months, HR 0.95, ORR 27.1 vs 26.0%; H-score ≥ 200: mOS 15.01 vs 13.34 months, HR 1.03, mPFS 5.59 vs 5.62 months, HR 0.94, ORR 39.6 vs 39.4%). Grade ≥ 3 treatment-emergent adverse events (AEs) occurring more frequently in Arm A included skin or subcutaneous disorders (14.1 vs 0.3%), thromboembolic events (9.5 vs 6.4%), hypomagnesaemia (7.6 vs 2.2%), asthenia (6.9 vs 1.9%), vomiting (6.6 vs 3.2%), dyspnea (5.3 vs 2.6%) and diarrhea (4.3 vs 2.2%). The frequency of study drug related deaths was 4.9% and 2.9% in Arms A and B, respectively.

      Conclusion
      In this study, the addition of necitumumab did not improve the efficacy outcome over cisplatin plus pemetrexed alone in advanced non-squamous-NSCLC. The EGFR H-score did not seem to predict the efficacy outcomes of necitumumab in combination with cisplatin plus pemetrexed. The addition of necitumumab resulted in a higher frequency of grade ≥ 3 AE (skin reaction, GI, asthenia and other) and an imbalance of grade ≥ 3 thromboembolic events. Further biomarker studies are ongoing.

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      O03.03 - Outcomes of NSCLC patients on Phase I Trials: The Importance of Molecular and Patient Selection (ID 3349)

      D.S. Tan, W. Ong, A. Ahmad, D.W. Tai, M. Ang, Q. Ng, R. Kanesevaran, S. Choo, M.C. Ng, E. Tan, W. Lim

      • Abstract
      • Presentation
      • Slides

      Background
      With recent successes of targeted therapeutics, there has been increased enthusiasm to enroll patients with NSCLC into phase I trials. Most phase I prognostic indices have been derived from patient populations where NSCLC is underrepresented.

      Methods
      Retrospective review of NSCLC patients enrolled between 2005-2012 at National Cancer Centre Singapore was performed, collating data on demographics, molecular profiles, trial characteristics and clinical outcomes (using RECIST criteria) to identify prognostic factors to improve patient selection.

      Results
      167 patients were treated on 20 phase I trials. Median (range) age 60.7 years (22.7–84.7), 58% male, adenocarcinoma/squamous/NOS/others (75.4%/9.6%/12.6%/2.4%). 13% were at high risk of nutritional deficiency (BMI<18.5), and ECOG 0(21%)/1(77%)/2(2.4%). Median (range) prior chemotherapy was 2 (0-6) and 99% received at least one treatment line. Class of agents include anti-angiogenics (50.3%), signal transduction pathway inhibitors (STPi) 46%. Only 4.2% received cytotoxics alone. 86.2% were on combination regimens, of which two-thirds on combinations of chemotherapy and small molecule. Between 2008-2012, proportion of patient tumors with molecular alterations identified increased from 5.5% to 62.5%, facilitating enrolment into trials designed for a specific genotype (or “matched” trials). 35% and 7.8% of patients participated on trials targeting EGFR and ALK alterations respectively. With a median follow up of 8.7 months, progression free survival was 3.9m (95%CI:3.4–5.8), overall survival (OS) 10.4m (95%CI:8.0–11.7). Among evaluable patients, 24.8% (95%CI:18.2–32.5) had complete/partial response; clinical benefit rate (CBR) 75.8% (95%CI:68.2–82.4). 90-day mortality (90DM) was 15%. Patients participating in “matched” trials had a lower risk of death (HR 0.55 [95%CI:0.38-0.78] p<0.001) compared to those on unselected or “unmatched” trials (median OS 11.9 v 7.6). On univariate analysis, low BMI<18.5, ECOG>0, ≥3 metastatic sites, presence of bone metastasis, low albumin (<35), low Hb (<12), ≥ 3 prior lines of chemotherapy and non-participation in a "matched" trial were significant negative prognostic factors for OS. On multivariate analysis, ECOG, number of metastatic sites, albumin and trial type (targeting EGFR/ALK/others), emerged as independent variables. These factors were used to construct a prognostic nomogram to predict OS at 3, 6 and 12m. Of 12 published prognostic indices, 8 models were validated in our patient cohort, with the highest c-index being 0.66. Pairwise comparison against these 8 (7 tumor agnostic; 1 NSCLC) prognostic indices, found the nomogram to be superior in predicting OS, with a c-index of 0.74.

      Conclusion
      This is the largest analysis of phase I NSCLC patients using individual patient data. Outcome of NSCLC patients in phase I trials is promising with CBR 76% and median OS 10.8m. Our nomogram – comprising of ECOG, albumin, number of metastatic sites, participation in a “matched” trial – is uniquely derived from NSCLC patients and was a better predictor of OS compared to 8 published phase I prognostic scores.

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      O03.04 - DISCUSSANT (ID 3949)

      B. Besse

      • Abstract
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      Abstract not provided

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      O03.05 - Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: Findings from three trials of afatinib in EGFR mutation-positive lung cancer (ID 1114)

      J.C. Yang, L.V. Sequist, S.L. Geater, C. Tsai, T.S.K. Mok, M. Schuler, N. Yamamoto, D. Massey, V. Zazulina, Y. Wu

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), approximately 10% of EGFR mutation-positive tumours harbour uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18–21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Here we present the first prospective data series on activity of afatinib, the irreversible ErbB Family Blocker, in patients with tumours harbouring uncommon EGFR mutations.

      Methods
      This analysis is based on data from EGFR mutation-positive patients included in the LUX-Lung 2 (Phase II), LUX-Lung 3 and LUX-Lung 6 (both Phase III) studies. EGFR mutations were identified prospectively by direct sequencing in LUX-Lung 2 and by central testing with TheraScreen EGFR RGQ PCR kit (TheraScreen29) in LUX-Lung 3 and 6. Patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Uncommon mutations were categorized into three groups: de novo T790M (alone or in combination with other mutations); exon 20 insertions; and other. Objective response rate (ORR), disease control (DCR), duration of response and progression-free survival (PFS) were assessed by independent review.

      Results
      Seventy-five patients (LUX-Lung 2: n=23; LUX-Lung 3: n=26; and LUX-Lung 6: n=26) had uncommon mutations, accounting for 12.5% of all afatinib patients in these studies. The majority of patients received afatinib first line; 13 patients from LUX-Lung 2 received afatinib after chemotherapy. Breakdown into the three groups was T790M: n=14; Exon 20 insertions: n=23; other: n=38 (most frequent types were L861Q: n=12; G719X: n=8; G719X+S768I: n= 5; G719X+L861Q: n=3). Efficacy results for each group are shown below. Further details by mutation status will be presented.

      Mutation ORR, % (n=) Median duration of response, months (95% confidence interval) DCR (ORR + stable disease), % (n) Median PFS, months (95% confidence interval) Median survival, months (95% confidence interval)
      De novo T790M alone or in combination with other mutations (n=14) 14.3 (2) Individual response durations: 4.1, 12.4 64.2 (9) 2.9 (1.2−8.3) 14.9 (8.1−24.9)
      Exon 20 insertions (n=23) 8.7 (2) Individual response durations: 4.2, 10.1 65.2 (15) 2.7 (1.8−4.2) 9.4 (4.1−21.0)
      Other (n=38) 71.1 (27) 11.1 (4.1, 15.2) 84.2 (32) 10.7 (5.6−14.7) 18.6 (16.4−not estimable)

      Conclusion
      Afatinib was active in lung tumours harbouring uncommon EGFR mutations, such as G719X, L861Q, S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in these trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients. To date this is the largest analysis of data for prospectively identified patients with uncommon EGFR mutations; treatment options in this heterogeneous group of tumours will be discussed.

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      O03.06 - First-In-Human Evaluation of CO-1686, an Irreversible, Highly, Selective Tyrosine Kinase Inhibitor of Mutations of EGFR (Activating and T790M) (ID 1354)

      J. Soria, L.V. Sequist, S. Gadgeel, J. Goldman, H. Wakelee, A. Varga, P. Fidias, A.J. Wozniak, J.W. Neal, R.C. Doebele, E.B. Garon, S. Jaw-Tsai, L. Caunt, P. Kaur, L. Rolfe, A. Allen, D..R. Camidge

      • Abstract
      • Presentation
      • Slides

      Background
      Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest greatest efficacy when plasma concentrations exceed 200ng/ml for >16hrs/day.

      Methods
      This is an ongoing first-in-human dose finding study (3+3) of oral CO-1686 administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. All patients must undergo tumor tissue biopsy within 28 days before study drug dosing for central EGFR genotyping. Endpoints include safety, pharmacokinetics (PK), and efficacy.

      Results
      As of 12 June 2013, 45 patients have been treated with CO-1686. 31/42 (74%) were T790M+; data for three patients is pending. The median age is 58 years, 82% are female, 75% are white, and 73% ECOG 1. The median number of previous therapies was 4 (range: 1- 6), with a median of 1 (range: 1- 4) previous EGFR TKI therapies. Dosing started at 150mg QD and escalated to 900mg QD, 900mg BID and 400mg TID, with a maximum tolerated dose not yet reached. Treatment-related AEs (all grades) occurring in > 5% patients were: fatigue (19%), diarrhea (15%), nausea (14%), anemia (10%), arthralgia (7%), muscle spasms (10%), myalgia (7%), headache (7%). The majority of events were mild or moderate. Unlike other EGFR inhibitors, rash and diarrhea were not commonly seen. This AE profile is consistent with the expected lack of wild type EGFR inhibition with CO-1686. The PFS for T790M+ patients with CO-1686 plasma concentrations > 200ng/mL for > 16 hours was 194 days compared with 72.5 days for those that achieved these concentrations for < 16 hours (Figure 1). At the highest evaluated dose, 900mg BID, four T790M+ patients were evaluable for response; 3 of the 4 achieved PRs, one achieved SD. One patient at a lower dose cohort also achieved a PR. Further safety and efficacy data will be presented at the meeting. Figure 1

      Conclusion
      CO-1686 has demonstrated good tolerability and efficacy against proven T790M+ EGFR mutant NSCLC with a strong suggestion of a dose-response relationship. Additional evaluation of the optimal dose and formulation of CO-1686 are underway to further explore its potential for improved activity and better tolerability over other existing EGFR TKIs.

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      O03.07 - Investigation of risk factors for developing interstitial lung disease (ILD) and poor prognostic factors for ILD death in Japanese patients with non-small-cell lung cancer (NSCLC): a final analysis of a large-scale erlotinib surveillance study (POLARSTAR) (ID 2208)

      K. Kuwano, S. Kudoh, M. Ando, Y. Ohe, K. Nakagawa, N. Yamazaki, H. Arakawa, Y. Inoue, M. Ebina, M. Kusumoto, A. Gemma, F. Sakai, T. Johkoh, H. Taniguchi, Y. Fukuda, A. Seki, M. Fukuoka

      • Abstract
      • Presentation
      • Slides

      Background
      A large-scale surveillance study (POLARSTAR) was implemented to investigate erlotinib safety and efficacy in Japanese patients, focusing on the pattern of occurrence of interstitial lung disease (ILD) and specific factors that may contribute to the onset of ILD in patients receiving erlotinib. The following risk factors for erlotinib-induced ILD have been previously reported: concurrent/previous ILD (adjusted hazard ratio [HR] =3.2), existing emphysema/chronic obstructive pulmonary disease (COPD) (HR=1.9) or lung infection (HR=1.6), smoking status (HR=2.2) and ECOG performance status 2–4 (HR=1.4). These were identified as the primary risk factors for ILD by multivariate analysis. The current analysis was carried out to identify factors linked with poor prognosis in terms of ILD-related death within the POLARSTAR surveillance study.

      Methods
      Enrolment of all patients in Japan receiving erlotinib for NSCLC took place between December 2007 and October 2009; the observation period was 12 months. All ILD-like events were assessed by an independent ILD review committee. ILD was defined as all ILD-like events excluding those events deemed non-ILD by the independent ILD review committee. Risk factors for poor prognosis concerning ILD death were analyzed by multivariate analysis using a logistic regression model.

      Results
      A total of 10,708 patients were enrolled by the data cut-off of 12 October 2009, with data available for 9,909 patients. The majority of ILD cases were reported within 4 weeks of receiving erlotinib. Among the 491 patients who experienced ‘ILD-like’ events, 93 could not be evaluated by the independent ILD review committee due to lack of imaging data; the remaining 398 patients were referred to the committee for evaluation. A total of 310 patients had confirmed ILD by the ILD review committee, based on image evaluation or clinical investigation; 125 had died as a result of ILD. These patients were assessed by multivariate analysis. Sixty-two events were deemed non-ILD and 26 events could not be evaluated due to a lack of clear clinical evidence (e.g. ILD could not be distinguished from progression or pneumonitis, or insufficient imaging data were available). The multivariate analysis identified ECOG performance status 2–4 (adjusted odds ratio [OR] =2.45 [95% CI 1.41–4.27]; p=0.0016), <50% remaining normal lung area (OR=3.12 [1.48–6.58]; p=0.0029) and interstitial pneumonia with concomitant honeycomb lung (OR=6.67 [1.35–32.94]; p=0.02) as poor prognostic factors for ILD death. However, pre-existing interstitial pneumonia by grade of severity was not identified as one of these factors. This result could be attributed to practical bias in this surveillance study, such as selection or treatment bias for patients with pre-existing interstitial pneumonia within the condition of careful dosage specified in the erlotinib label.

      Conclusion
      These final data from this large surveillance study in Japanese patients with recurrent and advanced NSCLC provide further information on the risk factors for poor prognosis with ILD, identifying those patients at greatest risk of ILD-related death. Improved awareness of these prognostic factors will help clinicians in monitoring those patients at highest risk.

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      O03.08 - DISCUSSANT (ID 3950)

      F. Cappuzzo

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      Abstract not provided

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    O04 - Molecular Pathology I (ID 126)

    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 8
      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma (AD) of patients who have never smoked frequently bear targetable genome kinase alterations, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These mutations correlate with kinase inhibitor sensitivity in mouse models or in patients. Unfortunately, therapeutically relevant kinase alterations are not present in all lung cancer specimens. Thus, additional genome alterations need to be discovered in order to provide a therapeutic opportunity for the remaining patients.

      Methods
      We collected a cohort of 25 AD specimens of never smokers lacking mutations in KRAS or EGFR, in which we performed transcriptome sequencing with the aim of identifying new oncogenic driver genes.

      Results
      We were able to identify known kinase fusions affecting ALK, ROS1 and RET genes in 3 cases each. Moreover, we detected one sample carrying a novel chimeric transcript fusing the first six exons of CD74 to the EGF-like domain of the NRG1 III-β3 isoform, leading to the expression of its EGF-like domain in an otherwise NRG1-negative tumor tissue. The fusion gene was further detected in four additional cases out of 94 pan-negative* ADs of never smokers. In total, all 5 cases were identified in stage I invasive mucinous lung adenocarcinomas (IMA) of never smoker females. This tumor type frequently presents with multifocal unresectable disease, for which no effective treatment has been yet established. IMA is highly associated with KRAS mutations; indeed, out of 15 IMA analysed, 6 carried a KRAS mutation (40%), and 4 the CD74-NRG1 fusion (27%). Given the fact that NRG1 signals through ERBB3 and ERBB4 receptors, we aimed to determine which receptor CD74-NRG1 provides the ligand for. We observed that ERBB4 was not expressed in the index case, while ERBB3 was relatively highly expressed and this expression also correlated with a positive phospho-ERBB3 (p-ERBB3) signal in the tumoral tissue of all 5 CD74-NRG1 positive cases. In order to test if this phosphorylation of ERBB3 was statistically significant, we stained a cohort of 241 ADs and found that p-ERBB3 was only positive in 6 of them (p-value<0.0001). Additionally, although both EGFR and ERBB2 were expressed in the index case, only ERBB2 expression correlated with a p-ERBB2 positive signal. These data suggest that CD74-NRG1 might provide the ligand for ERBB3, which may form heterodimers with ERBB2, since ERBB3 is devoid of intrinsic kinase activity and cannot support linear signaling in isolation. This is in line with previous studies showing that NRG1 induces an oncogenic signal through ERBB2-ERBB3 heterodimers engaging the PI3K-AKT pathway. This was further supported by the activation of the PI3K-AKT, but not the MAPK pathway, in CD74-NRG1 transduced H2052 lung cells, after 24h starvation. *pan-negative: EGFR, KRAS, ALK, HER2, BRAF, ROS1 and RET wild-type

      Conclusion
      Altogether, these data shows that CD74-NRG1 is a new recurrent oncogenic fusion gene, highly associated with IMA of never smokers. It also suggests that CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptors complex leading to the activation of the PI3K-AKT pathway, providing a therapeutic opportunity for a tumor type with, so far, no effective treatment.

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      O04.02 - Using NGS for Mutational Profiling of NSCLC in the Clinical Setting (ID 2571)

      S. Roy Chowdhuri, M. Routbort, K. Patel, R. Singh, R. Broaddus, A. Lazar, K. Aldape, R. Luthra, I.I. Wistuba, G.R. Simon

      • Abstract
      • Presentation
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      Background
      Recent advances in molecular characterization of lung cancer have led to the identification of potential therapeutic targets that play key roles in regulating cell growth and proliferation. With the introduction of new targeted therapies, it becomes increasingly important to accurately characterize mutation status in lung cancer patients to provide personalized care that define prognosis and predict response to therapy. The advent of next generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics has made multi-gene mutational profiling an affordable and highly successful methodology for massively parallel sequencing using small quantities of DNA.

      Methods
      Tumor specimens from 262 distinct samples of primary lung carcinoma including adenocarcinoma (n=228), squamous cell carcinoma (n=15), non small cell cancer not otherwise specified (NSC-NOS) (n=8), poorly differentiated carcinoma (n=4), neuroendocrine carcinoma (n=2), small cell carcinoma (n=1) and pleomorphic carcinoma (n=4) were tested by NGS. Tumor samples included formalin-fixed paraffin-embedded surgical core needle biopsies, resection specimens, cytopathology cell blocks, as well as cytopathology direct smears. Ten ng of DNA from each sample was tested for mutations in hotspot regions of 46 cancer related genes (Ion AmpliSeq Cancer Panel) using either a 316 chip or a 318 chip on an Ion Torrent Personal Genome Machine (PGM) Sequencer (Life Technologies, CA).

      Results
      Mutations were detected in 222/240 (93%) patients with a histologic diagnosis of adenocarcinoma, NSC-NOS or PDC. EGFR mutations were detected in 47 (20%) of these patients and double EGFR mutations identified in 13 cases, including acquired resistance mutations T790M (n=6) and S768I (n=3). KRAS mutations were detected in 61 (25%) cases, most commonly involving codons 12 and 13 (n= 58) and less frequently involving codons 61 and 146 (n= 3). TP53 was most frequently mutated (n=65; 27%) and was often seen in conjunction with EGFR mutations (n=14; 5%) and KRAS mutations (n=15; 6%). Mutations were detected in 10/15 (67%) squamous cell carcinomas with mutations in TP53 (n=5), CDKN2A (n=3) and PIK3CA (n=2) most frequently seen. Additional mutations detected at a lower frequency from the entire dataset were STK11, ATM, BRAF, PIK3CA, CTNNB1, IDH1, NRAS, CDKN2A, KDR, RET, MET, FBXW7, APC, RB1, FLT3, GNAS, ABL1, HRAS, PTPN11, JAK3, NOTCH1, SMAD4, SMARCB1, SMO, MLH1, AKT1, and ERBB4.

      Conclusion
      In summary, our results show that NGS-based mutational profiling using small amounts of DNA derived from FFPE as well as cytology smears can provide important information regarding mutation status of genes that play key roles in growth and progression of tumor in lung cancer patients and can provide insight into directing personalized cancer therapy.

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      O04.03 - Oncogene Mutations and Novel Transcript Fusions in Lung Adenocarcinoma from Never Smokers (ID 2939)

      J. Jen, J.S. Jang, A. Lee, J. Li, Y. Asmann, M. Erickson-Johnson, A.O. Bungum, V. Simon, E.S. Edell, K.J. Kopp, B. Eckloff, A. Oliveira, E. Wieben, M.C. Aubry, E. Yi, D.A. Wigle, P. Yang, R.B. Diasio

      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma from never smoker represents a unique disease entity in that they often involve females of younger age and have a distinct mutation spectrum compared to those of smoker population. Mutations from the tumors of these patients often involve oncogenes that can be targeted for therapy by small molecule kinase inhibitors. We surveyed for tumor specific genetic changes in lung adenocarcinomas from never smokers for common oncogene mutations and transcript fusions.

      Methods
      We first developed a multiplex assay detecting187 mutations in 10 actionable oncogenes frequently affected in lung cancer. We used this assay to examine 89 lung adenocarcinomas from never smokers identified through the Mayo Clinic Epidemiology and Genetics of Lung Cancer Program. NextGen sequencing (RNASeq) was used to identify transcript fusions affecting either a known kinase or an oncogene in 20 of 89 tumors. RT-PCR, FISH and IHC were used to verify the novel fusion identified in this study.

      Results
      Sixty-four tumors had mutation in at least one of the tested oncogenes involving EGFR (49 cases, 55%), k-RAS (5 cases, 6%), MET (9 cases, 10%), BRAF (4 cases, 5%), PIK3CA (2 cases, 2%), and ERBB2 (4 cases, 5%). RNAseq identified five transcript fusions among the 20 tested tumors, involving known fusions of EZR- ROS1 or KIF5B-RET and three novel fusions involving SND1-BRAF, EML4-BIRC6, and GMEB2-TERT genes. We used RT-PCR to confirm the presence of the SND1-BRAF fusion transcript that involved exons 1-9 of SND1 with exon 2 to 3’ end of the BRAF on chromosome 7. Screening all 89 tumors by RT-PCR identified a total of three tumors with the identical fusion. Interestingly, two of these three tumors with a BRAF fusion also had a concurrent mutation in EGFR gene (S768I) and a third tumor had an additional mutation in the ERBB2 gene (M774_A775ins). Four additional samples were positive for EML4-ALK fusion by IHC and FISH.

      Conclusion
      In our study of a primarily Caucasian population, a majority of lung adenocarcinomas from never smokers (70/89, or 78.6%) carry at least one genetic mutation in a targetable gene. For the first time, we report the presence of a transcript fusion involving SND1-BRAF in lung adenocarcinoma and that these fusions are present in tumors also having EGFR or ERBB2 mutations. Combined together, activation of BRAF by either point mutation or transcript fusion is one of the most frequent events in our study accounting for 7/89 (8%) cases. These findings support a rapid and targeted gene mutation testing strategy for lung adenocarcinoma from never smokers, as the knowledge of these mutations can be readily used to augment therapeutic management.

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      O04.04 - DISCUSSANT (ID 3982)

      I.I. Wistuba

      • Abstract
      • Presentation
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      Abstract not provided

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      O04.05 - Epidemiology of PI3K pathway alterations in patients with metastatic non-small cell lung cancer (NSCLC): findings from the international BASALT-1 study (ID 1810)

      G.K. Dy, J. Vansteenkiste, M. Thomas, T. De Pas, F. Grossi, J. De Grève, E. Felip, J. Canon, J. Gray, F. De Braud, M. Reck, S. Thongprasert, D. Planchard, C. Gridelli, P. Roussou, M. Gurnani, G. Atalla, D.W. Sternberg, J.A. Engelman

      • Abstract
      • Presentation
      • Slides

      Background
      Buparlisib (BKM120) is an oral PI3K inhibitor that inhibits all four isoforms of class I PI3K (α, β, γ, δ) and has demonstrated antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. NSCLC cell lines with PIK3CA mutations (muts) have demonstrated increased sensitivity to buparlisib in vitro. BASALT-1 – an ongoing, multicenter, open-label, two-stage Phase ll study (NCT01297491) – evaluates the safety and efficacy of single-agent buparlisib in patients (pts) with NSCLC and an activated PI3K pathway. Here we report data on the prevalence of PI3K pathway alterations in pts with squamous (sq) or non-squamous (non-sq) NSCLC prescreened for entry into BASALT-1.

      Methods
      Pts prescreened for BASALT-1 were ≥18 years of age with previously treated metastatic NSCLC of sq or non-sq histology. PI3K pathway activation (defined as PIK3CA mut and/or PTEN mut and/or PTEN negative [neg; <10% protein expression at 1+ by immunohistochemistry]) was measured in archival or newly acquired tumor tissue collected at prescreening. PIK3CA (exons 1, 5, 7, 9, and 20) and PTEN (exons 1–9) muts were detected primarily using Sanger sequencing in a centralized fashion. Local analysis was permitted at selected sites where a SnapShot approach was most commonly used.

      Results
      As of April 10, 2013, 1183 pts had submitted tumor samples to be assayed (1179 tumors had known histology). PI3K pathway activation was detected in 16.0% of sq and 11.3% of non-sq tumors. In sq tumors (N=612), loss of PTEN protein expression (8.2%) was the most common single alteration observed, followed by PIK3CA mut only (3.1%) and PTEN mut only (2.9%). In non-sq tumors (N=567), PTEN mut only was the most common alteration (4.9%), followed by PIK3CA mut only (2.6%) and PTEN neg only (2.1%). Frequencies of co-existing genetic alterations were: PTEN mut + PTEN neg only (1.0% sq vs 0.4% non-sq), PIK3CA mut + PTEN neg only (0.7% sq vs 0.4% non-sq), PIK3CA mut + PTEN mut only (0% sq vs 0.9% non-sq), and PIK3CA mut + PTEN mut + PTEN neg (0.2% sq vs 0% non-sq). No clear gender, age or ethnicity effects were observed (Table). Figure 1

      Conclusion
      The findings from our large dataset indicate that genetic alterations in the PI3K pathway occur in a clinically significant proportion of pts with sq and non-sq relapsed NSCLC. An accurate characterization of PI3K pathway alteration frequencies in NSCLC will help guide the design of future clinical trials of PI3K inhibitors.

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      O04.06 - An international standardization study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators (ID 2875)

      M.W. Wynes, M. Dietel, E. Schuuring, L.M. Sholl, M. Tsao, Y. Yatabe, R.R. Tubbs, F. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background
      The goal of personalized medicine is treating patients with a therapy predicted to be efficacious based on the molecular characteristics of the tumor, thereby sparing the patient futile or detrimental therapy. Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK positive non-small cell lung cancer (NSCLC) tumors, but to date the only US Food and Drug Administration approved companion diagnostic is a break-apart fluorescence in situ hybridization (FISH) assay. Immunohistochemistry (IHC) is a clinically applicable cost-effective test that is sensitive and specific for ALK protein expression. The purpose of this study was to assemble an international team of expert pathologists to evaluate and standardize the interpretation of a new automated standardized ALK IHC assay.

      Methods
      Archival NSCLC tumor specimens (n=103) previously tested for ALK rearrangement by FISH were provided by the international collaborators. These specimens were stained by IHC with the anti-ALK (D5F3) primary antibody (Ventana Medical Systems, Inc) combined with OptiView DAB IHC detection and OptiView amplification (Ventana Medical Systems, Inc). The evaluators went through an interpretation training session and scored the specimens as positive, if strong granular cytoplasmic brown staining was present in tumor cells, or negative. IHC results were compared to the FISH results and inter-evaluator agreement comparisons made.

      Results
      Overall for the 100 evaluable cases the ALK IHC assay was highly sensitive (90%), specific (95%) and accurate (93%) relative to the ALK FISH results. Similar results were observed using a majority score. For the discrepant cases IHC negativity was scored by 7/7 on 3 FISH positive cases and 6/7 evaluators on 2 additional FISH positive cases. IHC positivity was scored on 2 FISH negative cases by 7/7 readers. There was agreement among 7/7 and 6/7 readers on 88% and 96%% of the cases before a consensus review, respectively, and following a review there was agreement among 7/7 and 6/7 on 95% and 97% of the cases, respectively.

      Conclusion
      Based on expert evaluation the ALK IHC assay using the D5F3 antibody combined with Optiview Detction and Optiview amplification is sensitive, specific and accurate, relative to FISH, and a majority score of multiple readers does not improve these results over an individual reader’s score. Excellent inter-reader agreement was observed for the IHC assay. These data support the algorithmic use of ALK IHC as a screening procedure for ALK protein expression in NSCLC.

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      O04.07 - Distinguish synchronous multiple primary lung cancers from intrapulmonary metastasis by genome sequencing (ID 3193)

      Y. Liu, L. Li, G. Yin, D. Lin, X. Liu, Y. Gao

      • Abstract
      • Presentation
      • Slides

      Background
      Owing to use of high-resolution computed tomography (CT) scan for lung cancers, small nodules could be detected, so that more patients are identified carrying more than one lesion in lung synchronously at the time of diagnosis. Under this circumstance, precisely distinguish multiple primary lung cancers from intrapulmonary metastasis has important significance on clinical staging and appropriate therapy design.

      Methods
      We comprehensively compared genomic aberration profiles of each tumor in the patients with multifocal pulmonary lesions, assuming that metastasis shared a certain portion of genetic aberrations with the lesion it was originated. Therefore, whole-genome/exome sequencing were applied on 15 intrapulmonary tumors that had highly similar histological diagnosis, and 1 lymph node metastasis derived from six patients with synchronous multifocal lung cancers. The somatic nucleotide variations (SNVs) detected by whole-genome/exome sequencing were validated by either mass spectrometry or the Sanger sequencing.

      Results
      A total of 344 non-synonymous somatic point mutations were detected in whole genome sequencing analysis (3 lesions and 1 lymph node metastasis in 1 patient), corresponding to 306 unique mutation sites. Among the 70 mutations detected in the lymph node metastasis, 36 (51.4%) were also found in lesion 1 of the 3 intrapulmonary lesions, whereas no shared mutation were detected between the metastasis and either of the other two lesions. Meanwhile, there was only 1 common mutation between lesion 2 and 3, while no shared mutations were observed between lesion 1 and 2 or lesion 1 and 3. These results suggested that the metastasis was originated from lesion 1 and the 3 lesions were independent primary tumors. In whole exome sequencing analysis (12 lesions from 5 patient), among the 389 somatic non-synonymous mutations detected, we observed a similarity between each pair of tumors within one patient ranged from 0% to 5.3%, suggesting that all the lesions were independent primary tumors rather than intrapulmonary metastasis. We also reached a same conclusion when we included all somatic mutations found across the genome/exome in the analysis. These genomic abnormality profile-based diagnosis were consistent with the diagnosis based on histological examination except one lesion in patient 5, which had been considered as an intrapulmonary metastasis by histological judgment. At the same time, EGFR or KRAS mutations, which are therapy targets for adenocarcinoma in lung were detected in 7 or 3 out of the 15 tumors in 3 or 2 patients, respectively. Heterogeneity was also observed in mutation status of these two genes among different lesions in a single patient.

      Conclusion
      Comprehensive genomic aberration profiling is powerful for identification of multiple primary lung cancers. The lymph node metastasis in the study stands as a positive control, compared with which we could tell that lesions from multifocal primary lung cancers shared too few somatic mutations to be intrapulmonary metastasis. Considering the heterogeneous mutation status of EGFR or KRAS among different tumors derived from a single patient with multifocal primary lung cancer, molecular diagnosis should be taken for each accessible lesion when targeted adjuvant therapy is under consideration.

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      O04.08 - DISCUSSANT (ID 3983)

      S. Dacic

      • Abstract
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      Abstract not provided

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    O05 - Cancer Control (ID 130)

    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 8
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      O05.01 - The DANTE trial, a randomized study of lung cancer screening with spiral CT: 7-year results (ID 1428)

      M.V. Infante, S. Cavuto, F.R. Lutman, E. Passera, G. Chiesa, G. Brambilla, E. Angeli, M. Chiarenza, G. Aranzulla, M. Andresi, V. Errico, E. Bottoni, E. Voulaz, A. Santoro, M. Alloisio

      • Abstract
      • Presentation
      • Slides

      Background
      The purpose of this study was to explore the effect of screening with spiral CT on lung cancer mortality in comparison with no screening in a high-risk population. Secondary endpoints were incidence, stage and resectability.

      Methods
      Male subjects, aged 60-75, smokers of 20+ pack-years were randomized to screening with low-dose spiral CT or control. Prospective participants were pre-assessed for eligibility and randomized during a telephone interview, while formal enrolment took place at a later date. All enrolled participants underwent a structured medical interview and physical examination, a baseline, once-only chest X-ray (CXR) and sputum cytology examination. Screening-arm subjects had a LDCT upon accrual, which was repeated every year for four additional years (5 rounds), while controls had a yearly clinical review only, with further testing only if needed.

      Results
      Between March 2001 and February 2006, 2811 subjects were pre-assessed and randomized (CT arm: 1403, control arm:1408). 20 cases of double registration and two test records have been identified in the database, and 2540 subjects actually appeared for assessment (1229 CTR arm, 1299 CT arm), of whom 2450 (1264 CT arm and 1186 Controls) were eligible and enrolled. The two study groups are comparable for age, smoking exposure, and comorbid conditions. As per inclusion criteria, all subjects are males and 99.8 % are 60 or older. As of December 2012, median follow-up was 73.1 months in the control arm and 75.5 months in the screening arm. Altogether, 152 patients were detected during active follow-up with 161 lung cancers: 92 CT-arm subjects (7.27%) versus 60 controls (5.05%), p< 0,0237. 82% of CT-arm lung cancers were detected at scheduled CT examinations, and 55% were stage I disease at the time of diagnosis compared with 27% in the Control arm. The absolute number of lung cancer cases with stage II-IV disease was virtually the same as in the control arm. Resectability rate was similar in the two groups. After linkage with population registries, vital status information is now available for 2528 subjects (99.5%). Overall, 370 subjects have died, for 104 of whom we are currently investigating mortality causes.

      Conclusion
      While the number of participants is relatively small, smoking exposure and average age of participants are higher than in similar trials. A comparatively high number of events has been observed. To date, 28% of such events cannot yet be attributed to a specific cause. Health registry data necessary to complete mortality comparisons is expected to become available in the next few weeks. Merging of all European trials may yield robust data about this strategy in the future.

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      O05.02 - Local, Surrounding and Global Features for Improved Computer Aided Diagnosis of Lung Cancer (ID 318)

      J.C. Sieren, S. Dilger

      • Abstract
      • Presentation
      • Slides

      Background
      The National Lung Screening Trial reported a 20% reduction in lung cancer mortality achieved through low dose computed tomography (CT) screening of the at risk population, compared to screening with chest x-ray. Challenges with clinical implementation of CT screening for lung cancer include the high number of lesions detected that require further follow-up, approximately 97% of which are ultimately diagnosed as benign. A computer-aided diagnosis (CAD) tool can be designed to determine the probability of malignancy of a lung nodule based on objective measurements. While current CAD tools examine the pulmonary nodule’s shape, density, and border, analyzing the lung parenchyma surrounding the nodule is an area that has been minimally explored. By quantifying characteristics, or features, of the surrounding tissue, this study explores the hypothesis that textural differences in both the nodule and surrounding parenchyma exist between malignant and benign cases, which can be utilized to improve CAD performance.

      Methods
      From CT data, several novel feature extraction techniques were developed, including a three-dimensional application of Laws’ Texture Energy Measures to quantify the textures of the parenchyma as well as the nodule. In addition, the densities of the nodule and parenchyma were summarized through metrics such as mean, variance, and entropy of the intensities. The margins of the nodule were characterized following ray casting and rubber-band straightening to analyze mean and variance of border irregularity. Basic demographics and risk factor data were also included. The large feature set was reduced by statistical testing and stepwise forward selection to a few independent features that best summarize the dataset. A neural network was used to classify the cases in a leave-one-out method.

      Results
      To illustrate proof of concept, the CAD tool was applied to 27 lung nodule cases: 10 malignant and 17 benign. These data were diverse with regards to data acquisition protocol, reconstruction kernel and slice thickness – all of which can pose challenges to CAD. Through statistical testing, 36 features were found to be significant predictors of malignancy (p < 0.05), including many textural and parenchymal features. Two of these significant features, selected through stepwise forward selection, were utilized to classify the data: nodule variance (p = 0.0003) and parenchyma median intensity (p = 0.0028). CAD performance achieved a sensitivity of 90%, specificity of 100%, and an accuracy of 96.3%.

      Conclusion
      Preliminary findings indicate features from both the nodule and the surrounding parenchyma have value in distinguishing benign and malignant lesions. This is particularly valuable in the analysis of early detected, small pulmonary lesions (<10mm). In these small lesions, standard CAD approaches are hindered by few CT data voxels contained within the lesion. By incorporating local, surrounding and global features, more information is included and augmented CAD performance may be achieved. Finally, many significant features were identified despite diversity in the CT data acquisition parameters which indicates the suitability of the approach to broad clinical application. We are currently working on applying the CAD tool to a larger dataset.

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      O05.03 - Screening of Lung Cancer by Low-Dose CT (LDCT), Digital Tomosynthesis (DT) and Chest Radiography (CR) in a High Risk Population: A Comparison of Detection Methods (ID 3018)

      N. Triphuridet, S. Singharuksa, T. Sricharunrat

      • Abstract
      • Presentation
      • Slides

      Background
      LDCT has recently been recommended as a screening tool for lung cancer in a high risk population, provided a 20% reduction in lung-cancer specific mortality. Nevertheless, LDCT has some limitations with respect to its high false positive rate, accumulated radiation exposure and relatively high cost. Digital tomosynthesis (DT) is a multisection imaging technique which can improve detection ability of small lung nodules and renders much lower radiation dosage and operation costs.

      Methods
      Thai heavy smokers (>30 pack-years) were enrolled in a prospective study starting from July 2012 to April 2013 (n=580). LDCT, DT and CR were utilized as a screening tool for lung cancer screening. All participants underwent imaging studies on the same day and the results were independently reviewed within a 1-week interval. Abnormal findings were categorized into 3 groups: negative, indeterminate (maximum diameter of pulmonary nodule >5- 9.9 mm), and suspicious for malignancy (maximum diameter of pulmonary nodule > 10 mm, consolidation, obstructive atelectasis, pleural effusion or mediastinal lymphadenopathy).

      Results
      At baseline, LDCT and DT classified 16/580 cases as suspicious for primary lung cancer while CR detected 15/580 cases. Seven cases with positive LDCT and DT findings were tissue-proven primary lung cancer including 3 - stage I cancers, 1 - stage III cancer and 3 - stage IV cancers. CR detected only 3 proven cases of primary lung cancer and all of them were stage IV cancer. The lung cancer detection rate for pulmonary nodule > 10 mm and other suspicious findings was 1.2%, 1.2%, and 0.5% by LDCT, DT, and CR, respectively. LDCT classified 67 cases as indeterminate while DT and CR classified 21 and 11 as such cases, respectively. Two additional primary lung cancer cases were detected at a 3-month follow-up LDCT of the indeterminate group by LDCT (2 cases), DT (1 case) and CR (0 case), respectively. The lung cancer detection rate for pulmonary nodule > 5 mm and other suspicious findings was 1.6%, 1.4%, and 0.5% by LDCT, DT, and CR, respectively. The positive predictive value (PPV) for pulmonary nodule >10 mm and other suspicious findings by LDCT, DT and CR was 43.8%, 43.8%, and 20.0%, respectively, while the PPV for pulmonary nodules of> 5 mm and other suspicious for malignancy findings by LDCT, DT and CR were 10.8%, 21.6%, and 11.5%, respectively. The sensitivity and specificity was 100% and 87%, respectively, for LDCT, and 88.9% and 94.9%, respectively, for DT, and 33.3% and 96%, respectively, for CR.

      Conclusion
      DT is a lung cancer screening modality that is comparable to LDCT, particularly for pulmonary lesions that are larger than 10 mm. and other suspicious for malignancy findings while CR was far inferior to DT and LDCT.

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      O05.04 - DISCUSSANT (ID 3991)

      S. Lam

      • Abstract
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      Abstract not provided

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      O05.05 - Biennial lung cancer screening by low-dose CT scan - a simulation of cost effectiveness in Canada (ID 2313)

      J.R. Goffin, W.M. Flanagan, A.B. Miller, F.F. Liu, S. Cressman, N. Fitzgerald, S. Fung, M.C. Wolfson, W. Evans

      • Abstract
      • Presentation
      • Slides

      Background
      Randomized data support annual screening for lung cancer among smokers using low-dose CT scans. To compare the resource implications of annual versus biennial screening, a cost-effectiveness analysis was undertaken using the Cancer Risk Management Model (CRMM version 2.0.1) in the context of the Canadian publicly funded healthcare system.

      Methods
      The CRMM performs simulations at an individual level and incorporates demographic data, cancer risk factors, cancer registry data, diagnostic and treatment algorithms and health utilities. Outputs are aggregated and costs (in 2008 Cdn dollars) and life-years are discounted at 3% annually. Simulations were performed with a cohort 55-74 years and a ≥30 pack-year (p-y) smoking history recruited from 2012-2032. CT scan sensitivity (Sens) and specificity (Spec) and cohort outcomes were based on NLST and Canadian data. It was assumed 60% of the eligible population participates by 10 years, 70% adhere to the screening regimen, and smoking cessation rates are unchanged. Sensitivity analysis was undertaken.

      Results
      An annual screening program incurs net costs of $2.97 billion and saves 55,000 quality-adjusted life-years (QALYs) at an incremental cost-effectiveness ratio (ICER) of $53,700 per QALY. Under default biennial screening assumptions (Table 1, scenario 3), biennial screening costs are $1.81 billion, saving 32,000 QALYs and producing an ICER of $56,200. In the least favourable stage shift scenario (1) tested, the ICER is $275,000, whereas the most favourable shift (4) results in $49,300. Using Sens/Spec 0.90/0.73 for all scans in scenario 3 produces an ICER of $61,400, whereas changing all incidence scan Sens/Spec to 0.87/0.73 gives an ICER of $60,900. Increasing age of eligibility to 55-79 cost $2.25 billion at an ICER of $58,700 per QALY while requiring a 40 p-y smoking history reduced cost to $1.3 billion at an ICER of $49,800 per QALY. Table 1.

      Year Stage Shift Scenario Sens/ Spec
      1 2 3 4 5
      0 T0 T0 T0 T0 T0 0.9/0.73
      1 CD PS PS PS CD -
      2 T0 T0 T0/T1 T1 T1 0.89/0.84
      3* CD PS PS PS CD -
      4** T0 T0 T0/T1 T1 T1 0.89/0.84
      ICER $275,000 $65,000 $56,200 $49,300 $104,00
      T0, T1 refer to the NLST stage shift at specified time, where T0 equals shift at time zero screen, T1 shift at 12 month screen. T0/T1 indicates an average. CD: the unscreened Canadian stage distribution. PS: NLST post-screening stage shift. *Represents 3[rd] year and all future odd years. **Represents 4[th] year and all future even years. Hyphens indicate years without screening.

      Conclusion
      Compared to annual lung cancer screening, biennial screening reduces net cost but may have a similar ICER. Stage shift assumptions have a significant impact on ICER values. Minor adjustments in Sens/Spec modestly change the ICER. Widening the age range increases but increasing the p-y requirement reduces system costs.

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      O05.06 - Resource utilization and costs of screening high-risk individuals for lung cancer in Canada (ID 1520)

      S. Cressman, S.J. Peacock, I. Cromwell

      • Abstract
      • Presentation
      • Slides

      Background
      In September 2008 the Pan-Canadian early lung detection of lung cancer study recruited 2537 current or former smokers who were determined to have a high risk of developing lung cancer. An economic analysis was conducted to estimate the potential costs and benefits of screening with the aim of knowledge translation and decision aid for provincial screening programs. An analysis of prospectively collected resource utilization and cost data is presented.

      Methods
      Screening costs have been determined, accounting for the cost of all resources utilized to confirm true negative and false positive screen tests as well as early stage treatment costs for resources applied to obtain diagnostic confirmation of true positive and false negative results for screened individuals, treat the primary disease and any subsequent lung cancer within three years. All costs have been calculated from the Canadian public payer’s perspective. The average CT-screening cost over a fixed period of 18 months for the pan-Canadian study participants who did not have cancer was determined and compared with the phase specific costs of true positive and false negative lung cancer screening participants who had a lung cancer diagnosis proven prior to Dec. 31, 2012. The costs for early-detected lung cancer were determined and presented by diagnosis, treatment and surveillance phases of care.

      Results
      The average cost per screened individuals who did not end up having cancer in the first two years of the study was $456 (95%CI: $385-$570) per-person. The average rate of non-invasive investigations to pursue suspicious CT findings was 49% (CI: 45%-54%); depending significantly on the follow-up protocol observed in different participating sites. The rate of invasive investigations for individuals who had true negative or false positive results was low (<0.4%) as was the rate of complication (<0.004%). 85 individuals had lung cancer detected and diagnosed prior to December 31, 2012. The average cost of screening and the subsequent diagnostic workup for the most common detected lung cancer (stage IA and IB non-small cell lung cancer) was $4,233 (95%CI: $3,643-$4,822) per person. Per-person treatment and surveillance costs are presented by stage and mode of treatment for 84 lung cancers found in the early detection study.

      Conclusion
      This information indicates that screening costs are low on average, as are the rates of complications in the screened individuals that do not receive a cancer diagnosis in the first two years of screening. These numbers arrive while Canadian and other national healthcare systems must manage the impacts of several private, opportunistic, lung-screening clinics that are already operational. This study is sponsored by the Terry Fox Research Institute and the Canadian Partnership against Cancer

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      O05.07 - COPD-based eligibility increases lung cancer detection rate and lowers over-diagnosis in CT screening studies (ID 1721)

      R.P. Young, F. Duan, R.J. Hopkins, X. Deng, C. Chiles, G.D. Gamble, C. Gatsonis, D. Aberle

      • Abstract
      • Presentation
      • Slides

      Background
      Based on a 20% reduction in lung cancer deaths in the CT screening arm of the National Lung Screening Trial (NLST), yearly CT screening for lung cancer is now widely recommended. Eligibility for the NLST was based on age and smoking history only. However, we and others propose that multivariate risk models of lung cancer that incorporate variables for chronic obstructive pulmonary disease (COPD), improve risk prediction for lung cancer. The aim of this study was to examine recently published CT screening studies for lung cancer and the effect of having COPD on outcome.

      Methods
      We searched the literature for CT screening studies of lung cancer where spirometry had been done at baseline to assess the effects of spirometry-defined COPD on outcomes. We identified six studies where there was published data reporting spirometry results in lung cancer screening studies. Using this data we objectively measured outcomes stratified or pre-selected on spirometry-defined COPD.

      Results
      By comparing outcomes in these single arm and randomized studies we found the following lung cancer detection rates were between 1.5 to 6 fold higher in current and former smokers eligible for screening with spirometry-defined COPD compared to those with no airflow limitation or normal lungs (Table 1). Only 15% of those screened had advanced stage COPD (GOLD 3-4) The proportion of eligible current or former smokers with COPD had less indolent lung cancers with long doubling times (Table 2), and Survival after surgical resection of early stage CT-detected lung cancers was no different between those with or without COPD at baseline screening. Figure 1 Figure 2

      Conclusion
      We conclude that a COPD-centric approach to lung cancer screening offers a more efficient means of identifying lung cancer (higher lung cancer detection rate), with less over-diagnosis and comparable outcomes to screening those without COPD.

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      O05.08 - DISCUSSANT (ID 3992)

      H.M. Marshall

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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